Clinical trial NCT02990338
Conditions: Plasma Cell Myeloma
Keywords: Anti-CD38 monoclonal antibody
Sponsor: Sanofi
Start date: 2016-12-22; Completion date: 2023-11-01
Enrollment: 307 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To demonstrate the benefit of isatuximab in combination with pomalidomide and low-dose dexamethasone in the prolongation of Progression Free Survival (PFS) as compared to pomalidomide and low-dose dexamethasone in participants with refractory or relapsed and refractory multiple myeloma (MM).

Secondary Objectives:

* To evaluate the Overall Response Rate (ORR) as per International Myeloma Working Group (IMWG) criteria in each arm.
* To compare the Overall Survival (OS) between the two arms.
* To evaluate the Time To Progression (TTP) in each arm.
* To evaluate the PFS in high risk cytogenetic population in each arm.
* To evaluate the Duration of Response (DOR) in each arm.
* To evaluate the safety in both treatment arms.
* To determine the Pharmacokinetic profile of isatuximab in combination with pomalidomide.
* To evaluate the immunogenicity of isatuximab.
* To assess disease-specific and generic health-related quality of life (HRQL), disease and treatment-related symptoms, health state utility, and health status.

Detailed description:
The duration of the study for the participants included a period for screening of up to 21 days (or up to 28 days for women who can become pregnant). Participants continued study treatment until disease progression, unacceptable adverse reaction, participants' wish or other reason of discontinuation.

During follow-up, participants who discontinued the study treatment due to progression of the disease were followed every 3 months (12 weeks) for survival (or until cut-off date), and participants who discontinued the study treatment prior to documentation of disease progression were followed-up every 4 weeks until disease progression, and then every 3 months (12 weeks) for survival (or until cut-off date).

Arms: arm 1: Participants received pomalidomide 4 milligrams (mg) Per os (PO) on Days 1 to 21 of each 28-day treatment cycle plus dexamethasone 40 mg (participants greater than or equal to (\>=) 75 years of age received 20 mg dexamethasone) PO on Days 1, 8, 15 and 22 of each 28-day treatment cycle until disease progression or unacceptable toxicity or participant's wish to discontinue study treatment, or any other reason, whichever comes first (maximum exposure: 306.6 weeks). arm 2: Participants received isatuximab 10 milligrams per kilogram (mg/kg) intravenous (IV) infusion on Days 1, 8, 15, and 22 at Cycle 1, and then on Days 1 and 15 of subsequent cycles plus pomalidomide 4 mg PO on Days 1 to 21 of each 28-day treatment cycle and dexamethasone 40 mg (participants \>= 75 years of age received 20 mg dexamethasone), PO or IV on Day 1, 8, 15, 22 of each 28-day treatment cycle until disease progression or unacceptable toxicity or participant's wish to discontinue study treatment, or any other reason, whichever comes first (maximum exposure: 311.0 weeks).
Interventions: intervention 1: Isatuximab intervention 2: Pomalidomide intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Pharmaceutical form: solution for infusion Route of administration: intravenous intervention 2: Pharmaceutical form: capsule Route of administration: oral intervention 3: Pharmaceutical form: tablets or solution for infusion Route of administration: oral or intravenous

Protocol documents:
Prot_002.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002579 VERSION N°14.0 (04-FEB-2016) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 07 
COMPOUND: isatuximab/SAR650984 
A Phase 3 randomized, open-label, multicenter study comparing Isatuximab 
(SAR650984) in Combination with pomalidomide And low-dose dexamethasone 
veRsus pomalidomide and low-dose dexamethasone In patients with refractory or 
relapsed And refractory Multiple Myeloma 
STUDY NUMBER: EFC14335 
STUDY NAME: ICARIA-MM 
ClinicalTrials.gov Identifier: NCT02990338
VERSION DATE/STATUS: Approval date (26-Nov-2020)/APPROVED 
Version Number: 
1 
EudraCT  
2016-003097-41 
IND Number(s) 
103217 
WHO universal trial number: 
U1111-1180-6262 
Date: 
26-Nov-2020
Total number of pages: 
191 
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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
 
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE  
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 07 
All 
26-Nov-2020, version 1 (electronic 7.0) 
Amended Clinical Trial Protocol 06 
All 
21-Apr-2020, version 1 (electronic 6.0) 
Amended Clinical Trial Protocol 05 
All 
11-Jun-2019, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 04 
All 
25-Oct-2018, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 03 
Japan 
13-Sep-2018, version 1 (electronic 3.0) 
Protocol Amendment 03 
All 
18-May-2017, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 02 
All 
18-May-2017, version 1 (electronic 2.0) 
Protocol Amendment 02 (GB) 
United Kingdom 
24-Feb-2017, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 01 (GB) 
Amended Clinical Trial Protocol 01 
United Kingdom  
All 
24-Feb-2017, version 1 (electronic 1.0) 
01-Nov-2016, version 1 (electronic 1.0) 
Protocol Amendment 01 
All 
01-Nov-2016, version 1 (electronic 1.0) 
Clinical Trial Protocol 
All  
04-Aug-2016, version 1 (electronic 2.0) 
AMENDED PROTOCOL 07 (26-Nov-2020) 
This amended protocol (amendment 07) 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 
A risk of hepatitis reactivation has been identified in the SAR650984 Investigator’s Brochure 
edition 11 (30-Apr-2020).  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.2 Study Flow chart; 8.2.5 Other 
toxicities 
Additional hepatitis viral serology if HBV status 
unknown before treatment start, to be repeated if 
clinically indicated. 
A risk of hepatitis reactivation has 
been identified. 
8.2.5 Other toxicities; 10.1.6 Post PFS 
study cut-off date; 10.1.7 Post final OS 
study cut-off date 
Description of study treatment discontinuation 
and restart procedure in case of viral reactivation. 
A risk of hepatitis reactivation has 
been identified. 
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Section # and Name 
Description of Change 
Brief Rationale 
8.2.5 Other toxicities; 10.1.6 Post PFS 
study cut-off date; 10.1.7 Post final OS 
study cut-off date 
Description of monitoring of alanine 
aminotransferase (ALT) and aspartate 
aminotransferase (AST) in case of viral 
reactivation. 
A risk of hepatitis reactivation has 
been identified. 
8.2.1 Study treatments (IMP); 
8.2.4 Infusion reactions 
Infusion rate of isatuximab has been revised. 
In line with the currently approved 
infusion rate for the combination 
isatuximab, pomalidomide and 
dexamethasone. 
8.1.1.1 Pharmaceutical form; 
8.1.1.2 Dilution method 
Dextrose 5% can also be used for isatuximab 
dilution. 
Clarification 
Clinical Trial Summary; 
1.3 Pharmacokinetic/ 
Pharmacodynamic Flow Chart; 
10.1.7 Post final OS study cut-off date 
Removal of anti-drug antibodies tests after final 
analysis cut-off date leading to shortening of 
follow-up period to 30 days after last study 
treatment use for patients still on treatment at the 
time of amended protocol 07. 
ADA sampling obtained from all 
isatuximab studies have provided 
enough relevant information in 
terms of immunogenicity profile. 
10.4.3 Instructions for reporting serious 
adverse events 
Hospitalization and exams report for serious 
adverse events (SAEs) will not be systematically 
requested. 
Only necessary copies of medical 
records are to be shared with the 
Sponsor. 
10.4.3 Instructions for reporting serious 
adverse events 
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 
Correction of the instructions for 
the preparation of Investigators 
safety reports in case of SUSARs  
 
8 Study treatments; 8.2.6 Criteria for 
temporarily delaying administration of 
study intervention; 11.4.7 other 
analyse(s); 12.2 Informed consent; 
Appendix O Contingency measures for 
a regional or national emergency that 
is declared by a governmental agency 
Contingency measures to apply during a regional 
or national emergency declared by a 
governmental agency are described. 
To ensure trial continuity in case of 
regional or national emergency 
declared by a governmental 
agency. 
6.4 Study committees; 10.1.6 Post PFS 
study cut-off date; Appendix N 
Country-specific requirements 
Additional progression free survival (PFS) 
analysis in Japanese patients is cancelled. 
Japanese Health Authority granted 
the marketing authorization of 
isatuximab without requesting the 
updated data on PFS in Japanese 
population. 
Clinical Trial Summary; 8.2.2 
Premedication (NIMP) - Prevention of 
Infusion Associated Reactions (IARs); 
8.2.2.1 Ranitidine or equivalent 
Use of ranitidine or equivalent as premedication 
is left to medical judgement. 
To provide option to adapt the 
premedication. 
13.2 Responsibilities of the Sponsor 
Location of monitoring details has been added. 
Clarification 
Whole document 
Minor formatting, typo corrections, and 
consistency changes. 
Consistency. 
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CLINICAL TRIAL SUMMARY 
 
COMPOUND: SAR650984 (isatuximab) 
STUDY No.: EFC14335  
STUDY NAME: ICARIA-MM 
TITLE 
A Phase 3 randomized, open-label, multicenter study comparing isatuximab 
(SAR650984) in combination with pomalidomide and low-dose 
dexamethasone versus pomalidomide and low-dose dexamethasone in 
patients with refractory or relapsed and refractory multiple myeloma 
INVESTIGATOR/TRIAL LOCATION 
Worldwide 
PHASE OF DEVELOPMENT 
3 
STUDY OBJECTIVE(S) 
 
Primary objective: 
To demonstrate the benefit of isatuximab in combination with 
pomalidomide and low-dose dexamethasone in the prolongation of 
Progression Free Survival (PFS) as compared to pomalidomide and 
low-dose dexamethasone in patients with refractory or relapsed and 
refractory multiple myeloma (MM). 
Key Secondary objective(s): 
• 
To evaluate the Overall Response Rate (ORR)  as per 
International Myeloma Working Group (IMWG) criteria in each 
arm 
• 
To compare the Overall Survival (OS) between the two arms 
Other Secondary objective(s): 
• 
To evaluate the Time to Progression (TTP) in each arm 
• 
To evaluate the PFS in high risk cytogenetic population defined 
as patients carrying del(17p), t(4;14), t(14;16) in each arm 
• 
To evaluate the Duration of Response (DOR) in each arm 
• 
To evaluate safety in both treatment arms 
• 
To determine the pharmacokinetic (PK) profile of isatuximab in 
combination with pomalidomide  
• 
To evaluate the immunogenicity of isatuximab 
• 
To assess disease-specific and a generic health-related quality of 
life (HRQL), disease and treatment-related symptoms, health 
state utility and health status. 
Exploratory objective(s): 
• 
To explore the relationship between immune genetic 
determinants and efficacy endpoints 
• 
To explore PK and pharmacodynamic (PDy) relationships 
• 
To explore the minimal residual disease (MRD) rate in both 
treatment arms 
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STUDY DESIGN 
This is a prospective, multicenter, multinational, randomized, open-label, 
parallel group, 2-arm study evaluating the clinical benefit of isatuximab in 
combination with pomalidomide and low-dose dexamethasone as 
compared to pomalidomide and low-dose dexamethasone for the 
treatment of patients with refractory or relapsed and refractory multiple 
myeloma who have received at least two prior lines including lenalidomide 
and a proteasome inhibitor (bortezomib, carfilzomib or ixazomib) alone or 
in combination, and have demonstrated disease progression on or within 
60 days of completion of the last therapy. 
Randomization/treatment arms: 
After confirmation of eligibility criteria, patients will be randomly assigned 
using interactive response technology (IRT) in a 1:1 ratio to one of the two 
arms: 
• 
Isatuximab in combination with pomalidomide and low-dose 
dexamethasone (IPd, experimental arm) 
• 
Pomalidomide and low-dose dexamethasone (Pd, control arm) 
Isatuximab, pomalidomide and dexamethasone are defined in this 
protocol as “study treatments”. 
Randomization will be stratified by age (<75 years versus ≥75 years) and 
number of previous lines of therapy (two or three versus more than three). 
A complete transplant procedure (induction, mobilization, conditioning, 
transplant, consolidation and maintenance) will be considered as one line. 
Each other regimen will be considered as one line, whatever the reason of 
discontinuation (progression, adverse event or patient request). 
Duration of therapy 
Patients will be allowed to continue therapy until disease progression, 
unacceptable adverse events (AEs) or patient wish, whichever comes 
first. 
STUDY POPULATION  
Selection criteria 
Inclusion criteria: 
Eligible patients will be considered for inclusion in this study if they meet 
all of the following criteria: 
I 01. 
Age ≥18 years or country’s legal age of majority if the legal age is 
>18 years old 
I 02. 
Patients must have a documented diagnosis of multiple myeloma 
with evidence of measurable disease 
- 
Serum M protein ≥0.5 g/dL measured using serum protein 
immunoelectrophoresis 
and/or 
- 
Urine M protein ≥200 mg/24 hours measured using urine 
protein immunoelectrophoresis 
I 03. 
Patients must have received at least 2 prior lines of anti-myeloma 
therapy, which must include at least 2 consecutive cycles of 
lenalidomide and a proteasome inhibitor (bortezomib, carfilzomib 
or ixazomib) given alone or in combination. Note: An induction 
treatment followed by autologous stem cell transplantation (ASCT) 
and consolidation/maintenance is considered as one line of 
treatment 
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I 04. 
Patients must have failed treatment with lenalidomide and 
a proteasome inhibitor (bortezomib, carfilzomib or ixazomib) alone 
or in combination, defined by any of the following (failure to 
lenalidomide and a proteasome inhibitor can have occurred at any 
line of therapy): 
• 
Progression has occurred while on or within 60 days from end of 
the treatment with lenalidomide and/or a proteasome inhibitor 
• 
In case of previous response ≥ partial response (PR) to 
lenalidomide and/or a proteasome inhibitor, patient must have 
progressed within 6 months after discontinuation of the treatment 
• 
Patients who have developed intolerable toxicity after a minimum 
of 2 consecutive cycles of a regimen containing lenalidomide and 
a proteasome inhibitor (bortezomib, carfilzomib or ixazomib) alone 
or in combination. Intolerance is defined as below: 
- 
For proteasome inhibitor containing regimens: any toxicity 
leading to discontinuation of a proteasome inhibitor, like 
≥G2 peripheral neuropathy or ≥G2 neuropathic pain. 
Peripheral neuropathy must be ≤G1 before study entry 
(according to NCI-CTCAE v4.03) 
- 
For lenalidomide containing regimens: any toxicity leading 
to discontinuation of lenalidomide, like G3 rash. Rash must 
not have been G4 and other non-hematologic toxicities 
should not have been G4. All non-hematologic toxicities 
must be ≤G1 before study entry 
I 05. 
Patients must have progressed on or within 60 days after end of 
previous therapy before to study entry, ie, refractory to the last line 
of treatment. This patient population includes the following two 
categories: 
• 
Refractory disease: patients who were refractory to all previous 
lines of treatment but should have achieved at least a minimal 
response (MR) in one previous line 
• 
Relapsed and refractory disease: patients who were relapsed 
from at least one previous line of treatment and refractory to the 
last line of treatment. Patients can be refractory to other previous 
line/lines of treatment 
Note: Patients must have achieved a minimal response (MR) or better to 
at least one of the previous lines of treatment (ie, primary refractory 
disease is not eligible) 
I 06. 
Patient has given voluntary written informed consent before 
performance of any study related procedures not part of normal 
medical care, with the understanding that consent may be 
withdrawn by the patient at any time without prejudice to his/her 
medical care 
Exclusion criteria: 
Patients who have met all the inclusion criteria will be screened for the 
following exclusion criteria: 
E 01. 
Primary refractory multiple myeloma defined as: patients who 
have never achieved at least a MR with any treatment during the 
disease course 
E 02. 
Free Light Chain measurable disease only 
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E 03. 
Patient with prior anti-CD38 monoclonal antibody treatment with 
progression on or within 60 days after end of anti-CD38 
monoclonal antibody treatment or failure to achieve at least MR 
to treatment (ie, refractory to anti-CD38) 
E 04. 
Prior therapy with pomalidomide 
E 05. 
Any anti-myeloma drug treatment within 14 days before 
randomization, including dexamethasone 
E 06. 
Prior allogenic hematopoietic stem cell (HSC) transplant with 
active graft versus host disease (GvHD) (GvHD any grade 
and/or being under immunosuppressive treatment within the last 
2 months) 
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 
E 08. 
Patient who has received any other investigational drugs or 
prohibited therapy for this study within 28 days or 5 half-lives 
from randomization, whichever is longer 
E 09. 
ECOG status >2 
E 10. 
Platelets <75 000 cells/µL if <50% of bone marrow (BM) 
nucleated cells are plasma cells and, <30 000 cells/µL if ≥50% 
of BM nucleated cells are plasma cells. Platelet transfusion is 
not allowed within three days before the screening 
hematological test 
E 11. 
ANC <1000 μ/L (1 x 109/L). The use of G-CSF is not allowed to 
reach this level 
E 12. 
Creatinine clearance <30 mL/min (MDRD Formula, 
see Appendix A) 
E 13. 
Total bilirubin >2 x ULN 
E 14. 
Corrected serum calcium >14 mg/dL (>3.5 mmol/L) 
E 15. 
AST and/or ALT>3 x ULN 
E 16. 
Ongoing toxicity (excluding alopecia and those listed in eligibility 
criteria) from any prior anti-myeloma therapy >G1 (NCI-CTCAE 
v4.03) 
E 17. 
Hypersensitivity to IMiDs (thalidomide or lenalidomide) defined 
as any hypersensitivity reaction leading to stop IMiDs within the 
2 first cycles or toxicity, which does meet intolerance definition 
(see I 04) 
E 18. 
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 
E 19. 
Significant cardiac dysfunction; myocardial infarction within 
12 months; unstable, poorly controlled angina pectoris 
E 20. 
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 21. 
Known to be HIV+ or to have hepatitis A, B or C active infection 
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E 22. 
Malabsorption syndrome or any condition that can significantly 
impact the absorption of pomalidomide 
E 23. 
Active primary amyloid-light (AL) amyloidosis (evidence of end 
organ damage or receiving treatment for amyloidosis) 
E 24. 
Concomitant plasma cell leukemia  
E 25. 
Unable or unwilling to undergo to thromboprophylaxis 
E 26. 
Daily requirement for corticosteroids (equivalent to ≥10 mg/day 
of prednisone) for more than 7 days (except for inhalation 
corticosteroids) 
E 27. 
Pregnant or breastfeeding female or female who intends to 
become pregnant during the participation in the study. Females 
of childbearing potential (FCBP) unwilling to prevent pregnancy 
by the use of 2 reliable methods of contraception for ≥4 weeks 
before the start of study treatment, during treatment (including 
dose interruptions), and up to 3 or 5 months following the last 
dose of study treatment for Pd and IPd respectively, and/or who 
are unwilling or unable to be tested for pregnancy before study 
treatment initiation (2 negative tests), weekly during 1st month of 
treatment and then prior each treatment cycle administration or 
every 2 weeks in case or irregular menstrual cycles up to 3 or 
5 months following the last dose of study treatment for Pd and 
IPd respectively 
E 28. 
Male participants who disagree to practice true abstinence or 
disagree to use a condom during sexual contact with a pregnant 
female or a FCBP while participating in the study, during dose 
interruptions and at least 3 or 5 months following study 
treatment discontinuation for Pd and IPd respectively, even if 
has undergone a successful vasectomy 
Note 1: a FCBP is a female who: 1) has achieved menarche at some time 
point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 
3) 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)  
Note 2: True abstinence is acceptable when this is in line with the preferred 
and usual lifestyle of the patient. Periodic abstinence (eg, calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception. 
E 29. 
All patients who disagree to refrain from donating blood while on 
study treatment and for 4 weeks after discontinuation from this 
study treatment 
E 30. 
All patients who do not agree to keep study treatment for their 
personal use only 
E 31. 
Any country-related specific regulation that would prevent the 
patient from entering the study 
E 32. 
Any severe acute or chronic medical condition which could 
impair the ability of the patient to participate in the study or 
interfere with interpretation of study results (eg, systemic 
infection unless specific anti-infective therapy is employed) or 
patient unable to comply with the study procedures 
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Total expected number of patients 
Approximately 300 patients (150 patients per arm).  
Enrollment will be stopped after PFS analysis or when approximately 
300 patients will have been randomized, whichever is first. 
Expected number of sites 
Approximately 150 
STUDY TREATMENT(s) 
 
Investigational medicinal product(s) 
Isatuximab 
Formulation: 
The drug product is presented as a concentrate for solution for infusion in 
vials containing 20 mg/mL (500 mg/25 mL) of isatuximab in 20 mM histidine, 
10% (w/v) sucrose, 0.02% (w/v) polysorbate 80 at pH 6.0. It is packed in 
30 mL glass vials fitted with elastomeric closure. Each vial contains a 
nominal content of 500 mg of isatuximab. The fill volume has been 
established to ensure removal of 25 mL 
Route(s) of administration: 
IV 
Dose regimen: 
Isatuximab dosed at 10 mg/kg will be given IV on Days 1, 8, 15, and 22 in 
the first cycle, then Days 1 and 15 in subsequent cycles. Each cycle will 
be 28 days in duration. 
Dose modifications will be applied in case of toxicity. 
Investigational medicinal product(s) 
Pomalidomide 
Formulation: 
The drug product is presented as capsules, 1 mg, 2 mg, 3 mg and 4 mg. 
Route(s) of administration: 
PO 
Dose regimen: 
Pomalidomide will be given at 4 mg on Days 1 to 21 in a 28-day cycle. 
Patients will be asked to maintain a diary to record the doses of 
pomalidomide to document all oral administration (except those 
administered by the study nurse/doctor). 
Dose modifications will be applied in case of toxicity. 
Investigational medicinal product(s) 
Dexamethasone 
Formulation: 
The drug product is presented as tablets, 4 mg and 8 mg; and 3.3 mg/mL 
(6.6 mg/2 mL) ampoules for all countries except US, and 10 mg/mL vials 
for US, for intravenous injection  
Route(s) of administration: 
PO/IV 
Dose regimen: 
Dexamethasone will be given at 40 mg for patients <75 years of age and 
at 20 mg for patients ≥75 years of age, on Days 1, 8, 15 and 22 in a 
28-day cycle. Patients will be asked to maintain a diary to record the 
doses of dexamethasone PO to document all oral administration (except 
those administered by the study nurse/doctor). 
Dose modifications will be applied in case of toxicity 
Dexamethasone will also have intent of premedication for infusion acute 
reaction in IPd arm 
Non investigational medicinal product(s) 
(NIMP) Premedication (IPd arm only) 
 
Product  
Acetaminophen (paracetamol) 
Route(s) of administration: 
PO 
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Dose regimen: 
Acetaminophen (paracetamol) will be given 650 to 1000 mg 
15-30 minutes (but no longer than 60 minutes) before isatuximab infusion 
Product  
Ranitidine or equivalent (other approved H2 antagonists 
[eg, cimetidine], oral proton pump inhibitors [eg, omeprazole, 
esomeprazole]) 
Route(s) of administration: 
IV 
Dose regimen: 
Ranitidine or equivalent will be given 50 mg 15-30 minutes (but no longer 
than 60 minutes) before isatuximab infusion; the use of ranitidine or 
equivalent to be part or not of premedication is left to the medical 
judgement. 
Product  
Diphenhydramine or equivalent (eg, cetirizine, promethazine, 
dexchlorpheniramine, according to local approval and availability. 
Intravenous route is preferred for at least the first 4 infusions) 
Route(s) of administration: 
IV 
Dose regimen: 
Diphenhydramine or equivalent will be given 25 to 50 mg 15-30 minutes 
(but no longer than 60 minutes) before isatuximab infusion 
ENDPOINT(S) 
 
Primary endpoint: 
The primary endpoint is PFS. Progression free survival is defined as the 
time from the date of randomization to the date of first documentation of 
progressive disease (PD) (as determined by the Independent Response 
Committee [IRC]) or the date of death from any cause, whichever comes 
first. Response will be determined according to International Myeloma 
Working Group (IMWG) criteria (1). Progression will be confirmed based 
on two consecutive assessments. 
Key Secondary endpoint(s): 
• 
Overall Response Rate (ORR): defined as the proportion of 
patients with stringent complete response (sCR), complete 
response (CR), very good partial response (VGPR), and partial 
response (PR) as assessed by the IRC using the IMWG response 
criteria 
• 
Overall Survival (OS): defined as the time from the date of 
randomization to death from any cause 
Other Secondary endpoints: 
• 
Time to Progression (TTP) defined as time from randomization to 
the date of first documentation of PD (as determined by the IRC) 
• 
PFS as defined above in the high risk cytogenetic population 
patients carrying del(17p), t(4;14), t(14;16) determined by 
fluorescence in situ hybridization (FISH)  
• 
Duration of response (DOR): defined as the time from the date of 
the first IRC determined response to the date of first IRC-PD or 
death, whichever happens first. DOR will not be calculated for 
patients that do not achieve a response 
• 
Safety in terms of treatment-emergent AEs/serious adverse 
events (TEAE/SAE), laboratory parameters, and vital signs and 
assessment of physical examination, infusion associated 
reactions (IAR), second primary malignancies. TEAEs are defined 
as AEs that develop, worsen (according to the Investigator 
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opinion), or become serious during the TEAE period. The TEAE 
period is defined as the time from first dose of study treatments up 
to 30 days after last dose of study treatments. Adverse events 
and laboratory parameters will be graded using NCI-CTCAE 
v4.03 
• 
Pharmacokinetic evaluation: blood samples will be collected in all 
patients treated with isatuximab using a sparse sampling strategy 
in order to assess the PK profile of isatuximab using population 
PK approach. This analysis will involve an estimation of 
inter-patient PK variability, inter-occasion PK variability, the 
population PK parameters estimates and the assessment of 
pomalidomide and pathophysiologic covariate effects on the main 
PK parameters. Empirical Bayesian estimation of individual 
parameters and of individual exposure (AUC: Area Under the 
Curve) will also be performed 
• 
Presence of isatuximab Anti-Drug Antibodies (ADA) in the IPd 
arm will be assessed throughout the study. For patients still on 
treatment at the time of amended protocol 07, sample is no more 
required 
• 
The QLQ-C30, MY20 and EQ-5D-5L assessments will be 
captured electronically throughout the study. All patient reported 
outcomes (PRO) are to be completed by the patients at the 
centers prior to discussing their health/disease status, and prior to 
administration of study treatments, or other study-related 
procedures during treatment, at end of treatment visit (EOT; 
30 [±5] days after last study treatment administration) and 
60 days (±5 days) after last study treatment administration: 
- 
Disease-specific HRQL will be assessed using the EORTC 
QLQ-C30 
- 
Disease- and treatment-related symptoms will be assessed 
using the EORTC QLQ-C30 and the EORTC MY20 
questionnaires 
- 
Health state utility and health status will be assessed using 
the EQ-5D-5L 
Exploratory endpoints: 
• 
Blood sample will be collected and analyzed for immune genetic 
determinants (such as human leukocyte antigen (HLA) and killer 
cell inhibitory receptors (KIR) genotypes and FcγR polymorphism) 
and correlated with efficacy endpoints, including ORR, DOR, PFS 
and OS 
• 
PK estimates will be investigated as prognostic factors for clinical 
outcome including safety and efficacy endpoints if possible 
• 
Bone marrow aspiration will be collected to assess minimal 
residual disease (MRD) in CR patients, as clinically indicated 
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ASSESSMENT SCHEDULE 
The following evaluations will be performed at baseline only: 
• 
Demographic characteristics and medical history 
• 
Prior multiple myeloma history (diagnosis, stage at diagnosis and 
at study entry, prior anti multiple myeloma therapies) 
• 
Molecular analysis on blood (immune genetic determinant) and 
bone marrow samples (FISH for high risk cytogenetic and MRD) 
• 
Complete blood phenotyping including information of 
cross-matching and antibody screening if not yet available (local 
laboratory) (IPd arm only) 
Safety evaluation will be performed continuously throughout the study 
period and will include the following: 
• 
Vital signs and physical exam 
• 
Adverse event evaluation. Severity grade will be determined 
according to the NCI CTCAE v4.03 
• 
Laboratory tests in blood and urine, including pregnancy tests 
(urine or serum; with a minimum sensitivity of 25 mIU/mL) prior to 
each cycle in females with childbearing potential (local laboratory) 
• 
ECOG PS  
• 
Cytokines (tumor necrosis factor alpha (TNF-α), IL-1-β, 
interleukines (IL) IL-4, IL-6 and interferon gamma (IFN)), markers 
of complement activation (C3a, C4, CH50), serum tryptase in the 
IPd arm (central laboratory)  
• 
Tumor Lysis Syndrome (TLS) markers (uric acid, creatinine, 
potassium, phosphate, calcium and corrected calcium) if needed 
(local laboratory) 
• 
Level of human anti-drug antibodies (ADA) in the IPd arm (central 
laboratory) 
• 
Second primary malignancies during and any time after treatment 
until the end of the study 
The following disease assessment procedures will be performed at 
screening (for eligibility) and again at Cycle 1 Day 1 prior to study 
treatment administration (baseline for response assessment) and then 
Day 1 of every cycle during treatment up to progression and for patients 
who discontinue study treatment for reasons other than progression, 
every 4 weeks during follow-up until PD (even for patients who would 
initiate further anti-myeloma therapy without PD): 
• 
M-protein quantification (serum and 24-hour urine, protein 
immunoelectrophoresis and immunofixation) (local and central 
laboratory) 
• 
Free light chains quantification (local and central laboratory) 
• 
Quantitative immunoglobulins (local and central laboratory) 
Other examinations for disease assessment will be done as below: 
• 
Bone marrow aspiration (or biopsy as clinically indicated) at 
baseline, and then to confirm response or progression as clinically 
indicated (local laboratory for plasma cells involvement, and in 
case of CR central laboratory will be done to assess MRD) 
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• 
Bone disease assessment: 
- 
Skeletal survey or low-dose whole-body CT scan at 
baseline, then once a year and anytime during the study if 
clinically indicated 
• 
Extramedullary disease (plasmacytoma) assessment (including 
bone plasmacytoma): 
- 
If known or documented extramedullary disease 
(plasmacytoma) at baseline, CT scan or MRI is to be done 
at baseline and to be repeated every 12 weeks (±1 week), 
and if clinically indicated 
- 
CT scan or MRI to be done in case of suspicion of 
progression or if clinically indicated in a patient with no 
previous positive image for extramedullary disease 
Note: for bone lesion assessment or extramedullary 
disease, the same modality (skeletal survey or low-dose 
whole-body CT; CT or MRI) should be used throughout the 
study for each individual patient 
All imaging to be sent for central review.  
Further anti-myeloma therapies will be collected. 
PROs will be assessed electronically on Day 1 prior to first study 
treatment administration, on Day 1 of each cycle throughout the study 
treatment period, at EOT (30 [±5] days after last study treatment 
administration), and 60 days (±5 days) after last study treatment 
administration. 
PK samples will be collected in all patients receiving isatuximab using a 
sparse sampling strategy as depicted in the PK/PDy Flow Chart in 
Section 1.3 (central laboratory). 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
Progression Free Survival: Assuming proportional hazards, a total of 
162 PFS events will be needed to detect a hazard ratio of 0.6 using a log 
rank test at the one sided 0.025 level with a 90% power. Based on an 
anticipated median PFS time of 4 months in the Pd arm; this is expected 
to correspond to a median PFS of 6.67 months in the IPd arm. 
Overall Survival: Assuming proportional hazards, a total of 220 death 
events will be needed to detect a hazard ratio of 0.685 using a log rank 
test at the one sided 0.025 level with 79.3% power. Calculation takes into 
account an interim analysis on OS at the time of PFS analysis and one 
additional interim analysis of OS when approximately 90% of 220 events 
have occurred. Based on an anticipated median OS time of 13 months in 
the Pd arm; this is expected to correspond to a difference of 6 months in 
median OS between the Pd arm and the IPd arm. 
A maximum of 300 patients (150 in each arm) would be adequate to 
achieve the targeted number of events for both PFS and OS. Assuming a 
uniform accrual rate of 15 patients per month, cut-off dates for primary 
analyses of PFS and final OS will be approximately 18 and 51 months 
after first patient in (FPI) respectively.  
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Main analysis populations: 
Intent-to-treat (ITT) population: this population will include all patients 
who have given their informed consent and for whom there is 
a confirmation of successful allocation of a randomization number by the 
IRT. This population is the primary population for all efficacy parameters. 
All analyses using this population will be based on the treatment assigned 
at randomization. 
All treated (AT)/safety population: this population will include ITT 
patients who have actually received at least one dose or a part of a dose 
of the study treatment. This population is the primary population for the 
analysis of all safety parameters. All analyses using this population will be 
based on the treatment actually received. 
PRO population: is defined as the AT population who have completed 
the baseline (Cycle 1 Day 1) and at least 1 post baseline assessment for 
each of the three selected ePROs (EORTC QLQ-C30, MY20 and  
EQ-5D-5L). 
Analysis of primary efficacy endpoint: 
The primary analysis of PFS will be based on the following censoring 
rules: 
If progression and death are not observed before the analysis cut-off date, 
PFS will be censored at the date of the last valid disease assessment not 
showing disease progression performed prior to initiation of a new anti-
myeloma treatment (if any) and the analysis cut-off date, whichever 
comes first. 
PFS in the IPd arm will be compared to the Pd arm using the log-rank test 
procedure stratified by stratification factors as entered in the IRT at the 
one sided level of 0.025.  
The estimates of the hazard ratio and corresponding 95% confidence 
intervals (CI) will be provided using the Cox proportional hazard model 
stratified by stratification factors as entered in the IRT. The median PFS 
and probabilities of being progression free at different time points 
calculated using the Kaplan-Meier methods as well as corresponding 
CI will be presented by treatment arm. The Kaplan-Meier PFS curves will 
also be provided. 
Sensitivity analyses of PFS will be performed (eg, different censoring 
rules and PFS assessed by the Investigator). 
Cut-off date for primary analysis of PFS will be the date when 162 PFS 
events are observed. 
Analysis of secondary endpoints: 
Best overall response, ORR and clinical benefit rate (CBR) will be 
summarized with descriptive statistics by treatment arm. The 95% 
two-sided CI will be computed for ORR and CBR using the 
Clopper-Pearson method. Overall response rate will be compared 
between treatment groups using the Cochran Mantel Haenszel stratified 
method. Clinical benefit rate is defined as the proportion of patients with 
sCR, CR, VGPR, PR or minimal response (MR) according to IMWG 
criteria, as determined by the IRC. 
The analysis of OS will be similar to that described for PFS and will be 
based on the following censoring rules: Patients without death prior to the 
analysis cut-off date will be censored at the last date the patient was 
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known to be alive or the cut-off date, whichever is first. The final OS 
analysis (based on 220 deaths) is expected to be performed 
approximately 33 months after the final PFS analysis cut-off date 
(ie, 51 months after first patient in). 
The analysis of DOR will be similar to that described for PFS. The same 
censoring rules as PFS will be used. 
Analysis of PRO endpoints: 
• 
Disease-specific HRQL (EORTC QLQ-C30) will be assessed via 
a comparison of C30 health-related quality-of-life change scores 
from baseline to EOT and 60 days after last study treatment 
administration between treatment arms. In addition responder 
analyses will be conducted: 1. for those who improve and 2 for 
those who deteriorate utilizing the clinical important differences 
(CID) defined in Appendix H for all C30 HRQL summary and 
subscale scores for both treatment arms. 
• 
Disease- and treatment-related symptoms (EORTC QLQ-C30 
and MY20) will be assessed via a comparison of change scores 
in C30 (individual symptom change scores) and MY20 (disease- 
and treatment-related summary scores) from baseline to EOT and 
60 days after last study treatment administration between 
treatment arms. In addition responder analyses will be conducted 
1 for those who improve and 2 for those who deteriorate utilizing 
the CIDs defined in Appendix H for all individual symptom scores 
(C30) and disease- and treatment-related summary scores 
(MY20) for both treatment arms (Appendix I). 
• 
Health state utility (EQ-5D-5L) will be assessed via a comparison 
of health state utility change scores from baseline to EOT and 
60 days after last study treatment administration between 
treatment arms. In addition responder analyses will be conducted 
1 for those who improve and 2 for those who deteriorate utilizing 
the CIDs defined in Appendix J for health state utility scores for 
both treatment arms. 
• 
Health status (EQ-5D-5L Visual Analogue Scale) will be assessed 
via a comparison of EQ-5D-5L health status change scores from 
baseline to EOT and 60 days after last study treatment 
administration between treatment arms. In addition responder 
analyses will be conducted 1 for those who improve and 2 for 
those who deteriorate utilizing the CIDs defined in Appendix J for 
health status VAS scores for both treatment arms. 
• 
Clinically meaningful improvements for each PRO are defined 
(based on CIDs) in Appendix H, Appendix I and Appendix J. 
Analysis of the safety endpoints: 
Number (%) of patients experiencing TEAEs by primary system organ 
class and preferred term will be summarized by CTCAE grade (all grades 
and ≥ Grade 3) for the safety population. The same summaries will be 
prepared for drug-related TEAEs, TEAEs leading to treatment 
discontinuation, TEAEs leading to dose modification, serious TEAEs and 
TEAEs with fatal outcome. For patients with multiple occurrences of the 
same AE within the on-treatment period, the worst grade will be used. 
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Hematology and biochemistry results will be graded according to the 
CTCAE v4.03, when applicable. Number (%) of patients 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. Second 
primary malignancies will be analyzed throughout the study. 
Interim analysis 
An interim analysis for efficacy assessment on OS is planned at the time 
of primary analysis on PFS which is estimated to occur when about 42% 
of the OS events have been observed and a second interim analysis is 
planned when approximately 90% of the OS events have occurred. An 
O’Brien and Fleming α-spending function will be used to obtain the 
nominal significance levels for the interim and final analyses of survival. 
Planned database lock date: 
Estimated cut-off date for primary analysis of PFS will be approximately 
18 months after FPI. 
The estimated cut-off date for the second OS interim analysis will be 
approximately 43 months after FPI. 
The estimated final analysis cut-off date for OS analysis will be 
approximately 51 months after FPI. 
DURATION OF STUDY PERIOD 
(per patient)  
The duration of the study for a patient will include a period for screening of 
up to 21 days (or up to 28 days for FCBP). The cycle duration is 28 days. 
Patients will continue study treatment until disease progression, 
unacceptable AEs, patient wish, or any other reason. 
After study treatment discontinuation, patients will return to the study site 
30 days after the last dose of study treatment for EOT assessments, and 
60 days after the last dose of study treatment for assessments including 
ADA (IPd arm only). If ADA test at Day 60 is positive or inconclusive, ADA 
testing will be repeated every 30 days until negative. If isatuximab is 
stopped prior to pomalidomide and dexamethasone, ADA will be tested on 
D1 of the 2 next cycles. If ADA test at the second cycle administered 
without isatuximab is positive or inconclusive, ADA testing will be 
repeated every cycle until negative. 
During follow-up (FU), patients who discontinue the study treatment due 
to PD will be followed every 3 months (12 weeks) for further anti-myeloma 
therapy, second primary malignancies, and survival until death or OS 
cut-off date, whichever comes first. Patients who discontinue the study 
treatment prior to documentation of PD will be followed-up monthly until 
confirmation of PD (even for patients 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 therapy, 
second primary malignancies, and survival, until death or OS cut-off date, 
whichever comes first.  
Cut-off date for PFS analysis will be the date when the 162 PFS events 
have occurred.  
Cut-off date for OS will be the date when 220 deaths have occurred. 
If a patient is still on treatment at the time of the cut-off date for OS and 
benefitting from the study treatment, the patient can continue the study 
treatment until disease progression, unacceptable AEs, patient wish, or 
any other reason. For cycles completed after the cut-off date, study 
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treatment administration, pregnancy tests for FCBP, all related AEs, all 
serious AEs (regardless of relationship to study treatment), laboratory 
abnormalities if applicable, and reason of end of treatment will continue to 
be collected. For patients in the IPd arm, 1 ADA sample should be drawn 
60 ±5 days after last study treatment administration. If ADA is positive or 
inconclusive at 60 days, the repeat samples will be taken every 
30 ±7 days until the results become negative. 
STUDY COMMITTEES 
Steering Committee:  
 Yes    
 No 
The Steering Committee (SC) will include Study Chairmen, investigators 
and Sponsor’s representatives. The SC will provide guidance on study 
conduct to the study team and will evaluate recommendations by the Data 
Monitoring Committee 
Data Monitoring Committee: 
 Yes    
 No 
Independent from the Sponsor and the investigators, the Data Monitoring 
Committee (DMC) role will be to monitor the safety of the patients enrolled 
in the study (ie, exposed to study treatment and/or to study procedures) and 
to provide the SC with appropriate recommendations in due time to ensure 
the safety of the patients. During this exercise, the DMC will also institute 
any measures that may be required for ensuring the integrity of the study 
results during the execution of its primary mission.  
Independent Response Committee:  
 Yes    
 No 
The Independent Response Committee (IRC) will determine disease 
response and progression according to laboratory data for MM disease 
assessment (central laboratory results), bone marrow, and imaging as per 
IMWG criteria 
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1 
FLOW CHARTS  
1.1 
GRAPHICAL STUDY DESIGN  
 
