Clinical trial NCT01084252
Conditions: Hematological Malignancy
Keywords: Anti-CD38 monoclonal antibody
Sponsor: Sanofi
Start date: 2010-05-11; Completion date: 2023-07-13
Enrollment: 351 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

Phase 1:

To determine the maximum tolerated dose (MTD)/maximum administered dose (MAD) of SAR650984 (Isatuximab).

Phase 2 (stage 1):

To evaluate the activity of single-agent Isatuximab at different doses/schedules and to select dose and regimen to further evaluate the overall response rate (ORR) of Isatuximab as single agent or in combination with dexamethasone.

Phase 2 (stage 2):

To evaluate the activity in terms of overall response rate (ORR) of Isatuximab at the selected dose/schedule from stage1, as single agent (ISA arm) and in combination with dexamethasone (ISAdex arm).

Secondary Objectives:

Phase 1:

* To characterize the global safety profile including cumulative toxicities.
* To evaluate the pharmacokinetic (PK) profile of Isatuximab in the proposed dosing schedule(s).
* To assess the pharmacodynamics (PD), immune response, and preliminary disease response.

Phase 2 (stage 1): to evaluate the following objectives for Isatuximab as single agent:

* Safety
* Efficacy as measured by duration of response, clinical benefit rate, progression free survival, overall survival.

Phase 2 (stage 2): to evaluate the following objectives in each arm (ISA and ISAdex):

* Safety
* Efficacy as measured by duration of response, clinical benefit rate, progression free survival, overall survival.
* Participant-reported changes in health-related quality of life, symptoms of multiple myeloma and generic health status.
* Pharmacokinetic profile of Isatuximab.
* Immunogenicity of Isatuximab.
* Investigate the relationship between CD38 receptor density and CD38 receptor occupancy (Stage 1 only) on multiple myeloma cells and parameters of clinical response.

Detailed description:
The Phase 1 study duration for an individual participant included a screening period for inclusion of up to 2 weeks, treatment with Isatuximab QW (every week) or Q2W (every 2 weeks) unless discontinued earlier due to safety or disease progression. Participants were followed for a minimum of 30 days following the last use of study drug or more than 30 days in case of unresolved toxicity, or up to initiation of another anticancer treatment.

The Phase 2 study duration for an individual participant included a screening period for inclusion of up to 3 weeks, then a treatment period and a follow up period. Treatment was continued until disease progression, unacceptable adverse reactions or other reasons for discontinuation. Participants were followed every 3 months following the last use of study drug until death or study cutoff, whichever came first.

Arms: arm 1: Participants with CD38+ hematological malignancies (HM), received Isatuximab at any one of the dose less than or equal to (\<=) 1 milligram per kilogram (mg/kg) (i.e. either 0.0001 mg/kg or 0.001 mg/kg or 0.01 mg/kg or 0.03 mg/kg or 0.1 mg/kg or 0.3 mg/kg or 1 mg/kg) as intravenous (IV) infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal by participant, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). arm 2: Participants with CD38+ HM, received Isatuximab 3 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). arm 3: Participants with CD38+ HM, received Isatuximab 5 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). arm 4: Participants with CD38+ HM along with participants with standard risk multiple myeloma were included this arm and, received Isatuximab 10 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). arm 5: Participants with CD38+ HM along with participants with high risk multiple myeloma, received Isatuximab 10 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). arm 6: Participants with CD38+ HM, received Isatuximab 10 mg/kg, as IV infusion QW, i.e. on Day 1 and 8 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). arm 7: Participants with CD38+ HM, received Isatuximab 20 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). arm 8: Participants with CD38+ HM, received Isatuximab 20 mg/kg, as IV infusion QW, i.e. on Day 1 and 8 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). arm 9: Participants with multiple Myeloma received Isatuximab 3 mg/kg, as IV infusion on Day 1 and Day 15 of each 28-day cycle until unacceptable adverse event (AE), disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 414 weeks). arm 10: Participants with multiple Myeloma received Isatuximab 10 mg/kg, as IV infusion on Day 1 and Day 15 of each 28-day cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 414 weeks). arm 11: Participants with multiple Myeloma received Isatuximab 10 mg/kg, as IV infusion Q2W, i.e. on Day 1 and Day 15 of Cycle 1 and 2 (each cycle 28 days), then every 4 week (Q4W), i.e. on Day 1 of each 28-days cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 414 weeks). arm 12: Participants with multiple Myeloma received Isatuximab 20 mg/kg, as IV infusion QW, i.e. on Day 1, 8, 15 and 22 of Cycle 1 and 2 (each cycle 28 days), then Q2W, i.e. on Day 1 and Day 15 of each 28-days cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 92 weeks). arm 13: Participants with relapsed or relapsed/refractory multiple myeloma (RRMM), received Isatuximab 20 mg/kg, as IV infusion on Day 1, 8, 15 and Day 22 of Cycle 1 (28 days) and then on Day 1 and 15 of each subsequent 28-day cycles until unacceptable AE, disease progression, poor compliance to the study protocol, study termination, lost to follow up or investigator's decision (maximum exposure: 301 weeks). arm 14: Participants with relapsed or RRMM, received Isatuximab 20 mg/kg, as IV infusion on Day 1, 8, 15 and Day 22 of Cycle 1 (28 days) and then on Day 1 and 15 of each subsequent 28-day cycles along with dexamethasone: tablet or as IV infusion (40 mg/day for less than \[\<\] 75 years of age; 20 mg/day \[greater than or equal to \[\>=\] for 75 years of age) on Days 1, 8, 15 and 22 of each 28 days cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination, lost to follow up or investigator's decision (maximum exposure: 301 weeks).
Interventions: intervention 1: Isatuximab SAR650984 intervention 2: Dexamethasone intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Pharmaceutical form: solution for infusion

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

Route of administration: intravenous intervention 3: Pharmaceutical form: tablet

Route of administration: oral

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-003152 VERSION N°1.0 (20-JUL-2010)
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 14 
COMPOUND: SAR650984 (isatuximab) 
A Phase 1/2 dose escalation safety, pharmacokinetic and efficacy study of multiple 
intravenous administrations of a humanized monoclonal antibody (SAR650984) against 
CD38 in patients with selected CD38+ hematological malignancies  
STUDY NUMBER: SAR650984-TED10893 
VERSION DATE/STATUS: 22-Jul-2020/Approved 
Version Number: 
1 
EudraCT  
2013-001418-13 
IND Number(s) 
103217 
Date: 
22-Jul-2020
Total number of pages: 
235 
NCT01084252


Amended Clinical Trial Protocol 14  
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Page 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Amended Clinical Trial Protocol 14 
Version number: 1 (electronic 18.0) 
Date: 22-Jul-2020 
Amended Clinical Trial Protocol 13 
Version number: 1 (electronic 17.0) 
Date: 11-Jun-2019 
Amended Clinical Trial Protocol 12 
Version number: 1 (electronic 16.0) 
Date: 12-Jul-2017 
Protocol Amendment 12 
Version number: 1 (electronic 1.0) 
Date: 12-Jul-2017  
Amended Clinical Trial Protocol 11 
Version number: 1 (electronic 12.0) 
Date: 22-Apr-2016 
Protocol Amendment 11 
Version number: 1 (electronic 1.0) 
Date: 22-Apr-2016 
Amended Clinical Trial Protocol 10 
Version number: 1 (electronic 12.0) 
Date: 22-Aug-2014 
Protocol Amendment 10 
Version number: 1 (electronic 2.0) 
Date: 22-Aug-2014 
Amended Clinical Trial Protocol 9 
Version number: 1 (electronic 11.0) 
Date: 08-Apr-2014 
Protocol Amendment 9 
Version number: 1 (electronic 1.0) 
Date: 08-Apr-2014 
Amended Clinical Trial Protocol 8 
Version number: 1 (electronic 8.0) 
Date: 19-Mar-2014 
Protocol Amendment 8  
Version number: 1 (electronic 2.0) 
Date: 19-Mar-2014 
Amended Clinical Trial Protocol 7 
Version number: 1 (electronic 6.0) 
Date: 13-Aug-2013 
Protocol Amendment 7 
Version number: 1 (electronic 1.0) 
Date: 13-Aug-2013 
Amended Clinical Trial Protocol 6 
Version number: 1 (electronic 5.0) 
Date: 05-Apr-2013 
Protocol Amendment 6 
Version number: 1 (electronic 1.0) 
Date: 05-Apr-2013 
Amended Clinical Trial Protocol 5 
Version number: 1 (electronic 3.0) 
Date: 10-Sep-2012 
Protocol Amendment 5 
Version number: 1 (electronic 2.0) 
Date: 10-Sep-2012 
Amended Clinical Trial Protocol 4 
Version number: 1 (electronic 1.0) 
Date: 05-Jan-2011 
Protocol Amendment 4 
Version number: 1 (electronic 1.0) 
Date: 05-Jan-2011 
Amended Clinical Trial Protocol 3 
Version number: 1 (electronic 1.0) 
Date: 11-Oct-2010 
Protocol Amendment 3 
Version number: 1 (electronic 1.0) 
Date: 11-Oct-2010 
Amended Clinical Trial protocol 2 
Version number: 1 (electronic 3.0) 
Date: 07-Apr-2010 
Protocol Amendment 2 
Version number: 1 (electronic 1.0) 
Date: 07-Apr-2010 
Amended Clinical Trial Protocol 1 
Version number: 1 (electronic 2.0) 
Date: 16-Dec-2009 
Protocol Amendment 1 
Version number: 1 (electronic 2.0) 
Date: 16-Dec-2009 
Clinical Trial Protocol 
Version number: 1 (electronic 2.0) 
Date: 27-Oct-2009  
Amended protocol 14 (22 July 2020) 
This amended protocol (amendment 14) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 


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OVERALL RATIONALE FOR THE AMENDMENT  
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 
1.13 Study flowchart for Phase 2, Stage 1a; 1.14 Study 
flowchart for Phase 2, Stage 1b; 1.15 Study flowchart 
for Phase 2, Stage 2; 6.8 Guidance in case of hepatitis 
B reactivation occurring under study treatment 
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. 
6.8 Guidance in case of hepatitis B reactivation 
occurring under study treatment 
Description of study treatment 
discontinuation and restart procedure 
in case of viral reactivation. 
A risk of hepatitis 
reactivation has been 
identified. 
6.8 Guidance in case of hepatitis B reactivation 
occurring under study treatment; 12.3 Data collection 
after final analysis cutoff 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. 
8.1.6.3 Administration 
Oral dexamethasone may be 
provided to the participant via a 
Sponsor-approved courier company. 
Treatment supply option for 
patients who are unable to 
come to study site because 
of a regional or national 
emergency declared by a 
governmental agency. 
10.5.2 Serious adverse events 
Hospitalization and examination 
reports for serious adverse events 
(SAEs) will not be systematically 
requested. 
Only necessary copies of 
medical records are to be 
shared with the Sponsor. 
12.3 Data collection after final analysis cutoff date 
Patients will be followed for a 
minimum of 30 days following the last 
use of study drug. 
Consistency: anti-drug 
antibodies (ADA) are not 
tested anymore so a 
30-day follow-up is 
sufficient. 
All document 
Minor editiorial and format changes. 
Accuracy 


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NAMES AND ADDRESSES OF  
INVESTIGATOR 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
Company: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
CLINICAL STUDY 
DIRECTOR  
Company: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
 