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1.2 
STUDY FLOW CHART  
 
Evaluationa 
Screening/ 
Baseline 
Cycle 1c 
Subsequent 
cyclesc 
End of 
treatment 
(EOT) 
Post treatment 
Follow-up periodff 
D-21 to D-1 
D1 
D8 
D15 
D22 
D1 
D15 
30 days after 
last study 
treatment 
administration  
60 ±5 days 
after last 
study 
treatment 
administration 
Every 3 months 
(±7 days) after last 
study treatment 
administration 
Informed Consent, Inclusion/Exclusion Criteria  
X  
 
 
 
 
 
 
 
 
 
Contraception counselling for FCBP and partner 
≤ Day-28 
X 
 
 
 
X 
 
 
 
 
Randomizationb  
X 
 
 
 
 
 
 
 
 
 
Demography, Medical/Surgical Historyd 
X 
 
 
 
 
 
 
 
 
 
Prior anti-myeloma treatment and Myeloma historye 
X 
 
 
 
 
 
 
 
 
 
Physical examinationf 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hepatitis B virus (HBV) serology 
 
Xh 
 
 
 
12-Lead ECGi 
X 
As clinically indicated 
C2D1i and as 
clinically 
indicated 
X 
 
 
Performance status (ECOG PS) 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Electronic patient 
reported outcomes 
(ePRO) 
QLQ-C30j 
 
X 
 
 
 
X 
 
X 
X 
 
MY20j 
 
X 
 
 
 
X 
 
X 
X 
 
EQ-5D-5Lj 
 
X 
 
 
 
X 
 
X 
X 
 
LOCAL LAB 
Assessments 
Pregnancy testk 
X 
X 
X 
X 
X 
X 
 
X 
Xk 
Xk 
 
Blood chemistryl 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Hematologym 
X 
X 
X 
X 
X 
X 
C2, 
C3 
X 
 
 
 
Antibody screening test (IPd arm only)n 
X 
 
 
 
 
C2n 
 
 
 
 
 
Coagulationo 
X 
As clinically indicated 
 
 
 
 
Urinalysisp 
X 
As clinically indicated 
 
 
 
 
Thyroid function testsq 
X 
Once a year thereafter until EOT or as clinically 
indicated. 
X  
 
 
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Evaluationa 
Screening/ 
Baseline 
Cycle 1c 
Subsequent 
cyclesc 
End of 
treatment 
(EOT) 
Post treatment 
Follow-up periodff 
D-21 to D-1 
D1 
D8 
D15 
D22 
D1 
D15 
30 days after 
last study 
treatment 
administration  
60 ±5 days 
after last 
study 
treatment 
administration 
Every 3 months 
(±7 days) after last 
study treatment 
administration 
 
Serum β2-microglobulinr 
X 
 
 
 
 
 
 
 
 
 
 
Markers of potential TLSs 
 
As clinically indicated 
 
 
 
CENTRAL LAB 
Assessmentst 
Experimental arm only: 
 
 
 
 
 
 
 
 
 
 
     PKu 
 
X 
X 
X 
X 
X 
C2-C4 
X 
 
 
ADA v 
 
X 
 
X 
 
X 
 
X 
X 
X 
    Isatuximab IAR Labsw 
 
Prior C1D1 then if IAR >G2 
 
 
 
PD/Exploratory: 
 
 
 
 
 
 
 
 
 
 
FISH (Bone Marrow)x 
X 
 
 
 
 
 
 
 
 
 
MRD assessment (Bone Marrow)x 
X 
in case of CR  
Immune genetic determinants (blood) y 
 
X 
 
 
 
 
 
 
 
 
Pharmacogenetics (blood, optional)z  
 
X 
 
 
 
 
 
 
 
 
CENTRAL LABt 
& LOCAL LAB 
Assessment 
Disease assessment labs:  
 
 
 
 
 
 
 
 
 
 
Serum M-Protein  
Immunoelectrophoresis and Immunofixationaa 
X 
X 
 
 
 
X 
 
X 
if EOT without PD, disease assessment as 
during study treatment up to PDff 
Urine M-Protein (24-hour urine) 
Immunoelectrophoresis and Immunofixationaa 
X 
X 
 
 
 
X 
 
X 
if EOT without PD, disease assessment as 
during study treatment up to PDff 
Serum Free light chainsaa 
X 
X 
 
 
 
X 
 
X 
if EOT without PD, disease assessment as 
during study treatment up to PDff 
Immunoglobulins: IgG, IgA, IgM, IgD, IgEaa 
X 
X 
 
 
 
X 
 
X 
if EOT without PD, disease assessment as 
during study treatment up to PDff 
Other Disease assessments  
 
 
 
 
 
     Bone Marrow for disease assessmentx 
X 
To confirm CR and as clinically indicated 
     Bone disease assessmentbb 
X 
As clinically indicated  
 
if EOT without PD disease assessment as 
during study treatment up to PDff 
     Extramedullary disease (plasmacytoma) assessment (CT scan/MRI)bb  
X 
 If present at baselinebb 
 
if EOT without PD disease assessment as 
during study treatment up to PDff 
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Evaluationa 
Screening/ 
Baseline 
Cycle 1c 
Subsequent 
cyclesc 
End of 
treatment 
(EOT) 
Post treatment 
Follow-up periodff 
D-21 to D-1 
D1 
D8 
D15 
D22 
D1 
D15 
30 days after 
last study 
treatment 
administration  
60 ±5 days 
after last 
study 
treatment 
administration 
Every 3 months 
(±7 days) after last 
study treatment 
administration 
Study Treatments: 
 
 
 
 
 
 
 
 
 
 
     Isatuximab premedication (IPd arm only) 
 
X 
X 
X 
X 
X 
X 
 
 
 
     Isatuximab infusion:  10 mg/kg IV (IPd arm only)  
 
X 
X 
X 
X 
X 
X 
 
 
 
     Pomalidomide administration:  4 mg daily POcc 
 
D1-21 
 
 
 
 
     Dexamethasone administration:  40 (20) mg PO/IV )cc 
 
D1, 8, 15, 22 
 
 
 
Thromboprophylaxis 
 
Continuously throughout study period 
 
 
 
AE Assessmentdd  
X 
Continuously throughout study period 
X 
X (related AEs, all SAEs) 
Prior/Concomitant Medicationee 
X 
Continuously throughout study period 
X 
 
 
Further anti-myeloma therapy 
 
 
 
X 
X  
Survival status 
 
 
 
X 
X  
Second primary malignancies 
 
X 
X 
X 
X  
a Evaluation: Assessments are to be performed prior to study treatment administration and prior to premedication in the IPd arm unless otherwise indicated. 
b Randomization: To take place once the consented patient has completed all the necessary screening procedures and is deemed eligible (based on assessments including myeloma specific results from central 
laboratory (see footnote “z”) and hematology/biochemistry local laboratory results) for study entry by the investigator or designee. All eligible patients must be randomized by contacting the Interactive Response 
Technology (IRT). All efforts should be made to start treatment within 3 working days even if a maximum up to 5 working days can be allowed. 
c Cycle: A cycle duration is 28 days. Day 1 of Cycle 1 refers to the day the patient receives the first study treatment administration. Day 1 of each subsequent cycle corresponds to Day 29 of the previous cycle. 
Day 8, Day 15 and Day 22 time window at Cycle 1 is ±1 day. For subsequent cycles, Day 1 and 15 time window is ±2 days and any delay above these time windows or any omission due to AE will be documented 
in the electronic case report form (eCRF) (please refer to details for dose modification in Section 8.2.3) 
d Demography: Includes age, gender, ethnicity and race. Medical/Surgical History (other than multiple myeloma): Includes relevant history of previous/associated pathologies including respiratory function history; 
smoking status will also be collected. 
e Prior anti-myeloma treatment and myeloma history: Includes date of initial diagnosis of symptomatic multiple myeloma, stage of the disease at diagnosis and at study entry, type of disease at diagnosis and at 
study entry (heavy and light chain component), previous anti-myeloma therapy (drug name, including transplant, start and stop dates, intent, date of progression, best response and reason for discontinuation). 
f 
Physical Examination: To be performed at screening, then prior to study treatment administration on Day 1, Day 8, Day 15 and Day 22 of Cycle 1, within 24 hours prior to study treatment administration on Day 1 
of each subsequent cycle, and at the EOT visit. Consists of examination of major body systems, including neurological, digestive exam, respiratory (signs and symptoms, respiratory rate), hepatic and spleen 
span, lymph node examination, weight and height (height at baseline only). Only main diagnoses will be reported in the eCRF as AEs or medical history. Signs and symptoms related to multiple myeloma ongoing 
at baseline will be recorded in medical history and will be reported in AE page in case they worsen or become serious during study treatment. Laboratory abnormalities at baseline will be recorded in laboratory 
pages. 
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g Vital Signs: Blood pressure, heart rate and temperature required at screening and then on Day 1, Day 8, Day 15 and Day 22 of Cycle 1 in both arms. For subsequent cycles vital signs are to be taken on Day 1 of 
each cycle in both arms. In addition, in the IPd arm, vital signs are to be taken just before starting infusion and 1 hour after starting infusion and end of infusion on Day 1, Day 8, Day 15 and Day 22 of Cycle 1 and 
Day 1 and Day 15 of each subsequent cycle up to and including Cycle 4 and as clinically indicated. The final measurements will be performed at the EOT visit in both arms. 
h Includes HBsAg, anti-HBsAb, and anti-HBcAb (total and IgM) and HBV DNA in case of positive anti-HBsAg (see Section 8.2.5). Once at any time if HBV status unknown before treatment started and to be 
repeated if clinically indicated for patient still on treatment at the time of amended protocol 07. 
i 
12-Lead ECG: To be performed at screening, C2D1 (pre-dose), EOT, and as clinically indicated. 
j 
ePRO (EORTC QLQ-C30, MY20 and EQ-5D-5L): To be completed by the patient at the center prior to discussing their health/disease status, and prior to study treatment administration, or other study-related 
procedures on Day 1 of every cycle, at the EOT visit, and 60 days (±5 days) after last study treatment administration. The time estimated to complete the EORTC QLQ-C30 is approximately 10-15 minutes. The 
time estimated to complete the MY20 and EQ-5D-5L is approximately 5-10 minutes. 
k Pregnancy tests (urine or serum; with a minimum sensitivity of 25 mIU/mL) for FCBP must be performed within 10-14 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 and 28 days following discontinuation of study treatment and then monthly up to 
3 or 5 months after discontinuation of study treatment for Pd and IPd respectively. Females with irregular menstruation must have pregnancy testing weekly for the first 4 weeks of treatment then every 14 days 
while on therapy and during interruptions in therapy and on Days 14 and 28 following discontinuation of study treatment and then monthly up to 3 or 5 months after discontinuation of study treatment for Pd and IPd 
respectively. All patients must be counseled about pregnancy precautions, risks of fetal exposure and other risks. All patients enrolled into this trial must comply with all requirements of the Pomalidomide 
Pregnancy Prevention Plan (Appendix L) or the country specific risk management plan in countries where pomalidomide is not supplied by the Sponsor. FCBP - A female of childbearing potential is a sexually 
mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months.  
l 
Blood Chemistry: To be done at screening and to be repeated within 24 hours prior to study treatment administration on Cycle 1 Day 1 (prior to premedication in IPd arm and prior to pomalidomide administration 
in Pd control arm on Day 1), within 24 hours prior to study treatment administration on Day 8, Day 15 and Day 22 of Cycle 1 and within 24 hours prior to study treatment administration on Day 1 of every 
subsequent cycle, at the EOT visit and as clinically indicated. Blood chemistry includes: SGOT (AST), SGPT (ALT), bilirubin (total and direct), alkaline phosphatase, lactate dehydrogenase (LDH), sodium, 
potassium, chloride, bicarbonate/carbon dioxide, calcium, corrected serum calcium, magnesium, phosphate, uric acid, serum creatinine and estimated creatinine clearance (MDRD Formula), urea or BUN, fasting 
glucose (according to site guidelines), albumin and total protein. Biochemistry abnormalities will be recorded as AEs only if they are serious or lead to study treatment modification or discontinuation. 
m Hematology: To be done at screening and to be repeated within 24 hours prior to study treatment administration on Cycle 1 Day 1 (prior to premedication in IPd arm and prior to pomalidomide administration in Pd 
arm on Day 1), within 24 hours prior to study treatment administration on Day 8, Day 15 and Day 22 of Cycle 1, within 24 hours prior to study treatment administration on Day 1 and Day 15 at Cycle 2 and Cycle 3, 
and then within 24 hours prior to study treatment administration on Day 1 of every subsequent cycle, at the EOT visit, and as clinically indicated. Hematology includes: hemoglobin, hematocrit, RBC, WBC with 
differential, ANC and platelet count. If G4 neutropenia, assess ANC every 2-3 days until ANC ≥0.5 x 109/L and at least weekly thereafter until ANC ≥1.0 x 109/L. Hematological abnormalities will be recorded as 
AEs only if they are serious or lead to study treatment modification or discontinuation. 
n Antibody screening test (IPd arm only): 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 Coombs Test, Indirect Antiglobulin Test [IAT]) to be obtained after randomization prior to Cycle 1 Day 1 study treatment administration. IAT to be repeated at Cycle 2 Day 1; 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 eCRF, including those performed prior to any transfusion during study treatment. Transfusions are to be recorded 
in the eCRF. Blood type card will be kept by the patient with the study card and the blood bank needs to be informed that the patient is receiving a treatment with an anti-CD38 and a potential interference with the 
Indirect Coombs test is possible. 
o Coagulation: To be done at screening and then as clinically indicated. Coagulation includes: prothrombin time, international normalized ratio, and activated partial thromboplastin time. 
p Urinalysis: To be done at screening and then as clinically indicated. Quantitative urinalysis at baseline, and qualitative (dipstick) after start of study treatment. This includes for quantitative: red blood cells, protein, 
glucose, pH, ketones, bilirubin, leucocytes; and for qualitative: blood, protein, glucose, pH, ketones, bilirubin, leucocytes. 
q Thyroid function tests (TSH, T3 and T4 assessment): To be performed at baseline and once a year thereafter until EOT or as clinically indicated and at EOT. 
r 
Serum β2-microglobulin: To be performed at screening. 
s Tumor Lysis Syndrome (TLS) markers: to be done in case of suspicion of TLS (uric acid, creatinine, potassium, phosphate, calcium and corrected calcium). 
t 
Central Labs: Refer to laboratory manual for sample collection and shipping information. 
u Pharmacokinetics (PK; IPd arm only): Refer to Pharmacokinetics/Pharmacodynamics Flow Chart. 
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v ADA (Anti-Drug Antibodies [IPd arm only]): To be performed on Day 1 of every cycle prior to each isatuximab administration, Day 15 of Cycle 1, at the EOT visit and at 60 days (±5 days) after last study treatment 
administration. At 60 days, if the test is positive or inconclusive, additional ADA samples are required every 30 days (±7 days) until sample is negative. If isatuximab is stopped prior to pomalidomide and 
dexamethasone, ADA will be tested on Day 1 of the 2 next cycles. If ADA test at the second cycle administered without isatuximab is positive or inconclusive, ADA testing will be repeated every cycle until 
negative. 
w Isatuximab IAR labs: (TNF- α, IL-1-β, IL-4, IL-6, and IFN-γ) baseline sample to be drawn prior to first isatuximab administration at Cycle 1. Then if a isatuximab infusion associated reaction (IAR) 
of ≥ Grade 2 occurs, additional blood sampling during the AE is required for analysis of cytokine release (TNF-α, IL-1-β, IL-4, IL-6, and IFN-γ), markers of complement activation (C3a, C4, CH50) and serum 
tryptase.  
x Bone marrow biopsy/aspirate (as clinically indicated according to site’s standard).  
• 
At screening: bone marrow aspirate (BMA) will be collected for FISH (including, but may not be limited to, del(17p), t(4;14), t(14;16)) and MRD analyses in central laboratory. BMA or core biopsy (as clinically 
indicated) will be collected for disease assessment (local laboratory). Central laboratory samples will be collected for all patients but will be analyzed only for randomized patients. If local FISH assessment is done 
using purified CD138+ plasma cells or by cIg FISH, the most recent local FISH report will be collected in patients who fail central laboratory FISH testing, for central review. Baseline MRD sample will be analyzed 
in patients who achieve a CR.  
• 
During study treatment: to confirm CR (local laboratory), and to assess MRD in case of CR (central laboratory). If the first MRD is positive, BMA collection for MRD is to be repeated 3 months later for late 
negativity (one additional sample can be collected if patient remains MRD positive). No more than 3 post treatment samples are to be obtained. 
y Blood sample for immune genetic determinants (HLA and KIR genotype and FcγgR polymorphism): To be performed within 24 hours prior to study treatment administration on Cycle 1 Day 1 (central lab). 
z Pharmacogenetics (blood): Optional blood sample for pharmacogenetics in both arms in patients who signed the separate pharmacogenetics consent. To be performed within 24 hours prior to study treatment 
administration on Cycle 1 Day 1 (central lab). 
aa Laboratory evaluation of disease assessment (local and central laboratory for each planned time point): At screening, all lab assessments to be performed within 21 days prior to randomization. Eligibility will be 
assessed based on central laboratory results. Results for central serum and urine M-protein must be available before the patient may be randomized. In the absence of central lab results, sites may use local 
laboratory results for eligibility. Central laboratory results may not be available due to (but not limited to) the following reasons: samples were not able to be analyzed by central lab (for various reasons). 
All lab assessments to be performed again prior to (within 24 hours) first study treatment administration on Cycle 1 Day 1 and response evaluation will be calculated compared to Cycle 1 Day 1 assessments. In 
IPd arm only, an additional blood sample will be collected at all time-points to evaluate the potential interference of isatuximab with the M protein assessment (central laboratory). 
Response will be assessed on the basis of clinical and laboratory findings on Day1 of every cycle, to confirm response and whenever disease progression is suspected. Investigator decision to continue study 
treatment or not will be taken based on local laboratory results except in selected country(ies) where central laboratory results are available on an ongoing basis (in which case, one sample will be collected at each 
timepoint). Efficacy analyses will be done according to IRC assessment, which will use central laboratory data.  
• 
Serum M-Protein immunoelectrophoresis (SPEP) and immunofixation: To be performed at screening and again prior to (within 24 hours) first study treatment administration on Cycle 1 Day 1, then at 
Day 1 of every subsequent cycle within 24 hours prior to study treatment administration, and at the EOT visit. After C1D1 immunofixation to be done if SPEP is negative. 
• 
Urine M-Protein (24-hour urine) immunoelectrophoresis (UPEP) and immunofixation: To be performed at screening, sampling collection must be completed within 24 hours prior to study treatment 
administration on Cycle 1 Day 1, then within 24 hours prior to study treatment administration on Day 1 of every subsequent cycle and at the EOT visit. If urine M-protein is negative (negative immunofixation) 
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. After Cycle 1 Day 1, immunofixation to be done if UPEP is 
negative in patients whose disease is evaluable in urine. 
• 
Serum free light chains (sFLC, quantification and ratio): To be performed at screening, within 24 hours prior to study treatment administration on Cycle 1 Day 1, then within 24 hours prior to study treatment 
administration on Day 1 of every subsequent cycle, and at the EOT visit (central lab analysis to be triggered if M protein is undetectable and immunofixation negative after Cycle 1 Day 1). 
• 
Immunoglobulins (IgG, IgA, IgM, IgD and IgE): To be performed at screening, within 24 hours prior to study treatment administration on Cycle 1 Day 1 and within 24 hours prior to study treatment 
administration on Day 1 of every subsequent cycle, and at the EOT visit (IgD or IgE only if the heavy chain component of the disease is known to be IgE or IgD). 
For patients who discontinue study treatment for reasons other than disease progression serum M-protein, urine M-protein (plus or minus sFLCs if needed to confirm sCR) to be performed monthly (central and 
local laboratory) during the follow-up period until progression. 
bb Radiological assessment: All imaging to be sent for central review. Note: for bone lesion assessment or extramedullary disease, the same modality (skeletal survey or low-dose whole-body CT; CT or MRI) 
should be used throughout the study for each individual patient. 
Bone disease assessment: Skeletal survey (including skull, spine, all long bones, pelvis and chest) or low-dose whole-body CT scan at baseline (within 21 days prior to randomization), then once a year and 
anytime during the study if clinically indicated.  
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Extramedullary disease (plasmacytoma) assessment (including bone plasmacytoma): 
• 
If known or documented extramedullary disease (plasmacytoma) at baseline, CT scan or MRI is to be done at baseline and to be repeated every 12 weeks (±1 week), to confirm CR, and if clinically indicated. 
• 
CT scan or MRI to be done in case of suspicion of progression or if clinically indicated in a patient with no previous positive image for extramedullary disease. 
cc Oral pomalidomide and dexamethasone will be recorded in patient diaries. 
dd AE/SAE assessment: All AEs, including AEs of new onset as well as worsening of baseline signs and symptoms are to be reported from the signing of the informed consent to 30 days following the last 
administration of study treatment. When diagnosis can be done, only main diagnosis (without its signs and symptoms) will be recorded as AE. After the 30 day follow-up all ongoing related AEs, all ongoing SAEs 
whatever relationship with study treatment, and all new related AEs whatever seriousness, are to be reported and followed up until resolution or stabilization. Severity will be graded according to NCI-CTC v4.03. 
ee Prior medications (which are not prior anti-myeloma therapy) administered within 21 days prior to randomization will be collected.  
ff Post 60-Day Follow-up (Day 60 visit, Day 90 visit, then every 3 months). 
At 60 days (±5 days) after last treatment administration, the following are to be recorded for all patients: ECOG performance status, ePROs, pregnancy test (for FCBP), ADA, AE assessment, further anti-
myeloma therapy, survival status, and second primary malignancies.  
Patients who discontinue study treatment without PD will be followed monthly (ie, Day 60, Day 90 then every month thereafter) until confirmation of PD (even for patients who would initiate further 
anti-myeloma therapy). In addition to the above, the following will also be recorded at all monthly visits: disease assessment labs, bone disease assessment, radiological assessment every 12 weeks (±1 week) in 
case of known or documented extramedullary disease (plasmacytoma) at baseline, and skeletal survey (to be assessed yearly or if clinically indicated).  
At 90 days (±5 days) after last treatment administration, and every 3 months thereafter until death, the following are to be recorded for patients with PD: AE assessment, further anti-myeloma therapy, survival 
status and second primary malignancies.  
Every effort will be made to follow all patients. If survival follow-up is missed and is not obtained at the time of the scheduled interval, it should be retrieved immediately. For subsequent survival follow-up, the 
patient FU visit should be scheduled at the original scheduled survival follow-up interval. If the patient is unable to visit the clinical center, the follow-up may be done via phone from the Investigator or designee to 
the patient or the patient's caregiver or a family member, but this should be exception and all efforts should be made to schedule follow-up visit at clinical center.  
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If isatuximab is stopped prior to pomalidomide and dexamethasone, ADA will be tested on D1 of the 2 next cycles. If ADA test at the second cycle administered without isatuximab is positive or inconclusive, ADA 
testing will be repeated every cycle until negative. 
After the PFS cut-off date, no further PK samples will be collected. 
EOI = End of Infusion; ADA = Anti-Drug Antibody (immunogenicity); P = Plasma; 1 Cycle = 28 days. 
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2 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 07 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE .................................................................. 3 
1 
FLOW CHARTS ............................................................................................................................. 19 
1.1 
GRAPHICAL STUDY DESIGN ...................................................................................................... 19 
1.2 
STUDY FLOW CHART .................................................................................................................. 20 
1.3 
PHARMACOKINETIC/PHARMACODYNAMIC FLOW CHART .................................................... 26 
2 
TABLE OF CONTENTS ................................................................................................................ 28 
2.1 
LIST OF TABLES ........................................................................................................................... 35 
2.2 
LIST OF FIGURES ......................................................................................................................... 35 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 36 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 39 
4.1 
INTRODUCTION ............................................................................................................................ 39 
4.2 
MULTIPLE MYELOMA................................................................................................................... 39 
4.3 
POMALIDOMIDE ........................................................................................................................... 40 
4.4 
INVESTIGATIONAL PRODUCT .................................................................................................... 41 
4.4.1 
Preclinical data ............................................................................................................................... 41 
4.4.2 
Clinical data .................................................................................................................................... 42 
4.4.2.1 
Single agent ................................................................................................................................... 42 
4.4.2.2 
Combinations ................................................................................................................................. 44 
4.5 
RATIONALE ................................................................................................................................... 45 
4.5.1 
Study rationale ............................................................................................................................... 45 
4.5.2 
Dose and regimen rationale ........................................................................................................... 46 
4.5.3 
Benefit/Risk of isatuximab in combination with pomalidomide and low-dose 
dexamethasone .............................................................................................................................. 47 
4.5.4 
Study design .................................................................................................................................. 47 
5 
STUDY OBJECTIVES ................................................................................................................... 48 
5.1 
PRIMARY ....................................................................................................................................... 48 
5.2 
SECONDARY ................................................................................................................................ 48 
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5.2.1 
Key secondary objectives .............................................................................................................. 48 
5.2.2 
Other secondary objectives ........................................................................................................... 48 
5.3 
EXPLORATORY ............................................................................................................................ 48 
6 
STUDY DESIGN ............................................................................................................................ 49 
6.1 
DESCRIPTION OF THE STUDY ................................................................................................... 49 
6.2 
DURATION OF STUDY PARTICIPATION .................................................................................... 50 
6.2.1 
Duration of study participation for each patient ............................................................................. 50 
6.2.2 
Determination of end of clinical trial (all patients) .......................................................................... 51 
6.3 
INTERIM ANALYSIS ...................................................................................................................... 51 
6.4 
STUDY COMMITTEES .................................................................................................................. 51 
7 
SELECTION OF PATIENTS .......................................................................................................... 53 
7.1 
INCLUSION CRITERIA .................................................................................................................. 53 
7.2 
EXCLUSION CRITERIA ................................................................................................................ 54 
8 
STUDY TREATMENTS ................................................................................................................. 57 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) .......................................................................... 57 
8.1.1 
Isatuximab ...................................................................................................................................... 57 
8.1.1.1 
Pharmaceutical form ...................................................................................................................... 57 
8.1.1.2 
Dilution method .............................................................................................................................. 57 
8.1.2 
Pomalidomide ................................................................................................................................ 58 
8.1.3 
Dexamethasone PO/IV .................................................................................................................. 58 
8.2 
DOSAGE AND SCHEDULE .......................................................................................................... 58 
8.2.1 
Study treatments (IMP) .................................................................................................................. 58 
8.2.2 
Premedication (NIMP) - Prevention of Infusion Associated Reactions (IARs) .............................. 60 
8.2.2.1 
Ranitidine or equivalent ................................................................................................................. 61 
8.2.2.2 
Diphenhydramine or equivalent ..................................................................................................... 61 
8.2.2.3 
Acetaminophen (paracetamol) ....................................................................................................... 61 
8.2.3 
Dose modifications ......................................................................................................................... 62 
8.2.3.1 
General rules .................................................................................................................................. 62 
8.2.3.2 
Modification of isatuximab/pomalidomide/dexamethasone dose levels in case of dose 
reduction ........................................................................................................................................ 63 
8.2.3.3 
Dose adjustments in IPd arm ......................................................................................................... 64 
8.2.3.4 
Dose adjustments in Pd arm .......................................................................................................... 68 
8.2.4 
Infusion reactions ........................................................................................................................... 72 
8.2.5 
Other toxicities ............................................................................................................................... 73 
8.2.6 
Criteria for temporarily delaying administration of study intervention ............................................ 74 
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8.3 
TUMOR LYSIS SYNDROME MANAGEMENT .............................................................................. 74 
8.4 
BLINDING PROCEDURES ............................................................................................................ 74 
8.5 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP .............................................. 74 
8.6 
PACKAGING AND LABELING ...................................................................................................... 75 
8.6.1 
Isatuximab ...................................................................................................................................... 75 
8.6.2 
Dexamethasone IV/PO .................................................................................................................. 75 
8.6.3 
Pomalidomide ................................................................................................................................ 75 
8.7 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 75 
8.7.1 
Isatuximab ...................................................................................................................................... 75 
8.7.2 
Dexamethasone IV/PO .................................................................................................................. 76 
8.7.3 
Pomalidomide ................................................................................................................................ 76 
8.8 
RESPONSIBILITIES ...................................................................................................................... 76 
8.8.1 
Treatment accountability and compliance...................................................................................... 77 
8.8.2 
Return and/or destruction of treatments ........................................................................................ 77 
8.9 
CONCOMITANT MEDICATION ..................................................................................................... 77 
8.9.1 
Antithrombotic therapy ................................................................................................................... 78 
8.9.2 
G-CSF prophylaxis ......................................................................................................................... 78 
8.9.3 
Prohibited concomitant therapy ..................................................................................................... 78 
8.9.4 
Contraceptive measures and pregnancy counseling ..................................................................... 79 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 83 
9.1 
PRIMARY ENDPOINT ................................................................................................................... 83 
9.2 
KEY SECONDARY EFFICACY ENDPOINTS ............................................................................... 84 
9.3 
OTHER SECONDARY ENDPOINTS ............................................................................................. 85 
9.3.1 
Other secondary efficacy endpoints ............................................................................................... 85 
9.3.2 
Safety endpoints ............................................................................................................................ 85 
9.3.3 
Patient-reported outcomes (HRQL/health economic variables/other endpoints) .......................... 85 
9.3.3.1 
EORTC QLQ-C30 .......................................................................................................................... 86 
9.3.3.2 
EORTC QLQ-MY20 ....................................................................................................................... 87 
9.3.3.3 
EQ-5D-5L ....................................................................................................................................... 87 
9.3.4 
Pharmacokinetics ........................................................................................................................... 87 
9.3.4.1 
Sampling time ................................................................................................................................ 87 
9.3.4.2 
Pharmacokinetics handling procedure ........................................................................................... 88 
9.3.4.3 
Bioanalytical method ...................................................................................................................... 88 
9.3.4.4 
Pharmacokinetics parameters ....................................................................................................... 88 
9.3.5 
Immunogenicity .............................................................................................................................. 88 
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9.3.5.1 
Anti-drug antibodies ....................................................................................................................... 88 
9.4 
EXPLORATORY ENDPOINTS ...................................................................................................... 90 
9.4.1 
Pharmacogenetic assessment ....................................................................................................... 90 
9.4.1.1 
Optional stored DNA sample ......................................................................................................... 90 
9.4.2 
Exploratory biomarker analysis ...................................................................................................... 90 
9.4.3 
Minimal residual disease ................................................................................................................ 91 
9.5 
FUTURE USE OF SAMPLES ........................................................................................................ 91 
9.6 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 91 
10 
STUDY PROCEDURES ................................................................................................................ 92 
10.1 
VISIT SCHEDULE .......................................................................................................................... 92 
10.1.1 
Screening/baseline......................................................................................................................... 92 
10.1.2 
Randomization ............................................................................................................................... 94 
10.1.3 
Treatment period ............................................................................................................................ 94 
10.1.3.1 Cycle 1 (Day 1, Day 8, Day 15 and Day 22 all ±1 day) ................................................................. 94 
10.1.3.2 Subsequent cycles (Day 1 and 15) ................................................................................................ 96 
10.1.4 
End of treatment ............................................................................................................................. 99 
10.1.5 
Post treatment follow up .............................................................................................................. 100 
10.1.5.1 60 days visit ................................................................................................................................. 100 
10.1.5.2 Further follow-up visits (Day 90 ±7 days after last study treatment administration and then 
every 3 months [±7 days]) ............................................................................................................ 102 
10.1.6 
Post PFS study cut-off date ......................................................................................................... 103 
10.1.7 
Post final OS study cut-off date ................................................................................................... 105 
10.2 
DEFINITION OF SOURCE DATA ................................................................................................ 106 
10.3 
HANDLING OF PATIENT PERMANENT TREATMENT DISCONTINUATION AND OF 
PATIENT STUDY DISCONTINUATION ...................................................................................... 106 
10.3.1 
Permanent treatment discontinuation with investigational medicinal product(s) ......................... 106 
10.3.2 
List of criteria for permanent treatment discontinuation ............................................................... 106 
10.3.3 
Handling of patients after permanent treatment discontinuation ................................................. 107 
10.3.4 
Procedure and consequence for patient withdrawal from study .................................................. 108 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ........................ 108 
10.4.1 
Definitions of adverse events ....................................................................................................... 108 
10.4.1.1 Adverse event .............................................................................................................................. 108 
10.4.1.2 Serious adverse event ................................................................................................................. 109 
10.4.1.3 Adverse event of special interest ................................................................................................. 109 
10.4.1.4 Pregnancy .................................................................................................................................... 110 
10.4.1.5 Overdose ...................................................................................................................................... 111 
10.4.2 
General guidelines for reporting adverse events ......................................................................... 111 
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10.4.3 
Instructions for reporting serious adverse events ........................................................................ 112 
10.4.4 
Guidelines for reporting adverse events of special interest ......................................................... 113 
10.5 
OBLIGATIONS OF THE SPONSOR ........................................................................................... 113 
10.6 
SAFETY INSTRUCTIONS ........................................................................................................... 113 
10.6.1 
Guidelines for the management of potential infusion associated reactions................................. 113 
10.6.2 
Guidelines for the management of tumor lysis syndrome ........................................................... 113 
10.7 
ADVERSE EVENTS MONITORING ............................................................................................ 114 
11 
STATISTICAL CONSIDERATIONS ............................................................................................ 115 
11.1 
DETERMINATION OF SAMPLE SIZE ......................................................................................... 115 
11.2 
DISPOSITION OF PATIENTS ..................................................................................................... 116 
11.3 
ANALYSIS POPULATIONS ......................................................................................................... 116 
11.3.1 
Efficacy populations ..................................................................................................................... 116 
11.3.1.1 Intent-to-treat population .............................................................................................................. 116 
11.3.2 
Safety population ......................................................................................................................... 116 
11.3.3 
Pharmacokinetic population ......................................................................................................... 117 
11.3.4 
ADA population ............................................................................................................................ 117 
11.3.5 
Patient reported outcome population ........................................................................................... 117 
11.4 
STATISTICAL METHODS ........................................................................................................... 117 
11.4.1 
Extent of study treatment exposure and compliance ................................................................... 117 
11.4.2 
Analyses of efficacy endpoints ..................................................................................................... 119 
11.4.2.1 Analysis of primary efficacy endpoint(s) ...................................................................................... 119 
11.4.2.2 Analyses of secondary efficacy endpoints ................................................................................... 120 
11.4.2.3 Multiplicity considerations ............................................................................................................ 120 
11.4.3 
Analyses of safety data ................................................................................................................ 121 
11.4.3.1 Adverse events ............................................................................................................................ 121 
11.4.3.2 Treatment-emergent adverse events ........................................................................................... 122 
11.4.3.3 Deaths .......................................................................................................................................... 122 
11.4.3.4 Other safety evaluations .............................................................................................................. 123 
11.4.4 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................. 124 
11.4.4.1 Analysis of pharmacokinetic variables ......................................................................................... 124 
11.4.5 
Analyses of immunogenicity ........................................................................................................ 124 
11.4.6 
Analyses of patient reported outcomes (HRQL/health economics) variables ............................. 124 
11.4.7 
Other analyse(s) ........................................................................................................................... 125 
11.5 
INTERIM ANALYSIS .................................................................................................................... 125 
12 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................. 127 
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12.1 
ETHICAL AND REGULATORY STANDARDS ............................................................................ 127 
12.2 
INFORMED CONSENT ............................................................................................................... 127 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC) ................................................................................................. 128 
13 
STUDY MONITORING................................................................................................................. 129 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) ..................................................................... 129 
13.2 
RESPONSIBILITIES OF THE SPONSOR ................................................................................... 129 
13.3 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST .................................................................................................................................... 130 
13.4 
USE OF COMPUTERIZED SYSTEMS ........................................................................................ 130 
14 
ADDITIONAL REQUIREMENTS ................................................................................................. 131 
14.1 
CURRICULUM VITAE.................................................................................................................. 131 
14.2 
RECORD RETENTION IN STUDY SITES .................................................................................. 131 
14.3 
CONFIDENTIALITY ..................................................................................................................... 131 
14.4 
PROPERTY RIGHTS ................................................................................................................... 132 
14.5 
DATA PROTECTION ................................................................................................................... 132 
14.6 
INSURANCE COMPENSATION .................................................................................................. 133 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ............................... 133 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE .......................................................................................................................................... 133 
14.8.1 
By the Sponsor ............................................................................................................................. 133 
14.8.2 
By the Investigator ....................................................................................................................... 134 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................ 134 
14.10 
PUBLICATIONS AND COMMUNICATIONS ............................................................................... 134 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................ 135 
16 
BIBLIOGRAPHIC REFERENCES ............................................................................................... 136 
17 
APPENDICES .............................................................................................................................. 139 
APPENDIX A 
MODIFICATION OF DIET IN RENAL DISEASE (MDRD) EQUATION ............................. 140 
APPENDIX B 
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS 
SCALE ......................................................................................................................................... 141 
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APPENDIX C 
NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA FOR 
ADVERSE EVENTS..................................................................................................................... 142 
APPENDIX D 
IMWG RESPONSE CRITERIA.......................................................................................... 143 
APPENDIX E 
GUIDELINES FOR THE DETERMINATION OF THE NUMBER OF PRIOR LINES 
OF THERAPY IN MULTIPLE MYELOMA .................................................................................... 147 
APPENDIX F 
DEFINITION OF RELAPSED AND REFRACTORY MYELOMA ....................................... 149 
APPENDIX G 
INFUSION ASSOCIATED REACTIONS OBSERVED WITH ISATUXIMAB .................... 150 
APPENDIX H 
EORTC-QLQ-C30 SCALES, ITEMS AND CIDS ............................................................... 151 
APPENDIX I 
MY20 SCALES, ITEMS AND CIDS .................................................................................... 155 
APPENDIX J 
EQ-5D-5L SCALES, ITEMS AND CIDS ............................................................................. 158 
APPENDIX K 
CD38 BLOOD TEST INTERFERENCE GUIDELINE AABB2016 ..................................... 161 
APPENDIX L 
GLOBAL POMALIDOMIDE PREGNANCY PREVENTION PLAN ..................................... 165 
APPENDIX M 
GUIDANCE FOR NOTIFICATION OF EARLY TERMINATION OF THE TRIAL 
ACCORDING TO COUNTRY APPLICABLE REGULATORY REQUIREMENTS ....................... 179 
APPENDIX N 
COUNTRY-SPECIFIC REQUIREMENTS ......................................................................... 180 
APPENDIX O 
CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL EMERGENCY 
THAT IS DECLARED BY A GOVERNMENTAL AGENCY .......................................................... 181 
APPENDIX P 
PROTOCOL AMENDMENT HISTORY ............................................................................. 183 
 
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2.1 
LIST OF TABLES  
Table 1 - Dose levels for pomalidomide dose reduction ............................................................................... 63 
Table 2 - Dose levels for dexamethasone dose reduction ............................................................................ 63 
Table 3 - Guidelines for dose adjustments for hematologic toxicities - 
isatuximab/pomalidomide/dexamethasone combination ............................................................................... 64 
Table 4 - Guidelines for dose adjustments for non-hematologic toxicities - 
isatuximab/pomalidomide/dexamethasone combination ............................................................................... 65 
Table 5 - Guidelines for dose adjustments for hematologic toxicities - pomalidomide/dexamethasone 
combination ................................................................................................................................................... 68 
Table 6 - Guidelines for dose adjustments for non-hematologic toxicities - 
pomalidomide/dexamethasone combination ................................................................................................. 70 
Table 7 - Management of infusion associated reaction ................................................................................. 73 
Table 8 - Bioanalytical method for isatuximab pharmacokinetic analysis ..................................................... 88 
Table 9 - Bioanalytical method for isatuximab immune response assessment ............................................ 89 
Table 10 - Summary of adverse event reporting instructions...................................................................... 112 
Table 11 - Management of tumor lysis syndrome ....................................................................................... 114 
 
2.2 
LIST OF FIGURES  
Figure 1 - Pomalidomide and isatuximab combination effect on PBMCs ..................................................... 41 
Figure 2 - MOLP xenograft model isatuximab + pomalidomide .................................................................... 42 
Figure 3 - Main TEAEs reported in single agent studies according to formulation ....................................... 43 
Figure 4 - Study design ................................................................................................................................. 49 
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3 
LIST OF ABBREVIATIONS  
 
ADA: 
antidrug antibodies 
ADCC: 
antibody-dependent cellular-mediated cytotoxicity 
AEs: 
adverse events 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ANC: 
absolute neutrophil count 
ASCO: 
American Society of Clinical Oncology 
ASCT: 
autologous stem cell transplantation 
AST: 
aspartate aminotransferase 
AT: 
all treated 
AUC: 
area under the curve 
BM: 
bone marrow 
BMA: 
bone marrow aspirate 
cADPR: 
cyclic adenosine-diphosphate-ribose 
CBR: 
clinical benefit rate 
CDC: 
complement-dependent cytotoxicity 
CI: 
confidence interval 
CID: 
clinical important difference 
CLL: 
chronic lymphocytic leukemia 
CR: 
complete response 
DMC: 
Data Monitoring Committee 
DOR: 
duration of response 
DVT: 
deep vein thrombosis 
ECOG: 
Eastern Cooperative Oncology Group 
ELISA: 
enzyme linked immunoabsorbant assay 
EORTC: 
European Organisation for Research and Treatment of Cancer 
EOT: 
end of treatment 
ePROs: 
electronic patient reported outcomes 
EQ-5D-5L: 
European Quality of Life Group questionnaire with 5 dimensions and five levels 
per dimension 
FCBP: 
female of child-bearing potential 
FISH: 
fluorescence in situ hybridization 
FPI: 
first patient in study 
GVHD: 
graft versus host disease 
HBcAb: 
hepatitis B core antibody 
HBsAb: 
hepatitis B surface antibody 
HBsAg: 
hepatitis B surface antigen 
HBV: 
hepatitis B virus 
HDAC: 
hystone deacetylase 
HLA: 
human leukocyte antigen 
HLGT: 
high level general term 
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HLT: 
high level term 
HRQL: 
health-related quality of life 
HSC: 
hematopoietic stem cell 
IAR: 
infusion associated reaction 
ICF: 
informed consent form 
IEC: 
independent ethics committee 
IFN: 
interferon 
IL: 
interleukin 
IMiDs: 
immunomodulatory drugs 
IMWG: 
International Myeloma Working Group 
IPd: 
isatuximab pomalidomide dexamethasone 
IRB: 
institutional review board 
IRC: 
Independent Response Committee 
IRT: 
interactive response technology 
ITT: 
intent-to-treat 
IV: 
Intravenous 
kDa: 
kilodalton 
KIR: 
killer cell inhibitory receptor 
mAb: 
monoclonal antibody 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MM: 
multiple myeloma 
MR: 
minimal response 
MRD: 
minimal residual disease 
NAD+: 
nicotinamide adenine dinucleotide 
NCI-CTCAE: 
National Cancer Institute Common Terminology for Adverse Event 
NK: 
natural killer 
NSAIDs: 
non steroid anti-inflammatory drugs 
ORR: 
overall response rate 
OS: 
overall survival 
PBMC: 
peripheral blood mononuclear cells 
Pd: 
pomalidomide dexamethasone 
PD: 
progressive Disease 
PDy: 
pharmacodynamic 
PE: 
pulmonary embolism 
PFS: 
progression free survival 
PIs: 
proteasome inhibitors 
PK: 
pharmacokinetic 
PR: 
partial response 
PRO: 
patient reported outcome 
PT: 
preferred term 
QLQ-C30: 
quality of life questionnaire with 30 questions 
QLQ-MY20: 
EORTC myeloma module with 20 items  
RBC: 
red blood cell 
RRMM: 
relapsed refractory multiple myeloma 
SAE: 
serious adverse event 
SC: 
Steering Committee 
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SCT: 
stem cell transplant 
SOC: 
system organ class 
SPD: 
sum of the products of the maximal perpendicular diameters of measured lesions 
TEAE: 
treatment-emergent adverse event 
TLS: 
tumor lysis syndrome 
TNF: 
tumor necrosis factor alpha 
TTP: 
time to progression 
UPEP: 
Urine Protein immunoelectrophoresis 
URTI: 
Upper Respiratory Tract Infection 
VAS: 
visual analogic scale 
VGPR: 
very good partial response 
WBC: 
white blood cell 
 
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4 
INTRODUCTION AND RATIONALE  
4.1 
INTRODUCTION  
CD38 is a Type II glycosylated 45 kilodalton (kDa) membrane protein that was identified as 
a lymphocyte marker (2). CD38 has a role in leukocyte homeostasis through modulation of 
hematopoietic cell survival and differentiation (3). CD38 functions as a receptor binding to CD31 
and is involved in cell adhesion and signal transduction. The function of CD38 in signal 
transduction appears to be versatile depending on the cell lineage, the differentiation stage, and, 
possibly, the association with different co-receptors (3). CD38 is also an ecto-enzyme catalyzing 
the synthesis and hydrolysis of cyclic adenosine-diphosphate-ribose (cADPR) from nicotinamide 
adenine dinucleotide (NAD+) to ADP-ribose (4). These reaction products are implicated in 
calcium mobilization and intracellular signaling (5). 
The expression of CD38 in healthy humans can be detected on natural killer (NK) cells, 
monocytes, dendritic cells, macrophages, granulocytes, activated T and B cells, and plasma cells. 
In contrast, expression has not been detected in hematopoietic stem cells (HSC), resting T and 
B cells, or tissue macrophages. Several hematological malignancies express CD38 including those 
of B-lymphocyte, T-lymphocyte and myeloid origin. Moreover, CD38 was identified as 
a negative prognostic marker in some hematological malignancies, such as chronic lymphocytic 
leukemia (CLL). The expression of CD38 is especially notable in multiple myeloma (MM) as 
>98% of patients are positive for this protein (6, 7). The strong and uniform expression of CD38 
on malignant clonal MM cells contrasts with the restricted expression pattern on normal cells 
suggesting this antigen may be useful for specific targeting of tumor cells.  
4.2 
MULTIPLE MYELOMA  
Multiple myeloma is a malignant plasma cell disease that is characterized by clonal proliferation 
of plasma cells in the bone marrow (BM) and the production of excessive amounts of 
a monoclonal immunoglobulin (usually of the IgG or IgA type or free urinary light chain 
[paraprotein, M-protein or M-component]). It is a disease predominantly associated with 
advancing age with more than 80% of patients aged 60 years or older. Patients with MM can 
experience bone pain, bone fractures, fatigue, anemia, infections, hypercalcemia, and kidney 
problems (8). The disease course for MM varies with the aggressiveness of the disease and related 
prognostic factors. Certain chromosomal abnormalities in multiple myeloma have been shown to 
be associated with poor clinical outcome. High-risk cytogenetic changes include del(17p), t(4;14), 
and t(14;16), among others. During the 2 last decades, median survival has been improved from 
3 to 6 years; however, some patients can live longer than 10 years (8, 9). 
Treatment options and survival are based on the patient’s age, fitness and disease status. Patients 
under the age of approximately 65, presenting with symptomatic active disease in good physical 
health will generally receive initial therapy with autologous stem cell transplantation (ASCT). To 
achieve cytoreduction of the disease before collecting stem cells, induction chemotherapy is 
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administered. Induction treatment regimens include alkylating agents, dexamethasone alone, 
thalidomide plus dexamethasone, and vincristine, Adriamycin® (doxorubicin), and dexamethasone 
(VAD; or modifications to this regimen); however, the latter 2 regimens are associated with 
higher toxicity (10). Newer treatments with Velcade® (bortezomib) alone, bortezomib 
combinations, and Revlimid® (lenalidomide) plus dexamethasone have demonstrated improved 
outcomes as induction therapy, and these agents demonstrate higher response rates and lower 
toxicity (9, 10). In addition to these new treatments, daratumumab has been recently approved in 
US and Europe in single agent based on response rate of 29.2% (95%CI: 20.8-38.9) in late stage 
relapse and refractory multiple myeloma patients previously treated with IMiDs and PI, 
supporting the use of CD38 antibody in MM (11). 
The current aim of MM therapy is to control the disease as effectively as possible, to maximize 
quality of life and to prolong survival. Treatments for relapsed and/or refractory disease are often 
referred to as salvage therapy. The initial chemotherapy regimen (eg, bortezomib plus 
dexamethasone or bortezomib thalidomide plus dexamethasone or lenalidomide plus 
dexamethasone, or bortezomib plus melphalan plus prednisone depending if the patient was 
eligible for stem cell transplantation or not) can be reinstituted for relapsed/refractory disease if 
the disease relapsed more than 6 months after the last therapy ended. Subsequent treatment 
decisions are based on whether the patient experiences an indolent or aggressive relapse. In 
general, MM patients will receive an average of 4 to 8 different regimens during their lifespan 
utilizing agents such as proteasome inhibitors (eg, bortezomib, ixazomib and carfilzomib) and 
immune modulatory agents (eg, lenalidomide), monoclonal antibodies (elotuzumab), histone 
deacetylase (HDAC) inhibitors (panobinostat) alone or in combination. However, once a patient 
becomes refractory to those agents, survival is limited and newer treatment options are needed to 
treat patients after they have failed stem cell transplant (SCT), chemotherapy, proteasome 
inhibitors, and immunomodulatory drugs (IMiDs®). Despite the dramatic improvement in patient 
outcomes with newer therapies, MM remains an incurable disease. Thus, the treatment of patients 
who have received at least 2 different lines of therapy including a proteasome inhibitor and an 
immunomodulatory agent or who are double refractory to a proteasome inhibitor and an IMiD® 
remains an unmet medical need. 
4.3 
POMALIDOMIDE  
Pomalidomide is a thalidomide analogue indicated for patients with multiple myeloma who have 
received at least two lines therapies including lenalidomide and a proteasome inhibitor (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 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 natural killer cell and by inhibiting regulatory 
T cells (5). Pomalidomide has been approved following the data reported in the MM-003 trial 
where pomalidomide plus low-dose dexamethasone was compared to high-dose dexamethasone. 
In the MM-003 trial the most common Grade 3-4 hematological adverse events in the 
pomalidomide plus low-dose dexamethasone arm were neutropenia (48%), anemia (33%) and 
thrombocytopenia (22%); Grade 3-4 non-hematological AEs included pneumonia (13%), bone 
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pain (7%) and fatigue (5%). 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. 
The updated OS after crossover showed significant advantage in the pomalidomide arm (12), 
providing relapsed refractory multiple myeloma (RRMM) patients with a new therapeutic option. 
4.4 
INVESTIGATIONAL PRODUCT  
Based on the fact that CD38 is the most strongly and uniformly expressed antigen identified on 
the malignant clonal populations of myeloma cells compared with its pattern of expression on 
normal cells this antigen may be a useful target for the in vivo depletion of tumor cells while 
sparing normal cells (13). 
Isatuximab (SAR650984) is a naked chimeric monoclonal antibody (mAb) that binds selectively 
to a unique epitope on the human surface antigen CD38. Isatuximab kills tumor cells via multiple 
biological mechanisms, antibody-dependent cellular-mediated cytotoxicity (ADCC), complement-
dependent cytotoxicity (CDC), direct induction of apoptosis (pro-apoptosis) without crosslinking, 
and inhibition of CD38 enzymatic activity.  
4.4.1 Preclinical data  
In vitro experiments demonstrate that the combination of isatuximab and pomalidomide results in 
enhanced direct toxicity and lysis by effector cells (ADCC) of CD38+ MM cells compared to that 
of isatuximab alone. Pomalidomide significantly increased isatuximab induced toxicity against 
patient derived MM cell s both sensitive and resistant to pomalidomide or lenalidomide. 
Pretreatment of peripheral blood mononuclear cells (PBMC) with pomalidomide increased 
isatuximab induced lysis of MM1S cells from below 40% to above 80% (Figure 1) (14). 
Figure 1 - Pomalidomide and isatuximab combination effect on PBMCs  
 
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In vivo experiments using a MM xenograft model (MOLP-8) demonstrate that the combination of 
isatuximab and pomalidomide results in enhanced antitumor activity (T/C=22%) compared to the 
activity of isatuximab (T/C=56%) and pomalidomide alone (T/C=46%) (Figure 2). 
Figure 2 - MOLP xenograft model isatuximab + pomalidomide  
 
4.4.2 Clinical data  
Isatuximab has shown promising activity in heavily pretreated relapsed and refractory multiple 
myeloma (RRMM) patients both as single agent and in combination with lenalidomide and 
dexamethasone (7, 14).  
4.4.2.1 Single agent  
The TED10893 (NCT01084252) trial is a Phase I/II single agent trial of isatuximab in RRMM. In 
the Phase II dose finding part of the trial patients with RRMM (≥3 lines of anti-MM therapy or 
refractory to IMiDs and proteasome inhibitors [PIs]) were randomized to isatuximab 3 mg/kg 
Q2W, 10 mg/kg Q2W x 2 cycles then Q4W, or 10 mg/kg Q2W, furthermore a fourth treatment 
arm was enrolled at 20 mg/kg QW/Q2W. As of November 2015, the observed ORR was: 9% 
(2/23), 20% (5/25), 29% (7/24) and 24% (6/25) at isatuximab ISA 3 Q2W, 10 Q2W/Q4W, 
10 Q2W, and 20 mg/kg QW/Q2W, respectively; 14/20 responders continue without progression. 
Most common adverse events (AEs) were nausea (33%), fatigue (30%), dyspnea (26%), and 
cough (24%), which were typically Grade ≤2. Infusion associated reactions (IARs) occurred in 
49% of patients, mostly Grade ≤2, 94% during the first infusion. Six patients discontinued therapy 
due to AEs, 2 due to IARs. 
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The TED14154 (NCT02514668) is a Phase 1 dose escalation study where the P2F2 formulation is 
being evaluated, as of May 12, 2016 16 patients have been treated in the trial. The most frequent 
category of AEs consisted of IARs, with an incidence of 62.5% with no Grade 3-4 IARs reported. 
All the IARs were resolved without sequelae. In addition to the IARs, the most common TEAEs 
consisted of fatigue, nausea, and diarrhea. 
The incidence and severity of all the AEs in general, and of the most common AEs occurring in at 
least 15% of the patients, is shown in Figure 3. Treatment emergent AEs observed with P1F1 are 
illustrated as “TED10-ph1” and “TED10-ph2” (representing Studies TED10893 - Phase 1, and 
TED10893 - Phase 2 stage 1, respectively), while TEAEs observed with P2F2 are illustrated as 
“TED14154”. Overall, the safety profile appears similar between the two formulations. 
Figure 3 - Main TEAEs reported in single agent studies according to formulation  
 
*URTI: upper respiratory tract infection 
The safety data summarized from the ongoing study TED14154, which includes the qualitative 
analysis of the IARs, suggest that the characteristics of P2F2 are similar to P1F1. Any 
comparisons between the two formulations, however, is presently limited by the small population 
size treated with P2F2, and thereby should be analyzed with caution when evaluating the safety 
profile. 
Amongst the 16 patients (n=3 at 10 mg/kg QW/Q2W, n=13 at 20 mg/kg QW/Q2W) treated and 
assessed for at least 1 cycle. The median age was 71 years (range, 53 77 y). The median time from 
diagnosis to first isatuximab dosing was 6.0 years (range, 3.1-13.5 y). As with the TED10893 
study, patients were heavily pretreated and were exposed to most of the available anti-MM 
treatments. The median number of prior lines of therapy was 5.0 (range, 3-9) and all patients 
received at least 1 immunomodulatory drug (eg, lenalidomide, pomalidomide) and 1 proteasome 
inhibitor (ie, bortezomib, carfilzomib). 
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The median number of treatment cycles for 3 patients treated at 10 mg/kg was 3 (range 2:4) and 
for the 13 patients at 20 mg/kg was 2 (range, 1-3). At the 10 mg/kg dose level, the best overall 
response was MR for 1 patient and SD for 2 patients (including 1 patient with disease stabilization 
>6 months). At the 20 mg/kg dose level, the best overall response was partial response (PR) for 
2 patients, MR for 3 patients, SD for 5 patients and PD for 1 patient. 
4.4.2.2 Combinations  
4.4.2.2.1 Lenalidomide and low dose dexamethasone  
The TCD11863 (NCT01749969) trial is evaluating the combination of isatuximab with standard 
doses of lenalidomide and dexamethasone in RRMM and has enrolled 57 patients as of 
30 October 2015. Three dose levels were explored with the Q2W regimen, 3, 5 and 10 mg/kg with 
ORR of 63% at 10 mg/kg (n=24). Furthermore 2 additional cohorts of patients were enrolled and 
treated at 10 or 20 mg/kg using the QW/Q2W regimen. Amongst the efficacy evaluable patients 
the ORR was 50% in both cohorts (10 mg/kg [n=12]: VGPR 25%; PR 25%; 20 mg/kg [n=10]: 
VGPR 20%; PR 30%) with no difference in the safety profile although 1 DLT (pneumonia) was 
observed at 20 mg/kg as well as 3 G3 IARs leading to treatment discontinuation. Most frequent 
AEs were fatigue (46%), pyrexia (35%) and diarrhea (31%). IARs occurred in 65% of patients, 
mostly Grade ≤2, and >90% during the first infusion. MTD has not been reached.  
4.4.2.2.2 Pomalidomide and low dose dexamethasone  
The combination of isatuximab with pomalidomide and dexamethasone is being studied in the 
ongoing TCD14079 trial (NCT02283775). This is a Phase 1b dose escalation trial evaluating the 
combination in patients with refractory or relapsed and refractory multiple myeloma. 
Three isatuximab dose levels are planned to be evaluated, 5, 10 and 20 mg/kg weekly for 4 weeks 
followed by every other week (QW/Q2W). Pomalidomide is administered at 4 mg per day for 
21 days and dexamethasone 40 mg (20 mg if ≥75 years old) once a week as per the current label 
of pomalidomide, cycles are 28-day each. 
As of May 26th 2016, 18 patients were enrolled in the trial; all of them have received at least 
2 prior therapies including lenalidomide or proteasome inhibitor and have progressed during or 
within 60 days of the end of last therapy. Eight patients were treated at 5 mg/kg and 6 at 
10 mg/kg. Four patients have been enrolled at 20 mg/kg dose level although the data is not 
presented here as these is not mature enough for the first hint of efficacy (none of them have 
completed at least 2 cycles of treatment).  
Among the 14 patients for whom the data is available, 8 were treated at the dose of 5 mg/kg (with 
a median exposure of 21.2 weeks); and 6 patients at the dose of 10 mg/kg QW, then Q2W (with a 
median exposure of 8.1 weeks). Three patients discontinued treatment, 2 because of PD, and 
1 because of a reason classified as “other” (patient wish due to grade 2 infusion associated 
reaction). The most common TEAEs reported in more than 3 patients consisted of fatigue (all 
Grade 64.3%, Grade 3-4 in 1 patient, 7.1%), infusion related reaction (all Grade 57.1%, no 
Grade 3-4), upper respiratory tract infection, tremor, dyspnea, and cough (all Grade 28.6%, no 
Grade 3-4). Infections occurred in 6 patients (42.9%) with a severity of Grade 3-4 in 1 patient 
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(7.1%, pneumonia). According to laboratory values, neutropenia was reported in 13 patients 
(92.9%), with severity of Grade 3-4 in 12 patients (85.7%); lymphopenia was reported in 
11 patients (92.9%), with severity of Grade 3-4 in 11 patients (78.6%); thrombocytopenia was 
reported in 13 patients (92.9%), with severity of Grade 3-4 in 4 patients (56.0%); anemia was 
reported in all patients (100.0%), with no Grade 3-4. SAEs were reported in 6 patients (42.9%), 
with the most frequent being neutropenia, reported in 2 patients. DLTs occurred in 2 patients: 
1 patient from the 5 mg/kg cohort (Grade 4 neutropenia at C1, related to pomalidomide), and 
1 patient from the 10 mg/kg cohort (Grade 4 neutropenic infection consisting of cellulitis at C1, 
related to pomalidomide). Both DLTs resolved. No patient had AEs leading to death or 
discontinuation. One patient died while on study because of PD, at C2, 36 days after the last 
administration of study therapy.  
All Grade IARs occurred in 8 patients (57.1%) with no Grade 3-4 the majority of them during the 
first cycle of treatment and further resolved.  
At 5 mg/kg one patient was considered not evaluable for efficacy because of treatment 
discontinuation (due other reason than AE or PD) before completion of the first cycle, eventually 
7 patients were considered evaluable for efficacy. Among them and with a follow-up of at least 
2 cycles, one confirmed complete response (CR), two confirmed VGPRs and 2 PRs were 
reported. Four patients are still on treatment and have received 9, 9, 7 and 5 cycles respectively. 
Two patients have experienced disease progression after 9 and 4 cycles of treatment respectively.  
At 10 mg/kg, all patients have completed at least 2 cycles of treatment and have at least 
2 consecutive efficacy assessments. Two patients have their myeloma laboratory values with 
a decrease qualifying them to MR, one is in SD, one patient is in PR, and two are in VGPR. All of 
them are still on treatment and have completed 2, 3 and 4 cycles respectively. 
The dose level of 20 mg/kg is under enrolment. 
4.5 
RATIONALE  
4.5.1 Study rationale  
Multiple myeloma is a high unmet medical need and as a result, several agents are currently under 
clinical investigation in MM. Some of them (including isatuximab) have shown clinical activity as 
monotherapy, but the clinical avenue for development of most of them is to search for rationally 
based or pre-clinically oriented combinations of these novel agents with standard of care of MM, 
looking for potentiation. Monoclonal antibodies are one of the most promising groups of drugs in 
development in the treatment of MM with several of them demonstrating activity in this disease 
(13). One of the most important characteristics of this type of agents, apart from the clinical 
efficacy demonstrated, is the safety profile and the absence of potential cross-resistance with the 
agents currently utilized. This makes mAb an ideal combination partner with proteasome 
inhibitors, IMiDs and steroids. 
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Pre-clinical data demonstrate at least additive activity of isatuximab in combination with the 
immunomodulatory drug lenalidomide. The ongoing TCD11863 study evaluating this 
combination showed promising activity. Pomalidomide is the newest immunomodulatory drug 
which is a derivate from thalidomide. Pomalidomide in combination with low-dose 
dexamethasone has been studied in Phase I-III trials for patients with RR myeloma. It has shown 
activity in lenalidomide refractory patients and demonstrates superior OS and PFS compared to 
high dose dexamethasone. The effect of pomalidomide on the immune system coupled with the 
mechanism of action of isatuximab, suggests that the combination of both drugs may improve the 
benefit seen with pomalidomide in combination with low-dose dexamethasone in RRMM patients 
whose disease have previously failed to 2 or more anti-myeloma treatments. This study 
(EFC14335) will evaluate the efficacy and safety of isatuximab in combination with 
pomalidomide and dexamethasone compared to pomalidomide and dexamethasone. 
4.5.2 Dose and regimen rationale  
Isatuximab as a single agent have shown an efficacy dose effect between 3 mg/kg and 10 mg/kg 
and above.  
Although no evident difference is seen for tolerability, the available data in combination with 
lenalidomide (see Section 4.4.2.2.1) does not demonstrate major differences in efficacy between 
10 and 20 mg/kg with comparable response rate in heavily pretreated patients. There is no 
apparent increase on adverse events with the combination and no DDI was evidenced between 
isatuximab and lenalidomide. PK/PDy analyses including trial simulations and simulations of 
serum M protein-profiles showed higher predicted ORR and reduction in M-protein at 8/12 weeks 
at doses ≥10 mg/kg. However, the benefit in terms of ORR increase or in term serum M-protein 
reduction appeared limited when increasing the dose from 10 to 20 mg/kg QW x 4, Q2W. 
Therefore, based on clinical efficacy, safety, PK simulations and PK/PDy analyses, the dose 
selected for further lenalidomide/isatuximab combination studies is 10 mg/kg QW 
x 4 administrations followed by 10 mg/kg Q2W.  
The data available for the combination of isatuximab with pomalidomide and dexamethasone in 
the TCD14079 shows no apparent difference in efficacy and tolerability between the two doses 
currently studied (5 and 10 mg/kg). Isatuximab PK appeared not to be altered by pomalidomide 
and vice-versa, as it has been shown for isatuximab in combination with lenalidomide. It is not 
expected to have an increase on response rate with 20 mg/kg as this was not seen in single agent 
or in combination with lenalidomide, although no data is available yet as the cohort is under 
enrolment.  
In addition, the change in the formulation (P2F2 versus P1F2) appears not to modify the PK of 
isatuximab and therefore would not require a dose adjustment based on PK/PDy relationships.   
The current data show: 
• The single agent data coming from the TED14054 (P2F2) and TED10893 (P1F1) where 
there is no apparent difference between the 2 formulation, 
• No effect of pomalidomide or lenalidomide on isatuximab PK parameters and vice versa, 
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• The combination of isatuximab with lenalidomide and dexamethasone (TCD11863) where 
there is no benefit in response rate with increasing the dose from 10 to 20 mg/kg. 
Based on these data above, the dose of isatuximab 10 mg/kg was selected for the combination 
with pomalidomide and dexamethasone in this Phase 3 trial. 
4.5.3 Benefit/Risk of isatuximab in combination with pomalidomide and low-dose 
dexamethasone  
Based on the safety and efficacy data described above, isatuximab as a single agent has shown 
clinical benefit in response rate with a favorable safety profile. Infusion-associated reactions are 
manageable with mandatory prophylaxis, close monitoring, and supportive care.  
When isatuximab is combined with lenalidomide and low-dose dexamethasone or pomalidomide 
and low-dose dexamethasone, results appear promising. The overall safety profile of isatuximab 
in combination with lenalidomide does not appear to add morbidity to the clinical course of 
patients with RRMM, and is comparable with AEs observed with other established regimens. In 
the ongoing Phase 1b study TCD14079 (isatuximab, pomalidomide and dexamethasone), despite 
the high incidence of Grade 3 to 4 neutropenia (85.7%) reported as a laboratory abnormality 
(see Section 4.4.2.2.2), no increase in the incidence of febrile neutropenia or neutropenic infection 
has been observed compared to the available data on the combination of pomalidomide and 
dexamethasone (15). 
Thus, the collective clinical experience shows a positive balance of benefit over risk and warrants 
further evaluation of the combination of isatuximab with pomalidomide and low-dose 
dexamethasone in RRMM as proposed in this clinical trial. 
4.5.4 Study design  
The study protocol has been designed to demonstrate a progression free survival and an overall 
survival advantage of isatuximab at the dose of 10 mg/kg weekly during first month, followed by 
every 2 weeks administrations administered in combination with pomalidomide and 
dexamethasone compared to pomalidomide and dexamethasone in patients with relapse and 
refractory multiple myeloma previously treated with at least 2 lines of therapy.  
Patients will be randomly assigned in a 1:1 ratio to one of the two arms according 2 stratification 
factors: age (<75 years versus ≥75 years) and number of previous lines of therapy (two or 
three versus more than three).  
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5 
STUDY OBJECTIVES  
5.1 
PRIMARY  
To demonstrate the benefit of isatuximab in combination with pomalidomide and low-dose 
dexamethasone (IPd arm) in the prolongation of PFS as compared to pomalidomide and low-dose 
dexamethasone (Pd arm) in patients with refractory or relapsed and refractory multiple myeloma.  
5.2 
SECONDARY  
5.2.1 Key secondary objectives  
• To evaluate the ORR as per IMWG criteria in each arm (Appendix D) 
• To compare the OS between the 2 arms. 
5.2.2 Other secondary objectives  
• To evaluate the TTP in each arm. 
• To evaluate the PFS in high risk cytogenetic population defined as patients carrying 
del(17p), t(4;14), t(14;16) in each arm. 
• To evaluate the DOR in each arm. 
• To evaluate safety in both treatment arms.  
• To determine the PK profile of isatuximab in combination with pomalidomide.  
• To evaluate the immunogenicity of isatuximab. 
• To assess disease-specific and a generic health-related quality of life (HRQL), disease and 
treatment-related symptoms, health state utility and health status. 
5.3 
EXPLORATORY  
• To explore the relationship between immune genetic determinants and efficacy endpoints. 
• To explore PK and PDy relationships. 
• To explore the MRD rate in both treatment arms. 
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6 
STUDY DESIGN  
6.1 
DESCRIPTION OF THE STUDY  
This is a prospective, multicenter, multinational, randomized, open-label, parallel group, 2-arm 
study evaluating the efficacy of isatuximab in combination with pomalidomide and low-dose 
dexamethasone compared with pomalidomide and low-dose dexamethasone for the treatment of 
patients with refractory or relapsed and refractory multiple myeloma who have received at least 
2 prior lines of therapy including lenalidomide and a proteasome inhibitor (bortezomib, 
carfilzomib or ixazomib) alone or in combination and have demonstrated disease progression on 
or within 60 days of completion of the last therapy. 
After confirmation of eligibility criteria, patients will be randomly assigned using an IRT system 
in a 1:1 ratio to one of the two arms: 
• Isatuximab in combination with pomalidomide and low-dose dexamethasone 
(IPd, experimental arm), 
• Pomalidomide and low-dose dexamethasone (Pd, control arm). 
Isatuximab, pomalidomide and dexamethasone are defined in this protocol as “study treatments”. 
Randomization will be stratified by age (<75 years versus ≥75 years) and number of previous 
lines of therapy (2 or 3 versus more than 3). A complete transplant procedure (induction, 
mobilization, conditioning, transplant, consolidation and maintenance) will be considered as 
one line. Each other regimen will be considered as one line, whatever the reason of 
discontinuation (progression, adverse event or patient request). 
Patients will continue treatment until disease progression, unacceptable AEs or patient wish, 
whichever comes first. 
Study design is summarized in the graph below: 
Figure 4 - Study design  
 