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CLINICAL TRIAL SUMMARY  
COMPOUND: SAR650984 
STUDY No: TED10893 
TITLE: 
A Phase 1/2 dose escalation safety, pharmacokinetic and efficacy study of multiple 
intravenous administrations of a humanized monoclonal antibody (SAR650984) 
against CD38 in patients with selected CD38+ hematological malignancies 
STUDY OBJECTIVES: 
Primary 
Phase 1 
To determine the maximum tolerated dose (MTD)/maximum administered dose 
(MAD) of SAR650984 according to the investigational product (IP) related dose 
limiting toxicities (DLTs) observed in patients with selected CD38+ hematological 
malignancies. 
Phase 2 
In Stage 1: To evaluate the activity of single-agent SAR650984 at different 
doses/schedules and to select dose and regimen to further evaluate the overall 
response rate (ORR) of SAR650984 as a single agent or in combination with 
dexamethasone, in patients with relapsed or relapsed/refractory multiple myeloma in 
Stage 2. 
In Stage 2: To evaluate the activity in terms of overall response rate (ORR) of 
SAR650984 at the selected dose/schedule from Stage 1, as single agent (ISA arm) 
and in combination with dexamethasone (ISAdex arm) in patients with relapsed or 
relapsed/refractory multiple myeloma. 
Secondary 
Phase 1 
x 
To characterize the global safety profile including cumulative toxicities. 
x 
To evaluate the pharmacokinetic (PK) profile of SAR650984 in the 
proposed dosing schedule(s). 
x 
To assess the pharmacodynamics, immune response, and preliminary 
disease response. 
Phase 2 Stage 1 
To evaluate the followings objectives for SAR650984 as single agent: 
x 
Safety 
x 
Efficacy as measured by: 
- 
Duration of response (DOR) 
- 
Clinical benefit rate (CBR)  
- 
Progression free survival (PFS) 
- 
Overall survival (OS) 
Phase 2 Stage 2 
To evaluate the following objectives in each arm (ISA and ISAdex): 
x 
Safety 
x 
Efficacy as measured by 
- 
Duration of response (DOR) 
- 
Clinical benefit rate (CBR) 
- 
Progression free survival (PFS) 
- 
Overall survival (OS) 


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STUDY OBJECTIVES (cont’d) 
Exploratory 
Phase 2 
x 
To assess minimal residual disease (MRD) in patients achieving a 
complete response (CR) and correlate with clinical outcome  
x 
To investigate the relationship between tumor cell CD38 mRNA, multiple 
myeloma molecular subtype (as defined by marker expression, 
cytogenetics, and/or genomics) and parameters of clinical response 
x 
To investigate the relationship of soluble CD38 and parameters of PK and 
clinical response (Stage 1 only) 
x 
To investigate the relationship between immune genetic determinants, 
immune phenotype, adaptive immune response and parameters of clinical 
response  
STUDY DESIGN: 
This is an open-label, international multi-center study conducted in 2 parts (Phase 1 
and Phase 2). 
Phase 1 Part 
The Phase 1 part is a dose escalation study of SAR650984 administered as single 
agent as an intravenous (IV) infusion every week or every 2 weeks to adult patients 
with selected CD38+ hematological malignancies. 
The administration of the IP will start at 0.0001 mg/kg (representing 10% of 
theoretical CD38 receptor occupancy (RO) on normal B and T cells).  
Two dose escalation schemes will be used based upon toxicities observed during the 
first two cycles of treatment (28 days). In this first in man (FIM) study, potential DLTs 
are defined as any Grade 3 or higher non-hematological toxicity (excluding allergic 
reaction/hypersensitivity), Grade 4 neutropenia and/or Grade 4 thrombocytopenia 
lasting longer than 5 days, attributed to SAR650984 and as defined by the 
NCI-CTCAE v.4 (Section 9.1.2). 
In the Phase 1 part, a cycle is 14 days. 
Accelerated dose escalation scheme 
One evaluable patient per dose level (DL) unless Grade 4 neutropenia and/or 
Grade 4 thrombocytopenia lasting longer than 5 days, or Grade 1 or higher IP related 
non-hematological toxicity including fever, but excluding nausea, vomiting, diarrhea, 
fatigue, asthenia, anorexia, alkaline phosphatase elevation and local (injection site) 
reaction. Log dose escalation will be used between DLs until 0.1 mg/kg (representing 
the dose with minimal antitumor activity in an animal model) unless MAD reached. 
Cohort 1: 0.0001 mg/kg 
Cohort 2: 0.001 mg/kg 
Cohort 3: 0.01 mg/kg  
Cohort 4: 0.03 mg/kg 
Cohort 5: 0.1 mg/kg 
x 
Patient(s) will receive two administrations (cycles) of SAR650984 (at 
2 week intervals) followed by a 2-week post-second dose administration 
observation period. The data obtained from this 4-week period will be used 
for acute safety monitoring and to make decisions regarding cohort 
expansion and/or dose escalation for the next cohort. PK and CD38 RO 
data will be collected and may also be used for dose escalation decisions.  
x 
After completing two cycles, patients may continue to receive additional 
administrations of SAR650984 (at the same DL) every 2 weeks upon 
Investigator’s decision. If this dosing regimen is considered safe, the patient 
can continue treatment until unacceptable toxicity, disease progression, 
death, withdrawal of consent, Investigator’s decision and/or availability of 
study drug. Additional PK, safety and disease response will be assessed. 


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x 
In the event of a Grade 1 or higher treatment-emergent, IP related non-
hematological toxicity including fever, the cohort will be expanded to 
3 patients and a semi-log escalation will be used between DLs for all future 
doses. All successive cohorts will then include 3 patients per DL. In 
addition, in the event of a Grade 2 or higher treatment-emergent nausea, 
vomiting, diarrhea, fatigue, asthenia, anorexia, alkaline phosphatase 
elevation or local (injection site) reaction, the cohort will be expanded to 
3 patients with a switch to semi-log dose escalation. All successive cohorts 
will also include 3 patients. In the event that a potential DLT is reported 
during the accelerated dose escalation scheme, up to 6 patients will be 
assessed at this DL. If <2 out of 6 patients experienced an IP related DLT 
at this DL, the dose escalation will proceed with 3 patients per DL. 
x 
If 2 out of 6 patients experience an IP related DLT, the MAD is reached 
and dose escalation will be stopped.  
Basic dose escalation scheme 
Successive patient cohorts will include at least 3 evaluable patients if no potential 
DLT is reported, or up to 6 evaluable patients if a potential DLT is experienced by 1 of 
the first 3 patients, semi-log dose escalation will be used between DLs. In each 
cohort, at least 7 days must pass after dosing the first patient before dosing the 
second patient. 
Cohort 6: 0.3 mg/kg every 2 weeks 
Cohort 7: 1 mg/kg every 2 weeks 
Cohort 8: 3 mg/kg every 2 weeks 
Cohort 9: 5mg/kg every 2 weeks 
Cohort 10: 10 mg/kg every 2 weeks 
Cohort 11: 10 mg/kg every week 
Cohort 12: 20 mg/kg every 2 weeks 
Cohort 13: 20 mg/kg every week 
x 
Patients in Cohorts 6-10 and 12 will initially receive two administrations of 
SAR650984 (at 2 week interval) followed by a 2-week post-second dose 
administration observation period. Patients in Cohort 11 and 13 will initially 
receive four administrations of SAR650984 (at a 1 week interval) followed 
by a 1-week post-fourth dose administration observation period. The data 
obtained from this 4-week period will be used for acute safety monitoring. 
PK and CD38 RO data will be collected and may be used to make the dose 
escalation decision to the next cohort. 
x 
After completing two cycles, patient(s) may continue to receive additional 
administrations of SAR650984 (at the same DL and schedule). If this 
dosing regimen is considered safe patients can continue treatment until 
unacceptable toxicity, disease progression, death, withdrawal of consent, 
Investigator’s decision and/or availability of study drug. Additional PK, 
safety and disease response will be assessed. 
A Study Committee will be set up, including at least the Principal Investigator(s) and 
Clinical Study Director from sanofi-aventis. When needed, ad hoc members will be 
added. Upon completion of enrollment in each cohort, the Study Committee will 
review collected data and will make the decision to continue the enrollment in 
subsequent DL cohort. 
Additional (optional) cohort(s) beyond Cohort 13 may be evaluated (such as 
15 mg/kg every week, evaluation of a loading dose followed by a weekly or every 
2-week schedule, or evaluation of intermediate doses such as 7.5 mg/kg every week or 
15 mg/kg every 2 weeks), however, the decision to proceed to these optional 
cohort(s) will be discussed with the Study Committee and based on the totality of 
safety and PK data. 


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Dose escalation will stop when the MAD is reached with MAD defined as the dose at 
ZKLFK of evaluable patients have experienced an IP related DLT following the 
first administration of IP and occurring during the first two cycles (28 days) from a 
cohort of 3 to 6 patients.  
The MTD will then be defined as the highest DL at which no more than 1 patient of a 
maximum of 6 patients experienced an IP related DLT. Usually, the MTD is one DL 
below the MAD. The RP2D is defined as the dose selected for the expansion cohorts 
and for further evaluation in the Phase 2 part of the study. The Study Committee will 
review the overall safety and PK data observed up to and including Cohort 12 and will 
decide the dose and schedule for the RP2D. Once the MTD or RP2D dose and 
schedule is defined based on Cohorts 1-12, a cohort expansion is planned in 
standard risk MM patients. An additional (optional) expansion cohort may also be 
considered for high risk MM patients. The decision to proceed to these 2 expansion 
cohorts will be based on the overall safety and PK observed during dose escalation. 
Patients will be enrolled to the 2 expansion cohorts (up to 18 patients per expansion) 
for a maximum total enrollment of 36 patients treated at the MTD or RP2D dose to 
further evaluate the safety, PK and possible disease response. Patients enrolled in 
the expansion cohorts will follow the every 2 week schedule detailed in Section 1.5 
(PK/PD Flowchart) and Section 1.12 (Study Flowchart) corresponding to Cohort 12 
visit schedules. Patients enrolled in Cohort 13 will follow the every week schedule 
detailed in Section 1.6 (PK/PD Flowchart) and Section 1.11 (Study Flowchart) 
corresponding to Cohort 11 visit schedules. 
Phase 2 Part 
The Phase 2 Stage 1 part is to commence after the Phase 1 standard risk cohort has 
completed enrollment and will further evaluate the activity and safety of SAR650984 
as a single agent, in patients with multiple myeloma who have previously received an 
immunomodulatory imide drug (IMiD) and a proteasome inhibitor(PI) and have 
relapsed or relapsed/ refractory disease. In the Phase 2 part, a cycle is 28 days. The 
Phase 2 study will be conducted in 3 stages; Stage 1a dose finding to evaluate 
3 dose levels, Stage 1b dose finding to evaluate 1 dose level and Stage 2 expansion 
to evaluate the dose and schedule selected Stage 1:  
x 
Stage 1a will determine the dose and schedule of single agent SAR650984 
by evaluating the activity and safety of SAR650984 at 3 dose levels: 
- 
Arm 1: 3 mg/kg (Q2W) every 2 weeks (Day 1 and 15 of each 28-day 
cycle) 
- 
Arm 2: 10 mg/kg Q2W (Day 1 and 15 of each 28-day cycle) 
- 
Arm 3: 10 mg/kg Q2W for 2 cycles (Day 1 and 15 of each 28-day cycle), 
then 10 mg/kg Q4W (every 4 weeks (Day 1 of each 28-day cycle)) 
x 
Patients in Stage 1a will be randomly assigned to one of 3 treatment arms 
(Arm 1, 2 or 3), in a 1:1:1 ratio using an Interactive Voice Response 
System/Interactive Web Response System (IVRS/IWRS). Randomization 
will be stratified according to the patients prior multiple myeloma therapy; 
Stratum 1: prior treatment with pomalidomide and/or carfilzomib, Stratum 2: 
no prior treatment with pomalidomide and/or carfilzomib. 
x 
Stage 1b will commence after Cohort 13 has completed the DLT-
observation period and enrollment in Stage 1a is completed, whichever is 
last. The following dose/schedule will be evaluated if fewer than 1/3 or 
2/6 patients experiences a DLT in Cohort 13: 
- 
Arm 41: 20 mg/kg (QW) every week for 1 cycle (Day 1, 8, 15 and 22 of 
Cycle 1) then 20 mg/kg Q2W (Day 1 and 15 of each 28-day cycle) 
 
1 The planned dose for arm 4 is 20 mg/kg, however during the Phase 1, if 20 mg/kg QW is the MAD then a 
lower dose (such as 15 mg/kg QW) would be evaluated in this arm. 


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The Phase 2 Stage 2 will further evaluate the activity and safety of SAR650984 with 
or without dexamethasone at the dose and schedule selected based on response 
rate along with safety, PK, PD and overall efficacy from Phase 1 and the interim 
analysis of Stage 1a and 1b (see Section 13.5): 20 mg/kg every week for 4 infusions 
followed by 20 mg/kg every 2 weeks. For patients in the ISAdex arm, dexamethasone 
will be administered at the dose of 40 PJGD\PJGD\IRU y.o patients) on 
Days 1, 8, 15, 22 of each cycle. 
In Stage 2, patients will be randomly assigned to one of the 2 treatment arms in a  
2:1 ratio using an IVRS/IWRS. Enrollment will stop when the targeted number of 
patients is reached in both arms.  
In Phase 2, the primary efficacy endpoint is overall response rate defined as the 
proportion of patients with stringent complete response (sCR), (CR), very good partial 
response (VGPR) and partial response (PR) using the International Myeloma 
Working Group (IMWG) Uniform Response Criteria (1) in Stage 1 and the IMWG 
Response Criteria updated in 2014 (2): in Stage 2. 
Main selection criteria: 
Phase 1 Inclusion criteria 
 
I 01. 
A. For dose escalation Cohorts 1 to 10 and the Cohort 10 expansion: 
Patients with confirmed selected CD38+ hematological malignancies (as 
outlined below) who have progressed on or after standard therapy or for 
whom there is no effective standard therapy (refractory/relapsed patients) 
 
1. 
B-cell Non-Hodgkins Lymphoma (NHL) patients having at least 1 
measurable lesion 
 
2. 
Multiple Myeloma (MM) patients with measurable M-protein (serum and/or  
24-hr urine, or serum free light chains) 
 
3. 
Acute Myeloid Leukemia (AML) patients, all types except M3 based on FAB 
classification 
 
4. 
Acute Lymphoblastic Leukemia (B-cell ALL) patient 
 
5. 
Chronic Lymphocytic Leukemia (CLL) patients 
B. For dose escalation Cohorts 11, 12 and 13 (and additional optional 
cohorts): Patients must have relapsed/refractory MM with measurable M-
protein (serum M-protein of >0.5 g/dL and/or urine M-protein of >200 mg (24-hr 
urine)), or elevated serum free light chains (FLC >10 mg/dL with abnormal FLC 
ratio) who have progressed on or after standard therapy that includes an IMiD 
and a proteasome inhibitor. 
For the standard risk expansion cohort: Patients with relapsed/refractory MM 
with measurable M-protein (serum M-protein of >0.5 g/dL and/or urine M-protein 
of >200 mg [24-hr urine]), or elevated serum free light chains (FLC >10 mg/dL 
with abnormal FLC ratio) who meet the following criteria: 
x 
have progressed on or after at least 2 prior lines of standard therapy 
that includes an IMiD and a proteasome inhibitor 
For the high risk expansion cohort: Patients with relapsed/refractory MM with 
measurable M-protein (serum M-protein of >0.5 g/dL and/or urine M-protein 
of >200 mg [24-hr urine]), or elevated serum free light chains (FLC >10 mg/dL 
with abnormal FLC ratio) who have progressed on or after standard therapy that 
includes an IMiD and a proteasome inhibitor and who meet one of the following 
criteria: 
x 
have relapsed within 6 months of autologous transplantation 
x 
have 17p deletion, t (4, 14), t (14, 16), t (14, 20) or >3 copies of 1q21 
x 
have a high-risk gene expression profiling (GEP) signature (if 
available) 
 
I 02. 
Signed written informed consent 


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Phase 1 Exclusion criteria 
 
E 01. 
No previous treatment with any anti-CD38 agent is allowed 
 
E 02. 
Patient less than 18 years old 
 
E 03. 
Karnofsky performance status <60 
E 04. 
Poor bone marrow reserve as defined by absolute neutrophils count  
<1.0 x 109/L or hemoglobin <9.0 g/dL or platelets <50 x 109/L  
 
E 05. 
Poor organ function as defined by one of the following: 
 
x Liver function tests 
 
 AST, ALT, alkaline phosphatase, bilirubin >2.5 x upper limit of normal 
[ULN] if no liver metastasis; >5 x ULN if liver metastases 
 
 >5 x ULN alkaline phosphatase if bone involvement 
 
x Serum creatinine >2 x ULN (>3 x ULN for multiple myeloma) 
 
E 06. 
Received any investigational drug within 30 days or 5 half-lives of the 
investigational drug, whichever is longer 
 
E 07. 
Prior anticancer therapy (chemotherapy, targeted agents, radiotherapy, 
immunotherapy) within 21 days except for alkylating agents (eg, melphalan) 
where 28 days will be required. Hydroxyurea may be used up to 24 hours 
prior to the first IP administration and leukophoresis may be used up to 
1 week prior to the first drug infusion 
 
E 08. 
Known intolerance to infused protein products, sucrose, histidine, 
polysorbate 80 or known hypersensitivity to any of the components of study 
therapy that is not amenable to pre-medication with steroids and H2 blockers 
 
E 09. 
Allogeneic bone marrow transplant or an allogeneic peripheral blood stem 
cell transplant within 1 year prior to study entry or evidence of active graft 
versus host disease (GVHD) requiring >10 mg prednisone. Patients having 
undergone autologous stem cell transplantation(s) may be included in the 
study. For AML patients, prior allogeneic stem cell transplantation or donor 
lymphocytes infusion within 3 months preceding the first dose of SAR650984 
 
E 10. 
Any serious active disease (including clinically significant infection that is 
chronic, recurrent, or active) or co-morbid condition, which, in the opinion of 
the Investigator, could interfere with the safety, the compliance with the 
study or with the interpretation of the results 
 
E 11. 
Any other severe underlying medical conditions including presence of 
laboratory abnormalities, which could impair the ability to participate in the 
study or the interpretation of its results 
 
E 12. 
Concomitant or prior malignancy (other than the one under study) except 
adequately treated basal cell or squamous cell carcinoma of the skin, 
carcinoma in situ of the cervix, or other cancer for which the subject has 
been disease-IUHHIRU\HDUV 
 
E 13. 
Concurrent treatment with other anti-cancer therapy not specified in the 
protocol 
 
E 14. 
Central nervous system (CNS) metastatic disease 
 
E 15. 
Pregnant or breast-feeding women 
 
E 16. 
Female patients of childbearing potential and male subjects with female 
partners of childbearing potential who are not willing to avoid pregnancy by 
using an adequate method of contraception (2-barrier method or 1 barrier 
method with a spermicide or intrauterine device for 2 weeks prior to 
screening, during and 5 months after the last does of trial medication). 
Adequate methods of contraception are provided as examples. Other 
acceptable and effective methods of birth control are also permitted 
(eg, abstinence). 


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E 17. 
Known HIV seropositivity, AIDS, hepatitis C or active hepatitis B infection 
 
E 18. 
Autoimmune disease (eg, inflammatory bowel disease such as Crohn’s 
disease, systemic lupus or multiple sclerosis) 
 
E 19. 
Unresolved specific toxicities (excluding alopecia) related to any prior 
anti-FDQFHUWKHUDS\WR*UDGHDFFRUGLQJWRWKH1&,&7&$(Y4.03 
 
E 20. 
Any of the following within 6 months prior to enrollment: myocardial 
infarction, severe/unstable angina, or coronary/peripheral artery bypass 
graft surgery, clinically symptomatic and uncontrolled cardiovascular 
disease, or clinically significant cardiac arrhythmias (Grade 3-4) 
E 21. 
Mental condition rendering the patient unable to understand the nature, 
scope and possible consequences of the study. Patient unlikely to comply 
with protocol eg, uncooperative attitude, inability to return for follow up 
visits, and unlikelihood of completing the study 
 
Phase 2 Stage 1 and Stage 2 Inclusion criteria 
I 01. 
Patients must have a known diagnosis of multiple myeloma with evidence of 
measurable disease, as defined below: 
- 
Serum M-SURWHLQJG/JG/LQFDVHRI,J$GLVHDVH in 
Stage 2), or urine M-SURWHLQPJhrs. 
OR 
- 
in the absence of measurable m-protein, serum immunoglobulin free 
OLJKWFKDLQPJG/DQGDEQRUPDOserum immunoglobulin kappa 
lambda free light chain ratio (<0.26 or >1.65). 
I 02. 
3DWLHQWVPXVWKDYHUHFHLYHGSULRUWUHDWPHQWZLWKDQ,0L'IRUF\FOHVRU 
PRQWKVRIWUHDWPHQWDQGDSURWHDVRPHLQKLELWRU (PI) IRUF\FOHVRU 
PRQWKVRIWUHDWPHQW 
I 03. 
Patients must have received at least three prior lines of therapy (as defined 
in Appendix C) for multiple myeloma. Induction therapy and stem cell 
transplant (± maintenance) will be considered as one line 
OR 
Patients whose disease is double refractory to an IMiD and a PI. For 
patients who have received more than one type of IMiD and PI, their 
disease must be refractory to the most recent one.  
Refractory disease is defined as a disease that is progressive while being 
on treatment, or progressive within 60 days of the last administration of 
these therapies or never reached at least a minimal response (MR) with 
those drugs. 
I 04. 
Patients must have achieved an MR or better to at least one prior line of 
therapy.  
I 05. 
Patients must have received an alkylating agent (for 2 cycles or 
2 months of treatment) either alone or in combination with other MM 
treatments (history of stem cell transplant is acceptable). Treatment with 
high dose melphalan for stem cell transplantation meets this requirement. 
I 06. 
Patients must have evidence of disease progression on or after the most 
recent prior regimen based on IMWG criteria (2) and Appendix E  
(Phase 2 Stage 2)濁 
I 07. 
Signed written informed consent and be willing and able to complete all 
study-related procedures, including completion of patient-reported 
endpoints. 


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Phase 2 Stage 1 and Stage 2 Exclusion criteria 
E 01. 
Patients less than 18 years old 
E 02. 
Patients with multiple myeloma IgM subtype 
E 03. 
Previous treatment with any anti-CD38 therapy 
E 04. 
Patients with concurrent plasma cell leukemia 
E 05. 
Patients with known or suspected amyloidosis 
E 06. 
Patients treated with approved or investigative anticancer therapeutic 
agents (excluding dexamethasone in Phase 2 Stage 2 part), within 3 weeks 
or within five drug half-lives (t1/2) prior to first dose, whichever time is greater 
E 07. 
Patients treated with systemic radiation therapy within 4 weeks prior to 
first dose or localized radiation therapy within 1 week prior to first dose 
E 08. 
Patients who have had major surgery within 3 weeks prior to first dose 
E 09. 
Prior autologous stem cell transplant within 12 weeks of the first dose of 
study treatment and/ or prior allogeneic transplant within 1 year or has 
evidence of active graft versus host disease (GVHD) requiring >10 mg 
prednisone daily 
E 10. 
Patients with a life expectancy of less than three months 
E 11. 
In Stage 1 part, patient with Karnofsky performance status <60 
In Stage 2 part patient with Eastern Cooperative Oncology Group (ECOG) 
Performance status >2 
E 12. 
Patients with laboratory values of: 
a) 
7RWDOELOLUXELQ[ULN 
b) 
$67RU$/7[ULN 
c) 
In Phase 2 Stage 1: Calculated or measured creatinine clearance 
(CrCL) <30 mL/minute(min) (using Cockcroft and Gault formula 
[(140 - age) x mass (kg) / (72 x creatinine mg/dL)], multiply result by 
0.85 if female. 
In Phase 2 Stage 2: Serum creatinine >2 x ULN and/or estimated 
glomerular filtration rate (eGFR) according the Modification of diet in 
Renal Disease (MDRD) equation <15 mL/min/1.73 m2 (see formula in 
Appendix B), and/or on renal dialysis. 
d) 
$EVROXWHQHXWURSKLOFRXQWPP3 (use of colony-stimulating 
factors (CSFs) to achieve these counts is allowed) 
e) 
Hemoglobin <8.0 g/dL (patients may receive red blood cell transfusion 
or receive supportive care such as erythropoietin and darbepoetin in 
accordance with institutional guidelines) 
f) 
3ODWHOHWFRXQW 000/mm3 (patients should be platelet transfusion 
independent for 2 weeks prior to screening lab values) 
E 13. 
No resolution of all specific toxicities (excluding alopecia) related to any 
prior anti-FDQFHUWKHUDS\WR*UDGHDFFRUGLQJWRWKH1&,&7&$(Y 
E 14. 
Patients with concurrent POEMS syndrome (polyneuropathy, 
organomegaly, endocrinopathy, monoclonal protein, and skin changes) 
E 15. 
Patients with congestive heart failure (New York Heart Association class III 
to IV), symptomatic ischemia, conduction abnormalities uncontrolled by 
conventional intervention, or myocardial infarction in the 6 months prior to 
first dose 
E 16. 
Patients with active infection requiring systemic antibiotics, antivirals or 
antifungals within 2 weeks prior to first dose (except when used for chronic 
prophylaxis) 