D = study day, y = years, IPd = isatuximab, pomalidomide, dexamethasone, PD = pomalidomide, dexamethasone. 
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6.2 
DURATION OF STUDY PARTICIPATION  
6.2.1 Duration of study participation for each patient  
The patient will be considered in the study from informed consent signature until death consent 
withdrawal, or final OS cut-off date, whichever occurs first.  
The duration of the study for a patient will include a period for screening of up to 21 days (or up 
to 28 days for FCBP). A cycle duration is 28 days. Patients will continue study treatment until 
disease progression, unacceptable AEs, patient wish, or any other reason. All adverse events 
occurring after informed consent signature will be reported up to 30 days after last study treatment 
administration. 
After study treatment discontinuation, patients will return to the study site 30 days after the last 
dose of study treatments for end-of-treatment assessments, and 60 days after the last dose of study 
treatments for assessments including ADA (IPd arm only). If the ADA test at Day 60 is positive 
or inconclusive, ADA testing will be repeated every 30 days until negative (IPd arm only). If 
isatuximab is stopped prior to pomalidomide and dexamethasone, ADA will be tested on Day 1 of 
the 2 next cycles. If the ADA test at the second cycle administered without isatuximab is positive 
or inconclusive, ADA testing will be repeated every cycle until negative.  
The related AEs and all SAEs regardless of relationship to 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, any new related adverse events (regardless of 
seriousness) will be collected and followed until resolution or stabilization. 
During FU, patients who discontinue study treatment due to progressive disease (PD) will be 
followed every 3 months (12 weeks) for further anti-myeloma therapy, second primary 
malignancies, and survival until death or final OS cut-off date, whichever comes first. Patients 
who discontinue the study treatment prior to documentation of PD will be followed-up monthly 
until confirmation of PD (even for patients who would initiate further anti-myeloma therapy 
without PD), and then every 3 months (12 weeks) for further anti-myeloma therapy, second 
primary malignancies, and survival, until death or final OS cut-off date, whichever comes first. 
If a patient is still on treatment at the time of the cut-off date for OS and is benefitting from the 
study treatment, the patient can continue the study treatment until disease progression, 
unacceptable AEs, patient wish, or any other reason. For cycles completed after the cut-off date 
for OS, study treatment administration, pregnancy tests for FCBP, all related AEs, all serious AEs 
(regardless of relationship to study treatment), laboratory abnormalities if applicable, and reason 
of end of treatment (EOT) will continue to be collected. For patients in the IPd arm, 1 ADA 
sample should be drawn 60 ±5 days after last study treatment administration. If ADA is positive 
or inconclusive at 60 days, the repeat samples will be taken every 30 ±7 days until the results 
become negative (see Section 1.3). For patients still on treatment at the time of amended 
protocol 07, ADA sampling is no more required. 
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6.2.2 Determination of end of clinical trial (all patients)  
PFS analysis (primary endpoint analysis) is event driven and the cut-off date for PFS analysis will 
be when 162 PFS events (progression or death, whichever comes first) have occurred (around 
18 months from first patient being randomized).  
The OS analysis is event driven and the final cut-off date will be when 220 deaths have occurred 
(around 51 months from first patient being randomized). 
6.3 
INTERIM ANALYSIS  
No interim analysis of PFS is planned. An interim analysis of OS will be performed at time of the 
primary analysis of PFS and a second interim analysis will be performed when approximately 
90% of OS events have occurred. The procedure and criteria for undertaking an interim analysis 
are described in Section 11.5. 
6.4 
STUDY COMMITTEES  
The Steering Committee (SC) will include a Chairman, investigators and Sponsor’s 
representatives. The SC will be responsible for: 
• Supervising the progress of the trial towards its overall objectives. 
• Reviewing at regular intervals relevant information that may affect the study conduct. 
• Discussing the implementation of the recommendations of the independent DMC. 
An independent Data Monitoring Committee (DMC), consisting of 5 external independent 
members (4 physicians with multiple myeloma expertise and 1 statistician), not associated with 
the conduct of the study or other study committees will meet regularly to as specified in the DMC 
charter: 
• Review the progress of the trial.  
• Review the safety data. 
• Advise the Sponsor on potential modifications or communications that may be necessary 
to ensure the patient safety or protect the scientific integrity of the trial. The Sponsor will 
make the final decision(s). 
The first meeting will be set up to review early safety results (eg, after approximately 30 patients 
have completed at least 2 cycles), and then periodically. Ad-hoc DMC meetings may also be held 
if a significant safety issue or issue deemed important for discussion arise on this or any other 
studies of isatuximab. After each meeting, the DMC will advise the SC and the Sponsor’s 
representatives regarding the continued safety of treating ongoing and future study patients, as 
well as the course of action regarding the conduct of the trial.  
The DMC procedures will be detailed in the DMC charter and approved by the DMC members. 
The charter will be finalized before the first patient enrolled.  
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An Independent Response Committee (IRC) will determine disease response and progression 
according to efficacy MM laboratory data (central laboratory results), bone marrow, and imaging 
as per IMWG criteria and in line with the IRC charter up to primary analysis on PFS; no IRC 
review will be performed after the cut-off for the primary analysis. 
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7 
SELECTION OF PATIENTS  
7.1 
INCLUSION CRITERIA  
Eligible patients will be considered for inclusion in this study if they meet all of the following 
criteria (all necessary baseline studies for determining eligibility must be obtained within 21 days 
prior to randomization [or 28 days for FCBP]): 
I 01. Age ≥18 years or country’s legal age of majority if the legal age is >18 years old. 
I 02. Patients must have a documented diagnosis of multiple myeloma with evidence of 
measurable disease. 
• Serum M protein ≥0.5 g/dL measured using serum protein immunoelectrophoresis 
and/or, 
• Urine M protein ≥200 mg/24 hours measured using urine protein 
immunoelectrophoresis. 
I 03. Patients must have received at least 2 prior lines of anti-myeloma therapy, which must 
include at least 2 consecutive cycles of lenalidomide and a proteasome inhibitor 
(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 04. Patients must have failed treatment with lenalidomide and a proteasome inhibitor 
(bortezomib, carfilzomib or ixazomib) alone or in combination, defined by any of the 
following (failure to lenalidomide and a proteasome inhibitor can have occurred at any line 
of therapy): 
• Progression has occurred while on or within 60 days from end of the treatment with 
lenalidomide and/or a proteasome inhibitor. 
• In case of previous response ≥PR to lenalidomide and/or a proteasome inhibitor, 
patient must have progressed within 6 months after discontinuation of the treatment. 
• Patients who have developed intolerable toxicity after a minimum of 2 consecutive 
cycles of a regimen containing lenalidomide and a proteasome inhibitor (bortezomib, 
carfilzomib or ixazomib) alone or in combination. Intolerance is defined as below: 
- 
For proteasome inhibitor containing regimens: any toxicity leading to 
discontinuation of a proteasome inhibitor, like ≥G2 peripheral neuropathy or ≥G2 
neuropathic pain. Peripheral neuropathy must be ≤G1 before study entry (according 
to National Cancer Institute Common Terminology for Adverse Event 
(NCI-CTCAE v4.03), 
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- 
For lenalidomide containing regimens: any toxicity leading to discontinuation of 
lenalidomide, like G3 rash. Rash must not have been G4 and other 
non-hematologic toxicities should not have been G4. All non-hematologic 
toxicities must be ≤G1 before study entry. 
I 05. Patients must have progressed on or within 60 days after end of the previous therapy 
before study entry, ie, refractory to the last line of treatment. This patient population 
includes the following two categories: 
• Refractory disease: patients who were refractory to all previous lines of treatment but 
should have achieved at least a MR in one previous line. 
• Relapsed and refractory disease: patients who were relapsed from at least one previous 
line of treatment and refractory to the last line of treatment. Patients can be refractory to 
other previous line/lines of treatment. 
Note: Patients must have achieved a MR or better to at least one of the previous lines of treatment 
(ie, primary refractory disease is not eligible). 
I 06. Patient has given voluntary written informed consent before performance of any study 
related procedures not part of normal medical care, with the understanding that consent 
may be withdrawn by the patient at any time without prejudice to his/her medical care. 
7.2 
EXCLUSION CRITERIA  
Patients who have met all the inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria. 
E 01. Primary refractory multiple myeloma defined as: patients who have never achieved at least 
a MR with any treatment during the disease course. 
E 02. Free Light Chain measurable disease only.  
E 03. Patient with prior anti-CD38 monoclonal antibody treatment with progression on or within 
60 days after end of anti-CD38 monoclonal antibody treatment or failure to achieve at least 
MR to treatment (ie, refractory to anti-CD38).  
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). 
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. 
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E 08. Patient who has received any other investigational drugs or prohibited therapy for this 
study within 28 days or 5 half-lives from randomization, whichever is longer. 
E 09. ECOG status >2 (Appendix B). 
E 10. Platelets <75 000 cells/µL if <50% of bone marrow (BM) nucleated cells are plasma cells 
and, <30 000 cells/µL if ≥50% of BM nucleated cells are plasma cells. Platelet transfusion 
is not allowed within three days before the screening hematological test. 
E 11. ANC <1000 μ/L (1 x 109/L). The use of G-CSF is not allowed to reach this level. 
E 12. Creatinine clearance <30 mL/min (MDRD Formula, see Appendix A). 
E 13. Total bilirubin >2 x ULN. 
E 14. Corrected serum calcium >14 mg/dL (>3.5 mmol/L). 
E 15. AST and/or ALT >3 x ULN. 
E 16. Ongoing toxicity (excluding alopecia and those listed in eligibility criteria) from any prior 
anti-myeloma therapy >G1 (NCI-CTCAE v4.03). 
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 (see I 04). 
E 18. 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. 
E 19. Significant cardiac dysfunction; myocardial infarction within 12 months; unstable, poorly 
controlled angina pectoris. 
E 20. 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 21. Known to be HIV+ or to have hepatitis A, B or C active infection. 
E 22. Malabsorption syndrome or any condition that can significantly impact the absorption of 
pomalidomide. 
E 23. Active primary amyloid-light (AL) amyloidosis (evidence of end organ damage or 
receiving treatment for amyloidosis). 
E 24. Concomitant plasma cell leukemia. 
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E 25. Unable or unwilling to undergo to thromboprophylaxis. 
E 26. Daily requirement for corticosteroids (equivalent to ≥10 mg/day of prednisone) for more 
than 7 days (except for inhalation corticosteroids). 
E 27. Pregnant or breastfeeding female or female who intends to become pregnant during the 
participation in the study. Females of childbearing potential (FCBP) unwilling to prevent 
pregnancy by the use of 2 reliable methods of contraception for ≥4 weeks before the start 
of study treatment, during treatment (including dose interruptions), and up to 3 or 5 months 
following the last dose of study treatment for Pd and IPd respectively, and/or who are 
unwilling or unable to be tested for pregnancy before study treatment initiation (2 negative 
tests), weekly during 1st month of treatment and then prior each treatment cycle 
administration or every 2 weeks in case or irregular menstrual cycles up to 3 or 5 months 
following the last dose of study treatment for Pd and IPd respectively. 
E 28. Male participants who disagree to practice true abstinence or disagree to use a condom 
during sexual contact with a pregnant female or a FCBP while participating in the study, 
during dose interruptions and at least 3 or 5 months following study treatment 
discontinuation for Pd and IPd respectively, even if has undergone a successful vasectomy.  
Note 1: a FCBP is a female who: 1) has achieved menarche at some time point, 2) has not 
undergone a hysterectomy or bilateral oophorectomy or 3) 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). 
Note 2: True abstinence is acceptable when this is in line with the preferred and usual lifestyle of 
the patient. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
E 29. All patients who disagree to refrain from donating blood while on study treatment and for 
4 weeks after discontinuation from this study treatment. 
E 30. All patients who do not agree to keep study treatment for their personal use only. 
E 31. Any country-related specific regulation that would prevent the patient from entering the 
study. 
E 32. Any severe acute or chronic medical condition which could impair the ability of the patient 
to participate in the study or interfere with interpretation of study results (eg, systemic 
infection unless specific anti-infective therapy is employed) or patient unable to comply 
with the study procedures. 
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8 
STUDY TREATMENTS  
In case of a regional or national emergency declared by a governmental agency that results in 
travel restrictions, confinement, or restricted site access, the oral IMP may be supplied at the site 
or from the PI/site/Sponsor to the participant via a Sponsor-approved courier company where 
allowed by local regulations and agreed upon by the participant during the time the measures are 
applied. Contingency measures are included in Appendix O. 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S)  
8.1.1 Isatuximab  
8.1.1.1 Pharmaceutical form  
The drug product is presented as a concentrate for solution for infusion in vials containing 
20 mg/mL (500 mg/25 mL) isatuximab in 20 mM histidine, 10% (w/v) sucrose, 0.02% (w/v) 
polysorbate 80, pH 6.0 buffer. 
It is supplied for parenteral administration as a sterile, nonpyrogenic, injectable, colorless, 
20 mg/mL concentrate for solution for infusion that may contain white to off-white particulates 
and is packaged in 30 mL glass vials fitted with elastomeric closure. Each vial contains a nominal 
content of 500 mg of isatuximab. The fill volume has been established to ensure removal of 
25 mL. 
For administration to patients, the appropriate volume of isatuximab will be diluted in a 250 mL 
infusion bag of 0.9% sodium chloride solution or dextrose 5%.  
Please refer to the Pharmacy Manual for more information. 
8.1.1.2 Dilution method  
Isatuximab concentrate for solution for infusion will be diluted in a 250 mL infusion bag with 
0.9% sodium chloride solution or dextrose 5% to achieve the appropriate drug concentration for 
infusion. 
Infusion via a central line is preferred if available. In case of patients with local intolerance after 
peripheral IV infusion, decision to use central line is left to investigator decision. The final 
infusion volume corresponding to the dose of isatuximab will be administered by IV infusion for 
the period of time that will depend on total dose administered. 
Prior to dosing, each patient's dose will be individually prepared by the study pharmacist and 
labeled with protocol number, patient number, and treatment description. The patient’s weight 
should be measured prior to each cycle to allow calculation of the isatuximab dose. 
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For IV infusion, an IV tubing administration set with a 0.20-μm in-line filter will be used for 
infusion; if an in-line filter is unavailable, a 0.20-μm filter unit may be attached to the 
administration set before administration. Further details are provided in the Pharmacy Manual. 
Detailed instructions for dilution of the isatuximab concentrate for solution for infusion is 
provided in a Pharmacy Manual. 
8.1.2 Pomalidomide  
Pomalidomide from available commercial supplies will be used for this study where applicable; 
otherwise, it will be re-labeled by the Sponsor according to Good Manufacturing Practice (GMP) 
guidelines before supplies are provided to the study sites. 
When commercial supplies will be used: 
• Please refer to package insert for further details as regards to formulation, storage and 
handling procedures. 
• When applicable the Pomalidomide Pregnancy Prevention Plan (Appendix L) 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.  
8.1.3 Dexamethasone PO/IV  
Dexamethasone IV/PO from available commercial supplies will be used for this study where 
applicable; otherwise, it will be re-labeled by the Sponsor according to Good Manufacturing 
Practice (GMP) guidelines before supplies are provided to the study sites. 
8.2 
DOSAGE AND SCHEDULE  
There is no limitation in the number of cycles to be administered in the absence of major toxicity, 
disease progression or any other discontinuation criteria as defined in Section 10. In case of PD 
diagnosis made on laboratory criteria, this needs to be confirmed by two consecutive measures 
before treatment discontinuation. The treatment should continue until confirmation of the PD.  
The patient’s weight should be measured prior to each cycle to allow calculation of the isatuximab 
dose. 
Dose adjustment (dose delay, dose omission, and for pomalidomide and dexamethasone dose 
reduction) will be permitted for subsequent treatment cycles based on individual patient tolerance. 
No dose reductions are allowed for isatuximab infusion (see Section 8.2.5). 
8.2.1 Study treatments (IMP)  
Study treatment is defined as isatuximab/pomalidomide/dexamethasone in IPd experimental arm 
and pomalidomide/dexamethasone in Pd control arm. 
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Patients allocated to IPd arm should routinely receive pre-medications prior to isatuximab 
infusion to reduce the risk and severity of infusion associated reactions (IARs) commonly 
observed with monoclonal antibodies. Detailed guidelines for the premedication are provided in 
Section 8.2.2 and details for management of IARs are provided in Section 10.6.1. 
Pomalidomide may be taken with water and should be swallowed whole. Patients 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. Patients will be asked to maintain a diary to record 
the doses of pomalidomide (except those administered by the study nurse/doctor). 
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. 
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 patient is ≥75 years old). 
Patients will be asked to maintain a diary to record the doses of dexamethasone taken orally 
(except those administered by the study nurse/doctor).  
IPd arm (experimental arm) 
Drug administration (after pre-medication as described Section 8.2.2) for patients treated with 
isatuximab, pomalidomide and dexamethasone combination is as follows:  
• Dexamethasone 40 mg (or 20 mg if the patient is ≥75 years old), PO (the preferred route) 
or IV (if PO route cannot be used whatever the reason) on Days 1, 8, 15 and 22, between 
15-30 minutes (but no longer than 60 minutes) prior to isatuximab. Dexamethasone will be 
administered at the beginning or at the end of the isatuximab premedications depending on 
the route PO or IV (see Section 8.2.2). 
• Isatuximab 10 mg/kg on Days 1, 8, 15, and 22 at Cycle 1, and then 10 mg/kg on 
Days 1 and 15 for subsequent cycles. 
- 
Patients still receiving isatuximab at the time of amended protocol 07 will switch to the 
registered infusion rate as described below. For these patients, premedication for the 
prevention of IAR has to be given for the first 4 isatuximab infusions. Patients who do 
not experience an IAR upon 4 consecutive administrations of isatuximab may have 
their need for subsequent premedication reconsidered, at the Investigator’s discretion. 
- 
First isatuximab infusion: initiate infusion at 25 mL/hour. In the absence of IARs after 
1 hour of infusion, increase infusion rate by 25 mL/hour increments every 30 minutes, 
to a maximum of 150 mL/hour. In case of Grade 2 IAR during first infusion, infusion 
could be restarted at one-half of the initial infusion rate (12.5 mL/hour) when the IAR 
improves to Grade ≤1. If symptoms do not recur after 30 minutes of infusion, the 
infusion rate may be increased by 25mL/hour increments every 30 minutes, until the 
total volume is infused to a maximum rate of 150mL/hour. 
- 
Second infusion: Initiate infusion at 50 mL/hour. In the absence of Grade 2 IAR after 
30 minutes of infusion, increase rate to 100 mL/hour for 30 minutes, then, to 
200 mL/hour until the total volume is infused. In case of Grade 2 IAR during second 
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infusion, infusion could be restarted at one-half of the initial infusion rate 
(25 mL/hour) when the IAR improves to Grade ≤1. If symptoms do not recur after 
30 minutes, the infusion rate may be increased by 50 mL/hour increments every 
30 minutes, until the total volume is infused to maximum rate of 200 mL/hour, 
- 
Third and subsequent infusions: Initiate infusion at a fixed infusion rate of 
200 mL/hour, until the total volume is infused. In case of Grade 2 IAR during third 
infusion, infusion could be restarted at one-half (100 mL/hour) of the infusion rate 
(100 mL/hour) when the IAR improves to Grade ≤1. If symptoms do not recur after 
30 minutes, the infusion rate may be increased by 50 mL/hour increments every 
30 minutes, until the total volume is infused to maximum rate 200 mL/hour. 
- 
Guidelines for patients who develop IARs are provided in Section 10.6.1.  
• Pomalidomide will be given 4 mg on Days 1 to 21 in a 28-day cycle. On Day 1 of each 
cycle, pomalidomide should be taken 1h to 30 min prior to isatuximab. The other infusion 
days of isatuximab (Day 8 and Day 15 of Cycle 1 and Day 15 of subsequent cycles), 
pomalidomide will be taken at the time which is the most convenient for the patient after 
isatuximab infusion, preferably at the same time of the previous dose.  
Pd arm (control arm): 
Drug administration for patients treated with pomalidomide and dexamethasone combination is as 
follow: 
• Dexamethasone 40 mg (or 20 mg if the patient is ≥75 years old), PO or IV on Days 1, 8, 
15 and 22. 
• Pomalidomide will be given 4 mg on Days 1 to 21 in a 28-day cycle.  
8.2.2 Premedication (NIMP) - Prevention of Infusion Associated Reactions (IARs)  
Patients allocated to IPd arm should routinely receive premedication prior to isatuximab infusion 
to reduce the risk and severity of IARs commonly observed with monoclonal antibodies. The 
recommended premedication agents are: diphenhydramine 25-50 mg IV (or equivalent: 
eg, cetirizine, promethazine, dexchlorpheniramine, according to local approval and availability. 
Intravenous route is preferred for at least the first 4 infusions), dexamethasone IV/PO (dose 
defined below), ranitidine* 50 mg IV (or equivalent: other approved H2 antagonists 
[eg, cimetidine], oral proton pump inhibitors [eg, omeprazole, esomeprazole]) and acetaminophen 
(paracetamol) 650-1000 mg PO 15 to 30 minutes (but no longer than 60 minutes) prior to 
isatuximab infusion. Once the premedication regimen is completed, the isatuximab infusion must 
start immediately. 
*NOTE: The use of ranitidine or equivalent to be part or not of premedication is left to the 
medical judgement. 
On the day of isatuximab infusion, a total of 40 mg of dexamethasone (regular dose of 
dexamethasone when used in combination with pomalidomide), or 20 mg in patients ≥75years, 
will be administered as part of the premedication and study treatment before isatuximab and 
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pomalidomide. For patients who cannot tolerate dexamethasone during study treatment, 
methylprednisolone 100 mg IV can be administered as premedication only. However, both drugs 
cannot be used at the same time for premedication purposes. 
Patients who do not experience an IAR upon their first 4 administrations of isatuximab may have 
their need for subsequent premedication reconsidered, at the Investigator’s discretion.  
When dexamethasone is administered PO, the following order is recommended:  
• Dexamethasone 40 mg PO (or 20 mg PO for patients ≥75 years of age). 
• Acetaminophen (paracetamol) 650 mg to 1000 mg PO. 
• Ranitidine 50 mg IV (or equivalent). 
• Diphenhydramine 25 mg to 50 mg IV (or equivalent).  
When dexamethasone is administered IV, the following order is recommended:  
• Acetaminophen (paracetamol) 650 mg to 1000 mg PO. 
• Ranitidine 50 mg IV (or equivalent). 
• Diphenhydramine 25 mg to 50 mg IV (or equivalent). 
• Dexamethasone 40 mg IV (or 20 mg IV for patients ≥75 years of age). 
Whatever the route of administration (IV or PO), dexamethasone will be administered only once 
(the single administration is used for both premedication and study treatment). 
General guidelines for the management of the IAR are provided in Section 10.6.1.  
8.2.2.1 Ranitidine or equivalent  
Ranitidine is presented as a solution for IV infusion. Commercial supplies of ranitidine or 
equivalent will be used for this study. Please refer to package insert for further details as regards 
to formulation, storage and handling purposes. The use of ranitidine or equivalent to be part or not 
of premedication is left to the medical judgement. 
8.2.2.2 Diphenhydramine or equivalent  
Diphenhydramine is presented as a solution for IV infusion. Commercial supplies of 
diphenhydramine or equivalent will be used for this study. Please refer to package insert for 
further details as regards to formulation, storage and handling purposes. 
8.2.2.3 Acetaminophen (paracetamol)  
Commercial supplies of acetaminophen (paracetamol) will be used for this study. Please refer to 
package insert for further details as regards to formulation, storage and handling purposes. 
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8.2.3 Dose modifications  
8.2.3.1 General rules  
Dose modifications are permitted according to the guidelines described in this section. 
Dose reduction for pomalidomide and low-dose dexamethasone and/or cycle delay (ie, delay of all 
study treatments) are permitted in case of toxicity. Patient may have dose omitted (isatuximab 
and/or pomalidomide and/or dexamethasone) within a cycle if toxicity occurs and the patient does 
not recover by the day of planned infusion/administration. If a patient experiences several 
toxicities and there are conflicting recommendations, the most conservative dose adjustment 
recommended (dose reduction/omission/delay appropriate to the most severe toxicity) should be 
followed. Once a dose of pomalidomide or dexamethasone has been decreased, intra-patient 
re-escalation back to the previous dose level is not permitted. 
Administration of the study treatment (isatuximab and/or pomalidomide and/or dexamethasone) 
will be discontinued in the event of an AE that persists despite appropriate dose modifications or 
any other AE that, in the opinion of the Investigator, warrants discontinuation. 
All changes to study treatment administration must be recorded in the eCRF.  
Patients will receive the next cycle of study treatment after recovery of the toxicity as described 
below.  
A new cycle of study treatment may begin on the scheduled Day 1 of a subsequent cycle if the 
following criteria are met. 
• ANC ≥1000/mm3. 
• Platelet count ≥50 000/mm3. For patients with plasma cells ≥50% of 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. 
Any other pomalidomide, dexamethasone or isatuximab related AE that may have occurred in the 
previous cycle has recovered to ≤G1 or baseline severity (or according to the dose modifications 
shown in Section 8.2.3.3 and Section 8.2.3.4. 
If these criteria are not met on the scheduled Day 1, patients should be re-evaluated weekly. If 
these criteria are not met within 14 days of the scheduled Day 1 (planned Day 1 Cycle n+1 
corresponds to Day 29 Cycle n), the patient should be discontinued from study treatment, unless 
there is strong evidence of clinical benefit to justify continuation of dosing with study treatment, 
and the investigator must discuss the rationale with the Sponsor before a decision is taken.  
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If there are dose modifications within the previous cycle, these guidelines should be followed for 
the initiation of a new cycle: 
• If pomalidomide dosing was halted during the previous cycle and was restarted with 
a one-level dose reduction without requiring an interruption for the remainder of the cycle, 
then that reduced dose level will be initiated on Day 1 of the new cycle. Once a dose of 
pomalidomide or dexamethasone has been reduced, intra-patient re-escalation back to the 
previous dose level is not permitted. 
• Patients may have isatuximab dose omission within a cycle if toxicity occurs and does not 
recover on the day of planned infusion or within the following 3 days. Within a cycle, 
a delay of up to 3 days in cases of unresolved toxicity at the time of planned 
re-administration is permitted, otherwise infusion is omitted. Patients will receive the next 
isatuximab infusion after recovery of the toxicity as described in Section 8.2.3.2 No dose 
reduction of isatuximab is permitted. 
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 of 
further study treatment. The end of study treatment in this case will be 30 day after the date of the 
last study treatment administration.  
8.2.3.2 Modification of isatuximab/pomalidomide/dexamethasone dose levels in case of 
dose reduction  
No dose reduction of isatuximab is permitted. 
Dose reduction steps for pomalidomide are shown in Table 1. One or several doses of 
pomalidomide can be omitted. 
Table 1 - Dose levels for pomalidomide dose reduction  
Starting dose (PO) 
Dose level -1 
Dose level -2 
Dose level -3 
4 mg 
3 mg 
2 mg 
1 mg 
PO = per os  
Dose reduction steps for dexamethasone are shown in Table 2. One or several doses of 
dexamethasone can be omitted or dose of dexamethasone can be decreased to every other week. 
Table 2 - Dose levels for dexamethasone dose reduction  
Starting dose  
(PO or IV) 
Dose level -1 
Dose level -2 
Dose level -3 
Dose level -4 
40 mg 
20 mg 
12 mg 
8 mg 
4 mg 
20 mg  
(patients ≥75 years olda) 
12 mg 
8 mg 
4 mg 
- 
PO = per os; IV = intravenous  
a all patients ≥75 years old will start dexamethasone treatment at the dose of 20 mg. 
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8.2.3.3  Dose adjustments in IPd arm   
Dose adjustments for patients treated with isatuximab, pomalidomide and dexamethasone 
combination in the case of hematological toxicity are shown in Table 3. 
Table 3 - Guidelines for dose adjustments for hematologic toxicities - 
isatuximab/pomalidomide/dexamethasone combination  
Adverse event 
Recommended action  
Isatuximaba 
Dexamethasonea 
Pomalidomide 
Platelets 
Thrombocytopenia 
Grade 3  
Day 1 of cycle: delay until improvement ≥50 x 109/Lb and administer at same dose levelc 
Within cycle: maintain full dose of study treatment as planned 
Thrombocytopenia 
Grade 4 with or 
without bleeding 
Day 1 of cycle: delay Day 1 administration until improvement 
≥50 x 109/Lb and administer at the same dose levelc 
 
Within cycle: delay isatuximab until bleeding is controlled and 
platelet recover ≥50 x 109/L and then administer full dose.  
If delay is >3 days omit isatuximab and dexamethasone until 
next planned administration  
 
 
Further episodes: same recommendations 
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 x 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 
second episode: same recommendation 
with decrease of pomalidomide by a 
second dose level 
third episode: discontinue 
pomalidomide 
Neutropenia 
Neutropenia Grade 3 
(≥0.5 and 
<1.0 x 109/L) 
Day 1 of cycle: delay until recovery ≥1.0 x 109/L and administer at same dose levela 
Within cycle: maintain full dose as planned 
Neutropenia 
Grade 4d(<0.5 x 109/) 
Day 1 of cycle: delay until recovery ≥1.0 x 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 levelc 
Within cycle: hold pomalidomide until 
neutrophil counts recover ≥0.5 x 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 
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Adverse event 
Recommended action  
Isatuximaba 
Dexamethasonea 
Pomalidomide 
 
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 x 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 x 109/L. Then administer isatuximab and dexamethasone at the 
planned days at the same dose level and re-start pomalidomide up 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 Patients may have isatuximab dose omission within a cycle if certain toxicities do not recover within 3 days following the day of planned 
infusion (see Section 8.2.3) 
b For patients 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 patient´s baseline status. Beyond 14 days, the patient 
must be permanently discontinued from the study (see Section 8.2.3) 
d If G4 neutropenia, assess ANC every 2-3 days until ANC ≥0.5 x 109/L and at least weekly thereafter until ANC ≥1.0 x 109/L  
Dose adjustments for patients treated with isatuximab, pomalidomide and dexamethasone 
combination in the case of non-hematological toxicity are shown in Table 4. 
Table 4 - 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 
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Adverse event 
Recommended action 
 
Isatuximabc 
Dexamethasonec 
Pomalidomide 
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. 
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 (excluding infusion associated reaction) 
Grade 2 
Hold study treatment until < Grade 2, and patient clinically stable; then, resume study treatment 
at the same dose level a 
For infusion reaction related to isatuximab, refer to Section 10.6.1 
For allergic reaction related to pomalidomide, refer to site local protocol 
Grade ≥3 
Permanent discontinuation of the drug responsible of the allergic reaction.  
Infection 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  
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 
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Adverse event 
Recommended action 
 
Isatuximabc 
Dexamethasonec 
Pomalidomide 
Confusion or mood 
alteration Grade ≥2 
(interfering with function +/-
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 recoverya 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 
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 
CrCl <30 mL/min  
(MDRD formula) 
Day 1 of cycle: delay Day 1 administration until CrCl 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.  
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Adverse event 
Recommended action 
 
Isatuximabc 
Dexamethasonec 
Pomalidomide 
Any other drug related non-
hematologic 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 patient´s baseline status. Beyond 14 days, the patient 
must be permanently discontinued from the study (see Section 8.2.3). 
b 
See Section 10.6.1 for IAR management. 
c 
Patients 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 8.2.3). 
8.2.3.4 Dose adjustments in Pd arm  
Dose adjustments for patients treated with pomalidomide and dexamethasone combination in the 
case of hematological toxicity are shown in Table 5. 
Table 5 - Guidelines for dose adjustments for hematologic toxicities - 
pomalidomide/dexamethasone combination  
Adverse event 
Recommended action  
Dexamethasonea 
Pomalidomide 
Platelets 
Thrombocytopenia 
Grade 3 without 
bleeding 
Day 1 of cycle: delay until improvement ≥50 x 109/Lb and administer at same dose levelc 
Within cycle: maintain full dose of study treatment as planned 
Thrombocytopenia 
Grade 4 with or without 
bleeding 
Day 1 of cycle: delay Day1 administration 
until improvement ≥50 x 109/Lb and 
administer at the same dose levelc 
Within cycle: maintain full dose of study 
treatment as planned 
Further episodes: same recommendations 
 
Day 1 of cycle: delay Day 1 administration until 
recovery and decrease pomalidomide by one dose 
levelc 
Within cycle: hold pomalidomide until bleeding is 
controlled and platelet recover ≥50 x 109/L, and then 
re-start with1 dose level decrease up to planned 
Day 21. Next cycle will be re-started with this one 
dose level decrease 
Second episode: same recommendation with 
decrease of pomalidomide by a second dose level 
Third episode: discontinue pomalidomide 
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Adverse event 
Recommended action  
Dexamethasonea 
Pomalidomide 
Neutropenia 
 
Neutropenia Grade 3 
(≥0.5 and <1.0 x 109/L) 
Day 1 of cycle: delay until recovery ≥1.0 x 109/L and administer at same dose levela 
Within cycle: maintain the same dose level as planned  
Neutropenia Grade 4d 
(<0.5 x 109/) 
Day 1 of cycle: delay until recovery 
≥1.0 x 109/L and administer at the same dose 
levelc 
 
Within cycle: maintain the same dose level 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 levelc 
Within cycle: hold pomalidomide until neutrophil 
counts recover ≥0.5 x 109/L and then: 
- re-start with1 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 x 109/Lc Then administer D1 next cycle with dexamethasone at the same dose level and 
pomalidomide with dose recommendations below. 
Within cycle: omit dexamethasone, hold pomalidomide dose and add G-CSF until fever and infection 
have recovered and ANC>1 x 109/L. Then administer dexamethasone on the planned days at the 
same dose level and restart pomalidomide as planned on Day 21 with the dose modifications below:  
When fever/infection is resolved dexamethasone re-start at same dose. For pomalidomide:  
• 
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 Patients may have dexamethasone dose omission within a cycle if certain toxicities do not recover within 3 days following the day of planned 
infusion (see Section 8.2.3). 
b For patients 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 patient´s baseline status. Beyond 14 days, the patient 
must be permanently discontinued from the study (see Section 8.2.3). 
d If G4 neutropenia, assess ANC every 2-3 days until ANC ≥0.5 x 109/L and at least weekly thereafter until ANC ≥1.0 x 109/L. 
Dose adjustments for patients treated with pomalidomide and dexamethasone combination in the 
case of non-hematological toxicity are shown in Table 6. 
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Table 6 - Guidelines for dose adjustments for non-hematologic toxicities - 
pomalidomide/dexamethasone combination  
Adverse event 
Recommended action 
 
Dexamethasoneb 
Pomalidomide 
DVT/PE 
Grade 3 
Day 1 of cycle: initiate appropriate anticoagulation therapy and when efficient anticoagulation, 
administer cycle at the same dose level of dexamethasone and pomalidomidea 
Within cycle: Maintain 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 
stabilization and administer at the same dose 
levela  
Within cycle: delay dexamethasone until 
stabilization and resume without dose reduction 
at the next planned dates. If delay is >3 days 
omit dexamethasone until next planned 
administration 
Pomalidomide permanently discontinued. 
Edema Grade ≥3 (limiting 
function and unresponsive to 
therapy or anasarca), 
excluding infusion associated 
reaction 
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 
same dose level of pomalidomide as 
planned 
Allergic reaction/hypersensitivity (excluding infusion associated reaction) 
Grade 2 
Hold study treatment until < Grade 2, and patient clinically stable; then, resume study 
treatment at full dosea 
For allergic reaction related to pomalidomide, refer to site local protocol 
Grade ≥3 
Permanent discontinuation of the drug responsible for the allergic reaction.  
Infection 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  
Neuropathy 
Grade 2 with pain or Grade 3  
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 
Same dose level of dexamethasone 
Pomalidomide permanently discontinued 
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Adverse event 
Recommended action 
 