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E 17. 
Known intolerance to infused protein products, sucrose, histidine, 
polysorbate 80 or known hypersensitivity to any of the components of study 
therapy that is not amenable to pre-medication with steroids and H2 
blockers 
E 18. 
Patients with known HIV 
E 19. 
Patients with active hepatitis B, or C infection 
E 20. 
Patients diagnosed or treated for a malignancy within the past 3 years 
except: 
a) 
adequately treated basal cell or squamous cell skin cancer, or 
b) 
carcinoma in situ of the cervix, or 
c) 
prostate cancer with < Gleason Grade 6 and stable PSA 
E 21. 
Patients with myelodysplastic syndrome (MDS) 
E 22. 
3DWLHQWVZLWKVLJQLILFDQWQHXURSDWK\*UDGHZLWKSDLQRU Grade 3) within  
2 weeks prior to first dose 
E 23. 
Any clinically significant medical or psychiatric disease or condition that, in 
the Investigator's opinion, may interfere with protocol adherence, the ability 
to complete patient-reported measures or the ability to give informed 
consent 
E 24. 
Female patients of childbearing potential and male patients with female 
partners of childbearing potential who are not willing to avoid pregnancy by 
using an adequate method of contraception (2-barrier method or 1 barrier 
method with a spermicide or intrauterine device for 2 weeks prior to 
screening, during and 5 months after the last dose of trial medication) 
and/or who are unwilling or unable to be tested for pregnancy monthly for 
5 months after the last administration of SAR650984. Adequate methods of 
contraception are provided as examples. Other acceptable and effective 
methods of birth control are also permitted (eg, abstinence). 
E 25. 
Female patients who are pregnant or breast feeding 
E 26. 
For Phase 2 Stage 2: the patient is the Investigator or an Sub-Investigator, 
research assistant, pharmacist, study coordinator, other staff or relative 
thereof directly involved in the conduct of the protocol. 
Total expected number of 
patients: 
Phase 1: Approximately 85 patients 
Phase 2: Stage 1 approximately 96 patients (24 patients per arm) 
Stage 2 approximately 160 patients 
Expected number of sites: 
Phase 1: Approximately 12 sites 
Phase 2: Approximately 80 sites 
INVESTIGATIONAL 
PRODUCT(S): 
Formulation(s): 
SAR650984 Phase 1 and Phase 2 Stage 1 
 
The C1P1F1 drug product is presented as a concentrate for solution for infusion in 
vials containing 5 mg/mL (100 mg/20 mL) SAR650984 in 10 mM histidine, 10 % (w/v) 
sucrose, 0.005 % (w/v) polysorbate 80, pH 6.5 buffer. For administration to patients, 
the appropriate volume of SAR650984 will be diluted in an infusion bag of 
0.9% sodium chloride solution. The final infusion volume corresponding to the dose of 
SAR650984 will be administered for period of time that will depend on dose 
administered and will be based on protein amount given per hour.  
After the study cut-off in Phase 2 Stage 1 and the start of Phase 2 Stage 2, patients 
in Phase 2 Stage 1 receiving C1P1F1 may be switch to C1P2F2.  


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SAR650984 Phase 2 Stage 2 
The C1P2F2 drug product concentrated solution for infusion in vials containing 
20 mg/mL (500 mg/25 mL) SAR650984 in 20 mM histidine, 10%(w/v) sucrose, 
0.02% (w/v) polysorbate 80, pH 6.0 buffer. For administration to patients, the 
appropriate volume of SAR650984 will be diluted in an infusion bag of 0.9% sodium 
chloride solution. The final infusion volume corresponding to the dose of SAR650984 
will be administered for period of time that will depend on dose administered and will 
be based on protein amount given per hour. 
For dexamethasone please refer to Summary of Product Characteristics (SmPC) 
and United States product insert (USPI) of this compound 
Route(s) of administration: 
SAR650984 C1P1F1 will be administered by IV infusion.  
SAR650984 C1P2F2 will be administered by IV infusion. 
The appropriate volume of SAR650984 will be diluted in an infusion bag of 
0.9% sodium chloride solution. 
Dexamethasone (ISAdex arm), initially given at 40 mg/day (20 mg/day in patient  
\HDU-old) IV or by mouth (PO).  
During Phase 1, the initial rate of infusion per dose will be as follows: 
 
In the Phase 1 accelerated dose cohorts: 
 
0.0001 mg/kg -------------------------------------------------  0.042 mg/hr for a total of 3 mL 
 
0.001 mg/kg ----------------------------------------------------- 0.42 mg/hr for a total of 3 mL 
 
0.01 mg/kg --------------------------------------------------------------------------------- 1.4 mg/hr 
 
0.03 mg/kg --------------------------------------------------------------------------------- 4.2 mg/hr 
 
0.1 mg/kg ---------------------------------------------------------------------------------- 7 mg/hr 
 
In the Phase 1 basic dose cohorts: 
 
0.3 mg/kg -------------------------------------------------------------------------------- 10.5 mg/hr 
 
1 mg/kg ----------------------------------------------------------------------------------- 17.5 mg/hr 
 
3 mg/kg ----------------------------------------------------------------------------------- 52.5 mg/hr 
 
5 mg/kg ----------------------------------------------------------------------------------- 87.5 mg/hr 
 
10 mg/kg --------------------------------------------------------------- -------------------175 mg/hr 
20 mg/kg --------------------------------------------------------------- -------------------250 mg/hr 
In the Phase 2 
During Phase 2, the initial rate of infusion will be 175 mg/hr. 
Dose regimen/duration: 
During Phase 1, SAR650984 will be administered once every two weeks (Q2W) in 
the Accelerated dose escalation scheme and weekly or Q2W in the Basic dose 
escalation scheme. In each cohort, at least 7 days must pass after dosing the 
first patient before dosing the second patient. Subsequent cycles may be 
administered at the same dose and schedule until unacceptable toxicity, disease 
progression, death, withdrawal of consent, Investigator’s decision and/or availability 
of study drug.  
During Phase 2, Stage 1, SAR650984 will be administered as follows: 
x 
Arm 1: 3 mg/kg on Day 1 and 15 of each 28-day cycle 
x 
Arm 2: 10 mg/kg on Day 1 and 15 of each 28-day cycle 
x 
Arm 3: 10 mg/kg on Day 1 and 15 of Cycle 1 and 2, then 10 mg/kg on  
Day 1 of each 28-day cycle 
x 
Arm 4: 20 mg/kg on Day 1, 8, 15 and 22 of Cycle 1, then 20 mg/kg on  
Day 1 and 15 of each 28-day cycle  
During Phase 2 Stage 2, in ISA and ISAdex arms, SAR650984 will be administered 
at the dose of 20 mg/kg on Day 1, 8,15 and 22 (QW) of Cycle 1 followed by 20 mg/kg 
on Day 1 and 15 (Q2W) of subsequent cycles (Day 1 of Cycle n correspond to 
Day 29 of Cycle n-1). 


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In ISAdex arm, dexamethasone will be administered IV or PO on Day 1, 8, 15 and 
22 of each cycle, at the following dose: 
x 
Patients of <75 year-ROGPJGD\RULQSDWLHQWVRI\HDU-old: 
20 mg/day. 
On the days of SAR650984 infusion, the administration of dexamethasone will be 
used as part of premedication and should follow the premedication rules. 
Dexamethasone is both part of the back bone treatment regimen and isatuximab 
premedication (Section 8.2) 
PRIMARY ENDPOINT(S) AND 
MAIN 
SECONDARY ENDPOINT(S): 
Phase 1 primary endpoint 
The safety of SAR650984 will be evaluated using the following assessments 
x Incidence of DLT observed during the first two cycles (4 weeks); 
x Allergic reactions/hypersensitivity and cytokine release syndrome/acute 
infusion reactions; 
x All reported adverse events; 
x Changes from baseline laboratory findings, baseline vital signs, neurological 
exams, and safety related parameters will be evaluated for clinical 
significance; 
x Clinically important electrocardiogram (ECG) findings since the 
first administration of SAR650984 including QTc interval. 
For the purposes of dose escalation and determination of the MTD/RP2D dose, only 
DLTs that occur during the first 28 days (Cycle 1 and Cycle 2) of treatment will be 
considered for decisions regarding dose escalation. 
DLTs are defined as any Grade 3 or higher non-hematological toxicity (with the 
exception of allergic reaction/hypersensitivity), Grade 4 neutropenia and/or Grade 4 
thrombocytopenia lasting longer than 5 days, attributed to SAR650984 and as 
defined by the NCI-CTCAE v.4.03.  
Any other toxicity that the Investigator and the sponsor deem to be dose limiting, 
regardless of the grade, may also be considered as DLT. 
Before escalating SAR650984 dose to the next DL, the safety data and especially the 
reported potential DLTs will be reviewed to determine their relationship to the IP. 
Dose escalation or dose decrease decisions will be based on the assessment of IP 
related '/7VE\WKH6DIHW\&RPPLWWHH'RVHHVFDODWLRQZLOOEHVWRSSHGLI
 in up to 6 patients) of patients experienced an IP related DLT observed during 
the first two cycles (4 weeks). 
In case of available usable prophylactic and/or curative treatment for a dose limiting 
non-hematologic adverse event (eg, diarrhea, hypersensitivity, nausea-vomiting, 
hyperglycemia), this treatment may be evaluated in an additional cohort of up to 
6 patients treated at the same DL. Further dose escalation could be allowed if <33% 
of patients in this additional cohort experience DLT when receiving the 
prophylactic/corrective therapy. These prophylactic/corrective therapies will be 
systematically implemented in further DLs. In addition, in the expansion cohort at 
MTD, cumulative toxicities will be analyzed, in order to confirm the feasibility of the 
MTD selected in the dose escalation step. 
Although the dose escalation process is guided by the safety evaluation during 
two cycles of treatment, cumulative toxicities observed in subsequent administrations 
should also be considered for the dose escalation and the dose selection decisions 
(ie, smaller increases in dose, expansion of a given DL, intermediate DL), upon 
agreement by the Study Committee. 


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Phase 1 secondary endpoints 
1. 
Pharmacokinetic assessments: 
x 
Concentration observed at the end of an intravenous (IV) infusion (Ceoi) 
x Maximum observed concentration (Cmax); 
x 
Time to reach Cmax (tmax) 
x Concentrations just before drug infusion (Ctrough) 
x AUC over the dosing interval (AUC1 week or AUC2 week) 
2. 
Pharmacodynamic assessment:  
x Serum/plasma markers will include: 
- 
Hs-CRP. 
- 
Tumor necrosis factor alpha (TNF-Į). 
- 
IL-6. 
- 
IL-1-ȕ. 
- 
IFN-Ȝ. 
- 
CD38 receptor density and occupancy. 
Please refer to Section 1.4 to Section 1.9 (study flowchart tables for more information 
regarding measurement and time points) 
3. 
Immune response:  
x Antibodies to SAR650984 will be assessed (Section 9.4). 
4. 
Clinical assessment will include: 
x Disease response according to standard criteria for hematologic 
malignancies and staging (at baseline). 
x Karnofsky performance status evaluation. 
x Results of additional procedures performed as part of standard of care to 
assess the current disease status may also be collected. 
 