Dexamethasoneb 
Pomalidomide 
Confusion or mood alteration 
Grade ≥2 (interfering with 
function  
+/- daily activities) 
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) 
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 full 
dose pomalidomide as planned 
> Grade 3 (requiring 
hospitalization or surgery) 
Hold study treatment until symptoms adequately controlled.  
Then, restart the 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 recoverya and re-start the same dose level of pomalidomide  
Within cycle: hold all study treatment until recovery and re-start the same dose level of 
pomalidomide. 
Hyperglycemia 
≥ Grade 3  
Treatment with insulin or oral hypoglycemics 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 the 
same dose level of pomalidomide as 
planned 
Muscle weakness 
≥ Grade 2 (symptomatic and 
interfering with function  
+/- daily activities) 
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 
CrCl <30 mL/min  
Day 1 of cycle: delay Day 1 administration until CrCl returns to ≥30 mL/mina 
Within cycle: hold study treatment until improvement to ≥30 mL/min. Then re-start the same 
dose level of dexamethasone and pomalidomide up to planned Day 21. If delay is >3 days omit 
dexamethasone.  
Any other drug related 
non-hematologic 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 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 patient´s baseline status. Beyond 14 days, the patient 
must be permanently discontinued from the study (see Section 8.2.3) 
b Patients may have dexamethasone dose omission within a cycle if certain toxicities do not recover within 3 days following the day of planned 
infusion (see Section 8.2.3) 
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8.2.4 Infusion reactions  
Patients should routinely receive premedications prior to isatuximab infusion as detailed in 
Section 8.2.2 to reduce the risk and severity of IARs commonly observed with mAbs. Infusion 
associated reactions (for example, NCI-CTCAE version 4.03 terms “infusion related reaction”, 
“allergic reaction”, or “cytokine release syndrome”) are defined as AEs related to isatuximab with 
onset typically within 24 hours from the start of the infusion. 
Patients who experience Grade 2 IAR(s) may resume isatuximab after recovery, at half of the 
initial infusion rate under close monitoring and supportive care as needed. Additional medication 
can be provided for symptom treatment as per Investigator judgment including diphenhydramine 
25 mg IV (or equivalent) and methylprednisolone 100 mg IV. These patients must be informed of 
the potential risk of recurrent infusion associated reactions. The infusion must be completed 
within the time specified in the pharmacy manual. 
Further treatment (subsequent isatuximab infusions) with the fixed rate:  
• In case of Grade 2 IAR during the 2nd infusion, infusion could be restart at half of the 
initial infusion rate (25 mL/hour) when the IAR improves to Grade ≤1. If symptoms do not 
recur after 30 minutes, the infusion rate may be increased by 50 mL/hour increments every 
30 minutes, until the total volume is infused to maximum rate of 200 mL/hour. 
• In case of Grade 2 IAR during third infusion and subsequent, infusion could be restarted at 
one-half (100 mL/hour) of the infusion rate (100 mL/hour) when the IAR improves to 
Grade ≤1. If symptoms do not recur after 30 minutes, the infusion rate may be increased 
by 50 mL/hour increments every 30 minutes, until the total volume is infused to maximum 
rate of 200 mL/hr. 
Patients with a Grade 3 or 4 isatuximab IAR must have isatuximab permanently discontinued and 
appropriate supportive therapy should be administered. Should an isatuximab IAR of 
Grade ≥2 occur, additional blood sampling during the AE is required for analysis of cytokine 
levels (TNFα, IL-1β, IL-6, IL-4 and IFNγ), markers of complement activation (C3a, C4 and 
CH50) and serum tryptase, the IAR and the therapy administered must be documented in the 
eCRF. 
Grade 3 or higher IARs must be reported as AESIs (see Section 10.4.1.3).  
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Table 7 - Management of infusion associated reaction  
NCI-CTCAE version 4.03 criteria definition 
Intervention recommendation 
Mild (Grade 1) 
Infusion interruption or intervention not indicated 
Continuation of isatuximab infusion per the judgment of the 
Investigator following close direct monitoring of the patient’s 
clinical status. Isatuximab infusion may be stopped at any time 
if deemed necessary. If stopped, IAR will be classified as 
Grade 2 as per NCI-CTCAE  
Moderate (Grade 2) 
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); prophylactic medications 
indicated for ≤24 hours 
Stop isatuximab infusion. Give additional medication with IV 
diphenhydramine 25 mg IV (or equivalent, see Section 8.2.2.2) 
and/or IV methylprednisolone 100 mg (or equivalent) as 
needed. Isatuximab may be resumed only after patient 
recovery, with slower infusion rate and with close monitoring. 
Blood samples for additional safety labs will be collected. 
Important: additional blood sampling during the AE is required 
for analysis of cytokine levels (TNF-α, IL-4, IL-6, IL-1β, and 
IFN-γ), markers of complement activation (C3a, C4, CH50), 
serum tryptase 
Severe or life-threatening (Grade 3 or 4) 
Grade 3: prolonged (eg, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); recurrence of 
symptoms following initial improvement; hospitalization 
indicated for clinical sequelae 
Grade 4: life-threatening consequences; urgent intervention 
indicated 
Stop isatuximab infusion. Give additional medication with 
diphenhydramine 25 mg IV (or equivalent, see Section 8.2.2.2) 
and/or IV methylprednisolone 100 mg (or equivalent) and/or 
epinephrine as needed. Blood samples for additional safety 
labs will be collected. Definitive treatment discontinuation. 
Important: additional blood sampling during the AE is required 
for analysis of cytokine levels (TNF-α, IL-4, IL-6, IL-1β, and 
IFN-γ), markers of complement activation (C3a, C4, CH50), 
serum tryptase 
Note: The infusion should be completed within the time specified in the pharmacy manual. 
AE: adverse event; IAR: infusion associated reaction; IFN: interferon; IL: interleukin; IV: intravenous; NCI-CTCAE: National Cancer Institute 
Common Terminology Criteria for Adverse Events; NSAIDs: nonsteroidal anti-inflammatory drugs; TNF: tumor necrosis factor. 
8.2.5 Other toxicities  
For ≥ Grade 3 adverse reactions, except fatigue, local reaction, fluid retention, anemia and other 
reactions that do not cause serious morbidity, study treatment should be held for a maximum of 
2 weeks from the planned date of next cycle until improvement to ≤ Grade 1, then reinstituted, if 
medically appropriate. A reduction of subsequent doses will be left to the Investigator’s judgment.  
Guidance in case of hepatitis B reactivation occurring under study treatment 
Patient still on treatment at the time of amended protocol 07 will be tested for HBV serology and 
HBV viral DNA once at any time if HBV status was unknown before treatment started; test will 
be repeated if clinically indicated. 
In case of viral reactivation during study treatment (greater than 1 log10 IU/mL increase in HBV 
DNA or reappearance of hepatitis B surface antigen [HBsAg] or detection of HBV DNA in 
patients with resolved infection) study treatment will be held and specialist consulted for initiation 
of anti-viral treatment and monitoring of the patient. Resolved infection means previous known 
history of acute or chronic hepatitis B or the presence of total anti-hepatitis B core antibody 
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(HBcAb) with/without anti-hepatitis B surface antibody (HBsAb); HBsAg negative; undetectable 
serum HBV DNA; and normal ALT levels. Restart of study treatment should be agreed between 
the Sponsor, the Investigator and specialist (hepatologist) if infection is controlled. ALT and AST 
will be closely monitored every month up to study treatment discontinuation. HBV DNA to be 
done as per specialist advice. 
8.2.6 Criteria for temporarily delaying 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 proposed in  
Appendix O should be considered for IMP administration. 
8.3 
TUMOR LYSIS SYNDROME MANAGEMENT  
Management of tumor lysis syndrome is detailed in Section 10.6.2. 
8.4 
BLINDING PROCEDURES  
During the trial, administration of isatuximab is to be open-label, and no attempt will be made to 
blind administration. 
A centralized randomization system (IRT) will be used to prevent the investigators from knowing 
in advance the treatment assignment, as the randomization is the best method to avoid bias. 
Despite the open-label administration of isatuximab, assessment of outcomes will be based on 
objectively collected data, which are radiological and laboratory assessments for tumor response 
by IRC blinded to study treatment groups.  
Blinding rules for the Sponsor study team will be detailed in a separate document.  
8.5 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP  
All eligible patients will be randomly assigned to a treatment group (either IPd arm or Pd arm) in 
a 1:1 ratio using an IRT. Patient assignment to a treatment group will be performed according to a 
stratified randomization list according to age (<75 versus ≥75) and number of previous lines (2 or 
3 versus more than 3). 
After each patient has completed the necessary screening visit procedures, the corresponding 
baseline eCRFs have been completed and the patient is deemed eligible for study entry by the 
Investigator or designee based on the central laboratory (or local, only if central results are not 
available) evaluations (serum or urine M-protein), the study site will contact the IRT. The site will 
enter the following information regarding the clinical site and study patient: 
• Personal identifier number. 
• Patient’s date of birth (in line with country specific regulations). 
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• Number of previous lines of anti-MM treatment. 
• Serum or urine M-protein laboratory value. 
The information above will be used by IRT to assign the patients to the IPd or Pd arm according 
to the predefined randomization schedule. 
Details of the IRT procedure will be provided in the IRT Site Manual. 
All efforts should be made to start treatment within 3 working days even if a maximum up to 
5 working days can be allowed. 
8.6 
PACKAGING AND LABELING  
8.6.1 Isatuximab  
Isatuximab (SAR650984) is packaged in 30 mL glass vials fitted with elastomeric closure. 
The content of the labeling is in accordance with the local regulatory specifications and 
requirements. 
8.6.2 Dexamethasone IV/PO  
For dexamethasone supplied by the Sponsor, the content of the labeling is in accordance with the 
local regulatory specifications and requirements.  
For local commercial supplies, please refer to package insert for further details for formulation 
and handling purposes. 
8.6.3 Pomalidomide  
For pomalidomide supplied by the Sponsor, the content of the labeling is in accordance with the 
local regulatory specifications and requirements. 
For local commercial supplies, please refer to package insert for further details for formulation 
and handling purposes. 
8.7 
STORAGE CONDITIONS AND SHELF LIFE  
8.7.1 Isatuximab  
Investigators or other authorized persons (eg, Pharmacists) are responsible for storing isatuximab 
in a secure and safe place with restricted access in accordance with local regulations, labeling 
specifications, policies, and procedures.  
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Control of isatuximab storage conditions, especially control of temperature (eg, refrigerated 
storage), and information on in-use stability and instructions for handling the Sanofi compound 
should be managed according to the rules provided by the Sponsor. 
Isatuximab is to be stored at +2°C to +8°C (36°F to 46°F). All vials must be kept in their box until 
use. 
No protection from light is required for storage in the infusion bags. 
Details of the storage conditions for the diluted solution are provided in the Pharmacy Manual. 
8.7.2 Dexamethasone IV/PO  
For dexamethasone supplied by the Sponsor, the content of the labeling is in accordance with the 
local regulatory specifications and requirements.  
For local commercial supplies, please refer to package insert for further details for storage 
conditions. 
8.7.3 Pomalidomide  
For pomalidomide supplied by the Sponsor, the content of the labeling is in accordance with the 
local regulatory specifications and requirements. 
For local commercial supplies, please refer to package insert for further details for storage 
conditions. 
8.8 
RESPONSIBILITIES  
The Investigator, the Hospital Pharmacist, or other personnel allowed to store and dispense IMP 
will be responsible for ensuring that the IMP used in the clinical trial is securely maintained as 
specified by Sanofi and in accordance with the applicable regulatory requirements. 
All IMP will be dispensed in accordance with the Investigator’s prescription and it is the 
Investigator’s responsibility to ensure that an accurate record of Investigational Product issued 
and returned is maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of the IMP may be subject to initiation by Sanofi of a recall 
procedure. In this case, the Investigator will be responsible for promptly addressing any request 
made by Sanofi, in order to recall the IMP and eliminate potential hazards. 
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Under no circumstances will the Investigator supply the IMP to a third party, allow the IMPs to be 
used other than as directed by this Clinical Trial Protocol, or dispose of the IMPs in any other 
manner. 
8.8.1 Treatment accountability and compliance  
Administration of the study treatment will be supervised by the Investigator or Subinvestigator. 
The person responsible for drug dispensing is required to maintain adequate records of the study 
treatment. These records (eg, drug movement form) include the date the study treatment is 
received from the Sponsor, dispensed for patient and destroyed or returned to the Sponsor. The 
packaging batch number (PR Nr) on the vial must be recorded on the drug accountability form. 
The person responsible for study treatment administration to the patient will record precisely the 
date and the time of the study treatment administration to the patient. 
For pomalidomide and dexamethasone PO, a patient diary will be used to document all oral 
pomalidomide and dexamethasone drug administrations (except those administered by the study 
nurse/doctor). 
8.8.2 Return and/or destruction of treatments  
Partially-used and used study treatment will be destroyed at the study site according to the 
standard practices of the site after an accurate accountability has been performed and signed by 
the Investigator (or the Pharmacist). A detailed treatment log form of the destroyed study 
treatment will be established with the Investigator (or the Pharmacist) and countersigned by the 
Investigator and the Monitoring Team. 
The Investigator must not destroy the unused IMP unless Sanofi provides written authorization. 
8.9 
CONCOMITANT MEDICATION  
A concomitant medication is any treatment received by the patient concomitantly to any study 
treatment(s). 
All treatments being taken by the patient 21 days prior to randomization, at any time during the 
treatment period and up to 30 days after the last dose are regarded as prior and concomitant 
treatments respectively, and will be reported on the appropriate pages of the eCRF. 
Concomitant medications are allowed if not listed in prohibited medications and if these are 
considered necessary for the patient's welfare and are unlikely to interfere with the investigational 
product. They may be given at the discretion of the investigator and recorded in the CRF. 
Co-treatment of dexamethasone with CYP3A inhibitors should be avoided unless the benefit 
outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should 
be monitored for systemic corticosteroid side-effects (please refer to dexamethasone package 
insert). 
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8.9.1 Antithrombotic therapy  
Pomalidomide increases the risk of venous thromboembolism. Anticoagulation prophylaxis is 
required after an assessment of each patient’s underlying risk factors. Unless there is an excess 
risk of bleeding, all patients should receive prophylactic antithrombotic treatment. If aspirin is 
contraindicated, patients will receive another form of antithrombotic therapy according to hospital 
guidelines or physician preference. 
Aspirin prophylaxis is recommended for patients with standard risk and low-molecular weight 
heparin for patients with at least one risk factor (ie, history of prior venous thromboembolism, 
immobilization, concomitant use of an erythropoiesis-stimulating agent). 
8.9.2 G-CSF prophylaxis  
Prophylactic administration of G-CSF in a patient who is experiencing recurrent difficulties with 
neutropenia, or therapeutic use in patients with serious neutropenic complications (such as tissue 
infection, sepsis syndrome or fungal infection) may be considered at the investigator’s discretion, 
consistent with American Society of Clinical Oncology (ASCO) guidelines (2006) during the first 
3 treatment cycles in order to decrease the risk of neutropenia specially in patients with baseline 
extensive bone marrow involvement and/or low neutrophil count (16). 
8.9.3 Prohibited concomitant therapy  
• Concurrent treatment with any other anti-myeloma therapy not specified in the protocol, 
including immunotherapy, hormonal therapy, targeted therapy or biological therapies, or 
other investigational drug, or curative radiotherapy. However, palliative radiotherapy may 
be given to control pain. The irradiated area should be as small as possible and should 
never involve more than 20% of the bone marrow in any given 3-week period. In all such 
cases, the possibility of tumor progression should be ruled out by physical, biochemical 
and radiological assessments of the tumor. The irradiated area cannot be used as 
a parameter for response assessment. 
• Concomitant systemic corticosteroids, other than as part of the protocol-specified 
therapeutic regimen or for treatment of hypersensitivity reaction, are prohibited. 
Additional glucocorticoids (or inhaled glucocorticosteroids whenever indicated), 
antihistamines, and analgesics, for the management of IARs are permitted.  
• Live vaccines should be avoided. However, given the increased risk of infection, routine 
vaccinations are recommended for the patients and their contacts. Prophylactic vaccination 
is recommended for influenza A and B virus, pneumococci and haemophilus influenza. 
• Avoid co-administration of strong inhibitors of CYP1A2: 
- 
Cinafloxacin 
- 
Ciprofloxacin 
- 
Enoxacin 
- 
Fluvoxamine 
- 
Oltipraz 
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- 
Rofecoxib 
- 
Zafirlukast 
8.9.4 Contraceptive measures and pregnancy counseling  
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 L) or the country specific risk management plan in countries where 
pomalidomide is not supplied by the Sponsor.  
Criteria for Females of Childbearing Potential 
This protocol defines a FCBP as a sexually mature female who:  
1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (ie, has had menses at any time in the 
preceding 24 consecutive months). 
The investigator must ensure that: 
• Females of childbearing potential comply with the conditions for pregnancy risk 
minimization, including confirmation that she has an adequate level of understanding. 
• Females NOT of childbearing potential acknowledge that they understand the hazards and 
necessary precautions associated with the use of pomalidomide. 
• Male patients taking pomalidomide acknowledge that they understand that traces of 
pomalidomide have been found in semen, that they understand the potential teratogenic 
risk if engaged in sexual activity with a FCBP or pregnant female, and that they 
understand the need for the use of a condom even if they have had a vasectomy.   
Contraception 
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: 1) for at least 28 days before starting 
pomalidomide; 2) throughout the entire duration of pomalidomide treatment; 3) during dose 
interruptions; and 4) for at least 3 or 5 months after study treatment discontinuation for Pd and IPd 
respectively.  
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. A FCBP must be referred to a qualified provider of 
contraceptive methods if needed. The following are examples of highly effective and additional 
effective methods of contraception:  
• Highly effective methods: 
- 
Intrauterine device (IUD) 
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- 
Hormonal (birth control pills, injections, implants) 
- 
Tubal ligation 
- 
Partner’s vasectomy 
• Additional effective methods: 
- 
Male condom 
- 
Diaphragm 
- 
Cervical Cap 
Because of the increased risk of venous thromboembolism in patients with multiple myeloma 
taking pomalidomide and dexamethasone, combined oral contraceptive pills are not 
recommended. If a patient is currently using combined oral contraception the patient should 
switch to one of the effective method listed above. The risk of venous thromboembolism 
continues for 4 to 6 weeks after discontinuing combined oral contraception. The efficacy of 
contraceptive steroids may be reduced during co-treatment with dexamethasone. 
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of 
infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be 
considered particularly in patients with neutropenia.  
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. 
Before starting pomalidomide 
Female Patients: 
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 patient may not receive 
pomalidomide until the Investigator has verified that the results of these pregnancy tests are 
negative. 
Male Patients: 
Must agree to practice complete abstinence or agree to use a condom during sexual contact with 
pregnant females or FCBP throughout the entire duration of pomalidomide treatment, during dose 
interruptions and for at least 3 or 5 months following study treatment discontinuation for Pd and 
IPd respectively, even if he has undergone a successful vasectomy.  
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During study participation and up to 3 or 5 months following study treatment 
discontinuation  
Female Patients: 
• Females of childbearing potential with regular or no menstrual cycles must agree to have 
pregnancy tests weekly for the first 28 days of pomalidomide treatment, including dose 
interruptions and then every 28 days throughout the remaining duration of pomalidomide 
treatment, including dose interruptions, at pomalidomide discontinuation, and monthly up 
to 3 or 5 months following study treatment discontinuation for Pd and IPd respectively. If 
menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 
28 days of pomalidomide treatment, including dose interruptions, and then every 14 days 
throughout the remaining duration of pomalidomide treatment, including dose 
interruptions, at pomalidomide discontinuation, and at Days 14 and monthly up to 3 or 
5 months following study treatment discontinuation for Pd and IPd respectively.  
• At each visit, the Investigator must confirm with the FCBP that she is continuing to use 
two reliable methods of birth control at each visit during the time that birth control is 
required.  
• If pregnancy or a positive pregnancy test does occur in a study patient, pomalidomide 
must be immediately discontinued. 
• Pregnancy testing and counseling must be performed if a patient misses her period or if 
her pregnancy test or her menstrual bleeding is abnormal. Pomalidomide treatment must 
be temporarily discontinued during this evaluation. 
• Females must agree to abstain from breastfeeding during study participation and for at 
least 3 or 5 months after study treatment discontinuation for Pd and IPd respectively. 
Male Patients: 
• Must practice complete abstinence or use a condom during sexual contact with pregnant 
females or FCBP throughout the entire duration of pomalidomide treatment, during dose 
interruptions and for at least 3 or 5 months following study treatment discontinuation for 
Pd and IPd respectively, even if he has undergone a successful vasectomy.   
• If pregnancy or a positive pregnancy test does occur in the partner of a male study patient 
during study participation, the investigator must be notified immediately. 
• Male patients should not donate semen or sperm during therapy or for at least 3 or 
5 months following discontinuation of study treatment for Pd and IPd respectively. 
Additional precautions 
• Female caregivers of childbearing potential should not touch the pomalidomide capsules 
or bottles unless they are wearing gloves. 
• Patients should be instructed never to give pomalidomide to another person. 
• Patients should not donate blood during therapy and for at least 3 or 5 months following 
discontinuation of study treatment for Pd and IPd respectively. 
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• 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 L) or the country specific risk management plan in countries 
where pomalidomide is not supplied by the Sponsor. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT  
9.1 
PRIMARY ENDPOINT  
The primary endpoint is Progression Free Survival (PFS).  
Progression free survival is defined as the time from the date of randomization to the date of first 
documentation of PD (as determined by the IRC) or the date of death from any cause, whichever 
comes first.  
The following disease assessment procedures will be performed at screening (for eligibility) and 
again prior to (within 24 hours) 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 patients 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) (local and central laboratory). After C1D1, immunofixation will be done 
in case of undetectable M protein (serum and urine) 
• Free light chains quantification (local and central laboratory). 
• Quantitative immunoglobulins (local and central laboratory) 
• Other examinations for disease assessment will be done as below: 
• Bone marrow aspiration (or biopsy as clinically indicated) at baseline, and then to confirm 
response (local laboratory, and in case of CR central laboratory will be done to assess 
MRD) 
• Bone disease assessment: 
- 
Skeletal survey (including skull, spine, all long bones, pelvis and chest) or low-dose 
whole-body CT scan at baseline, then once a year and anytime during the study if 
clinically indicated. 
• Extramedullary disease (plasmacytoma) assessment (including bone plasmacytoma): 
- 
If known or documented extramedullary disease (plasmacytoma) at baseline, CT scan 
or MRI is to be done at baseline and to be repeated every 12 weeks (±1 week), and if 
clinically indicated. 
- 
CT scan or MRI to be done in case of suspicion of progression or if clinically indicated 
in a patient with no previous positive image for extramedullary disease 
Note: for bone lesion assessment or extramedullary disease, the same modality 
(skeletal survey or low-dose whole-body CT; CT or MRI) should be used throughout 
the study for each individual patient. 
All imaging to be sent for central review. 
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Efficacy assessments leading to treatment continuation will be performed according to local 
laboratory results and based on the Investigator assessment. Efficacy assessments for the primary 
and secondary endpoints will be performed on the basis of central laboratory findings on Day 1 of 
every cycle. Response/progression will be determined according to IMWG criteria (Appendix D). 
Response/progression based on paraprotein will be confirmed based on 2 consecutive 
assessments. A blinded IRC will evaluate disease assessments at each cycle and determine the 
progression and response status of each patient per IMWG (Appendix D) and as described in the 
IRC Charter. Further details on the handling of missing disease assessments and the IRC process 
for determining the date of disease progression and overall objective response are described in the 
IRC Charter and/or the statistical analysis plan. 
Progressive disease (IMWG criteria) is defined for patients with measurable serum and/or urine 
M protein as any one of the following: 
• Increase of ≥25% in Serum M-component from nadir (the absolute increase must be 
≥0.5 g/dL) in 2 consecutive assessments; serum M component increases ≥1 g/dL in 
2 consecutive assessments are sufficient to define relapse if starting M component is 
≥5 g/dL and/or, 
• Increase of ≥25% in Urine M-component from nadir (the absolute increase must be 
≥200 mg/24 h) in 2 consecutive assessments and/or,  
• Definite development of new bone lesions or soft tissue extramedullary disease or increase 
≥50% from nadir in the sum of perpendicular diameters of existing soft tissue 
extramedullary disease lesions if >1 lesion or ≥50% increase in the longest diameter of 
a previous soft tissue extramedullary disease lesion >1 cm in short axis, 
• Clinical deterioration will not be considered progression in the primary analysis of PFS 
and progression cannot be diagnosed on FLC progression only. 
Patients with only FLC measurable disease are not allowed in the protocol.  
In case of both serum and urine M protein becomes below level of eligibility on efficacy 
laboratory performed on Cycle 1 Day 1, please refer to Appendix D for assessment of progression 
and overall response. 
9.2 
KEY SECONDARY EFFICACY ENDPOINTS  
Two key secondary efficacy endpoints are considered:  
• Overall Response Rate (ORR), as per IMWG criteria. 
• Overall Survival (OS).  
Overall response rate (ORR): is defined as the proportion of patients with stringent complete 
response (sCR), complete response (CR), very good partial response (VGPR), and partial 
response (PR), as assessed by the IRC using the IMWG response criteria. 
Overall survival (OS): is defined as the time from the date of randomization to date of death 
from any cause.  
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9.3 
OTHER SECONDARY ENDPOINTS  
9.3.1 Other secondary efficacy endpoints  
Other secondary efficacy endpoints will be evaluated as follows: 
Time to Progression (TTP): is defined as the time from the date of randomization to the date of 
first documentation of PD (as determined by IRC). The same definition of progression as for the 
PFS endpoint will be used. 
PFS in the high risk cytogenetic population: is defined as PFS as defined in Section 9.1 in the 
subgroup of patients carrying high risk cytogenetic changes including del(17p), t(4;14) or t(14;16) 
assessed by FISH.  
Duration of response (DOR): is defined as the time from the date of the first IRC determined 
response to the date of first IRC PD or death, whichever happens first. Duration of response is 
determined only for patients who have achieved a response of ≥PR.  
9.3.2 Safety endpoints  
Safety in terms of treatment-emergent adverse events/serious adverse events (TEAE/SAE), 
laboratory parameters, vital signs (blood pressure, heart rate and temperature), weight, ECOG 
performance status, and physical examination will be assessed throughout the study and will be 
reported in the eCRF. 
Adverse event data will be collected by reporting at specified intervals throughout the study. 
TEAEs are defined as AEs that develop, worsen (according to the Investigator opinion), or 
become serious during the TEAE period. The TEAE period is defined as the time from first dose 
of study treatments up to 30 days after last dose of study treatments. Adverse events and 
laboratory parameters will be graded using NCI-CTC v4.03 (Appendix C). 
Specific safety laboratory tests are planned in case of infusion reaction (see study flow chart in 
Section 1.2 and Section 10.6.1). 
Full details of safety reporting and adverse event monitoring procedures are provided in 
Section 10.4 and Section 10.7. 
9.3.3 Patient-reported outcomes (HRQL/health economic variables/other endpoints)  
Patient-reported outcome measures to be included are the European Organisation for Research 
and Treatment of Cancer (EORTC) Quality of Life questionnaire with 30 questions (QLQ-C30), 
the EORTC Myeloma Module with 20 items (QLQ-MY20), and the European Quality of Life 
Group measure with 5 dimensions and 5 levels per dimension (EQ-5D-5L). Each questionnaire is 
described in this section. 
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Timing of Assessments 
All three questionnaires have been designed for self-completion. 
Cycle 1 Day 1 (prior to study treatment administration) will serve as the baseline assessment for 
all patients. All the electronic patient-reported outcomes (ePROs) are to be completed by the 
patient using the tablet provided via the study, before other clinician assessments are conducted, 
and before his/her clinical condition, treatment plan, AEs, etc are discussed. The latter is to ensure 
the objectivity of the patient responses free from their emotional reactions to prevent bias. The 
patient is to complete ePRO questionnaires on his or her own.  
There will be a minimum of 20 minutes time allocated to train patients on ePRO technology at 
Cycle 1 Day 1 visit. Training assistance will be provided for subsequent cycles, EOT, and 
follow-up if the patient requests a refresher. 
While on treatment, ePROs are to be administered prior to treatment on Day 1 of every cycle, at 
the EOT visit and at 60 (±5 days) days after last study treatment administration. The time 
estimated to complete the EORTC QLQ-C30 and the EORTC QLQ-MY20 is approximately  
10-15 minutes. The time estimated to complete the EQ-5D-5L is approximately 5 to 10 minutes.  
In order to optimize compliance of the patient, and to ensure the completeness of the ePRO data, 
it is recommended that a key person (eg, research nurse) is assigned and responsible at each center 
for ePRO data collection. 
A statistical analysis plan for the three ePROs will be detailed in the SAP. 
9.3.3.1 EORTC QLQ-C30  
The EORTC QLQ-C30 is a cancer-specific instrument that contains 30 items and provides a 
multi-dimensional assessment of HRQL (17, 18, 19). The validity and reliability of the EORTC 
QLQ-C30 has been established in various types of cancers (20). 
The EORTC QLQ-C30 provides a comprehensive assessment of the principal HRQL dimensions 
identified as relevant by cancer patients (physical functioning, emotional functioning, cognitive 
functioning, role functioning, social functioning, global HRQL, impact of symptoms and of 
toxicities). 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 
five functional scales (physical, role, emotional, cognitive, and social functioning), three 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 
difficulties). 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 functioning/HRQL, where 
a higher score for symptoms/items represents a higher level of symptomatology/problems. The 
recall period for this instrument is 1 week. 
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9.3.3.2 EORTC QLQ-MY20  
The EORTC QLC-MY20 will be administered in conjunction with the EORTC QLQ-C30 to 
assess disease- and treatment-specific symptoms and side effects in patients with multiple 
myeloma (21, 22). 
The MY20 contains 20 items, 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. 
These are reliable and valid measures of HRQL in cancer patients and the two instruments 
together (50 items) take approximately 15 minutes on average to administer. The instruments have 
been validated and used in many countries. 
9.3.3.3 EQ-5D-5L  
The EQ-5D-5L is a standardized measure of health status that provides a general assessment of 
health and wellbeing. For this study, the updated 2011 version will be used. 
The instrument is composed of a descriptive section that includes the 5 dimensions and a VAS. 
The EQ-5D descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has a 5-level response: no problems, 
slight problems, moderate problems, severe problems, and extreme problems. The EQ VAS 
records the respondent’s self-rated health on a 20 cm vertical, visual analogue scale with 
endpoints labelled ‘the best health you can imagine’ and ‘the worst health you can imagine’. This 
information provides a quantitative measure of health as judged by the individual respondents. 
Response options are measured with a 5-point Likert scale (for the 5L version). Global scores are 
available while higher scores indicate better HRQL. 
9.3.4 Pharmacokinetics  
Pharmacokinetics samples will be collected for isatuximab, and therefore will be done only in IPd 
arm. 
9.3.4.1 Sampling time  
It is of utmost importance to collect all blood samples at the specified times and according to the 
specifications. 
Samples not collected, missed or lost, for any reason should be recorded. Actual days and times of 
blood collection should be recorded in the eCRF. The days and the times of drug administration 
should also be precisely recorded. The sampling times for blood collection can be found in the 
PK/PDy Flow Chart (Section 1.3). 
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9.3.4.2 Pharmacokinetics handling procedure  
Special procedures for collection, storage, and shipment will be provided in a separate laboratory 
manual. 
9.3.4.3 Bioanalytical method  
The bioanalytical method is summarized in Table 8.  
Table 8 - Bioanalytical method for isatuximab pharmacokinetic analysis  
Analyte 
Isatuximab 
Matrix 
Plasma 
Analytical technique 
ELISA 
Lower limit of detection 
0.500 ng/mL 
Assay volume 
100 µL 
Site of bioanalysis 
Covance, Harrogate. UK 
ELISA enzyme linked immunosorbant assay 
9.3.4.4 Pharmacokinetics parameters  
Blood concentrations of isatuximab will be used for population PK analysis by non-linear mixed 
effects modeling. Additional details of the analysis plan and the results will be provided in a 
separate document. This analysis will involve an estimation of inter-patient PK variability, the 
population pharmacokinetic parameters estimates and the assessments of pathophysiologic 
covariate effects on CL and possibly on volume if warranted. Empirical Bayesian estimation of 
individual parameters and of individual exposure (AUCs) will also be performed. The PK 
estimates will then be investigated as prognostic factors for clinical outcome including safety and 
efficacy endpoints, if possible. 
9.3.5 Immunogenicity  
9.3.5.1 Anti-drug antibodies  
Human anti-drug antibodies (ADA) to isatuximab will be assessed throughout the study for the 
IPd arm only. Blood samples will be collected for ADA detection according to the Flow Charts 
(see Section 1.2 and Section 1.3). The sampling times for ADA detection can be modified based 
on the updated knowledge of isatuximab on immunogenicity.  
A sample will be considered as ADA positive if ADA is detected ie, sample generates an assay 
signal equal to or greater than the cut-point in the screening assay and is tested positive in the 
confirmatory assay. 
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In case of positivity or inconclusive sample at 60 days post last isatuximab administration, 
additional assessment of ADA will be performed at 90 days and then every 30 days until the 
sample is negative. If isatuximab is stopped prior to pomalidomide and dexamethasone, ADA will 
be tested on D1 of the 2 next cycles. If ADA test at the second cycle administered without 
isatuximab is positive or inconclusive, ADA testing will be repeated every cycle until negative. 
Pre-existing ADA is defined as ADA that were present in samples drawn during the pretreatment 
period (ie, before the first isatuximab administration). Treatment-induced ADA is defined as ADA 
that developed at any time during the ADA on-study observation period in patients without pre-
existing ADA, including patients without pretreatment samples. Treatment boosted ADA is 
defined as preexisting ADA with an increase in titer during ADA on-study observation period. 
Transient ADA response:  
• Treatment-induced ADA detected only at one sampling time point during the treatment or 
follow-up observation period (excluding the last sampling time point, which ought to be 
considered persistent unless shown to be undetectable at a later time) or,  
• Treatment-induced ADA detected at two or more sampling time points during the 
treatment (including follow-up period if any), where the first and last ADA-positive 
samples (irrespective of any negative samples in between) are separated by a period less 
than 16 weeks, and the patient’s last sampling time point is ADA-negative.  
Persistent ADA response:  
• Treatment-induced ADA detected at two or more sampling time points during the 
treatment (including follow-up period if any), where the first and last ADA-positive 
samples (irrespective of any negative samples in between) are separated by a period of 
16 weeks or longer or,  
• Treatment-induced ADA incidence only in the last sampling time point of the treatment 
study period or at a sampling time point with less than 16 weeks before an ADA-negative 
last sample. 
Bioanalytical method used for immunogenicity assessment is summarized in Table 9. 
Table 9 - Bioanalytical method for isatuximab immune response assessment  
Analyte 
Isatuximab 
Matrix 
Plasma 
Analytical technique 
P and A method 
Lower limit of detection 
NA 
Assay volume 
100 µL 
Site of bioanalysis 
Sanofi R&D, DSAR (Alfortville, France) 
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9.4 
EXPLORATORY ENDPOINTS  
9.4.1 Pharmacogenetic assessment  
9.4.1.1 Optional stored DNA sample  
For those patients (in both arms) who sign the optional pharmacogenetic informed consent form 
(ICF), a blood sample will be collected at Cycle 1 Day 1 and DNA extracted from this blood will 
be stored.  
This sample may be used to determine a possible relationship between genes and response to 
treatment with isatuximab, how the body processes isatuximab, and possible side effects to 
isatuximab. Genes that may be studied include those for the immune system. 
This blood sample will be transferred to a site (managed by Covance) that will extract DNA from 
the sample. 
This blood sample, and the DNA that is extracted from it, will be assigned a second number, 
a genetic ID (de-identification code) that is different from the patient ID. This “double coding” is 
performed to separate a patient’s medical information and DNA data. 
The clinical study data (coded by patient ID) will be stored in the clinical data management 
system (CDMS), which is a distinct database in a separate environment from the database 
containing the pharmacogenetic data (coded by genetic ID). The key linking patient ID and 
genetic ID will be maintained by a third party, under appropriate access control. The matching of 
clinical data and pharmacogenetic data, for the purpose of data analysis, will be possible only by 
using this key, which will be under strict access control. All data will be reported only in coded 
form in order to maintain confidentiality. 
The DNA will be stored for up to 15 years from the completion of the clinical study report. 
9.4.2 Exploratory biomarker analysis  
A blood sample will be collected at Cycle 1 Day 1. Leukocyte DNA will be extracted and 
analyzed for immune genetic determinants (such as FcγR polymorphisms, HLA and KIR 
genotypes) and correlated with parameters of clinical response. This germline genetic analysis is 
a mandatory part of the protocol and will not be performed under separate pharmacogenetic 
consent. 
In the IPd arm only, an additional blood sample will be collected to evaluate the potential 
interference of isatuximab with the M protein assessment in immunoelectrophoresis and 
immunofixation assays. This additional sample will be collected at all time-points that central M 
protein analysis is performed and analyzed by a central laboratory. 
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9.4.3 Minimal residual disease  
Minimal residual disease (MRD) will be assessed by next-generation sequencing in bone marrow 
samples from patients who achieve CR, to determine the depth of response at the molecular level. 
Bone marrow aspirates will be collected at baseline/screening and the time of CR confirmation. If 
the patient presents with CR but is determined MRD positive, another bone marrow sample will 
be collected 3 months (3 cycles) later, in order to identify late negativity. A third sample may be 
collected after another 3 months, if the patient remains MRD positive and is still being treated. No 
more than 3 on-treatment bone marrow samples are to be obtained. 
9.5 
FUTURE USE OF SAMPLES  
For patients who have consented to it, the samples that are unused or left over after testing may be 
used for other research purposes (excluding genetic analysis providing information on the 
likelihood of developing a disease) related to isatuximab efficacy, safety, metabolism or related to 
MM. 
These other research analyses will help to understand either disease subtypes or drug response, or 
to develop and/or validate a bioassay method, or to identify new drug targets or biomarkers.  
These samples will remain labelled with the same identifiers used during the study 
(ie, patient ID). They will be transferred to a Sanofi site (or a subcontractor site) which can be 
located outside of the country where the study is conducted. The Sponsor has included safeguards 
for protecting patient confidentiality and personal data (see Section 14.3 and Section 14.5). These 
samples may be stored for a period of up to five years after completion of the final study report. 
After that period, any samples remaining will be destroyed. 
9.6 
 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. In addition, suitable steps have been built 
into each of these assessments to ensure their reliability and accuracy and to minimize any risks to 
patient safety. 
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10 
STUDY PROCEDURES  
10.1 
VISIT SCHEDULE  
All patients entering the study must be evaluated according to the schedule outlined in the Flow 
Charts (see Section 1.2 and Section 1.3) and described below. The results of the evaluation will be 
recorded in the eCRF pages until the patients are no longer followed. 
10.1.1 Screening/baseline  
The screening assessments are to be performed within 21 days prior to randomization (or 28 days 
for FCBP), unless indicated otherwise. All of the inclusion criteria (and none of the exclusion 
criteria) must be met, and informed consent must be signed by the patient before any 
study-specific procedure is performed. 
The following procedures are to be performed/assessed: 
• Signed informed consent.  
• Contraception counselling for FCBP and partner (28 days prior to randomization). 
• Demography (age, gender, ethnicity, and race) and medical/surgical history (other than 
multiple myeloma; including smoking status). 
• Myeloma history and prior anti-myeloma treatment (including date of initial diagnosis of 
symptomatic multiple myeloma, stage and type of disease at diagnosis and study entry, 
heavy and light chain component, previous anti-myeloma therapy - including drug name, 
transplant dates, intent, date of progression, best response and reason for discontinuation). 
• Physical examination to be performed at screening to include examination of main body 
systems including neurological, digestive exam, respiratory (signs and symptoms, 
respiratory rate), hepatic and spleen span, lymph node examination, weight and height 
(height at baseline only). 
• Vital signs including blood pressure, heart rate and body temperature. 
• Prior medication use within 21 days prior randomization. 
• 12-lead ECG. 
• ECOG PS. 
• All AEs/SAEs occurring after signed informed consent for all patients. 
Local laboratory assessments 
• Pregnancy test (urine or serum; with a minimum sensitivity of 25 mIU/mL) to be 
performed within 10 to 14 days prior first study treatment administration for FCBP. 
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• Blood chemistry: to be done at screening: SGOT (AST), SGPT (ALT), bilirubin (total and 
direct), alkaline phosphatase, lactate dehydrogenase (LDH), sodium, potassium, chloride, 
bicarbonate/carbon dioxide, calcium, corrected serum calcium, magnesium, phosphate, 
uric acid, serum creatinine and estimated creatinine clearance (MDRD Formula), urea or 
BUN, fasting glucose (according to site guidelines), albumin and total protein.  
• Hematology: hemoglobin, hematocrit, RBC, WBC with differential (including ANC), and 
platelet count. 
• Coagulation: prothrombin time, international normalized ratio, and activated partial 
thromboplastin time. 
• Quantitative urinalysis: red blood cells, leukocytes, protein, glucose, ketone, pH, bilirubin. 
• Thyroid function tests: TSH, T3 and T4.  
• Serum β2-microglobulin.  
Disease assessment: 
• Laboratory disease assessment (local and central laboratory): measurable disease for 
eligibility will be assessed on central laboratory results. 
- 
Serum M-protein (immunoelectrophoresis and immunofixation), 
- 
Urine M-protein (immunoelectrophoresis and immunofixation), 
- 
Serum free light chains (sFLC, quantification and ratio), 
- 
Immunoglobulins: IgG, IgA, IgM, IgD and IgE (IgD or IgE only if the heavy chain 
component of the disease is known to be IgE or IgD). 
• Bone marrow aspirate (or biopsy as clinically indicated): 
- 
Bone marrow aspirate (BMA) for FISH including but may not be limited to (t(4;14), 
t(14;16), del(17q) to determine risk status (central laboratory). If local FISH 
assessment is done using purified CD138+ plasma cells or by cIg FISH, the most 
recent local FISH report will be collected in patients who fail central FISH testing, for 
a central review, 
- 
BMA for MRD assessment (central laboratory), 
- 
Bone marrow plasma cell infiltration (local laboratory). 
• Bone disease assessment: 
- 
Skeletal survey (including skull, spine, all long bones, pelvis and chest) or low-dose 
whole-body CT scan at baseline, then once a year and anytime during the study if 
clinically indicated. 
• Extramedullary disease (plasmacytoma) assessment (including bone plasmacytoma): 
- 
If known or documented extramedullary disease (plasmacytoma) at baseline, CT scan 
or MRI is to be done at baseline and to be repeated every 12 weeks (±1 week), to 
confirm CR, and if clinically indicated. 
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Note: for bone lesion assessment or extramedullary disease, the same modality 
(skeletal survey or low-dose whole-body CT; CT or MRI) should be used throughout 
the study for each individual patient. 
All imaging to be sent for central review. 
10.1.2 Randomization  
Randomization will take place once the consented patient has completed all the necessary 
screening procedures and is deemed eligible for study entry by the investigator or designee.  
Results for central serum and urine M-protein must be available before the patient may be 
randomized. In the absence of central lab results, sites may use local laboratory results for 
eligibility. Central laboratory results may not be available due to (but not limited to) the following 
reasons: samples were not able to be analyzed by central lab (for various reasons) or lab-
dependent decisions needed for patient treatment had to be made before the availability of central 
lab results.  
All eligible patients must be randomized by contacting the IRT (see Section 8.4). 
The results of the screening examinations will be recorded in each patient’s CRF. Source 
documentation to support the screening results must be maintained in the patient’s medical record. 
All efforts should be made to start treatment within 3 working days even if a maximum up to 
5 working days can be allowed. 
10.1.3 Treatment period  
10.1.3.1 Cycle 1 (Day 1, Day 8, Day 15 and Day 22 all ±1 day)  
The following procedures are to be performed/assessed/completed within 24 hours prior to the 
start of study treatment on Day 1 in both arms unless specified otherwise: 
• Physical examination to be performed within 24 hours prior to study treatment 
administration: main diagnoses to be reported in the eCRF as AEs and newly occurring 
laboratory abnormalities to be recorded in laboratory pages.  
• Vital signs including blood pressure, heart rate and body temperature on D1, D8, D15, and 
D22. In addition in IPd arm, prior to start of each isatuximab infusion, 1 hour after start of 
each infusion and at the end of each infusion. 
• ECOG PS on D1, D8, D15, and D22. 
• Study treatment administration. 
• ePROs (EORTC QLQ-C30, MY20 and EQ-5D-5L).  
• All AEs/SAEs throughout the cycle.  
• Concomitant medications from randomization and used throughout the cycle. 
• Second primary malignancies. 
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• Patient diaries for oral study treatment (dexamethasone when taken orally and 
pomalidomide; except for study treatment doses administered by the study nurse/doctor). 
• Contraception and counselling for FCBP and partner (Day 1). 
• Thromboprophylaxis as described in Section 8.9.1. 
Local laboratory assessments 
• Pregnancy test (urine or serum; with a minimum sensitivity of 25 mIU/mL) to be 
performed and results available on Day 1 within 24 hours prior to study treatment start and 
then weekly (independently of treatment delay/hold) for FCBP. 
• Blood chemistry to be assessed within 24 hours prior to study treatment administration on 
Day 1, Day 8, Day 15, and Day 22: SGOT (AST), SGPT (ALT), bilirubin (total and 
direct), alkaline phosphatase, lactate dehydrogenase (LDH), sodium, potassium, chloride, 
bicarbonate/carbon dioxide, calcium, corrected serum calcium, magnesium, phosphate, 
uric acid, serum creatinine and estimated creatinine clearance (MDRD Formula), urea or 
BUN, fasting glucose (according to site guidelines), albumin and total protein.  
• Hematology, to be assessed weekly within 24 hours prior to study treatment administration 
on Day 1, Day 8, Day 15, and Day 22: hemoglobin, hematocrit, RBC, WBC with 
differential (including ANC), and platelet count. If G4 neutropenia, assess ANC every 
2-3 days until ANC ≥0.5 x 109/L and at least weekly thereafter until ANC ≥1.0 x 109/L. 
Central and local laboratory disease assessment 
Value of the tests performed/completed prior to study treatment administration on Cycle 1 Day 1 
will be the reference value to assess response during study treatment. The following are to be 
performed within 24 hours prior to study treatment administration on Day 1: 
• Serum M-protein (immunoelectrophoresis and immunofixation). 
• Urine M-protein (immunoelectrophoresis and immunofixation). 
• Serum free light chains (sFLC, quantification and ratio). 
• Immunoglobulins: IgG, IgA, IgM, IgD and IgE (IgD or IgE only if the heavy chain 
component of the disease is known to be IgE or IgD). 
Central laboratory assessments 
To be performed within 24 hours prior to study treatment administration on Cycle 1 Day 1: 
• Immune genetic determinants (HLA and KIR genotype and FcγR polymorphism) in blood. 
• Pharmacogenetics: optional blood sample for pharmacogenetics, under separate consent. 
IPd arm only 
• IAR laboratory tests on Day 1 prior to first isatuximab administration: (TNF- α, IL-1-β, 
IL-4, IL-6, and IFN-γ). If a isatuximab infusion associated reaction of Grade ≥2 occurs 
during the cycle, additional blood sampling during the AE is required for analysis of 
cytokine release (TNF-α, IL-1-β, IL-4, IL-6, and IFN-γ), markers of complement 
activation (C3a, C4, CH50), serum tryptase (central laboratory).  
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• Blood sample collection for PK/PDy and ADA evaluation (see Section 1.3) (central 
laboratory).  
• Antibody screening test before the first isatuximab dose: 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 Coombs 
Test/Indirect Antiglobulin Test [IAT]). Blood type card will be kept by the patient with the 
study card and the blood bank needs to be informed that the patient is receiving a 
treatment with an anti-CD38 and a potential interference with the Indirect Coombs test is 
possible (Appendix K). 
• One additional blood sample will be collected for testing potential interference of 
isatuximab with the M protein assessment. The sample will be collected at the same time 
as for serum M protein sample above (central laboratory). 
If clinically indicated only: 
• Coagulation at any time during the cycle. 
• Qualitative urinalysis: blood, leukocytes, protein, glucose, ketone, pH, bilirubin at any 
time during the cycle. 
• Thyroid function tests (TSH, T3 and T4) at any time during the cycle. 
• Markers for TLS (uric acid, creatinine, potassium, phosphate, calcium and corrected 
calcium) at any time during the cycle. 
• Any other exams clinically indicated. 
• Disease assessment (BM, radiological, laboratory). The same method of assessment as at 
baseline is to be used throughout the study.  
10.1.3.2 Subsequent cycles (Day 1 and 15)  
The following procedures are to be performed/assessed on Day 1 prior to study treatment 
administration in both arms unless specified otherwise: 
• Physical examination to be performed within 24 hours prior to study treatment 
administration: main diagnoses to be reported in the eCRF as AEs and newly occurring 
laboratory abnormalities to be recorded in laboratory pages.  
• Vital signs including blood pressure, heart rate and body temperature. In addition in IPd 
arm, prior to start of each isatuximab infusion, 1 hour after start of each infusion and at the 
end of each infusion on D1 and on D15 up to and including Cycle 4 and as clinically 
indicated. 
• 12-lead ECG at C2D1 pre-dose. 
• ECOG PS. 
• Study treatment administration. 
• ePROs (EORTC QLQ-C30, MY20 and EQ-5D-5L).  
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• All AEs/SAEs throughout the cycles.  
• Concomitant medications used throughout the cycle. 
• Second primary malignancies. 
• Patient diaries for oral study treatment (dexamethasone when taken orally and 
pomalidomide; except for study treatment doses administered by the study nurse/doctor). 
• Contraception and counselling for FCBP and partner (Day 1). 
• Thromboprophylaxis as described in Section 8.9.1. 
Local laboratory assessments  
• Pregnancy test (urine or serum; with a minimum sensitivity of 25 mIU/mL) for FCBP 
every 4 weeks with results available prior to study treatment administration on Day 1 if 
regular menstruation and every 2 weeks if irregular menstruation even in case of treatment 
delay/hold.  
• Blood chemistry to be assessed within 24 hours prior to study treatment administration on 
Day 1: SGOT (AST), SGPT (ALT), bilirubin (total and direct), alkaline phosphatase, 
lactate dehydrogenase (LDH), sodium, potassium, chloride, bicarbonate/carbon dioxide, 
calcium, corrected serum calcium, magnesium, phosphate, uric acid, serum creatinine and 
estimated creatinine clearance (MDRD Formula), urea or BUN, fasting glucose (according 
to site guidelines), albumin and total protein. 
• Hematology, to be assessed within 24 hours prior to study treatment administration on 
Day 1 and Day 15 at Cycle 2 and Cycle 3 and then within 24 hours prior to study 
treatment administration on Day 1 and as clinically indicated: hemoglobin, hematocrit, 
RBC, WBC with differential (including ANC), and platelet count. If G4 neutropenia, 
assess ANC every 2-3 days until ANC ≥0.5 x 109/L and at least weekly thereafter until 
ANC ≥1.0 x 109/L. 
• Thyroid function tests (TSH, T3 and T4) once a year and at any time during the cycle if 
clinically indicated. 
• IAT on Cycle 2 Day 1 (IPd arm only); if the test is not performed at this visit, it can be 
done at the next blood sampling. Additional IAT data will be collected whenever a blood 
transfusion is needed. 
Disease assessment 
Investigator decision to continue study treatment or not will be done on local laboratory efficacy 
data (except in selected country[ies] where central laboratory results are available on an ongoing 
basis [in which case, one sample will be collected at each timepoint]) plus radiological and bone 
marrow assessments when planned by the protocol or if indicated according to IMWG criteria.  
• Local and Central laboratories to be assessed within 24 hours prior to study treatment 
administration on Day 1 of each cycle (reference value to assess response will be value 
from the lab taken on Cycle 1 Day 1): 
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- 
Serum M-protein: immunoelectrophoresis and if M protein undetectable, 
immunofixation will be performed? 
- 
Urine M-protein: immunoelectrophoresis and if M protein undetectable, 
immunofixation will be performed. If urine M-protein is negative (negative 
immunofixation) 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, 
- 
A sample for FLC assay is to be obtained on Day 1 of every cycle; samples to be 
centrally analyzed only in case of CR (M-protein undetectable in SPEP/UPEP and 
negative immunofixation), 
- 
Immunoglobulins: IgG, IgA, IgM, IgD and IgE (IgD or IgE only if the heavy chain 
component of the disease is known to be IgE or IgD). 
• Bone marrow aspirate (or biopsy as clinically indicated): 
- 
Bone marrow plasma cell infiltration (local laboratory) to confirm CR, or if suspicion 
of disease progression in the absence of biochemical progression and as clinically 
indicated, 
- 
BMA for MRD assessment in case of CR (central laboratory). In case of MRD 
positive, another bone marrow sample will be collected 3 months (3 cycles) later, in 
order to identify late negativity. A third sample may be collected after another 
3 months, if the patient remains MRD positive and is still being treated. No more than 
3 on-treatment bone marrow samples are to be obtained. 
• Bone disease assessments: 
- 
Skeletal survey or low-dose whole-body CT scan once a year and anytime during the 
study if clinically indicated. 
• Extramedullary disease (plasmacytoma) assessment (including bone plasmacytoma): 
- 
If known extramedullary disease, CT scan or MRI is to be repeated every 12 weeks 
(±1 week), to confirm CR, and if clinically indicated, 
- 
CT scan or MRI to be done in case of suspicion of progression or if clinically indicated 
in a patient with no previous positive image for extramedullary disease. 
Note: for bone lesion assessment or extramedullary disease, the same modality 
(skeletal survey or low-dose whole-body CT; CT or MRI) should be used throughout 
the study for each individual patient. 
All imaging to be sent for central review. 
IPd arm only 
• If a isatuximab infusion associated reaction of Grade ≥2 occurs during the cycle, 
additional blood sampling during the AE is required for analysis of cytokine release 
(TNF-α, IL-1-β, IL-4, IL-6, and IFN-γ), markers of complement activation (C3a, C4, 
CH50), serum tryptase (central laboratory). 
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• Blood sample collection for PK/PDy and ADA evaluation (see Section 1.3) (central 
laboratory). 
• One additional blood sample will be collected for testing potential interference of 
isatuximab with the M protein assessment. The sample will be collected at the same time 
as for serum M protein sample above (central laboratory).  
If clinically indicated only: 
• Coagulation at any time during the cycle. 
• Qualitative urinalysis: blood, leukocytes, protein, glucose, ketone, pH, bilirubin at any 
time during the cycle.  
• Markers for TLS (uric acid, creatinine, potassium, phosphate, calcium and corrected 
calcium) at any time during the cycle. 
• Any other exams clinically indicated. 
10.1.4 End of treatment  
The EOT visit will occur 30 days after last study treatment administration or prior to start of 
further anti-myeloma therapy, whichever comes first  
The following procedures are to be performed at the EOT visit: 
• Physical examination. 
• Vital signs. 
• 12-lead ECG. 
• ECOG PS. 
• ePROs (EORTC QLQ-C30, MY20 and EQ-5D-5L). 
• All AEs/SAEs occurring up to 30 days after last study treatment administration (will be 
collected in last treatment cycle). 
• Concomitant medications up to 30 days from last study treatment administration. 
• Second primary malignancies. 
Local laboratory tests 
• Pregnancy test (urine or serum; with a minimum sensitivity of 25 mIU/mL) for FCBP. 
• Blood chemistry: SGOT (AST), SGPT (ALT), bilirubin (total and direct), alkaline 
phosphatase, lactate dehydrogenase (LDH), sodium, potassium, chloride, 
bicarbonate/carbon dioxide, calcium, corrected serum calcium, magnesium, phosphate, 
uric acid, serum creatinine and estimated creatinine clearance (MDRD Formula), urea or 
BUN, fasting glucose (according to site guidelines), albumin and total protein. 
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• Hematology: hemoglobin, hematocrit, RBC, WBC with differential (including ANC), and 
platelet count. If G4 neutropenia, assess ANC every 2-3 days until ANC ≥0.5 x 109/L and 
at least weekly thereafter until ANC ≥1.0 x 109/L. 
• Thyroid function tests (TSH, T3 and T4). 
Disease assessment 
Investigator decision to discontinue study treatment due to PD will be done on local laboratory 
efficacy data plus radiological and bone marrow assessments when planned by the protocol or if 
indicated according to IMWG criteria.  
• Local and Central laboratories  
- 
Serum M-protein: immunoelectrophoresis and if M protein undetectable, 
immunofixation will be performed 
- 
Urine M-protein: immunoelectrophoresis and if M protein undetectable, 
immunofixation will be performed, 
- 
Serum free light chains (sFLC, quantification and ratio), 
- 
Immunoglobulins: IgG, IgA, IgM, IgD and IgE (IgD or IgE only if the heavy chain 
component of the disease is known to be IgE or IgD), 
- 
Bone marrow aspirate (or biopsy as clinically indicated): 
- 
Bone marrow plasma cell infiltration (local laboratory) to confirm CR, or if 
suspicion of disease progression in the absence of biochemical progression and as 
clinically indicated, 
- 
MRD assessment in case of CR if indicated (central laboratory). 
• Radiological disease assessments if needed for bone disease assessment or extramedullary 
disease assessment. 
IPd arm only 
• Blood sample collection for PK/PDy and ADA evaluation (see Section 1.3). 
• One additional blood sample will be collected for testing potential interference of 
isatuximab with the M protein assessment. The sample will be collected at the same time 
as for serum M protein sample above (central laboratory). 
10.1.5 Post treatment follow up  
10.1.5.1 60 days visit  
The following procedures are to be performed 60 ±5 days after the last study treatment: 
• AE assessment: related AEs and all serious AEs (regardless of relationship to study 
treatment) ongoing at the time of study treatment discontinuation will be followed until 
resolution or stabilization. All (serious or non-serious) new AEs related to study treatment 
will be collected and followed until resolution or stabilization. 
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• Further anti-myeloma therapy. 
• Second primary malignancies. 
• Survival status. 
• ePROs (EORTC QLQ-C30, MY20 and EQ-5D-5L). 
• ECOG PS. 
• Pregnancy test (urine or serum; with a minimum sensitivity of 25 mIU/mL) for FCBP will 
be done monthly up to 3 or 5 months after last study treatment (local laboratory) for Pd 
and IPd respectively.  
IPd arm only:  
• One ADA sample should be drawn 60 ±5 days after the last study treatment administration 
(see Section 1.3).  
Disease assessment (only for patients without confirmed disease progression at the Day 60 
visit, including patients who would have initiated further anti-myeloma therapy without PD) 
• Central and local laboratory tests 
- 
Serum M-protein: immunoelectrophoresis and if M-protein undetectable, 
immunofixation will be performed, 
- 
Urine M-protein: immunoelectrophoresis and if M-protein undetectable, 
immunofixation will be performed, 
- 
Serum free light chains in case of CR (sFLC, quantification and ratio), 
- 
Immunoglobulins: IgG, IgA, IgM, IgD and IgE (IgD or IgE only if the heavy chain 
component of the disease is known to be IgE or IgD), 
- 
One additional blood sample will be collected for testing potential interference of 
isatuximab with the M protein assessment for patient treated in IP arm. The sample 
will be collected at the same time as for serum M protein sample above (central 
laboratory only). 
• If needed BMA (or biopsy as clinically indicated): 
- 
Bone marrow plasma cell infiltration (local laboratory) to confirm CR, or if suspicion 
of disease progression in the absence of biochemical progression and as clinically 
indicated, 
- 
BMA for MRD assessment in case of CR (central laboratory). 
• Bone disease assessments (skeletal survey or low-dose whole-body CT scan) if applicable. 
• Extramedullary disease (plasmacytoma) assessment (CT scan or MRI, including bone 
plasmacytoma) if applicable. 
Note: for bone lesion assessment or extramedullary disease, the same modality (skeletal 
survey or low-dose whole-body CT; CT or MRI) should be used throughout the study for 
each individual patient. 
All imaging to be sent for central review. 
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10.1.5.2 Further follow-up visits (Day 90 ±7 days after last study treatment administration 
and then every 3 months [±7 days])  
Pregnancy tests (urine or serum; with a minimum sensitivity of 25 mIU/mL) for FCBP will be 
done monthly up to 3 or 5 months after last study treatment (local laboratory) for Pd and IPd 
respectively. 
IPd arm only, if ADA is positive or inconclusive at 60 days, repeat samples will be taken every 
30 ±7 days until the results become negative (see Section 1.3). 
For patients with confirmed disease progression (at EOT or during follow-up): the 
post-treatment follow-up period includes visits every 3 months (±7 days) after administration of 
the last study treatment. 
The following procedures are to be performed during the post-treatment follow up period: 
• AE assessment: related AEs and all serious AEs (regardless of relationship to 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 will be collected and followed 
until resolution or stabilization. 
• Further anti-myeloma therapy. 
• Survival status.  
• Second primary malignancies.  
For patients discontinued without disease progression (including patients who would have 
initiated further anti-myeloma therapy without PD): the post-treatment follow-up period 
includes visits every month after last study treatment administration. The following procedures 
are to be performed up to PD (after PD, FU visit will be done every 3 months [±7 days] as 
described above):  
Disease assessment  
• Central and local laboratory tests 
- 
Serum M-protein: immunoelectrophoresis and if M protein undetectable, 
immunofixation will be performed, 
- 
 Urine M-protein: immunoelectrophoresis and if M protein undetectable, 
immunofixation will be performed, 
- 
Serum free light chains in case of CR (sFLC, quantification and ratio), 
- 
Immunoglobulins: IgG, IgA, IgM, IgD and IgE (IgD or IgE only if the heavy chain 
component of the disease is known to be IgE or IgD). 
• Bone marrow aspirate (or biopsy as clinically indicated): 
- 
Bone marrow plasma cell infiltration (local laboratory) to confirm CR, as clinically 
indicated, 
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- 
BMA for MRD assessment in case of CR (central laboratory). 
• Bone disease assessments if applicable: 
- 
Skeletal survey or low-dose whole-body CT scan once a year and anytime during the 
study if clinically indicated. 
• Extramedullary disease (plasmacytoma) assessment (including bone plasmacytoma) if 
applicable: 
- 
If known extramedullary disease, CT scan or MRI is to be repeated every 12 weeks 
(±1 week), to confirm CR, and if clinically indicated, 
- 
CT scan or MRI to be done in case of suspicion of progression or if clinically indicated 
in a patient with no previous positive image for extramedullary disease. 
Note: for bone lesion assessment or extramedullary disease, the same modality 
(skeletal survey or low-dose whole-body CT; CT or MRI) should be used throughout 
the study for each individual patient. 
All imaging to be sent for central review. 
• AE assessment: related AEs and all serious AEs (regardless of relationship to 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 new 
related AEs (regardless of seriousness) will be collected and followed until resolution or 
stabilization. 
• Further anti-myeloma therapy. 
• Survival status.  
• Second primary malignancies.  
10.1.6 Post PFS study cut-off date  
Patients still on treatment at the PFS cut-off date will continue study treatment until at least 
1 treatment discontinuation criterion as defined in Section 10.3.2 is met. The following 
information will be collected during the study treatment administration: 
• Study treatment administration. 
• Physical examination: main diagnoses to be reported in the eCRF as AEs and newly 
occurring laboratory abnormalities to be recorded in laboratory pages.  
• Vital signs including blood pressure, heart rate and body temperature. In addition in IPd 
arm, prior to start of each isatuximab infusion, 1 hour after start of each infusion and at the 
end of each infusion on Day 1 and on Day 15 up to and including cycle 4 and as clinically 
indicated. 
• ECOG PS.  
• Concomitant medications used throughout the cycle. 
• Second primary malignancies. 
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• Patient diaries for oral study treatment (dexamethasone when taken orally and 
pomalidomide; except for study treatment doses administered by the study nurse/doctor). 
• AE assessment: all related AEs and all serious AEs (regardless of relationship to study 
treatment) ongoing at the time of cut-off will be followed until resolution or stabilization. 
All new related AEs (regardless of seriousness) will be collected and followed until 
resolution or stabilization.  
Disease assessment  
• Only overall response according to assessment per Investigator and based on local 
laboratories and local reading of radiological assessment will be collected.  
• Bone marrow aspirate (or biopsy as clinically indicated): 
- 
Bone marrow plasma cell infiltration (local laboratory) to confirm CR, and as 
clinically indicated, 
- 
BMA for MRD assessment in case of CR (central laboratory). 
Local laboratory assessments 
• 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 patients with resolved 
infection), ALT and AST will be closely monitored every month up to study treatment 
discontinuation. HBV DNA to be done as per specialist advice. 
• Pregnancy test (urine or serum; with a minimum sensitivity of 25 mIU/mL) to be 
performed for FCBP on Cycle 1 Day 1, Day 8, Day 15, and Day 22 and then on Day 1 of 
subsequent cycles (independently of treatment delay/hold), within 24 hours prior to study 
treatment administration. Females with irregular menstruation must have pregnancy 
testing on Cycle 1 Day 1, Day 8, Day 15, and Day 22 and then every 14 days while on 
study treatment(independently of treatment delay/hold). 
• Blood chemistry within 24 hours prior to study treatment administration on Cycle 1 Day 1, 
Day 8, Day 15, and Day 22 and within 24 hours prior to study treatment administration on 
Day 1 of every subsequent cycle: SGOT (AST), SGPT (ALT), bilirubin (total and direct), 
alkaline phosphatase, lactate dehydrogenase (LDH), sodium, potassium, chloride, 
bicarbonate/carbon dioxide, calcium, corrected serum calcium, magnesium, phosphate, 
uric acid, serum creatinine and estimated creatinine clearance (MDRD Formula), urea or 
BUN, fasting glucose (according to site guidelines), albumin and total protein.  
• Hematology, to be done within 24 hours prior to study treatment administration on Cycle 1 
Day 1, Day 8, Day 15, and Day 22, within 24 hours prior to study treatment administration 
on Days 1 and 15 of Cycles 2 and 3, and then within 24 hours prior to study treatment on 
Day 1 of ever subsequent cycle: hemoglobin, hematocrit, RBC, WBC with differential 
(including ANC), and platelet count. 
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IPd arm only 
• If an isatuximab IAR of Grade ≥2 occurs during the cycle, additional blood sampling 
during the AE is required for analysis of cytokine release (TNF-α, IL-1-β, IL-4, IL-6, and 
IFN-γ), markers of complement activation (C3a, C4, CH50), serum tryptase (central 
laboratory). 
• One additional blood sample will be collected for testing potential interference of 
isatuximab with the M protein assessment. The sample will be collected at the same time 
as for serum M protein sample above (central laboratory).  
If clinically indicated only: 
• Coagulation at any time during the cycle. 
• Qualitative urinalysis: blood, leukocytes, protein, glucose, ketone, pH, bilirubin at any 
time during the cycle.  
• Markers for TLS (uric acid, creatinine, potassium, phosphate, calcium and corrected 
calcium) at any time during the cycle.  
• Any other exams clinically indicated. 
10.1.7 Post final OS study cut-off date  
Patients still on study treatment at the final OS analysis cut-off date can continue study treatment 
until at least 1 treatment discontinuation criterion as defined in Section 10.3.2 is met and patients 
will be managed according to local clinical practice. The following information will be collected 
during the study treatment administration:  
• Study treatment administration. 
• 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 patients with resolved 
infection), ALT and AST will be closely monitored every month up to study treatment 
discontinuation. HBV DNA to be done as per specialist advice. 
• Pregnancy tests for FCBP. 
• AE assessment: all related AEs and all serious AEs (regardless of relationship to study 
treatment) ongoing at the time of cut-off will be followed until resolution or stabilization. 
All new related AEs (regardless of seriousness) will be collected and followed until 
resolution or stabilization. 
• Laboratory abnormalities will continue to be collected as AEs if the results have an impact 
on the study treatment or meet seriousness criteria.  
• End of treatment reason.  
No follow-up information will be collected after these patients discontinue study treatment except 
all SAEs still ongoing at the end of study treatment and all adverse events considered as related to 
study treatment still ongoing or occurring after the end of study treatment, which will be followed 
until resolution/stabilization. 
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10.2 
DEFINITION OF SOURCE DATA  
Source data includes all information in original records and certified copies of original records of 
clinical findings, observations, or other activities necessary for the reconstruction and evaluation 
of the trial. Source data are contained in source documents. 
Source documents are original documents, data, and records (eg, hospital records, clinical and 
office charts, laboratory notes, memoranda, patient diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcripts certified after 
verification as being accurate and complete, microfiches, photographic negatives, microfilm or 
magnetic media, X-rays, patient files, and records kept at the pharmacy, at the laboratories, and at 
medical-technical departments) involved in the clinical study. Source documentation must be 
maintained to support information provided within a CRF. 
10.3 
HANDLING OF PATIENT PERMANENT TREATMENT DISCONTINUATION AND OF 
PATIENT STUDY DISCONTINUATION  
The study treatment should be continued whenever possible. Study treatment discontinuation 
should be a last resort. Any study treatment discontinuation should be fully documented in the 
CRF. In any case, the patient should remain in the study as long as possible. 
Patients are free to withdraw their participation at any time during this study. The Investigator has 
the right to remove any patient from study treatment or participation in the study. 
Any study treatment discontinuation should be fully documented in the eCRF. 
Pregnancy in patients will lead to definitive treatment discontinuation in all cases.  
10.3.1 Permanent treatment discontinuation with investigational medicinal product(s)  
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the study 
treatment at any time. 
10.3.2 List of criteria for permanent treatment discontinuation  
The patients may withdraw from treatment with the study treatment if they decide to do so, at any 
time and irrespective of the reason, or this may be the Investigator’s decision. All efforts should 
be made to document the reason(s) for treatment discontinuation and this should be documented 
in the eCRF. 
Isatuximab and/or pomalidomide and/or dexamethasone can be discontinued prematurely. Patient 
will remain on study treatment until the last study treatment is discontinued. The reason for 
premature discontinuation will be captured in the appropriate eCRF page. 
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All efforts should be made to document the reason for discontinuation of treatment with the study 
treatment:  
• At the patient’s request, at any time and irrespective of the reason (consents withdrawal), 
or at the request of their legally authorized representative. “Legally authorized 
representative” is considered to be an individual or judicial or other body authorized under 
applicable law to consent on behalf of a prospective patient to the patient’s participation in 
the procedure(s) involved in the research. Withdrawal of consent for treatment should be 
distinguished from withdrawal of consent for follow-up visits and from withdrawal of 
consent for non-patient contact follow-up, eg, medical records check. Patients requesting 
withdrawal should be informed that withdrawal of consent for follow-up may jeopardize 
the public health value of the study. The Investigator should make every effort to 
re-contact the patient, to identify the reason why he/she decided to withdraw, and to 
determine his/her health status, including at least his/her vital status.  
• If, in the Investigator’s opinion, continuation of the study treatment would be detrimental 
to the patient’s wellbeing, such as: 
- 
Disease progression, 
- 
Unacceptable AE, 
- 
Poor compliance to the study protocol, 
- 
Any other reason such as intercurrent illness that prevents further administration of 
study treatment (will be specified). 
• Patient is lost to follow-up. 
If patients are clinically stable, and possibly deriving clinical benefit from therapy with minimal 
toxicity, the patient will be maintained on treatment for the maximum period of time defined in 
Section 6.2. 
Patients who have been withdrawn from the study treatment cannot be re-included in the study. 
Their inclusion and treatment number must not be re-used. 
10.3.3 Handling of patients after permanent treatment discontinuation  
Patients will be followed-up according to the study procedures specified in this protocol up to the 
scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
If possible, and after the permanent discontinuation of treatment, the patients will complete the 
evaluations scheduled for the EOT and follow-up visits as detailed in the Study Flow Chart 
(Section 1.2). 
All treatment discontinuation should be recorded by the Investigator in the appropriate eCRF 
pages when considered as confirmed. 
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10.3.4 Procedure and consequence for patient withdrawal from study  
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. Withdrawal of consent for treatment should be distinguished 
from withdrawal of consent for follow-up visits and from withdrawal of consent for non-patient 
contact follow-up, eg, medical records check. Patients requesting withdrawal should be informed 
that withdrawal of consent for follow-up may jeopardize the public health value of the study. 
If possible, the patients are assessed using the procedure normally planned for the EOT visit ADA 
and PK assessments. If ADA test is positive or inconclusive, ADA testing should be repeated 
every 30 days until negative. 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented. Preferably 
the patient should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unavailable, the site should document and sign the reason for the patient’s 
failure to withdraw consent in writing.  
All study withdrawals should be recorded by the Investigator in the eCRF and in the patient’s 
medical records when considered as confirmed. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
For patients who fail to return to the site, unless the patient withdraws consent for follow-up, the 
Investigator should make every effort to re-contact the patient (eg, contact patient’s family or 
private physician, review available registries or health care databases), and to determine his/her 
health status, including at least his/her vital status. Attempts to contact such patients must be 
documented in the patient’s records (eg, times and dates of attempted telephone contact, receipt 
for sending a registered letter). 
The statistical analysis plan will specify how these patients lost to follow-up for their primary 
endpoints will be considered. 
Patients who have withdrawn from the study cannot be re-randomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused.  
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING  
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event  
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have 
a causal relationship with the treatment. 
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10.4.1.2 Serious adverse event  
A SAE is any untoward medical occurrence that at any dose: 
• Results in death, or 
• Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect. 
• Is a medically important event 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which conditions are to be considered a medically important events. 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. 
• Suicide attempt or any event suggestive of suicidality. 
• Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling). 
• Bullous cutaneous eruptions. 
• Cancers diagnosed during the study or aggravated during the study, if judged 
unusual/significant by the Investigator. 
10.4.1.3 Adverse event of special interest  
An AE of special interest (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. 
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The following AEs are considered AESIs: 
Acute infusion associated reactions Grade 3 or 4 (IARs; Appendix G for diagnosis and symptoms 
typical of an IAR). An IAR is a related adverse event typically with onset within 24 hours from 
the start of isatuximab infusion. 
Pregnancy of a female patient entered in a study as well as pregnancy occurring in a female 
partner of a male patient entered in a study with IMP (see Section 10.4.1.4): 
• Pregnancy occurring in a female patient entered in the clinical trial or in a female partner 
of a male patient entered in the clinical trial will be qualified as an SAE only if it fulfills 
one of the seriousness criteria (see Section 10.4.1.2). 
• 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 has been determined and for up to 1 year after 
the delivery of a newborn. 
Symptomatic overdose (serious or nonserious) with IMP (isatuximab or pomalidomide or 
dexamethasone) or NIMP (see Section 10.4.1.5): 
• An overdose (accidental or intentional) with the IMP or NIMP is an event suspected by the 
Investigator or spontaneously notified by the patient (not based on systematic pills count) 
and defined as: 
• For IMP, an increase of at least 30% of the dose to be administered in the specified 
duration. 
• For NIMP (acetaminophen [paracetamol], ranitidine or equivalent, diphenhydramine or 
equivalent), an increase of at least twice the intended dose within the intended therapeutic 
interval. 
Of note, asymptomatic overdose has to be reported as a standard AE. 
Second primary malignancies are to be reported using the AE report form and must be considered 
AESIs; these AEs must also be documented in the appropriate page(s) of the eCRF and patient’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, CT scans, etc). 
10.4.1.4 Pregnancy  
Pregnancy of a female patient entered in a study (as well as pregnancy occurring in a female 
partner of a male patient entered in this study) will be recorded as an AE in all cases. It will be 
qualified as a SAE only if it fulfills SAE criteria. 
In the event of pregnancy in a female patient, study treatment should be discontinued and the 
Monitoring Team should be informed immediately (within 24 hours), even if the event does not 
fulfill a seriousness criterion, using the AE form together with the SAE complementary form to be 
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sent to the representative of the Monitoring Team whose name, address and fax number appear on 
page 2 of the clinical trial protocol. 
Follow-up of the pregnancy is mandatory until the outcome has been determined and for up to 
1 year after the delivery of a newborn. 
10.4.1.5 Overdose  
In case of accidental or intentional overdose (at least 30% above the intended administered dose at 
each cycle) with the study treatment, even not fulfilling a seriousness criterion, is to be reported to 
the Sponsor immediately (within 24 hours) using the AE form together with the SAE 
complementary form to be entered in the eCRF. 
10.4.2 General guidelines for reporting adverse events  
All AEs, regardless of seriousness or relationship to study treatment, spanning from the signature 
of the ICF until the end of the study (30 days after the last dose of study treatment), are to be 
recorded on the corresponding page(s) or screen(s) of the eCRF for included patients. For screen 
failed patients, recording in the eCRF is only performed in case of SAE occurring during the 
screening period or in case of AE when some screening procedures expose the patient to safety 
risks (eg, any substance administered as premedication, invasive tests performed or chronic 
treatment interrupted). 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. The 
Investigator should specify the date of onset, intensity, action taken with respect to study 
treatment, corrective treatment/therapy given, additional investigations performed, outcome and 
his/her opinion as to whether there is a reasonable possibility that the AE was caused by the study 
treatment. 
All study treatment-related AEs and all SAEs (regardless of their causal relationship to study 
treatment) ongoing at the time of study treatment discontinuation need to be followed until 
resolution or stabilization. Any AE or SAE assessed as study treatment-related that are new 
during the follow-up period are to be reported and followed until resolution or stabilization.  
When treatment is discontinued, observations will continue for that patient as defined by the 
protocol. 
Vital signs or ECG abnormalities are to be recorded as AEs only if they are symptomatic and/or 
require corrective treatment and/or lead to treatment discontinuation and/or modification of 
dosing and/or fulfilling a serious criterion and/or are defined as an AESI. 
Laboratory abnormalities are to be recorded as AEs only if they lead to treatment discontinuation 
and/or modification of dosing and/or fulfill a serious criterion and/or are defined as an AESI. 
Laboratory values will be reported in the appropriate pages of eCRF. 
Instructions for AE reporting are summarized in Table 10. 
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Table 10 - Summary of adverse event reporting instructions  
Event category 
Reporting 
timeframe 
Specific events in this 
category 
Case Report Form completion 
AE 
form 
Safety  
Complementary 
Form 
Other 
specific 
forms 
Adverse event 
(non-SAE, 
non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious adverse 
event (non-AESI or 
AESI) 
Expedited (within 
24 hours) 
Any AE meeting seriousness 
criterion per Section 10.4.1.2 
Yes 
Yes 
No 
Adverse event of 
special interest  
Expedited (within 
24 hours) 
IARs of Grade ≥3 
Yes 
Yes 
No 
 