Phase 2 Primary endpoint 
ORR is defined as the proportion of patients with stringent complete response (sCR), 
(CR), (VGPR), and partial response (PR) based on responses as assessed by the 
Independent Adjudication Committee (IAC) using the International Myeloma Working 
Group (IMWG) Uniform Response Criteria (1) in Stage 1 and the IMWG Response 
Criteria updated in 2014 (2) in Stage 2. 
Response evaluation will include: 
x 
M-protein quantification (serum and 24-hr urine). 
x 
Serum free light chain levels. 
x 
Bone marrow biopsy/aspiration. 
x 
PET-CT and/or CT/MRI scan of plasmacytoma. 
x 
Bone skeletal survey and/or low dose whole body CT scan. 
x 
Corrected serum calcium. 
Phase 2 secondary endpoints 
1. 
Safety profile of SAR650984 in terms of treatment-emergent adverse 
events/serious adverse events (TEAE/SAE) and changes in laboratory 
parameters, vital signs, ECGs and assessment of physical examination. 
2. 
Secondary efficacy endpoints: 
x 
Duration of Response (DOR): defined as the time from the date of the first 
IAC determined response to the date of subsequent IAC determined PD or 
death, whichever happens earlier. DOR will not be calculated for patients 
that do not achieve a response.  


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x 
CBR: defined as the proportion of patients with sCR, CR, VGPR, PR or MR 
according to IMWG criteria, as determined by the IAC. 
x 
PFS: defined as the time interval from the date of first study treatment 
administration to the date of the first IAC-assessed disease progression or 
the date of death due to any cause, whichever comes first. 
x 
OS: defined as the time interval from the date of first study treatment 
administration to death from any cause. 
3. 
HRQOL and disease-related symptoms will be assessed through the EORTC  
QLQ-C30 and MY20 questionnaires; generic health status will be assessed 
through the EQ-5D. These will be captured electronically throughout the study 
(Stage 1 only). 
4. 
Pharmacokinetic parameters evaluated:  
x 
The PK profile of isatuximab will be assessed using population PK 
approach. This analysis will involve an estimation of inter-patient PK 
variability and the population PK parameters estimates. Empirical Bayesian 
estimation of individual parameters and of individual exposure (Ctrough and 
AUC) will also be performed. 
5. 
Antibodies to SAR650984 (ADA, Anti-Drug Antibodies) will be assessed 
throughout the study. 
6. 
CD38 receptor density from baseline bone marrow aspirates will be correlated 
with parameters of clinical response, including ORR, CBR, DOR, PFS and/or OS  
(Stage 1 only). 
7. 
CD38 receptor occupancy from bone marrow aspirates will be correlated with 
PK and clinical response parameters (Stage 1 only). 
 
Phase 2 exploratory endpoints 
1. 
MRD by sequencing and/or flow cytometry will be assessed in patients achieving 
a CR and correlated with clinical outcome. 
2. 
Bone marrow and/or blood samples will be analyzed for genomic profiling and 
multiple myeloma molecular subtype (using cytogenetics and gene sequencing) 
and bone marrow for the levels of CD38 mRNA. These markers will be 
correlated with clinical response. 
3. 
Blood samples will be analyzed for immune genetic determinants (such as FcGR 
polymorphisms, HLA and KIR genotypes, etc) and correlated with clinical 
response. 
4. 
Correlation of immune phenotype (such as B-cell, T-cell, and NK-cell subsets) in 
bone marrow and peripheral blood with parameters of clinical response. 
5. 
Blood samples will be analyzed to investigate the relationship between soluble 
CD38 and parameters of PK and clinical response. (Stage 1 only). 
6. 
Blood samples will be analyzed for changes in the diversity of the adaptive 
immune response, including TCR repertoire, humoral and cellular immune 
responses to myeloma-related tumor antigens and correlated with clinical 
response. (Stage 2 only). 
7. 
Additional molecular analysis, not specified in the protocol but related to the drug 
action and/or effect of SAR650984, may be conducted on remaining samples 
pending evolving literature. 
EVALUATION CRITERIA: 
Safety will be evaluated from physical examination, laboratory tests, and reports of 
adverse events, according to the NCI-CTCAE v. 4.03 grading scale. In the Phase 1 
part, safety review will be conducted by the Study Committee. This review must take 
place prior to enrollment of patients in subsequent cohort. 


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For Phase 1:  
Response information, ie, category of disease response such as CR (complete 
response or complete remission), PR (partial response), SD (stable disease) or PD 
(progressive disease) will be obtained and evaluated based on standard criteria for 
underlining disease. 
x 
Lymphomas: NCI-sponsored international Working Group (3) 
x 
Leukemias : NCI-sponsored International Working Group for CLL (4) and  
AML (5)  
x 
Multiple Myeloma: International Group of multiple myeloma and bone 
marrow transplant experts (6)  
For Phase 2: 
Stage 1 IMWG Uniform Response Criteria (1) 
Stage 2 updated IMWG Uniform Response Criteria (2) 
ASSESSMENT SCHEDULE: 
Safety evaluation 
 
Safety evaluation will be performed continuously throughout the Phase 1 and 
Phase 2 parts, please refer to the Study Flowcharts for the assessment timings of the 
following: 
 
x 
PSA and pituitary hormones levels (GH, FSH/LH, ACTH, TSH) (Phase 1 
only) 
 
x 
Cytokines (TNF-Į,/-1-ȕ,/-6, IFN-ȖPDUNHUVRIFRPSOHPHQW&&
CH50), serum tryptase (Phase 1 and Phase 2 Stage 1 only) 
 
x 
Pulmonary function tests (Phase 1 only) 
 
x 
ECG and Holter (Phase 1 only) monitoring 
 
x 
Chest x-ray 
 
PK evaluation 
 
During the Phase 1 and Phase 2 parts, PK samples will be collected per PK Study 
Flowcharts. 
 
Disease response evaluation 
 
The disease assessment in Phase 1 and Phase 2 will be performed according to the 
Study Flowcharts. 
 
x 
Multiple Myeloma (Phase 1 and Phase 2): 
 
- 
Bone marrow biopsy/aspiration. 
 
- 
Radiologic imaging of plasmocytoma.  
 
- 
Bone skeletal survey.  
 
- 
M-protein quantification (serum and/or 24-hr urine), serum free light 
chain levels. 
 
- 
Serum ȕ2-microglobulin. 
 
x 
B-cell NHL (Phase 1 only): 
 
- 
Bone marrow biopsy/aspiration (leukemia) as clinically indicated. 
 
- 
Lymph node biopsy as clinically indicated. 
 
- 
Radiologic tumor assessment (by X-ray, computed tomography [CT] 
scan, PET scan, or magnetic resonance imaging [MRI]; ultrasound is 
not sufficient) (lymphoma). 
 
x 
B-cell ALL (Phase 1 only): 
 
- 
Bone marrow biopsy/aspiration. 
 
- 
Blood count with differential including blast count. 


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x 
AML (Phase 1 only): 
 
- 
Bone marrow biopsy/aspiration. 
 
- 
Blood count with differential including blast count. 
 
x 
CLL (Phase 1 only): 
 
- 
Clinical examination. 
 
- 
Bone marrow biopsy/aspiration. 
 
- 
Lymph node biopsy as clinically indicated. 
 
- 
Blood count with differentials. 
- 
Serum ȕ-microglobulin. 
 
Other evaluations 
 
During the Phase 1 and Phase 2 parts, the following evaluations will be performed 
according to the Study Flowcharts 
 
x 
Receptor density (RD) on bone marrow samples (Phase 1 and Phase 2 
Stage 1 only). 
x 
Receptor occupancy (RO) on bone marrow samples (Phase 1 and Phase 2 
Stage 1 only). 
 
x 
Level of soluble CD38 (Phase 2 Stage 1 only). 
x 
Level of human anti-drug antibodies (ADA). 
x 
Immune phenotyping and molecular analysis on blood and bone marrow 
samples (Phase 2). 
STATISTICAL 
CONSIDERATIONS: 
Determination of the sample size 
 
Phase 1 
The Phase 1 part of this study aims to establish the MTD/RP2D of SAR650984 
according to DLTs observed. The number of DLs examined and the emerging 
SAR650984 related toxicities will determine the sample size. It is anticipated that up 
to approximately 85 patients will be required to establish the selected dose of 
SAR650984.  
In Cohort 11, 12 and 13, approximately 6-12 patients may be enrolled in order to 
determine the RP2D dose. In addition, up to 18 patients in the standard risk and up to 
18 patients in the (optional) high risk expansion cohorts will be enrolled and treated at 
the MTD. 
Phase 2 
Stage 1: 
Although Stage 1b has been added in protocol amendment 10 and will start after 
enrollment in Stage 1a is completed (ie, patients will not be randomized between the 
4 doses/schedules tested), sample size for Stage 1 will be calculated considering 
Stage 1a and 1b as a whole with 4 arms. 
Stage 1 of the Phase 2 study is based on a selection design (7) Such a design is 
used to maximize the probability of selecting the best of the four SAR650984 doses 
tested during Stage 1 using ORR as endpoint. No statistically significant difference 
between the four treatment arms is required to select a recommended Stage 2 dose. 
A total of 96 patients (24 patients by arm) will provide at least 80% probability to 
select the better SAR650984 dose assuming an ORR of 10% in the 3 mg/kg arm and 
assuming the difference in ORR between the best dose and 3 mg/kg arm is at least 
15%. 


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Phase 2 Stage 2:  
ISA arm: 105 patients will be randomized in the SAR650984 arm. Given an assumed 
WUXH255RIWKHQXOOK\SRWKHVLV255ZLOOEHUHMHFWHGXVLQJDQH[DFW
binomial test at a one-sided alpha of 0.025 with 90% power, if the observed ORR is 
greater than or equal to 22.9% (ie, 24 responders). 
ISAdex arm: 55 patients will be randomized in the SAR650984+dexamethasone arm. 
Given an assumed true ORR of WKHQXOOK\SRWKHVLV25515% will be rejected 
using an exact binominal test at a one-sided alpha of 0.025 with at least 85% power, 
if the observed ORR is greater than or equal to 27.3% (15 responders). 
Main analysis populations 
For both Phase 1 and Phase 2 parts of the study, the all treated/safety population will 
include all patients who have given their informed consent and who have received at 
least one dose (even incomplete) of SAR650984. This population is the primary 
population for the analyses of efficacy and safety parameters. All analyses using this 
population will be based on the treatment actually received. For Phase 2 Stage 2, 
patients who received dexamethasone in addition to isatuximab (excluding when 
given as part of premedication) will be included in the ISAdex arm. 
In the Phase 1 part, the DLT evaluable population is the subset of patients from the 
all treated population with a DLT assessment at the end of Cycle 2. 
 
General statistical approach 
 
Data from Phase 1 and each stage of the Phase 2 will be analyzed and reported 
separately. In particular data from Stage 1a and Stage 1b will be presented in the 
same set of tables. Summary tables will be presented by dose levels/arm (when 
appropriate) and overall, unless otherwise noted. 
Phase 1 Dose escalation step. 
 
IP related DLTs will be assessed and analyzed on all treated patients. 
 
The type, frequency, seriousness and relatedness of IP emergent adverse events 
(TEAEs) will be summarized and listed according to MedDRA (Medical Dictionary for 
Regulatory Affairs). Laboratory abnormalities will be summarized according to the 
NCI-CTCAE v. 4.03. 
 
Pharmacokinetics parameters will be summarized with descriptive statistics (mean, 
geometric mean, median, standard deviation, standard error of the mean, coefficient 
of variation, minimum and maximum). 
 
Immune response, pharmacodynamics marker results will be descriptively 
summarized and tabulated. 
 