 
Pregnancy 
Second primary malignancies 
Yes 
Yes 
Yes 
Yes 
Yes 
No 
 
 
Symptomatic overdose 
Yes 
Yes 
No 
AESI = adverse event of special interest; SAE = serious adverse event. 
10.4.3 Instructions for reporting serious adverse events  
In the case of occurrence of an SAE, the Investigator or any designees must immediately: 
• ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the eCRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the eCRF or after a standard delay. 
• There may be instances when copies of medical records for certain cases are requested by 
Sanofi. In such case, care should be taken to ensure that the patient's identity is protected 
and the patient's identifiers in the study are properly mentioned on any copy of a source 
document provided to the Company. For laboratory results, include the laboratory normal 
ranges. 
• All further data updates should be recorded in the eCRF as appropriate within 24 hours of 
knowledge of the SAE. In addition, every effort should be made to further document any 
SAE that is fatal or life-threatening within 1-week (7 days) of the initial notification. 
• A back-up plan (using a paper CRF process) is available and should be used when the 
eCRF system does not work. 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
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. 
Instructions for SAE reporting are summarized in Table 10. 
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10.4.4 Guidelines for reporting adverse events of special interest  
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.3, even if not fulfilling a seriousness criterion, 
using the corresponding pages of the CRF (to be sent) or screens in the eCRF.  
Instructions for AESI reporting are summarized in Table 10. 
10.5 
OBLIGATIONS OF THE SPONSOR  
During the course of the study, the Sponsor will report in an expedited manner: 
• All SAEs that are both unexpected and at least reasonably related to the IMP (suspected 
unexpected serious adverse reaction), to the regulatory authorities, independent ethics 
committees (IECs)/institutional review boards (IRBs) as appropriate and to the 
Investigators.  
• All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
• The AESIs listed in Section 10.4.1.3 to the regulatory authorities requiring such reporting 
Adverse events that are considered expected are specified in the reference safety information 
within the Investigator’s Brochure, Section 8 (see the Table entitled “Expected adverse drug 
reactions for isatuximab in combination with pomalidomide and dexamethasone”).  
Sanofi will report all safety observations made during the conduct of the study in the clinical 
study report. 
10.6 
SAFETY INSTRUCTIONS  
10.6.1 Guidelines for the management of potential infusion associated reactions  
Patients should routinely receive premedications prior to isatuximab infusion as detailed in 
Section 8.2.2 to reduce the risk and severity of IARs commonly observed with mAbs.  
Details for management of IARs are provided in Section 8.2.4. 
10.6.2 Guidelines for the management of tumor lysis syndrome  
Tumor lysis syndrome may occur. The patients at greatest risk of TLS are those with high tumor 
burden prior to treatment. These patients should be monitored closely and appropriate precautions 
should be taken. 
General guidelines for the management of TLS are provided in Table 11.  
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Table 11 - Management of tumor lysis syndrome  
TLS diagnosis 
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 
• 
Phosphorus >4.5 mg/dL (>1.5 mmol/L) 
• 
Corrected calcium <7.0 mg/dL (<1.75 mmol/L), ionized 
calcium <1.12 mg/dL (<0.3mmol/L)a 
Omit study treatment until all serum chemistries have 
resolved.  
Ensure normal hydration, correct laboratory abnormalities, 
fluid overload, 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, 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 
TLS: tumor lysis syndrome. 
a The corrected calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter + 0.8 x (4-albumin in grams per 
deciliter). 
10.7 
ADVERSE EVENTS MONITORING  
All AEs will be managed and reported in compliance with all applicable regulations, and included 
in the final clinical study report.  
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11 
STATISTICAL CONSIDERATIONS  
The statistical considerations presented in this section forms the basis for the Statistical Analysis 
Plan (SAP), which will provide accurate definitions and detailed specifications for the analyses to 
be performed on the data collected from this study. A final SAP will be issued prior to first patient 
treated. 
11.1 
DETERMINATION OF SAMPLE SIZE  
The sample size calculation is based on the primary efficacy endpoint (ie, PFS). The following 
assumptions were used: 
• PFS has an exponential distribution in both treatment groups. 
• Pd arm has a median PFS of 4.0 months.  
• IPd arm will have 40% risk reduction in hazard rate in comparison to Pd arm. The targeted 
hazard ratio is 0.60, which corresponds to an improvement in the true median progression 
free survival time from 4 months to 6.67 months. 
• A log-rank test at a one-sided 2.5% significance level. 
Based on the above assumptions, a total of 162 PFS events are needed to achieve a 90% power for 
the study. 
Objective for OS also support the sample size calculation using the following assumptions: 
• OS has an exponential distribution in both treatment groups. 
• Pd arm has a median OS of 13.0 months. 
• IPd will have 31.5% risk reduction in hazard rate in comparison to Pd arm. The targeted 
hazard ratio is 0.685 and this is expected to correspond to a difference of 6 months in 
median OS between the control arm and the experimental arm. 
• A log-rank test at a one-sided 2.5% significance level. 
• An interim analysis for efficacy assessment on OS is planned at the time of primary 
analysis on PFS which is estimated to occur when about 36% of the OS events will be 
observed and a second interim analysis is planned when approximately 90% of the OS 
events have occurred. An O’Brien and Fleming α-spending function will be used to obtain 
the nominal significance levels for the interim and final analyses of survival (see 
Section 11.5). 
Based on the above assumptions, a total of 220 deaths are needed to achieve 79.3% power for the 
study. 
A maximum of 300 patients (150 in each arm) would be adequate to achieve the targeted number 
of events for both PFS and OS. After the PFS analysis, no more patients will be randomized and 
OS analysis will be performed on the number of patient already randomized. 
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Assuming a uniform accrual rate of 15 patients per month, cut-off dates for primary analyses of 
PFS and final OS analysis will be approximately 18 and 51 months after first patient in (FPI) 
respectively. 
PFS, ORR and OS will be tested according to a closed test procedure according this order. Please 
refer to Section 11.4.2.3 for further details on the closed test procedure. 
11.2 
DISPOSITION OF PATIENTS  
Screened patients are defined as any patients who signed the study informed consent.  
Randomized patients will consist of all patients who have been allocated a randomization number 
by the IRT, regardless of whether the patient was treated or not. 
Patients treated without being randomized will not be considered as randomized and will not be 
included in any analysis population. The safety experience of such patients will be reported 
separately. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
The number of screened patients as well as the number and percentage of patients included in the 
analysis populations defined in Section 11.3 will be provided.  
Reasons for treatment discontinuation will be summarized using the safety population. 
11.3 
ANALYSIS POPULATIONS  
11.3.1 Efficacy populations  
11.3.1.1 Intent-to-treat population  
The Intent-to-treat (ITT) population will include all patients who have given their informed 
consent and for whom there is confirmation of successful allocation of a randomization number 
by the IRT. Patients will be included in a treatment arm as randomized, regardless of whether 
patients receive any study treatment or receive a different study treatment from which they were 
randomized.  
This population is the primary population for all efficacy parameters. 
11.3.2 Safety population  
The safety population will include ITT patients who receive at least one dose or a part of a dose of 
the study treatments.  
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This population is the primary population for the analysis of all safety parameters. All analyses 
using this population will be based on the treatment actually received. For instance, patients who 
receive at least 1 isatuximab dose (even incomplete) during the trial, will be allocated to the IPd 
arm. 
11.3.3 Pharmacokinetic population  
The PK population will include patients from the safety population who receive at least 1 dose of 
Isatuximab, even if incomplete, with data for at least 1 PK parameter available. 
11.3.4 ADA population  
The ADA population will include patients with at least one sample taken post-baseline after drug 
administration during the treatment or follow-up observation period that is appropriate for ADA 
testing with a reportable result. 
11.3.5 Patient reported outcome population  
The PRO population will comprise patients from the safety population who have also completed 
the baseline and at least 1 post baseline assessment for each of the 3 selected PRO/HRQL and 
health utility instruments (EORTC QLQ-C30, MY20 and EQ-5D-5L). 
11.4 
STATISTICAL METHODS  
A list of study endpoints and their definitions are provided in Section 9. 
Continuous data will be summarized for each treatment group using number of available 
observations, mean, standard deviation, median, minimum, and maximum. Categorical and 
ordinal data will be summarized using number and percentage of patients. 
The analysis cut-off date for the primary analysis of PFS is the date when the 162 events have 
been observed. This is estimated to be approximately 18 months after FPI. 
The cut-off date for the final analysis of OS is the date when approximately 220 events have been 
observed. This is estimated to be approximately 51 months after FPI. 
11.4.1 Extent of study treatment exposure and compliance  
The following variables will be described to summarize the overall study treatment exposure (all 
study treatments together): 
• Overall number of cycles started. 
• Overall duration of exposure in weeks defined as [(Last day of last cycle - first day of 
first cycle) / 7]. 
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The last day of last cycle is defined as the last date among the following: 
IPd arm: 
- 
Date of last dose of isatuximab +7 days if last cycle is Cycle 1 or date of last dose of 
isatuximab + 14 days if last cycle is Cycle 2 or later, 
- 
Min(date of last dose of pomalidomide +8 days, date of death), 
- 
Date of last dose of dexamethasone +7 days. 
Pd arm: 
- 
Min(date of last dose of pomalidomide + 8 days, date of death), 
- 
Date of last dose of dexamethasone + 7 days. 
The first day of first cycle is defined as the date of first dose of study treatment at Cycle 1. 
In addition, the following variables will be summarized with descriptive statistics for each IMP 
(ie, isatuximab, pomalidomide and dexamethasone): 
• Number of cycles started with each drug. 
• Duration of exposure of each drug in weeks, defined as. 
- 
For isatuximab: [date of last dose of isatuximab + 7 days - first dose of isatuximab] / 7 
if last cycle is Cycle 1 or [date of last dose of isatuximab + 14 days - first dose of 
isatuximab] / 7 if last cycle is Cycle 2 or later, 
- 
For pomalidomide: [Min(date of last dose of pomalidomide + 8 days, date of 
death) - first dose of pomalidomide] / 7, 
- 
For dexamethasone: [date of last dose of dexamethasone + 7 days - first dose of 
dexamethasone] / 7. 
• Isatuximab: number of infusions. 
• Cumulative dose (in mg) for each compound: The cumulative dose at is the sum of all 
doses administered from first to last dose. 
• Actual dose intensity (ADI): defined as the cumulative dose divided by the duration of 
exposure. 
• Relative dose intensity (RDI): defined as the ratio of the actual dose intensity to the 
planned dose intensity. The RDI is an indicator of the feasibility of the chosen schedule of 
administration. 
• Dose reduction of pomalidomide or dexamethasone: 
- 
Reduction of the administered dose for cycle number n+1, Day 1, compared to 
Cycle n, Day 1, 
- 
A dose is deemed to have been reduced if the dose level a patient receives differs from 
the previous actual dose level. 
• Cycle delays: A cycle is deemed to have been delayed if the start date is >3 days beyond 
the scheduled Day 1. 
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• Isatuximab infusion delays (within cycle): a dose is deemed to have been delayed if the 
study treatment is ≥2 days beyond the theoretical day of treatment for weekly dose, and 
≥3 days beyond the theoretical day of treatment for Q2W schedule of administration. 
• Isatuximab infusion interruption: administration of isatuximab treatment was temporarily 
stopped during the infusion. Dose interruptions are not applicable for dexamethasone 
when given orally or pomalidomide since they are orally administered. 
• Dose omission (isatuximab infusion or pomalidomide dose or dexamethasone dose). 
Partially administered cycle: Cycle with at least one isatuximab/pomalidomide 
dexamethasone dose omitted. 
11.4.2 Analyses of efficacy endpoints  
11.4.2.1 Analysis of primary efficacy endpoint(s)  
The primary analysis of PFS will be based on the following censoring rules: If progression and 
death are not observed before the analysis cut-off date, PFS will be censored at the earliest of 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. 
Primary analysis will consist of PFS comparison between IPd group versus Pd group through 
a 1-sided log-rank test procedure stratified by stratification factors as entered in the IRT (ie, age 
and number of previous lines of therapy).  
This analysis will be performed on the ITT population.  
Response will be determined according to IMWG criteria (1). The date of disease progression is 
the date of the first documented (and further confirmed) progression according to IMWG criteria 
as assessed by IRC. For patients without measurable M protein on Cycle 1 D1 efficacy laboratory 
results, progression and date of progression will be assessed by IRC according to criteria defined 
in Appendix D. 
A patient without an event (death or disease progression) and without any valid post-baseline 
disease assessments will be censored at the day of randomization (Day 1).  
The cut-off date for the analysis of PFS is expected to be the date when the 162nd event (first 
occurrence of either disease progression or death due to any cause) has been observed.  
The estimates of the hazard ratio and corresponding 95% confidence interval will be provided 
using a Cox proportional hazard model stratified by the same stratification factors as those used 
for the log-rank test described above. The survival curves will be estimated using Kaplan-Meier 
estimates. At the time of PFS final analysis, critical value for the logrank test on PFS hazard rate 
would be 0.734. 
Sensitivity analyses of PFS will be performed (eg, different censoring rules and PFS assessed by 
the Investigator). 
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11.4.2.2 Analyses of secondary efficacy endpoints  
11.4.2.2.1 Analysis of key secondary efficacy endpoints  
The key secondary efficacy endpoints are ORR and OS.  
Best overall response, ORR and clinical benefit rate will be summarized using the ITT population 
with descriptive statistics at the time of the primary analysis on PFS (based on data collected up to 
the PFS analysis cut-off date). Confidence intervals will be computed using the Clopper-Pearson 
method. ORR will be compared between treatment groups using Cochran Mantel Haenszel 
stratified method.  
The analysis on key secondary endpoint will also consist of OS comparison between the IPd 
group versus the Pd group through a 1-sided log-rank test procedure. Patients without death prior 
to the analysis cut-off date will be censored at the last date the patient was known to be alive or 
the cut-off date, whichever is earlier. This analysis will be performed on the ITT population at the 
time of the primary analysis on PFS (at about 36% information fraction), at the time when 
approximately 90% of OS events have occurred, and at the end of the study (final analysis on 
OS). An O’Brien and Fleming α-spending function will be used to obtain the nominal significance 
levels for the interim and final analyses of survival. The nominal significance (one-sided) level for 
the final survival comparisons would be of 0.0200 for 220 death events (corresponding to a HR of 
0.758). 
If death is not observed before the analysis data cut-off date, data on OS will be censored at the 
date patient is known to be alive or at the cut-off date, whichever comes first. 
11.4.2.2.2 Analysis of other secondary efficacy endpoints  
Other secondary efficacy endpoints include: TTP, PFS in the high risk cytogenetic population, 
and DOR. These time-to-event endpoints will be analyzed at the time of the primary analysis on 
PFS using Kaplan-Meier methods. Among patients who achieve a CR, the number of patients 
without MRD will be provided. 
Similarly to the primary analysis of PFS, if progression and deaths (excluding TTP) are not 
observed before the analysis data cut-off date, TTP, PFS in the high risk cytogenetic population, 
and DOR will be censored at the date of the last valid disease assessment not showing disease 
progression performed prior to initiation of further anti-myeloma treatment (if any) or the data 
cut-off date, whichever comes first. The DOR will not be calculated for patients that do not 
achieve a response.  
Analysis of the prespecified secondary endpoints will be descriptive only. Any testing procedure 
carried out on these endpoints will be considered as exploratory. 
11.4.2.3 Multiplicity considerations  
Hypothesis testing of the key secondary efficacy endpoints will be carried out. A closed test 
procedure will be used to control the Type I error rate meaning that not further testing will be 
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performed unless the significance level had been reached on PFS. The hierarchical procedure will 
be then carried out at the one-sided 2.5% significance level in the following order: 
• ORR at the time of the primary analysis on PFS (first cut-off date). 
• OS tested at the time of the primary analysis on PFS (at about 36% information), at the 
time when approximately 90% of OS events have occurred, and at the end of the study 
(final analysis on OS). 
11.4.3 Analyses of safety data  
The summary of safety results will be presented by actual treatment group. Analysis of TEAEs 
and laboratory data, vital signs will be descriptive and conducted on the safety population. 
Summary of safety data will also be performed by patient. For each of the safety parameters, a 
baseline value will be defined as the last value or measurement taken up to the first dose in the 
study.  
11.4.3.1 Adverse events  
Adverse events will be collected from informed consent is signed until the EOT (at least 30 days 
after last dose of study treatment). 
Adverse events will be graded according NCI-CTCAE v4.03 (Appendix C) and classified by 
system organ class (SOC)/preferred term (PT) according the last available version of the 
MedDRA dictionary. 
The observation period will be divided into 3 segments: screening, TEAE and post-treatment: 
• The screening period is defined as the time informed consent is signed until the first dose 
of study treatments administration. 
• The TEAE observation period is defined as the time from the first dose of study treatments 
up to 30 days after last dose of study treatments. 
• The post-treatment period is defined as the time starting 31 days after the last dose of 
study treatments to study closure or death, whichever comes first. 
Pre-treatment AEs are defined as any AE during the screening period. 
Treatment-emergent AEs are defined as AEs that develop, worsen (according to the Investigator 
opinion), or become serious during the TEAE period. 
Post-treatment AEs are defined as AEs that occur during the post-treatment period. 
The severity grade will be taken into account in the summary. For patients with multiple 
occurrences of the same PT, the maximum grade will be used. 
The primary focus of AE reporting will be on TEAEs. Pre-treatment and post-treatment AEs will 
be described separately. 
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Similar analysis will be presented for SAEs and AEs that cause dose modification (reduction 
and/or delay, interruption) and treatment discontinuation. 
11.4.3.2 Treatment-emergent adverse events  
An overall summary of TEAEs will be provided. The number and percentage of patients who 
experience any of the following will be provided: 
• TEAEs 
• TEAEs of ≥ Grade 3 
• Grade 5 TEAE (any TEAE with a fatal outcome during the treatment period) 
• Serious TEAEs 
• Serious treatment-related TEAEs 
• TEAE leading to permanent (full study treatment) discontinuation/premature (partial study 
treatment) discontinuation 
• AESIs: IARs of ≥ Grade 3, pregnancy, overdose reports, and second primary malignancies 
• IARs of all severity grade and by grade 
• Treatment-related TEAEs 
• Treatment-related TEAEs of ≥ Grade 3 
The number and percentage of patients experiencing TEAEs by primary SOC and PT will be 
summarized by NCI CTCAE grade (all grades and ≥ Grade 3). Similar tables will be prepared for 
treatment related TEAEs, AESIs, TEAEs leading to permanent/premature discontinuation, TEAEs 
leading to dose modification, serious TEAEs, TEAEs with fatal outcome and AEs/SAEs occurring 
during the post-treatment dosing period.  
Sorting within tables should ensure the same presentation for the set of all AEs within the 
observation period (screening, TEAE and post-treatment). For that purpose, the table of all 
TEAEs will be presented by SOC and PT sorted by internationally agreed order unless otherwise 
specified. 
11.4.3.3 Deaths  
The following death summaries will be generated: 
• Number (%) of patients who died by study period (TEAE and post-treatment) and reasons 
for death summarized on the safety population by treatment received. 
• Deaths in non-randomized patients or, randomized and not treated patients. 
• TEAEs with fatal outcome (on the AE eCRF page as reported by the Investigator), and 
related TEAEs with fatal outcome summarized by primary SOC and PT. 
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• TEAE with fatal outcome summarized by primary system organ class (SOC), high level 
general term (HLGT), high level term (HLT) and preferred term (PT) sorted by 
internationally agreed order of SOC and alphabetic order of HLGT, HLT, and PT. 
11.4.3.4 Other safety evaluations  
Laboratory data 
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. Complete blood count and serum 
chemistry results will be graded according to NCI-CTCAE Version 4.03, when applicable. For 
patients with multiple occurrences of the same laboratory variable during the TEAE period, the 
maximum grade (worst) per patient will be used. The denominator used for percentage calculation 
is the number of patients with at least 1 evaluation of the laboratory test during the considered 
observation period. 
The number and proportion of patients with abnormal laboratory tests at baseline (ie, last 
assessment before the first dose of study treatments administration) will be presented for 
≥ Grade 3, all grades together and Grade 3 and Grade 4 separately. Similar tables showing 
abnormalities during the TEAE period will be provided. 
When the NCI-CTCAE V4.03 scale is not applicable, the number of patients with a laboratory 
abnormality out-of-normal laboratory range value will be displayed. 
Vital signs 
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 incidence of PCSAs prior to study treatment administration at any cycle 
during the TEAE period (on-treatment PCSAs) 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 PCSA during and after study treatment administration at any cycle during the 
TEAE period in the IPd arm will also be summarized. 
Other evaluations 
Cytokines (TNF-α, IL-1-β, IL-4, IL-6, IFN-γ), markers of complement activation (C3a, C4, 
CH50), serum tryptase will be summarized with descriptive statistics.  
Number (%) of patients with second primary malignancies will be summarized. 
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11.4.4 Analyses of pharmacokinetic and pharmacodynamic variables  
11.4.4.1 Analysis of pharmacokinetic variables  
The population PK of isatuximab will be characterized in the population of patients in the 
experimental arm, using a nonlinear mixed effect modeling approach. Both rich and sparse 
sampling pharmacokinetic data available from Phase 1, 2 and 3 studies will be used for the 
analysis. Additional details of the analysis plan and the results will be provided in a separate 
document. The population estimates from this analysis will provide a prior distribution from 
which individual Bayesian estimates of the PK parameters for each patient in this study will be 
derived. 
Pharmacokinetic parameters of isatuximab will be summarized by descriptive statistics (such as 
mean, geometric mean, median, SD, SEM, CV, minimum, and maximum). 
11.4.5 Analyses of immunogenicity  
The immunogenicity for isatuximab will be assessed by summarizing the number of evaluable 
patients, the percentage of ADA positive patients (either treatment induced, or those with 
increased titers during treatment), and the percentage of ADA negative patients.  
ADA prevalence (proportion of patients tested positive at any point in time) and ADA incidence 
(proportion of patients seroconverted - treatment induced ADAs - or having increased titers 
during the study) will be calculated. 
In addition, ADA titers will be summarized by descriptive statistics and time of measurement. 
The impact of positive immune response will be evaluated on efficacy, PK and safety endpoints.  
11.4.6 Analyses of patient reported outcomes (HRQL/health economics) variables  
Change from baseline for the following variables from EORTC QLQ-C30: global HRQL, 
five functional scales (physical, emotional, cognitive, role and social) and nine symptom domains 
(fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and 
financial difficulties); for the MY-20: future perspective, body image, disease symptoms and side 
effects of treatment; and for the EQ-5D-5L: health state utility value and VAS scores will be 
analyzed with an MMRM approach. Descriptive statistics including number of patients, mean and 
standard error will be provided. In addition, LS means, difference in LS means, the corresponding 
95% CI’s and the p-values will be provided for comparison between treatment arms. 
Responder analyses will also be conducted using established MIDs (to be described in SAP) for 
each of the above variables. 
Each of the following criteria will be assessed via a comparison of change scores from baseline to 
EOT and 60 days after last study treatment administration between treatment arms: 
A) Disease-specific HRQL (EORTC QLQ-C30) 
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B) Disease- and treatment-related symptoms (EORTC QLQ-C30 and MY20) 
C) Health state utility (EQ-5D-5L) 
D) Health status (EQ-5D-5L visual analogue scale). 
In addition, responder analyses will be conducted: 
1. For those who improve. 
2. For those who deteriorate. 
3. For those who stay the same. 
4. Time to definitive improvement, and time to definitive deterioration will be based using 
the CIDs defined in Appendix H, Appendix I, and Appendix J. 
5. Deterioration will be considered definitive if no later improvement above the defined 
thresholds (CIDs defined in Appendix H, Appendix I, and Appendix J) are observed, prior 
to further anticancer therapy. 
6. Improvement will be considered definitive if no later deterioration above the defined 
thresholds (CIDs defined in Appendix H, Appendix I, and Appendix J) are observed, prior 
to further anticancer therapy. 
Full details will be provided in the SAP.  
11.4.7 Other analyse(s)  
The impact of a 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 the SAP. 
11.5 
INTERIM ANALYSIS  
No interim analysis is planned for PFS. However, at the time of final PFS analysis, once 162 PFS 
events have been observed, secondary efficacy data (ORR and OS) will be reviewed (according to 
the outcome of the final analysis of the primary endpoint). An interim analysis on OS could be 
performed at that stage. An additional interim analysis on OS will be performed when 
approximately 90% of events have occurred. 
At the time of final PFS analysis, formal comparisons of PFS, ORR and OS will be made 
according to a closed test procedure at the level of 2.5% one-sided. 
If an improvement in median PFS is demonstrated (according to the PFS final analysis presented 
in Section 11.4.2), the analysis on ORR and interim analysis on OS will be performed. The ORR 
will be tested, at the one sided 2.5%-level. Then, if the improvement in ORR is also significant, 
OS will be tested as a formal comparison that would allow for early stopping for overwhelming 
efficacy.  
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The stopping boundaries for efficacy on OS endpoint will be derived based on the O’Brien and 
Fleming α spending functions and will depend on the actual number of deaths observed at the 
time of the interim analyses.  
At the first interim analysis on OS, in case where exactly 80 deaths are observed, the Sponsor 
could stop the study for overwhelming efficacy if the p-value is ≤0.000184 (corresponding to a 
HR of 0.448). Under current accrual assumptions of 15 patients per month, the 162 PFS events 
milestone (and interim analysis on OS) is estimated to occur at about 18 months after FPI. 
At the second interim analysis on OS, the 1-sided nominal significance level to stop the study for 
efficacy at approximately 90% information fraction (198 OS events) is 0.0181 (corresponding to 
an HR of 0.742). This is estimated to occur at about 43 months after FPI. 
The final analysis of survival will take place after approximately 220 deaths have been observed, 
which is projected to occur approximately 51 months after the first patient is randomized. The 
nominal significance level for the final survival comparisons will be determined by an O’Brien 
and Fleming alpha spending function. It would be of 0.0200 for 220 events (corresponding to a 
HR of 0.758). 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS  
12.1 
ETHICAL AND REGULATORY STANDARDS  
This clinical trial will be conducted by the Sponsor, the Investigator, and delegated Investigator 
staff and Subinvestigator, in accordance with consensus ethics principles derived from 
international ethics guidelines, including the Declaration of Helsinki, and the ICH guidelines for 
Good Clinical Practice (GCP), all applicable laws, rules and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT  
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the ethics committee (IRB/IEC). All participants should be informed to the fullest 
extent possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written ICF should be signed, name filled 
in and personally dated by the patient or by the patient’s legally acceptable representative, and by 
the person who conducted the informed consent discussion. A copy of the signed and dated 
written ICF will be provided to the patient.  
Prior to collection of blood for pharmacogenetics, the optional pharmacogenetic ICF (written) 
should be signed, name filled in, and personally dated by the patient or by the patient’s legally 
acceptable representative, and by the person who conducted the informed consent discussion. A 
copy of the signed and dated written optional ICF will be provided to the patient. 
The ICF and the optional pharmacogenetic ICF used by the Investigator for obtaining the patient's 
informed consent must be reviewed and approved by the Sponsor prior to submission to the 
appropriate ethics committee (IRB/IEC) for approval/favorable opinion. 
Participants who can read the consent form will do so before writing their name and dating or 
signing and dating the form. 
Participants who can write but cannot read will have the assent form read to them before writing 
their name on the form. 
Participants who can understand but who can neither write nor read will have the assent form read 
to them in presence of an impartial witness, who will sign and date the assent form to confirm that 
assent was given. 
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The ICF and the assent form used by the Investigator for obtaining the Patient’s Informed Consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics 
committee (IRB/IEC) for approval/favorable opinion. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix O. 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)  
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the health authorities (competent regulatory authority) and the appropriate IRB/IEC, 
and is required to forward to the respective other party a copy of the written and dated 
approval/favorable opinion signed by the chairman with IRB/IEC composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, ICF, Investigator’s Brochure with any addenda or labeling 
documents (summary of product characteristics, package insert) Investigator’s curriculum vitae, 
etc) and the date of the review should be clearly stated on the written (IRB/IEC) 
approval/favorable opinion. 
The IMP will not be released at the study site and the Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC should be informed as soon as possible. They should also 
be informed of any event likely to affect the safety of patients or the continued conduct of the 
clinical trial, in particular any change in safety. All updates to the Investigator’s Brochure or 
labeling information, will be sent to the IRB/IEC and to health authorities (competent regulatory 
authority), as required by local regulation. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING  
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S)  
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR  
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the eCRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data source document requirements. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in separate study documents. 
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According to the ICH GCP, the monitoring team must check the eCRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF. The ICF will 
include a statement by which the patient allows the Sponsor’s duly authorized personnel, the 
ethics committee (IRB/IEC), and the regulatory authorities to have direct access to original 
medical records which support the data on the CRFs (eg, patient's medical file, appointment 
books, original laboratory records, etc). These personnel, bound by professional secrecy, must 
maintain the confidentiality of all personal identity or personal medical information (according to 
confidentiality and personal data protection rules). 
13.3 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST  
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All CRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the eCRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the eCRF. 
13.4 
USE OF COMPUTERIZED SYSTEMS  
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
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14 
ADDITIONAL REQUIREMENTS  
14.1 
CURRICULUM VITAE  
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES  
The Investigator must maintain the confidentiality of all study documentation, and take measures 
to prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents for at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that 
a longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to 
a mutually agreed upon designee.  
14.3 
CONFIDENTIALITY  
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator's Brochure and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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14.4 
PROPERTY RIGHTS  
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff/Subinvestigator not to 
mention any information or the product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION  
• The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
• The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
Patient race or ethnicity (including “Caucasian/white, Black, Asian/Oriental”) will be collected in 
this study because these data are required by several regulatory authorities (eg, on Afro-American 
population for the Food and Drug Administration, on the Japanese population for the 
Pharmaceuticals and Medical Devices Agency in Japan, or on the Chinese population for the 
China Food and Drug Administration in China). 
The data collected in this study will only be used for the purpose(s) of the study and to document 
the evaluation of the benefit/risk ratio, efficacy, and safety of the product(s). Data may be further 
processed if they have been anonymized. 
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14.6 
INSURANCE COMPENSATION  
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES  
For the purpose of ensuring compliance with the clinical trial protocol, GCP, and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, it being understood that these personnel are bound by professional secrecy, 
and as such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in the inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor for corrective actions for 
all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE  
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• The information on the product leads to doubt as to the benefit/risk ratio. 
• Patient enrollment is unsatisfactory. 
• The Investigator has received from the Sponsor all IMP, means, and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon. 
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• Noncompliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP. 
• The total number of patients are included earlier than expected. 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
14.8.2 By the Investigator  
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements (see Appendix M). 
14.9 
CLINICAL TRIAL RESULTS  
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS  
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS  
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the ICF. The Investigator must receive 
an IRB/IEC approval/favorable opinion concerning the revised ICF prior to implementation of the 
change and patient signature should be re-collected if necessary. 
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16 
BIBLIOGRAPHIC REFERENCES  
1. 
Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International 
Myeloma Working Group consensus criteria for response and minimal residual disease 
assessment in multiple myeloma. Lancet Oncol 2016;17(8):e328-46. 
2. 
Reinherz EL, Kung PC, Goldstein G, Levey RH, Schlossman SF. Discrete stages of human 
intrathymic differentiation: analysis of normal thymocytes and leukemic lymphoblasts of T-
cell lineage. Proc Natl Acad Sci U S A. 1980;77(3):1588-92. 
3. 
Campana D, Suzuki T, Todisco E, Kitanaka A. CD38 in Hematopoiesis. Chem Immunol. 
2000;75:169-88. 
4. 
Howard M, Grimaldi JC, Bazan JF, Lund FE, Santos-Argumedo L, Parkhouse RM, et al. 
Formation and hydrolysis of cyclic ADP-ribose catalyzed by lymphocyte antigen CD38. 
Science. 1993;262(5136):1056-9. 
5. 
Dimopoulos MA, Leleu X, Palumbo A, Moreau P, et al. Expert panel consensus statement 
on the optimal use of pomalidomide in relapsed and refractory multiple myeloma. 
Leukemia. 2014;28:1573-85. 
6. 
Goldmacher VS, Bourret LA, Levine BA, Rasmussen RA, Pourshadi M, Lambert JM, et al. 
Anti-CD38-blocked ricin: an immunotoxin for the treatment of multiple myeloma. Blood. 
1994;84(9):3017-25. 
7. 
Lin P, Owens R, Tricot G, Wilson CS. Flow cytometric immunophenotypic analysis of 306 
cases of multiple myeloma. Am J Clin Pathol. 2004;121(4):482-8. 
8. 
Rollig C, Knop S, Bornhäuserr M. Multiple Myeloma. Lancet. 2015;385(9983):2197-208. 
9. 
Palumbo A, Rajkumar SV, San Miguel JF, Larocca A, Niesvizky R, Morgan G, et al. 
International Myeloma Working Group Consensus Statement for the management, treatment 
and supportive care of patients with myeloma not eligible for standard autologous stem-cell 
transplantation. J Clin Oncol. 2014;32(6):587-600. 
10. Terpos E, Rahemtulla A, Dimopoulos MA. Current treatment options for myeloma. Expert 
Opin Pharmacother. 2005;6(7):1127-42. 
11. Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahliset NJ, et al. Phase II study of 
daratumumab (DARA) monotherapy in patients with 3 lines of prior therapy or double 
refractory multiple myeloma (MM): 54767414MMY2002 (Sirius). J Clin Oncol. 
2015;33(18):LBA8512. 
12. Bedard G, Zeng L, Zhang L, Lauzon N, Holden L, Tsao M, et al. Minimal important 
differences in the EORTC QLQ-C30 in patients with advanced cancer. Asia Pac J Clin 
Oncol. 2014;10:109-17. 
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13. Ocio EM, Mitsiades CS, Orlowski RZ, Anderson KC. Future agents and treatment directions 
in multiple myeloma. Expert Rev Hematol. 2014;7(1):127-41. 
14. Jiang H, Acharya C, An G, Zhong M, Feng X, Wang L, et al. SAR650984 directly induces 
multiple myeloma cell death via lysosomal-associated and apoptotic pathways; which is 
further enhanced by pomalidomide. Leukenia. 2016;30:399-408. 
15. San Miguel J, Weisel K, Moreau P, Lacy M, Song K, Delforge M, et al. Pomalidomide plus 
low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed 
and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet 
Oncol. 2013;14:1055-66. 
16. Dimopoulos MA, Leleu X, Palumbo A, Moreau P, Delforge M, Cavo M, et al. Expert panel 
consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple 
myeloma. Leukemia. 2014;28:1573-85. 
17. Aaronson NK, Bullinger M, Ahmedzai S. A modular approach to quality-of-life assessment 
in cancer clinical trials. Recent Results Cancer Res. 1988;111:231-49. 
18. Aaronson NK, Ahmedzai S, Bullinger M, Crabeels D, Estape J, Filiberti AN, et al. The 
EORTC Core Quality of Life Questionnaire: Interim Results of an International Field Study. 
In: OSOBA D, editor. Effect of Cancer on Quality of Life. Vancouver. 1991:185-202. 
19. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The Europena 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life 
instrumentfor use in international clinical trials in oncology. J Natl Cancer Inst. 
1993;85(5):365-76. 
20. EORTC QLQ-C30 Scoring Manual (3rd edition). Fayers PM, Aaronson NK, Bjordal K, 
Groenvold M, Curran D, Bottomley A. On behalf of the EORTC Quality of Life Group. 
Brussels: EORTC. 2001.  
21. Stead ML, Brown JM, Velikova G, Kaasa S, Wisløff F, Child JA, et al. Development of an 
EORTC questionnaire module to be used in health-related quality-of-life assessment for 
patients with multiple myeloma. European Organization for Research and Treatment of 
Cancer Study Group on Quality of Life. Br J Haematol. 1999;104(3):605-11. 
22. Graham L, Phillips A, Stead M, Velikova G, Brown J; EORTC Quality of Life Group. An 
international field study of the reliability and validity of a disease-specific questionnaire 
module (the QLQ-MY20) in assessing the quality of life of patients with multiple myeloma. 
Eur J Cancer. 2007;43(11):1670-8. 
23. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5:649-55. 
24. Rajkumar VS, Richardson P, San Miguel F. Guidelines for the determination of the number 
of prior lines of therapy in multiple myeloma. Blood. 2015;127(7):921-2. 
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25. Rajkumar SV, Harousseau J-L, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. 
Consensus recommendations for the uniform reporting of clinical trials: report of the 
International Myeloma Workshop Consensus Panel 1. Blood. 2011;117(18):4691-5. 
26. Fonseca R, Abouzaid S, Bonafede M, Cai Q, Parikh K, Cosler L, et al. Trends in overall 
survival and costs of multiple myeloma, 2000-2014. Leukemia. 2017;31(9):1915-21. 
27. Kristinsson SY, Landgren O, Dickman PW, Derolf AR, Björkholm M. Patterns of survival 
in multiple myeloma: a population-based study of patients diagnosed in Sweden from 1973 
to 2003. J Clin Oncol. 2007;25(15):1993-9. 
28. Mateos MV, Cavo M, Blade J, Dimopoulos MA, Suzuki K, Jakubowiak A, et al. Overall 
survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed 
multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 
2020;395(10218):132-41.  
 
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17 
APPENDICES  
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Appendix A 
Modification of Diet in Renal Disease (MDRD) equation  
GFR (mL/min/1.73 m2) =  
175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if Female) x (1.212 if African-American) 
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Appendix B 
Eastern Cooperative Oncology Group Performance Status scale  
 
Performance 
Status 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more 
than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
Developed by the Eastern Cooperative Oncology Group, Robert L. Comis, MD, Group Chair (23) 
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Appendix C 
National Cancer Institute Common Terminology Criteria for Adverse 
Events  
Refer to NCI CTCAE v4.03 in the Study Reference Manual, or online at the following NCI 
website:  
http://ctep.cancer.gov/reporting/ctc.html 
Toxicity grade should reflect the most severe degree occurring during the evaluated period, not an 
average. 
When 2 criteria are available for similar toxicities, the one resulting in the more severe grade 
should be used. 
The evaluator must attempt to discriminate between disease/treatment and related 
signs/symptoms. 
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Appendix D 
IMWG Response Criteria  
Disease response will be assessed using the updated International Myeloma Working Group 
Response Criteria (IMWG) (1). A confirmation assessment for disease response within 4 weeks is 
required in this protocol (either MR or better, or PD). 
As a reminder, patients with measurable FLC only at screening are not eligible in the study. 
M protein value on Cycle 1 day 1 will be taken as baseline value for response assessment. 
PD cannot not be diagnosed on serum FLC increase only, even in patients for whom serum 
and urine M-protein become below level of eligibility on efficacy laboratory performed on 
Cycle 1 Day 1 (see below the table for assessment of overall response and progression diagnosis 
of these patients). 
Adapted from updated International Myeloma Working Group Response Criteria 
IMWG MRD criteria (requires 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 and 
• 
<5% plasma cells in bone marrow aspirates. 
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 
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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. 
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 
• 
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 
Two consecutive assessments are needed. 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)  
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.  
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. 
Patients with disease only measurable by FLC are not allowed. 
A plasmacytoma that has been irradiated is not suitable for response assessment; however, it must 
be monitored to assess for progressive disease. 
For patients achieving very good partial response by other criteria, a soft tissue plasmacytoma 
must decrease by more than 90% in the sum of the maximal perpendicular diameter (SPD) 
compared with baseline. 
For IgA and IgD myeloma, quantitative immunoglobulin measurements are preferred for disease 
assessments; the same percentage changes apply for serum M-spike (see above table).  
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 
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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 partial response or minor response if baseline 
urine M-protein was not measurable; however, it is still required for complete response 
and very good partial response. 
• Documentation of response requires two consecutive readings of the applicable disease 
parameter (serum M-protein, urine M-protein), performed at any time (no minimum 
interval is required, it can be done the same day); however, to confirm response or 
progressive disease, two discrete samples are required; testing cannot be based upon the 
splitting of a single sample. 
• Patients will continue in the last confirmed response category until there is confirmation of 
progression or improvement to a higher response status; patients cannot move to a lower 
response category. 
• Percent decreases for response calculations are from baseline values (Cycle 1, Day 1). 
• Percent increases for progression calculations are from lowest response values or baseline 
values, whichever is the smaller number. The lowest value does not need to be confirmed. 
• The lowest confirmed value before suspected progression will be used as baseline for 
calculation of progression; if a serum and/or urine spike is considered too low to 
quantitate, this value can be assigned as zero as a baseline for documentation of 
subsequent progressive disease. Patients will be considered to have progressive disease if 
they meet the criteria for progression by a variable that was not considered measurable at 
baseline; however, for patients who had a measurable serum or urine M-spike at baseline, 
progression cannot be defined by increases in serum FLC alone. 
• Radiographic and bone marrow assessments do not need to be confirmed. 
Patients with serum and urine M-Protein below level of eligibility on efficacy laboratory 
performed on Cycle 1 Day 1 (eg, patients with only FLC measurable disease according to 
IMWG, M-protein value >0 [or IFX positive] and <0.5 g/dL): 
• Patients with M-protein (urine and/or serum) below the level of measurability (M-protein 
value >0 [or IFX positive] and <0.5 g/dL) can have CR, non-PD or PD responses only 
according to the increase or decrease of M protein or extramedullary disease if applicable, 
following the IMWG criteria. 
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• Patients with FLC measurable disease only only (M-protein =0 and IFX negative), can 
have either non-PD or PD responses (PD will be an absolute increase of >10 mg/dL in the 
difference between involved and uninvolved FLC). 
• Patients with serum M-protein value >0 g/dL (or serum IFX positive) and <0.5 g/dL, 
independently of FLC can only be qualified as: CR, non-PD, or PD 
AND/OR 
• Patients with urine M-protein value >0 mg/24 h (or urine IFX positive) and <200 mg/24 h, 
independently of FLC can only be qualified as: CR, non-PD, or PD 
OR 
• Patients with serum M-protein value =0 g/dL and serum IFX for intact Ig negative and 
urine M-protein =0 mg/24 h and urine IFX negative, independently of FLC can only be 
qualified as: non-PD or PD 
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Appendix E 
Guidelines for the determination of the number of prior lines of 
therapy in Multiple Myeloma  
Line of Therapy 
A line of therapy consists of ≥1 complete cycle of a single agent, a regimen consisting of 
a combination of several drugs, or a planned sequential therapy of various regimens  
(eg, 3-6 cycles of initial therapy with bortezomib-dexamethasone followed by stem cell 
transplantation consolidation, and lenalidomide maintenance is considered 1 line). 
New line of Therapy 
A treatment is considered a new line of therapy if any 1 of the following 3 conditions are met: 
1. Start of a new line of treatment after discontinuation of a previous line. If a treatment 
regimen is discontinued for any reason and a different regimen is started, it should be 
considered a new line of therapy. A regimen is considered to have been discontinued if all 
the drugs in that given regimen have been stopped. A regimen is not considered to have 
been discontinued if some of the drugs of the regimen, but not all, have been discontinued. 
The reasons for discontinuation, addition, substitution, or SCT do not influence how lines 
are counted. It is recognized that reasons for change may include end of planned therapy, 
toxicity, progression, lack of response, inadequate response. 
2. The unplanned addition or substitution of 1 or more drugs in an existing regimen. 
Unplanned addition of a new drug or switching to a different drug (or combination of 
drugs) due to any reason is considered a new line of therapy. 
3. Stem cell transplantation (SCT): In patients undergoing >1 SCT, except in the case of a 
planned tandem SCT with a predefined interval (such as 3 months), each SCT (autologous 
or allogeneic) should be considered a new line of therapy regardless of whether the 
conditioning regimen used is the same or different. It is recommend that data on type of 
SCT also be captured. 
Planned tandem SCT is considered 1 line. Planned induction and/or consolidation, 
maintenance with any SCT (frontline, relapse, autologous or allogeneic) is considered 
1 line. 
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Interruptions and dose modifications 
• If a regimen is interrupted or discontinued for any reason and the same drug or 
combination is restarted without any other intervening regimen, then it should be counted 
as a single line.  
• However, if a regimen is interrupted or discontinued for any reason, and then restarted at a 
later time point but 1 or more other regimens were administered in between, or the 
regimen is modified through the addition of 1 or more agents, then it should be counted as 
2 lines.  
• Modification of the dosing of the same regimen should not be considered a new line of 
therapy. 
(Based on Rajkumar, Richardson and San Miguel. Guidelines for the determination of the 
number of prior lines of therapy in multiple myeloma. Blood. 2015;126[7]:921-2) (24). 
 
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Appendix F 
Definition of Relapsed and Refractory Myeloma  
Refractory Myeloma: 
Refractory myeloma is defined as disease that is non-responsive (failure to achieve minimal 
response or develops PD while on therapy) while on primary or salvage therapy, or progresses 
within 60 days of last therapy. There are 2 categories of refractory myeloma. 
• Relapsed and refractory myeloma: Relapsed and refractory myeloma is defined as disease 
that is non-responsive while on salvage therapy or progresses within 60 days of last 
therapy in patients who have achieved minimal response or better at some point previously 
to then progressing in their disease course. 
• Primary refractory myeloma: refractory myeloma is defined as disease that is 
non-responsive in patients who have never achieved minimal response or better with any 
therapy. It includes patients who never achieve MR or better in whom there is no 
significant change in M protein and no evidence of clinical progression; as well as primary 
refractory, progressive disease where patients meet criteria for true progressive disease. 
Relapsed myeloma 
Relapsed myeloma is defined as previously treated myeloma which progresses and requires the 
initiation of salvage therapy but does not meet the criteria for either primary refractory myeloma 
or relapsed and refractory myeloma. 
(Adapted from Rajkumar SV, Harousseau J-L, et al. Consensus recommendations for the uniform 
reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. 
Blood. 2011;117[18]:4691-95) (25). 
 
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Appendix G 
Infusion Associated Reactions Observed with Isatuximab  
Main types of infusion associated reactions 
• Anaphylactic reaction 
• Cytokine release syndrome 
• Drug hypersensitivity 
• Infusion related reaction 
Symptoms typically associated with infusion reactions 
• Abdominal pain 
• Apnea 
• Bronchospasm 
• Chest discomfort 
• Chest tightness  
• Chills 
• Cough 
• Dizziness 
• Dysgeusia 
• Dyspnea 
• Feeling hot 
• Flushing 
• Headache 
• Head discomfort 
• Hoarseness  
• Hot flush 
• Hypertensive crisis 
• Hypoxia 
• Influenza like illness  
• Injection site pain 
• Lacrimation increased 
• Laryngospasm 
• Myalgia  
• Nasal congestion 
• Nausea 
• Pruritus 
• Pyrexia 
• Respiratory distress  
• Rhinitis  
• Rhinorrhea 
• Stridor  
• Tachycardia  
• Throat irritation 
• Tracheal stenosis 
• Tremor 
• Urticaria 
• Vision blurred 
• Vomiting 
• Wheezing 
 
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Appendix H 
EORTC-QLQ-C30 scales, items and CIDs  
 
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Scale/subscale/item 
(abbreviation) 
No. Items 
Item Nos 
CIDa 95%CI 
Reference 
1. 
Global health status/HRQL 
(QL 2) 
2 
29 and 30 
Improved ≥7 
Deteriorated ≥-7  
Delforge 2015 
Delforge 2015 
Functional scales 
2. 
Physical functioning (PF) 
5 
1 to 5 
Improved ≥9 
Deteriorated ≥-9  
Dimopoulos 2012 
Delforge 2015 
3. 
Role functioning (RF) 
2 
6 and 7 
Improved ≥15.8 
Deteriorated ≥-13.5  
Bedard 2014 
Bedard 2014 
4. 
Emotional functioning (EF) 
4 
21 to 24 
Improved ≥14.7 
Deteriorated ≥-12.2  
Bedard 2014 
Bedard 2014 
5. 
Cognitive functioning (CF) 
2 
20 and 25 
Improved ≥9.1 
Deteriorated ≥-3  
Bedard 2014 
Bedard 2014 
6. 
Social functioning (CF) 
2 
26 and 27 
Improved ≥5.3 
Deteriorated ≥11.1  
Bedard 2014 
Bedard 2014 
CID: clinically important difference 
RF, EF, CF and SF CIDs from Bedard 2014 while QL2 and PF CIDs from Delforge 2015 
a In addition, CIDs to be empirically derived from dataset using anchor-based methodology (calculate CID using performance status as an 
anchor (if performance status determined to be a reasonable anchor), examine the magnitude of change in the MY-20 patients who changed 
"meaningfully" on performance status. Best to have more than one anchor; and anchor(s) should be at least moderately correlated with the 
MY-20 to be considered useful (Cocks 2007, Revicki 2008, Wright 2012). Calculation of CIDs as mean score changes or by ROC analysis 
suggested that a change in the EORTC QLQ-C30 score in the range of approximately 6–17 is considered important by patients with MM, for 
patients with MM, the CIDs are closer to a medium ES than a small ES. Mean score changes smaller than 6 are unlikely to be important to 
the patients, even if these changes are statistically significant (Kvam 2010) 
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Scale/subscale/item 
(abbreviation) 
No. Items 
Item Nos 
CIDa 95%CI 
Fatigue (FA)  
3 
10, 12,18 
Improved ≥-10 
Deteriorated ≥10  
Nausea and vomiting (NV) 
2 
14, 15 
Improved ≥-10.2 
Deteriorated ≥1.9  
Pain (PA) 
2 
9, 19 
Improved ≥-12 
Deteriorated ≥12 
Dyspnea (DY) 
1 
8 
Improved ≥12.7 
Deteriorated ≥5.6  
Insomnia (SL) 
1 
11 
Improved ≥-3.7 
Deteriorated ≥8.5 
Appetite loss (AP) 
1 
13 
Improved ≥-12.2 
Deteriorated ≥9.7  
Constipation (CO) 
1 
16 
Improved ≥-5.4 
Deteriorated ≥7.1  
Diarrhea (DI) 
1 
17 
Improved ≥3.4 
Deteriorated ≥1.3  
Financial difficulties (FI) 
1 
20 
Improved ≥9.8 
Deteriorated ≥2.7  
CID: clinically important difference 
NV, DY, SL, AP, CO, DI, and FI CIDs from Bedard 2014 while FA and PA CIDs from Delforge 2015 and Dimopoulos 2012 
a In addition, CIDs to be empirically derived from dataset using anchor-based methodology (calculate CID using performance status as an 
anchor (if performance status determined to be a reasonable anchor), examine the magnitude of change in the MY-20 patients who changed 
"meaningfully" on performance status. Best to have more than one anchor; and anchor(s) should be at least moderately correlated with the 
MY-20 to be considered useful (Cocks 2007, Revicki 2008, Wright 2012) Calculation of CIDs as mean score changes or by ROC analysis 
suggested that a change in the EORTC QLQ-C30 score in the range of approximately 6–17 is considered important by patients with MM, for 
patients with MM, the CIDs are closer to a medium ES than a small ES. Mean score changes smaller than 6 are unlikely to be important to 
the patients, even if these changes are statistically significant (Kvam 2010) 
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Appendix I 
MY20 scales, items and CIDs  
 
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Functional scales 
(abbreviations) 
No. Items 
Item Nos 
CIDa 
Future perspective (MYFP) 
3 
18 to 20 
TBD 
Body image (MYBI) 
1 
17 
TBD 
Symptom scales 
(abbreviations) 
 
 
 
Disease symptoms (MYDS) 
6 
1 to 6 
-10b 
Side effects of treatment (MYSE) 
10 
7 to 16 
-6b 
CID: clinically important difference 
a CID to be empirically derived from dataset using anchor-based methodology (calculate CID using performance status as an anchor (if 
performance status determined to be a reasonable anchor), examine the magnitude of change in the MY-20 patients who changed 
"meaningfully" on performance status. Best to have more than one anchor; and anchor(s) should be at least moderately correlated with the 
MY-20 to be considered useful (Cocks 2007, Revicki 2008, Wright 2012). *CID unknown CID will be calculated using performance status 
(PS) (0, 1, or 2 as compared to 3 or 4) as clinical outcome, 
b CID for improvement, Dimopoulos 2012 
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Appendix J 
EQ-5D-5L scales, items and CIDs  
 
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The worst health 
you can imagine 
• We would like to know how good or bad your health is TODAY. 
• This scale is numbered from 0 to 100. 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• Mark an X on the scale to indicate how your health is TODAY. 
• Now, please write the number you marked on the scale in the box 
below. 
 
  
 
YOUR HEALTH TODAY = 
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
 
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No. Items 
Item Nos 
CIDa 
Health status utility index 
 
 
0.07 (Delforge 2015) 
Mobility 
1 
1 
TBD 
Self-care 
1 
2 
TBD 
Usual activities 
1 
3 
TBD 
Pain/discomfort 
1 
4 
TBD 
Anxiety/depression 
1 
5 
TBD 
VAS scale 
 
 
 
Health today 
1 
6 
11 (Picard 2007) 
CID: clinically important difference 
a CID to be empirically derived from dataset using anchor-based methodology (calculate CID using performance status as an anchor (if 
performance status determined to be a reasonable anchor), examine the magnitude of change in the MY-20 patients who changed 
"meaningfully" on performance status. Best to have more than one anchor; and anchor(s) should be at least moderately correlated with the 
MY-20 to be considered useful (Cocks 2007, Revicki 2008, Wright 2012) 
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Appendix L 
Global Pomalidomide Pregnancy Prevention Plan  
 
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Appendix M 
Guidance for notification of early termination of the trial according 
to country applicable regulatory requirements  
Detailed guidance from the European Commission, CT-1 4.2.2- 163 states that in case of early 
termination of the trial, the Sponsor must notify the end of the trial to the national competent 
authority and the Ethics Committee of the Member State concerned immediately, and at the latest 
within 15 days after the trial is halted. This notification should clearly explain the reasons for 
termination and describe follow-up measures, if any, taken for safety reasons.  
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Appendix N 
 Country-specific requirements   
Not applicable. 
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Appendix O 
Contingency measures for a regional or national emergency that is 
declared by a governmental agency  
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 (Section 8.2.6). 
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 (Section 8). 
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 
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impact on efficacy (eg, missing data due to the emergency) and safety will be detailed in the SAP 
(Section 11.4.7). 
For a regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency. The participant or their legally authorized 
representative should be verbally informed prior to initiating any changes that are to be 
implemented for the duration of the emergency (eg, study visit delays/treatment extension, use of 
local labs) (Section 12.2). 
 
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Appendix P 
Protocol amendment history  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the clinical trial summary. 
Amended protocol 06 (21-Apr-2020) 
This amended protocol (amendment 06) 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 because it significantly impacts the safety or physical/mental integrity of 
participants. 
OVERALL RATIONALE FOR THE AMENDMENT 
The introduction of proteasome inhibitors, immunomodulatory drugs, and more recently 
monoclonal antibodies in the treatment of multiple myeloma have steadily improved patient’s 
survival. Patients diagnosed and treated after introduction of these agents have better survival 
outcomes (26, 27, 28). It is expected that survival in study EFC14335 will be longer than 
originally projected per protocol consistent with this observed trend reported in the literature. 
Based on the projection, the study cut-off date for the final overall survival (OS) analysis will be 
substantially later than originally planned. Therefore, the Sponsor decided to add a second interim 
analysis of OS at approximately 90% of events, while keeping control of multiplicity and 
statistical validity as the final analysis will still be performed once approximately 220 OS events 
will be reported. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical trial summary; 6.2.1 Duration of study 
participation for each patient; 6.3 Interim analysis; 
10.1.7 Post final OS study cut-off date; 
11.1 Determination of sample size; 11.4 Statistical 
methods; 11.4.2.2.1 Analysis of key secondary 
efficacy endpoints; 11.4.2.3 Multiplicity 
considerations; 11.5 Interim analysis 
An additional interim analysis on OS will be 
performed when approximately 90% of 
events have occurred. 
Because the survival of 
multiple myeloma patients 
has improved.  
All document 
Typos were corrected 
 
 
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Amended protocol 05 (11-Jun-2019) 
This amended protocol (amendment 05) 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 because it significantly impacts the safety or physical/mental integrity of 
participants. 
OVERALL RATIONALE FOR THE AMENDMENT 
Based on updated pharmacokinetic characterization of isatuximab, the plasma half-life has been 
re-estimated to 28 days. As duration of contraceptive measures is required to last for 5 half-lives, 
a revised duration of contraceptive measures and pregnancy testing of 5 months after the last 
isatuximab dose is required. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Tabulated clinical trial summary and  
Section 7.2 Exclusion criteria 
E27 and E28 amended to indicate that females of 
child-bearing potential will be required to use 
contraception and to be tested for pregnancy for 
3 or 5 months after discontinuation of study 
treatment for Pd and IPd respectively; and that 
male patients will be required to use contraception 
for 3 or 5 months after discontinuation of study 
treatment, for Pd and IPd respectively. 
Change from 3 months due to 
re-estimation of isatuximab plasma 
half-life 
Flow Chart foot note j 
Amended to indicate that females of child-bearing 
potential will be required to be tested for pregnancy 
for 3 or 5 months after discontinuation of study 
treatment for Pd and IPd respectively. 
Change from 3 months due to re 
estimation of isatuximab plasma 
half-life 
Section 8.9.4 Contraceptive 
measures and pregnancy counseling 
Amended to indicate that females of child-bearing 
potential will be required to use contraception, 
abstain from breastfeeding or blood donation and 
to be tested for pregnancy for 3 or 5 months after 
discontinuation of study treatment for Pd and IPd 
respectively; and that male patients will be required 
to use contraception and abstain from sperm or 
blood donation for 3 or 5 months after 
discontinuation of study treatment for Pd and IPd 
respectively. 
Change from 3 months due to 
re-estimation of isatuximab plasma 
half-life 
Section 10.1.5.1 60 days visit 
Amended to indicate that females of child-bearing 
potential will be required to be tested for pregnancy 
for 3 or 5 months after discontinuation of study 
treatment for Pd and IPd respectively. 
Change from 3 months due to re 
estimation of isatuximab plasma 
half-life 
Section 10.1.5.2 Further follow-up 
visits 
Amended to indicate that females of child-bearing 
potential will be required to be tested for pregnancy 
for 3 or 5 months after discontinuation of study 
treatment for Pd and IPd respectively. 
Change from 3 months due to re 
estimation of isatuximab plasma 
half-life 
 
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Amended clinical trial protocol 4 (25-OCT-2018) 
This amended protocol (amendment 04) is considered to be nonsubstantial 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 because it neither significantly impacts the safety or physical/mental integrity 
of participants nor the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT 
Following a request from the French Health Authorities, wording about the precautions of using 
dexamethasone together with CYP3A inhibitors has been added in to Section 8.9 concomitant 
medications. Other changes are to address inconsistencies between tables and the protocol body 
and to allow the collection of minimal residual disease (MRD) data after the primary analysis 
cut-off date.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Schedule of assessment table 
Section 1.2 
Addition of minimal residual disease (MRD) 
assessment to be performed in case of complete 
response (CR) at end of treatment (EOT) ie. 
30 days after last study treatment administration 
and post treatment Follow-up period ie 60±5 days 
and every 3 months (±7 days) after last study 
treatment administration 
To provide clarity on he MRD 
assessment to be performed at EOT 
and post treatment follow-up visits in 
case of CR. 
Schedule of assessment table 
footnote c 
Addition of Day 1 time window of ±2 days for any 
delay ablow these time windows to be reported in 
electronic case report form (eCRF) 
To clarify on the time window of 
±2 days for subsequent cycles on 
day 1 and any delay above these to be 
reported in eCRF. 
Section 8.2.3.3 Dose adjustments 
in IPd arm Table 3 (footnote) - 
Guidelines for dose adjustments 
for hematologic toxicities 
isatuximab/ 
pomalidomide/dexamethasone 
combination and 8.2.3.4 Table 5 
(footnote) - Guidelines for dose 
adjustments for hematologic 
toxicities - pomalidomide/dexamet
hasone combination and Section 
10.1.3.1 Cycle 1 (Day 1, Day 8, 
Day 15, and Day 22 all ±1 day) 
and Section 10.1.3.2 Subsequent 
cycles (Day 1 and 15) 
The following additional guidance on neutropenia 
monitoring was added. If G4 neutropenia, assess 
absolute neutrophil count every 2-3 days until 
ANC ≥0.5 x 109/L and at least weekly thereafter 
until ANC ≥1.0 x 109/L. 
To provide additional guidance on 
monitoring of Grade 4 neutropenia 
events for dose adjustments. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.2.3.4 Modification of 
isatuximab/pomalidomide/dexame
thasone dose levels in case of 
dose reduction Table 5 - 
Guidelines for dose adjustments 
for hematologic 
toxicities - pomalidomide/dexamet
hasone combination 
Clarification to maintain full dose of study 
treatment as planned within cycle for Grade 4 
thrombocytopenia events.  
To provide clarity on the dose 
adjustments to be followed for patients 
with Grade 4 thrombocytopenia events. 
Section 8.9 Concomitant 
medications 
Addition of description about precautions and 
consideration of risk-benefit ratio while using 
dexamethasone with CYP3A inhibitors.  
To advise that the co-treatment of 
dexamethasone with CYP3A inhibitors 
should be avoided unless the benefit 
outweighs the increased risk. 
Section 9.1 Primary endpoint and 
Section 10.1.1.1 
Screening/baseline 
Addition of details about various body parts (skull, 
spine, all long bones, pelvis, and chest) to be 
assessed during skeletal survey. 
To provide clarity on the various body 
parts to be assessed during skeletal 
survey. 
Section 10.1.3.1 Cycle 1 (Day 1, 
Day 8, Day 15 and Day 22 and all 
±1 day) and Section 10.1.3.2 
Subsequent cycles (Day 1 and 
15) 
Addition of contraception details for females of 
childbearing potential (FCBP) and partner on 
Day 1 and thromboprophylaxis. 
This addition is to provide clarity on 
providing contraception councelling for 
FCBP and partner on Day 1 and 
thromboprophylaxis (as per 
Section 8.9) 
Section 10.1.3.2 Subsequent 
cycles (Day 1 and 15) 
Addition of details included if urine M-protein 
shows negative results at Screening and Cycle 1 
Day 1 then a repeat assessment should be 
performed at every 3 cycles (Cycle 4, Cycle 7, 
Cycle 10, etc). 
To provide clarity on repeat 
assessment for urine M-protein. 
Section 10.1.6 Post PFS study 
cut-off date 
Addition of details of bone marrow aspirate (BMA) 
or biopsy as a parameter for MRD assessment. 
To provide additional details on BMA as 
disease assessment parameter and to 
allow collection of minimal residual 
disease after the primary cut-off date. 
Section 10.4.2 General guidelines 
for reporting of adverse events 
Table 10 - Summary of adverse 
event reporting instructions 
Addition of second primary malignancies in the 
adverse event of special interest (AESI) category. 
To provide additional details on 
inclusion of second primary 
malignancies as AESI. 
Amended Clinical Trial Protocol 3: [13-Sep-2018] 
This amended protocol (amendment 03) is considered to be nonsubstantial 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 because it neither significantly impacts the safety or physical/mental integrity 
of participants nor the scientific value of the study. 
Rationale for amendment: 
At the request of the Japanese regulatory authorities, the Sponsor has to provide progression free 
survival (PFS) data of the Japanese population enrolled into the study based on the assessment of 
the Independent Review Committee. This amendment allows the Sponsor to continue collecting 
and analyzing central laboratory disease assessment of Japanese patients after the global study 
cut-off date.  
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Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 6.4 Study 
Committee 
Added text to specify that for Japanese patients, 
the IRC review will continue after the cut-off for the 
primary analysis until at least 7 PFS events in the 
Japanese population are reported 
At the request of the Japanese regulatory 
authorities, to allow the assessment of progression 
free survival in the Japanese population by the 
Independent Review Committee after the global cut-
off date for the primary analysis 
Section 10.1.6 Post 
PFS study cut-off 
date 
Added text to clarify how data will continue to be 
collected to evaluate efficacy both as per 
Investigator and as per IRC 
All data should continue to be collected for 
Japanese patients until PFS event occur to keep 
homogeneity in PFS events diagnosis.  
Appendix N 
Country Specific 
Requirements 
Added an Appendix with details of country specific 
requirements for Japan as per the new template 
requirements 
Added this Appendix as per the new template 
requirements 
Appendix O 
Protocol 
Amendment History 
Added an Appendix with details of past protocol 
amendment changes as per the new template 
requirements 
Added this Appendix as per the new template 
requirements 
Amended Clinical Trial Protocol 2 based on Protocol Amendment 03: [18-May-2017] 
This amendment 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. 
Rationale for the amendment 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.2 Study flow chart, 
Section 6.2.1 duration of study 
participation for each patient, 
Section 7.1 Inclusion criteria and 
Section 10.1.1 Screening/baseline 
The Screening window was extended to 
28 days for female of childbearing 
potential (FCBP) 
In order to comply with contraception 
requirements outlined in the Global 
Pomalidomide Pregnancy Prevention Plan, 
FCBP must use highly effective methods of 
contraception 28 days before receiving 
treatment with pomalidomide, therefore the 
screening window has been extended for 
FCBP 
Tabulated clinical trial summary 
and Section 7.2 Exclusion criteria 
E03 was amended to clarify the 
ineligibility of a patient previously treated 
with an anti-CD38 antibody. 
An exclusion criterion E32 was added in local 
Amendment 02 (GB), to exclude patients with 
severe acute and chronic medical conditions. 
This criterion is now added to the global 
protocol for patients from any country. 
Section 1.2 Study flow chart 
Addition of visit windows to Post 
treatment Visits 
To keep consistency amongst the visits and 
assessments 
Tabulated clinical trial summary, 
Section 1.2 Study flow chart and 
Section 10.1 Visit Schedule 
Clarification for pregnancy testing 
requirements 
To clarify and keep consistency across the 
documents and with the Pomalidomide 
Pregnancy Prevention Plan. 
Section 1.2 Study flow chart and 
Section 10.1.3.2 Subsequent 
cycles Day 1 and Day 15 
Clarification on Investigator decision to 
continue study treatment based on local 
laboratory results 
In certain countries, the local laboratory is not 
able to quantify M protein in serum and/or 
urine, leading to the need to have this analysis 
performed at the central laboratory. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.2 Study flow chart and 
Section 10.1.1 Screening/baseline 
Additional assessments regarding 
antibody screening tests and clarification 
on blood phenotyping 
According to the label of the approved anti 
CD38 daratumumab, and according to the 
literature, daratumumab can cause 
interference with red blood cell antibody 
screening for blood transfusions. Currently, 
there is no clinical data with isatuximab, so in 
order to investigate if the interference is 
common to isatuximab, an antibody screening 
test is added after 4 infusions of isatuximab 
and anytime a red blood cell transfusion is 
needed. 
Section 1.2 Study flow chart and 
Section 10.1 Visit Schedule 
Clarification on timing of Day 1 laboratory 
assessments and physical examinations 
Laboratory assessments and physical 
examinations can be performed within 
24 hours prior to study treatment 
administration on Day 1 (ie, they may be 
performed the day before). 
Section 1.2 Study flow chart, 
Section 8.1.2, Pomalidomide, 
Section 8.9.4 Contraceptive 
measures and pregnancy 
counseling, new Appendix L - 
Global Pomalidomide Pregnancy 
Prevention Plan 
Addition of the Global Pomalidomide 
Pregnancy Prevention Plan 
To update the protocol with the global 
Pomalidomide Pregnancy Prevention Plan and 
keep consistency between the requirements of 
anti-conception counseling and the screening 
window. 
Section 6.4 Study committees 
Deletion of description of IRC review of 
extramedullary disease 
The IRC will not confirm presence or absence 
of extramedullary disease, the IRC will review 
and assess response only. 
Section 4.5.3 Benefit/Risk 
Addition of benefit/risk summary 
To add the missing benefit/risk assessment in 
rationale section of the protocol. 
Section 8.2 Dosage and schedule 
Pre-medication reconsideration for IARs 
To add a paragraph explaining that patients 
who do not experience IARs upon the first 
4 administrations of isatuximab are able to 
have their need for pre-medication 
reconsidered at the Investigator’s discretion, in 
accordance with recommendations across the 
isatuximab program. Also, to allow the use of 
methylprednisolone 100mg IV whenever 
dexamethasone is not tolerated as 
premedication. 
Section 8.2.3.1 General rules 
Clarification regarding dose reductions for 
pomalidomide 
To avoid inconsistencies between the protocol 
body and Tables 3 and 5. 
Section 8.2.4 Infusion reactions 
Update information regarding the stability 
of diluted isatuximab solution (infusion 
bag) 
To clarify that, in case of infusion interruption, 
re-administration should be done within the 
time specified in the pharmacy manual. 
Section 10.1.7 Post OS study cut-
off date 
Clarification on the management of 
patients still receiving treatment at the OS 
cut off date and addition of pregnancy 
testing and reporting of laboratory 
abnormalities 
To better define the data to be collected in 
patients who are still receiving treatment at the 
OS cut-off date. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.4.1.3 Adverse events of 
special interest 
Addition of instructions for overdose of 
Non-Investigational Medicinal Product 
(NIMP) 
To add definition and instructions for the 
reporting of symptomatic overdose of NIMP 
during the study 
Section 10.5 Obligations of the 
Sponsor 
Inclusion of reference to Investigator 
Brochure table for expected adverse 
reactions 
Following a request from the UK health 
authority and subsequent local Amendment 02 
(GB), a reference to the table of expected 
adverse reactions per the Investigator 
Brochure was added. 
Section 11.5 Interim Analysis 
Update of the number of OS events 
observed before interim analysis occurs 
Following implementation of Amendment 01, 
the estimation of PFS analysis had to be 
adjusted due to a reduction of the enrollment 
window.  
Appendix B ECOG Performance 
Status Scale 
Updates to ECOG performance status 
scale 
To update the ECOG performance scale with 
the latest version, including a reference. 
Appendix D IMWG Response 
Criteria 
Updates to IMWG response criteria 
To add clarification and make editorial 
updates. 
Appendix M (new) Guidance for 
notification of early termination of 
the trial according to country 
applicable regulatory requirements 
Addition of guidance for notification of 
early trial termination 
To address the request of the Swedish health 
authority, the corresponding information on 
trial termination according to the European 
legislation was added in Appendix M.  
 
Amended Clinical Trial Protocol 01 (GB) based on Protocol Amendment 02 (GB)  
[24-Feb-2017] 
This amendment is not 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 protocol was amended following the request of the United Kingdom Medicines and Health 
Care Products. 
Rationale for the amendment 
Section # and Name 
Description of Change 
Brief Rationale 
Tabulated clinical trial 
summary and Section 7.2 
Exclusion criteria  
Addition of exclusion criterion 
32 
Following the request of the United Kingdom Medicines and 
Health Care Products Regulatory Agency, an exclusion criterion, 
E32, is added to prevent the enrolment of patients with serious 
acute or chronic medical conditions such as systemic infections 
unless specific anti-infective therapy is employed. 
Section 10.5 Obligations of 
the Sponsor 
Clarification regarding the 
reference safety information 
in the protocol 
Following the request of the United Kingdom Medicines and 
Health Care Products Regulatory Agency, the specific location of 
the reference safety information for isatuximab in the Investigator 
Brochure has been clarified. The number of the table containing 
the reference safety information has not been referenced as this 
could potentially change in a subsequent version of the 
Investigator’s Brochure, so the table title has been referenced 
instead. 
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Amended Clinical Trial Protocol 01 based on Protocol Amendment 01: [01-Nov-2016] 
This amendment 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 
Rationale for the amendment 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.2 Study flow 
chart, Section 1.3 PK/PD 
Flow chart, Section 
10.1.3.2 and Section 10.1.4 
End of treatment 
Addition of electrocardiogram (ECG) 
assessments 
Isatuximab being a monoclonal antibody, ie, a large 
protein, has a low likelihood to inhibit hERG. 
Available clinical data does not show any evidence 
of repolarization problems. After interaction with US 
Federal Drug Administration, the agency agrees with 
this fact, although they encouraged the Sponsor to 
add the ECG assessments as a precautionary 
measure at the end of treatment and once during the 
study; electrocardiogram assessments were 
therefore added at Cycle 2 Day 1 (pre-dose) and at 
end of treatment. 
Section 8.2.1 Study 
treatments (IMP) 
Removal of fasting requirements for 
pomalidomide administration 
 
The requirement for pomalidomide to be taken 
without food (at 2 hours before or 2 hours after a 
meal) was removed, this change was made to reflect 
updates to the pomalidomide prescribing 
information. 
Tabulated clinical trial 
summary, Section 1.2 
Study flow chart, Section 
9.1 Primary endpoint, 
Section 10.1.1 
Screening/Baseline Section 
10.1.3.2 Subsequent cycles 
Day 1 and Day 15, Section 
10,1.5.1 60 Days visit and 
Section 10.1.5.2 Further 
follow-up visits 
Clarification of radiographic assessments 
for bone disease 
Updates were made to state there are two options 
for assessment of bone disease: skeletal survey and 
low-dose whole-body CT scan. This change was 
made in order to improve and optimize the way bone 
disease is assessed at baseline and during the 
study. The assessment of extramedullary disease 
was updated in order to clarify that in patients with 
known extramedullary disease at baseline a CT-
scan or MRI is to be done at baseline and every 
12 weeks (+/- 1 week) and for those with suspicion 
of extramedullary involvement (including bone 
plasmacytoma) a CT scan or MRI is to be performed 
to confirm or rule-out its presence at baseline. If 
confirmed, the same approach as known 
involvement is to be followed. 
Section 1.2 Study flow 
chart and Section 10.1.3.2 
Subsequent cycles Day 1 
and Day 15 
Add clarification regarding the sampling for 
Free Light Chain assay for the central 
laboratory 
In order to clarify that a sample is to be obtained and 
to be analyzed only to confirm and document CR in 
samples obtained for FLC assessment after C1D1. 
Section 1.2 Study flow 
chart and Section 10.1.1 
Screening/baseline 
Add wording allowing to explore 
cytogenetic abnormalities other than 
del(17p); t(4:14); t(14:16) 
The reason for this change is that even if three 
alterations defining the high-risk disease are well 
established there are emerging data showing that 
some cytogenetic alterations would have additional 
impact on the prognosis of patients. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.1 and 
Appendix D 
Update of International Myeloma Working 
Group (IMWG) criteria for disease 
assessment 
Criteria for assessment of disease status in this 
study was updated to the most recent IMWG 
guidance according to Kumar et al, 2016. This is to 
reflect the most recent best practice in assessment 
of myeloma. 
Section 1.2 Study flow 
chart and Section 1.3 
PK/PD Flow chart 
Removal of PK sampling on Day 15 of 
cycles subsequent to Cycle 4 
This change was made to optimize the schedule of 
PK assessments. 
Tabulated clinical trial 
summary, Section 1.2 
Study flow chart, Section 
9.3.3, patient-reported 
outcomes, Section 10.1.2 
Randomization, Section 
10.1.4 End of treatment 
and Section 10.1.5 Post 
treatment follow-up 
Patient-reported outcomes assessed at 
EOT and 60 days after last study treatment 
PRO data for those that progress should continue to 
be collected per EMA recommendation (and 1 to 
2 time points post progression should suffice); the 
data will be collected twice up to Day 60 after the 
last study treatment administration. The rationale for 
collecting PRO data for those who do not progress 
nor discontinue was recommended as useful 
information to collect for comparison. PRO data 
collection is not recommended for those who have 
discontinued treatment without progression, so 
these assessments will not be collected any more 
after the End of Treatment visit. 
Section 10.4.1.3 Adverse 
events of special interest 
Addition of second primary malignancy as 
adverse events of special interest 
To facilitate accurately and timely report second 
primary malignancies as potential AEs of IMiDs. 
 
 
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