ORR and duration of response will be listed along with relevant patient/disease 
characteristics. In addition, ORR and duration of response will be summarized with 
descriptive statistics and 95% confidence interval (for ORR only) for patients with 
MM. 
 
Phase 1 Expansion cohort 
Similar analyses as described above will be performed. 
Phase 2 
Analysis of primary efficacy endpoint: 
ORR will be summarized with descriptive statistics. A 95% two-sided confidence 
interval will be computed using Clopper-Pearson method. For Stage 2, the null 
hypothesis that the true response rate (ORR) is <15% will be tested in each arm 
using a one-sided exact binomial test with a significance level of 0.025. 


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Analysis of secondary efficacy endpoints: 
DOR, PFS and OS will be analyzed using Kaplan-Meier methods. 
Analysis of PRO endpoints: 
Changes from baseline in HRQOL, disease-related symptoms, and health status will 
be descriptively summarized, along with an evaluation of PRO responses in relation 
to clinical responders. 
Analysis of safety endpoints: 
Number (%) of patients experiencing treatment-emergent adverse events (TEAEs) by 
primary system organ class and preferred term will be summarized by CTCAE grade 
DOOJUDGHVDQG*UDGHIRUWKHVDIHW\SRSXODWLRQ6DPHWDEOHZLOOEHSUHSDUHGIRU
drug-related TEAEs, TEAEs leading to treatment discontinuation, 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. 
Hematology and biochemistry results will be graded according to the CTCAE 
version 4.03, when applicable. Number (%) of patients with laboratory abnormalities 
(ie, all grades DQG*UDGHXVLQJWKHZRUVWJUDGHGXULQJWKHRQ-treatment period 
will be provided for the safety population. 
Interim Analysis 
Interim analysis may be performed for Phase 2 Stage 2 if enrollment is not completed 
in December 2017. 
DURATION OF STUDY PERIOD  
Per patient 
For the Phase 1 part, study duration for an individual patient will include a screening 
period for inclusion of up to 2 weeks, up to 4 weeks of SAR650984 administration 
unless discontinued earlier due to safety or disease progression, followed by a 
minimum of 30 days following the last use of study drug or more than 30 days in case 
of unresolved toxicity, or up to initiation of another anticancer treatment. Patients with 
SD, or objective response (CR, PR) and no DLT at the end of 4 weeks of SAR650984 
dosing may be considered for continue treatment as long as clinical benefit is 
possible, or until PD or for other reasons for discontinuation (see Section 11.2). 
During the follow-up period IP-related adverse events and all serious adverse events 
(regardless of relationship to study treatment) ongoing at the time of study treatment 
discontinuation will be followed until resolution or stabilization. 
For the Phase 2 part, study duration for an individual patient will include a screening 
period for inclusion of up to 3 weeks prior to the first administration of IP, then a 
treatment and a follow-up period. Following the screening period, eligible subjects will 
receive SAR650984 according to their assigned schedule. Treatment will continue 
until disease progression, unacceptable adverse reaction or other reason for 
discontinuation (see Section 11.2). 
Patients with documented disease progression at the end of treatment visit will 
receive follow-up visits at 30, 60 and 90 days after the last dose (in Phase 2 Stage 1 
part) and at 60 days after the last dose of study treatment, in Phase 2 Stage 2 part, 
and the further follow up according to following rules.  
Patients discontinuing SAR650984 +/- dexamethasone for reason other than disease 
progression at the end of study treatment visit and have not started treatment with 
another anti-cancer therapy will be followed-up for efficacy and safety every 4 weeks 
until disease progression, death, cutoff date whichever comes first. Then, after 
documentation of disease progression, patients will be followed every 3 months until 
death or cutoff date whichever comes first.  
Patients discontinuing study treatment due to disease progression at the end of 
treatment visit will be followed every 3 months until death or cutoff date whichever 
comes first. However, female patients of childbearing potential will have the serum 
pregnancy test every month for 5 months after the last administration of SAR650984. 


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During the follow-up period study treatment -related adverse events and all serious 
adverse events (regardless of relationship to study treatment) ongoing at the time of 
study treatment discontinuation will be followed until resolution or stabilization. 
Per study 
The Phase 1 study final analysis cutoff date will be 4 months after the date of the 
first dose of the last patient on the Phase 1 study. 
For the Phase 2 Stage 1 part, the cutoff date for the primary analysis of ORR and for 
the secondary analysis will be 12 months after the date of the first dose of the last 
patient.  
For the Phase 2 Stage 2 part, the cutoff date for the primary analysis of ORR will be 
4 months after the date of the first dose of the last patient. Final analysis cutoff date 
for the updated analysis of ORR and final analysis of secondary endpoints will be 
12 months after the date of the first dose of the last patient. 
Patients still on treatment at time of the final analysis cutoff dates who still continue 
benefiting from treatment with SAR650984 will have the option to continue treatment 
under this protocol until disease progression, unacceptable AEs, patient wish, or any 
other reason. For cycles completed after the cut-off date, all new related AEs (serious 
or not), all ongoing SAE (related or not) and all ongoing related non serious AEs, and 
reason of end of treatment will continued to be collected. Additionally, study treatment 
administration will be collected. No PK or ADA samples will be collected post data 
cut-off. If last ADA before cut-off date is positive, one additional sampling time for 
ADA evaluation should be collected 3 months later. No further ADA will be sampled, 
even if this 3-month sample is positive. 




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1.2 
DIAGRAM 2: PHASE 1 BASIC DOSE ESCALATION PHASE - METHODOLOGY  
  


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1.3 
DIAGRAM 3: PHASE 2 STUDY DESIGN  
 
 
 












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6. 
Sample can be collected during the screening period. 
7. 
If the PK sample at EOI is not collected on D15 of Cycle 1, this can be collected after the next IP administration. 
8. 
Sample to be collected on D15 of Cycle 2 and 3 even though no SAR650984 is administered on D15 of Cycle 3. 
9. 
If the PK sample at EOI is not collected on D1 of Cycle 4, this can be collected after the next IP administration. 
10. At 60 days, if patient is positive for ADA or the sample is inconclusive, additional ADA sample are required every 30 days (±5 days) until sample is interpretable or negative. This will only be for Phase 2 Stage 1. 
11. Only for Stage 1 patients enrolled at selected sites. 
12. PK and ADA samples for patients in Phase 2 Stage 2 will be collected up to Cycle 10, inclusive. If ADA is positive at Cycle 10, one additional ADA sample will be collected 3 months later. For patients treated with 
less than 10 cycles at the cut-off or early discontinuation, both PK and ADA samples collection will be stopped from the cut-off or discontinuation date, If the ADA is positive, one additional ADA sample will be 
collected 3 months later.  
13. PK and ADA sample only if the patient does not complete 10 cycles of treatment. If ADA is postive, one additional ADA sample should be collected 3 months later.  


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1.9 
STUDY FLOWCHART FOR PHASE 1 ACCELERATED DOSE ESCALATION PHASE  
 
Evaluation
1 
Screening/Baseline 
Treatment Cycle 1 
Treatment Cycle 2 
Subsequent 
cycles
22 
End of 
treatment 
(EOT)
23 
Follow-up period
24 
D-15 to D1 
D1
2 D2 D3 D8 D14 
D1
2 
(D15) 
D2 D3 D8 D14 
D1
2 
(D15)
 
D2 
30 days  
(+/-5 days) 
after last IP 
administration 
>30 Days 
Informed Consent/Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography/Medical/Surgical and Disease 
History
3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination
4 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
X 
 
Weight/Height (height at baseline only) 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
X 
 
Vital Signs
5 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Chest X-ray, Spirometry, Diffusion Capacity
6 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X  
 
Performance Status (Karnofsky) 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
X 
 
CD38 Expression
7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serumȕ2-microglobulin (CLL, MM only) 
X 
 
 
 
 
X 
 
 
 
 
X 
X (end of even-
numbered 
cycles) 
 
X 
 
Immunoglobulins: IgG, IgA, IgM (MM only) 
X 
 
 
 
 
X 
 
 
 
 
X 
X (end of even-
numbered 
cycles) 
 
X 
 
Disease Assessment
8 † (baseline within 
28 days) 
X† 
 
 
 
 
 
 
 
 
 
X 
X (end of even-
numbered 
cycles) 
 
X 
 
Pregnancy Test
9 ‡ (baseline within 7 days) 
X‡ 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Blood Chemistry
10 
X 
X
11 
X
12 
 
X 
X 
X
11 
X
12 
 
X 
X 
X 
 
X 
 
Hematology
13 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
X 
 




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1. 
Evaluation: Assessments should be performed prior to IP administration unless otherwise indicated. Results should be reviewed by the Investigator prior to the administration of the next dose. A Cycle is 
14 days. 
2. 
D1: Day 1 of Cycle 1 refers to the day the patient receives the first IP administration. Day 1 of each subsequent cycle corresponds to Day 15 (+/-1 day) of the previous cycle. Before Cycle 1, blood chemistry, 
hematology, coagulation, and urinalysis assessments are not required if acceptable screening assessment is performed within 1 day prior to first IP administration; before subsequent cycles, assessments not 
required if acceptable assessment is performed on D14 of previous cycle. 
3. 
Demography: Includes age, gender and race. Medical/Surgical History: Includes relevant history of previous/associated pathologies, other than the tumor. Disease History: Includes date of initial diagnosis, 
stage and extent of the disease, previous anti-tumor therapy (type and response to), disease status at inclusion (primary refractory, refractory to last therapy, or recurrent). In addition, results of additional procedures 
(such as karyotype, FISH, etc) performed as part of standard of care to assess the current disease status may also be collected. 
4. 
Physical Examination: Consists of examination of major body systems, including neurological, digestive exam, extramedullary myeloma localizations, respiratory, hepatomegaly, splenomegaly, lymphadenopathy. 
Only clinically relevant findings will be reported in the CRF as AEs.  
5. 
Vital Signs: Blood pressure, heart rate, temperature, and respiration rate required at screening, Day 1 (just before starting infusion, end of infusion, and 1, 2, 4, 6, and 24 hours post-infusion) in each cycle, Day 8 
and Day 14 (Cycles 1 and 2), and as clinically indicated. The final measurements will be performed at the EOT visit. 
6. 
Chest X-ray, Spirometry, Diffusion Capacity: To be done within one week prior to IP administration in each cycle. The final measurements will be performed at the EOT visit. 
7. 
CD38 Expression: Archival samples may be used. If no archival sample, will be assessed at screening by flow cytometry and/or immunohistochemistry using malignant cells from peripheral blood, bone marrow 
and/or lymph node tissue depending on the disease type. When feasible, bone marrow and tissue samples will be obtained by Fine Needle Aspiration (FNA).  
8. 
Disease Assessment: To be done at screening up to 28 days prior to first IP administration. Response is assessed on the basis of clinical, laboratory, radiologic, and pathologic (ie, bone marrow) findings at the 
end of Cycle 2 to determine if patient is eligible to continue treatment. Patients continuing after Cycle 2 should be evaluated for disease status at least every 4 weeks (even-numbered cycles), whenever disease 
progression is suspected (eg, symptomatic deterioration), to confirm a partial or complete response (4-6 weeks after initial documentation of response), and at the EOT visit.)  
x 
MM: Bone marrow biopsy/aspiration, radiologic imaging of plasmocytoma as clinically indicated, bone skeletal survey as clinically indicated, M-protein quantification (serum and/or 24-hr urine), serum free 
light chain levels, or urinary light chain levels as clinically indicated 
x 
B-cell NHL: Bone marrow biopsy/aspiration as clinically indicated, lymph node biopsy as clinically indicated, radiologic tumor assessment (by X-ray, computed tomography [CT] scan, PET scan or magnetic 
resonance imaging [MRI]; ultrasound is not sufficient) 
x 
B-cell ALL: Bone marrow biopsy/aspiration, Blood count with differential including blast count 
x 
AML: Bone marrow biopsy/aspiration, Blood count with differential including blast count 
x 
CLL: Clinical examination, bone marrow biopsy/aspiration, lymph node biopsy as clinically indicated, Blood count with differential 
9. 
Pregnancy Tests: Women of child bearing potential must have a negative serum pregnancy test result within 7 days prior to first IP administration and at the EOT visit; negative urine pregnancy test required prior 
to each subsequent IP administration.  
10. Blood Chemistry:  
x 
Liver function tests: SGOT (AST), SGPT (ALT), bilirubin (total and direct), alkaline phosphatase, lactate dehydrogenase (LDH) 
x 
Renal function: sodium, potassium, chloride, bicarbonate/carbon dioxide, calcium, magnesium, phosphate, uric acid, blood urea nitrogen (BUN), serum creatinine and estimated creatinine clearance 
(Cockcroft-Gault Formula).  
x 
Other: glucose, albumin, total protein, peptide C  
x 
Erythrocyte sedimentation rate (ESR)  
11. Samples to be drawn immediately before the start of infusion, at the end of infusion, and 6 hours after the end of infusion.  
12. Sample to be drawn 24 hours after the end of infusion on D1.  
13. Hematology: Hemoglobin, hematocrit, RBC, WBC with differential, MCV, platelet counts, blast counts (AML/B-cell ALL). If grade 4 neutropenia, assess ANC every 2-3 days until ANC t0.5 x 109/L and at least 
weekly thereafter until ANC t1.0 x 109/L. 
14. Urinalysis: blood, protein, glucose, pH, ketones, bilirubin, leucocytes, nitrates, specific gravity.  
15. hs-CRP: To be done at Cycle 1 Day 1 prior to first IP administration, and 6 and 24 hours post-infusion in each cycle.  


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16. 12-Lead ECG: To be performed Day 1 (just before starting infusion and end of infusion) in each cycle, Day 8 (Cycles 1 and 2) and Day 14 (Cycle 2), and as clinically indicated. The final measurements will be 
performed at the EOT visit. 
17. Holter Monitoring: To be placed on the patient 2 hours before starting the infusion and remain on the patient until 24 hours after the infusion (Cycles 1 and 2). 
18. SAR650984 Administration: At the start of each treatment cycle, the patient’s weight will be determined. The following clinical assessments are required: blood pressure, heart rate, temperature, and respiration 
rate required just before starting infusion, end of infusion, and 1, 2, 4, and 24 hours post-infusion in each cycle and as clinically indicated.  
19. Cytokines (TNF-Į,/-1-ȕ,/-6, IFN-Ȗ Baseline sample to be drawn prior to first IP administration at Cycle 1, then at 6 and 24 hours post-infusion in each cycle. Samples to be shipped directly to Singulex (Refer 
to lab manual).  
20. RO: See details regarding sampling times on Pharmacokinetics/Pharmacodynamics Flowchart Accelerated Phase. Samples to be shipped directly to Biocytex (Refer to lab manual). 
21. PK, Anti-Drug Antibodies: See details regarding sampling times on Pharmacokinetics/Pharmacodynamics Flowchart Accelerated Phase. Samples to be shipped to Covance (Refer to lab manual). 
22. Subsequent Cycles: After completing two cycles, patients may receive additional administrations of SAR650984 at Investigator’s discretion. 
23. End of Treatment (EOT): Assessments to be performed 30 days (+/-5 days) after last IP administration. 
24. Follow-up Period: Patients will be followed beyond 30 days if IP-related AE and/or unresolved toxicity. PK and ADA samples required 60 days (+/-5 days) after last IP administration. 
25. If disease assessment bone marrow biopsy/aspiration required at screening is completed within 7 days prior to IP administration, RO in bone marrow can be measured at that time. 
26. RO in bone marrow for MM patients is optional for Cohorts 1-3. 


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1.10 
STUDY FLOWCHART FOR PHASE 1 BASIC DOSE ESCALATION PHASE (SAR650984 ADMINISTRATION EVERY 2 WEEKS - FOR 
COHORTS 6-10)  
 
Evaluation
1 
Screening/Baseline 
Treatment Cycle 1 
Treatment Cycle 2 
Subsequent cycles
22 
End of 
treatment 
(EOT)
23 
Follow-up 
period
24 
D-15 to D1 
D1
2 D2 D3 D8
27 D14
27 
D1
2 
(D15) 
D2 D8
27 D14
27 
D1
2 
(D15)
 
D2 
30 days  
(+/-5 days) 
after last IP 
administration 
>30 Days 
Informed Consent/Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography/Medical/Surgical and Disease 
History
3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination
4 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
Weight/Height (height at baseline only) 
X 
X 
 
 
 
X 
X 
 
 
X 
X 
 
X 
 
Vital Signs
5 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chest X-ray, Spirometry, Diffusion Capacity
6 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
Performance Status (Karnofsky) 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
CD38 Expression
7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serumȕ2-microglobulin (CLL, MM only) 
X 
 
 
 
 
X 
 
 
 
X 
X (end of even-
numbered cycles) 
 
X 
 
Immunoglobulins: IgG, IgA, IgM (MM only) 
X 
 
 
 
 
X 
 
 
 
X 
X (end of even-
numbered cycles) 
 
X 
 
Disease Assessment
8 † (baseline within 28 days) 
X† 
 
 
 
 
 
 
 
 
X 
X (end of even-
numbered cycles) 
 
X 
 
Pregnancy Test
9 ‡ (baseline within 7 days) 
X‡ 
X 
 
 
 
 
X 
 
 
X 
X 
 
X 
 
Blood Chemistry
10 
X 
X
11 
X
12 
 
X 
X 
X
11 
X
12 
X 
X 
X 
 
X 
 
Hematology
13 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
PSA, Pituitary Hormones (GH, FSH/LH, ACTH, 
TSH) 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
X 
 
Coagulation (PT/INR, PTT) 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 




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2. 
D1: Day 1 of Cycle 1 refers to the day the patient receives the first IP administration.  Day 1 of each subsequent cycle corresponds to Day 15 (+/-1 day) of the previous cycle.  Before Cycle 1, blood chemistry, 
hematology, coagulation, and urinalysis assessments not required if acceptable screening assessment is performed within 1 day prior to first IP administration; before subsequent cycles, assessments not required 
if acceptable assessment is performed on D14 of previous cycle. If necessary treatment with SAR650984 may be slightly delayed (max 7 days) for subsequent cycles following Cycle 2 Day 14 while awaiting results 
of disease assessment parameters. 
3. 
Demography: Includes age, gender and race. Medical/Surgical History: Includes relevant history of previous/associated pathologies, other than the tumor. Disease History: Includes date of initial diagnosis, 
stage and extent of the disease, previous anti-tumor therapy (type and response to), disease status at inclusion (primary refractory, refractory to last therapy, or recurrent). In addition, results of additional procedures 
(such as karyotype, FISH, etc) performed as part of standard of care to assess the current disease status may also be collected. 
4. 
Physical Examination: Consists of examination of major body systems, including neurological, digestive exam, extramedullary myeloma localizations, respiratory, hepatomegaly, splenomegaly, lymphadenopathy. 
Only clinically relevant findings will be reported in the CRF as AEs. 
5. 
Vital Signs: Blood pressure, heart rate, temperature, and respiration rate required at screening, Day 1 (just before starting infusion, middle of infusion, end of infusion, and 1, 2, 4, 6, and 24 hours post-infusion) in 
each cycle, Day 8 and Day 14 (Cycles 1 and 2), and as clinically indicated. The final measurements will be performed at the EOT visit. 
6. 
Chest X-ray, Spirometry, Diffusion Capacity: To be done within one week prior to IP administration for the first 2 cycles and then as clinically indicated. The final measurements will be performed at the EOT 
visit. 
7. 
CD38 Expression: Archival samples may be used. If no archival sample, will be assessed at screening by flow cytometry and/or immunohistochemistry using malignant cells from peripheral blood, bone marrow 
and/or lymph node tissue depending on the disease type. When feasible, bone marrow and tissue samples will be obtained by Fine Needle Aspiration (FNA).  
8. 
Disease Assessment: To be done at screening up to 28 days prior to first IP administration. Response is assessed on the basis of clinical, laboratory, radiologic, and pathologic (ie, bone marrow) findings at the 
end of Cycle 2 to determine if patient is eligible to continue treatment. Patients continuing after Cycle 2 should be evaluated for disease status at least every 4 weeks (end of every even-numbered cycle), whenever 
disease progression is suspected (eg, symptomatic deterioration), to confirm a partial or complete response (4-6 weeks after initial documentation of response), and at the EOT visit.  
x 
MM: Bone marrow biopsy/aspiration as clinically indicated, radiologic imaging of plasmocytoma as clinically indicated, bone skeletal survey as clinically indicated, M-protein quantification (serum and/or 
24-hr urine), serum free light chains, or urinary light chain levels as clinically indicated 
x 
B-cell NHL: Bone marrow biopsy/aspiration as clinically indicated, lymph node biopsy as clinically indicated, radiologic tumor assessment (by X-ray, computed tomography [CT] scan, PET scan or magnetic 
resonance imaging [MRI]; ultrasound is not sufficient) 
x 
B-cell ALL: Bone marrow biopsy/aspiration as clinically indicated, Blood count with differential including blast count 
x 
AML: Bone marrow biopsy/aspiration as clinically indicated, Blood count with differential including blast count 
x 
CLL: Clinical examination, Bone marrow biopsy/aspiration as clinically indicated, Lymph node biopsy as clinically indicated, Radiologic imaging (CT scan) as clinically indicated, Blood count with differential 
9. 
Pregnancy Tests: Women of child bearing potential must have a negative serum pregnancy test result within 7 days prior to first IP administration and at the EOT visit; negative urine pregnancy test required prior 
to each subsequent IP administration.  
10. Blood Chemistry:  
x 
Liver function tests: SGOT (AST), SGPT (ALT), bilirubin (total and direct), alkaline phosphatase, lactate dehydrogenase (LDH) 
x 
Renal function: sodium, potassium, chloride, bicarbonate/carbon dioxide, calcium, magnesium, phosphate, uric acid, blood urea nitrogen (BUN), serum creatinine and estimated creatinine clearance 
(Cockcroft-Gault Formula).  
x 
Other: glucose, albumin, total protein, peptide C  
x 
Erythrocyte sedimentation rate (ESR)  
11. Samples to be drawn immediately before the start of infusion, at the end of infusion, and 6 hours after the end of infusion.  
12. Sample to be drawn 24 hours after the end of infusion on D1.  
13. Hematology: Hemoglobin, hematocrit, RBC, WBC with differential, MCV, platelet counts, blast counts (AML/B-cell ALL). If Grade 4 neutropenia, assess ANC every 2-3 days until ANC t 0.5 x 109/L and at least 
weekly thereafter until ANC t1.0 x 109/L. 
14. Urinalysis:  blood, protein, glucose, pH, ketones, bilirubin, leucocytes, nitrates, specific gravity.  
15. hs-CRP:  To be done at Cycle 1 Day 1 prior to first IP administration, and 6 and 24 hours post-infusion in each cycle. 


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16. 12-Lead ECG: To be performed Day 1 (just before starting infusion, middle of infusion and end of infusion) in each cycle, Day 8 (Cycles 1 and 2) and Day 14 (Cycle 2), and as clinically indicated.  The final 
measurements will be performed at the EOT visit. 
17. Holter Monitoring:  To be placed on the patient 1-2 hours before starting the infusion and remain on the patient until 24 hours after the infusion (Cycles 1 and 2). 
18. SAR650984 Administration: At the start of each treatment cycle, the patient’s weight will be determined. The following clinical assessments are required: blood pressure, heart rate, temperature, and respiration 
rate required just before starting infusion, middle of infusion, end of infusion, and 1, 2, 4, and 24 hours post-infusion in each cycle and as clinically indicated.        
19. Cytokines (TNF-į, IL-1-Ȗ,/-6, IFN-ȗ Baseline sample to be drawn prior to first IP administration at Cycle 1, then at 6 and 24 hours post-infusion in each cycle.  Samples to be shipped directly to Singulex (Refer 
to lab manual).  
20. RO:  See details regarding sampling times on Pharmacokinetics/Pharmacodynamics Flowchart Section 1.5 .  Samples to be shipped directly to Biocytex (Refer to lab manual). 
21. PK, Anti-Drug Antibodies: See details regarding sampling times on Pharmacokinetics/Pharmacodynamics Flowchart Section 1.5 . Samples to be shipped to Covance (Refer to lab manual). 
22. Subsequent Cycles: After completing two cycles, patients may receive additional administrations of SAR650984. 
23. End of Treatment (EOT): Assessments to be performed 30 days (+/-5 days) after last IP administration. 
24. Follow-up Period: Patients will be followed beyond 30 days for IP-related AE, all SAEs (regardless of relationship to study treatment) and/or unresolved toxicity. PK and ADA samples required 60 days (+/-5 days) 
after last IP administration. At 60 days, if patient is positive for ADA or the sample is inconclusive, additional ADA and PK samples are required every 30 days (±5 days) until sample is interpretable or negative. All 
IP-related AEs and all SAEs (regardless of relationship to study treatment) to be followed until ADA sample is negative. 
25. If disease assessment bone marrow biopsy/aspiration required at screening is completed within 14 days prior to IP administration, RO in bone marrow can be measured at that time. 
26. RO in bone marrow for MM patients is optional for Cohorts 1-3. 
27. Day 8 and Day 14 +/-1 day 


Amended Clinical Trial Protocol 14  
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SAR650984-TED10893-isatuximab 
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Property of the sanofi-aventis group - strictly confidential 
Page 40 
1.11 
STUDY FLOWCHART FOR PHASE 1 BASIC DOSE ESCALATION PHASE (SAR650984 ADMINISTRATION EVERY WEEK - FROM 
COHORT 11)  
 
Evaluation
1 
Screening/ 
Baseline 
Treatment Cycle 1 
Treatment Cycle 2 
Treatment Cycle 3 
Subsequent 
cycles
21 
End of 
treatment 
(EOT)
22 
Follow-up 
period
23 
D-15 to D1 D1
2 D2 D3 D4 D8
25 D14
25 
D1
2 
(D15) 
D2 D8
25 D14
25 
D1
2 
(D15) 
D2 D3 D4 D8 
D1
2 
 (D15) 
D8 
D8 
30 days (+/-5 
days) after 
last IP 
administration 
>30 Days 
Informed 
Consent/Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography/Medical/Surgical 
and Disease History
3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination
4 
X 
X 
 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
Weight/Height (height at 
baseline only) 
X 
X 
 
 
 
 
X 
X 
 
 
X 
X 
 
 
 
 
X 
 
X 
 
Vital Signs
5 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
Chest X-ray, Spirometry, 
Diffusion Capacity
6 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
 
Performance Status 
(Karnofsky) 
X 
X 
 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
Serumȕ2-microglobulin 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X (end of 
even-
numbered 
cycles) 
 
X 
 
Immunoglobulins: IgG, IgA, 
IgM 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X (end of 
even-
numbered 
cycles) 
 
X 
 
Disease Assessment
7 
 † (baseline within 28 days) 
X† 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X (end of 
even-
numbered 
cycles) 
 
X 
 




Amended Clinical Trial Protocol 14  
22-Jul-2020 
SAR650984-TED10893-isatuximab 
Version number: 1 
Property of the sanofi-aventis group - strictly confidential 
Page 42 
Evaluation
1 
Screening/ 
Baseline 
Treatment Cycle 1 
Treatment Cycle 2 
Treatment Cycle 3 
Subsequent 
cycles
21 
End of 
treatment 
(EOT)
22 
Follow-up 
period
23 
D-15 to D1 D1
2 D2 D3 D4 D8
25 D14
25 
D1
2 
(D15) 
D2 D8
25 D14
25 
D1
2 
(D15) 
D2 D3 D4 D8 
D1
2 
 (D15) 
D8 
D8 
30 days (+/-5 
days) after 
last IP 
administration 
>30 Days 
AE/SAE Assessment 
Continuously throughout the study period 
X (related AE, 
all SAE) 
Prior/Concomitant Medication 
Continuously throughout the study period 
X (related AE, 
all SAE) 
1. 
Evaluation: Assessments should be performed prior to IP administration unless otherwise indicated. Results should be reviewed by the Investigator prior to the administration of the next dose. A Cycle is 
14 days. 
2. 
D1: Day 1 of Cycle 1 refers to the day the patient receives the first IP administration.  Day 1 of each subsequent cycle corresponds to Day 15 (+/-1 day) of the previous cycle. Before Cycle 1, blood chemistry, 
hematology, coagulation, and urinalysis assessments not required if acceptable screening assessment is performed within 1 day prior to first IP administration; before subsequent cycles, assessments not required 
if acceptable assessment is performed on D14 of previous cycle. If necessary treatment with SAR650984 may be slightly delayed (max 7 days) for subsequent cycles following Cycle 2 Day 14 while awaiting results 
of disease assessment parameters. 
3. 
Demography: Includes age, gender and race. Medical/Surgical History: Includes relevant history of previous/associated pathologies, other than the tumor. Disease History: Includes date of initial diagnosis, 
stage and extent of the disease, previous anti-tumor therapy (type and response to), disease status at inclusion (primary refractory, refractory to last therapy, or recurrent). In addition, results of additional procedures 
(such as karyotype, FISH, etc) performed as part of standard of care to assess the current disease status may also be collected. 
4. 
Physical Examination: Consists of examination of major body systems, including neurological, digestive exam, extramedullary myeloma localizations, respiratory, hepatomegaly, splenomegaly, lymphadenopathy. 
Only clinically relevant findings will be reported in the CRF as AEs.  
5. 
Vital Signs: Blood pressure, heart rate, temperature, and respiration rate required at screening, Day 1 and Day 8 (just before starting infusion, middle of infusion, end of infusion, and 1, 2, 4 and 6 hours post-
infusion) in each cycle, Day 2, Day 8 and Day 14 (Cycles 1 and 2), and as clinically indicated. The final measurements will be performed at the EOT visit. 
6. 
Chest X-ray, Spirometry, Diffusion Capacity: To be done within one week prior to IP administration on Day 1 for the first 2 cycles and then as clinically indicated. The final measurements will be performed at the EOT 
visit. 
7. 
Disease Assessment: To be done at screening up to 28 days prior to first IP administration. Response is assessed on the basis of clinical, laboratory, radiologic, and pathologic (ie, bone marrow) findings at the 
end of Cycle 2 to determine if patient is eligible to continue treatment. Patients continuing after Cycle 2 should be evaluated for disease status at least every 4 weeks (end of every even-numbered cycle), whenever 
disease progression is suspected (eg, symptomatic deterioration), to confirm a partial or complete response (4-6 weeks after initial documentation of response), and at the EOT visit. Bone marrow biopsy/aspiration 
as clinically indicated, radiologic imaging of plasmocytoma as clinically indicated, bone skeletal survey as clinically indicated, M-protein quantification (serum and/or 24-hr urine), serum free light chains, or urinary 
light chain levels as clinically indicated. If necessary treatment with SAR650984 may be slightly delayed (max 7 days) for subsequent cycles while awaiting results of disease assessment parameters. 
8. 
Pregnancy Tests: Women of child bearing potential must have a negative serum pregnancy test result within 7 days prior to first IP administration and at the EOT visit; negative urine pregnancy test required prior 
to each subsequent IP administration on Day 1.  
9. 
Blood Chemistry:  
x 
Liver function tests: SGOT (AST), SGPT (ALT), bilirubin (total and direct), alkaline phosphatase, lactate dehydrogenase (LDH) 
x 
Renal function: sodium, potassium, chloride, bicarbonate/carbon dioxide, calcium, magnesium, phosphate, uric acid, blood urea nitrogen (BUN), serum creatinine and estimated creatinine clearance 
(Cockcroft-Gault Formula).  
x 
Other: glucose, albumin, total protein, peptide C  
x 
Erythrocyte sedimentation rate (ESR)  


Amended Clinical Trial Protocol 14  
22-Jul-2020 
SAR650984-TED10893-isatuximab 
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Property of the sanofi-aventis group - strictly confidential 
Page 43 
10. Samples to be drawn immediately before the start of infusion, at the end of infusion, and 6 hours after the end of infusion.  
11. Sample to be drawn 24 hours after the end of infusion on Day 1.  
12. Hematology: Hemoglobin, hematocrit, RBC, WBC with differential, MCV, platelet counts, blast counts (AML/B-cell ALL). If grade 4 neutropenia, assess ANC every 2-3 days until ANC t0.5 x 109/L and at least 
weekly thereafter until ANC t1.0 x 109/L. 
13. Urinalysis: blood, protein, glucose, pH, ketones, bilirubin, leucocytes, nitrates, specific gravity.  
14. hs-CRP: To be done at Cycle 1 Day 1 prior to first IP administration, on Day 1 and Day 8 at 6 hours post-infusion in each cycle and Day 2 (24 hours post-infusion) in Cycle 1 and 2 only. 
15. 12-Lead ECG: To be performed Day 1 and Day 8 (just before starting infusion, middle of infusion and end of infusion) in each cycle, and Day 14 (Cycle 2), and as clinically indicated. The final measurements will 
be performed at the EOT visit. 
16. Holter Monitoring: To be placed on the patient 1-2 hours before starting the Day 1 infusion and remain on the patient until 24 hours after the infusion (Cycles 1 and 2). 
17. SAR650984 Administration: At the start of each treatment cycle, the patient’s weight will be determined. The following clinical assessments are required: blood pressure, heart rate, temperature, and respiration 
rate required just before starting infusion, middle of infusion, end of infusion, and 1, 2, and 4 hours post-infusion in each cycle and as clinically indicated.     
18. Cytokines (TNF-į,/-1-Ȗ,/-6, IFN-ȗ Baseline sample to be drawn prior to first IP administration on Cycle 1 Day 1, then at 6 hours post-infusion on Day 1 and Day 8 of each cycle, and Day 2 (24 hours post-
infusion) of Cycle 1 and 2. Samples to be shipped directly to Singulex (Refer to lab manual).  
19. RO: See details regarding sampling times on Pharmacokinetics/Pharmacodynamics Flowchart Section 1.6. Samples to be shipped directly to Biocytex (Refer to lab manual). 
20. PK, Anti-Drug Antibodies: See details regarding sampling times on Pharmacokinetics/Pharmacodynamics Flowchart Section 1.6. If patient modifies to an every 2 week schedule (see Section 6.4), the D8 PK and 
ADA sample should be collected on D1 just before IP administration. Samples to be shipped to Covance (Refer to lab manual). 
21. Subsequent Cycles: After completing two cycles, patients may receive additional administrations of SAR650984. 
22. End of Treatment (EOT): Assessments to be performed 30 days (+/-5 days) after last IP administration. 
23. Follow-up Period: Patients will be followed beyond 30 days for IP-related AE, SAEs (regardless of relationship to study treatment) and/or unresolved toxicity. PK and ADA samples required 60 days (+/-5 days) 
after last IP administration. At 60 days, if patient is positive for ADA or the sample is inconclusive, additional ADA and PK samples are required every 30 days (±5 days) until sample is interpretable or negative. All 
IP-related AEs and all SAEs (regardless of relationship to study treatment) to be followed until ADA sample is negative. 
24. If disease assessment bone marrow biopsy/aspiration required at screening is completed within 14 days prior to IP administration, RO in bone marrow can be measured at that time. 
25. Day 8 and Day 14 +/-1 day. 
 


Amended Clinical Trial Protocol 14  
22-Jul-2020 
SAR650984-TED10893-isatuximab 
Version number: 1 
Property of the sanofi-aventis group - strictly confidential 
Page 44 
1.12 
STUDY FLOWCHART FOR PHASE 1 BASIC DOSE ESCALATION PHASE (SAR650984 ADMINISTRATION EVERY 2 WEEKS - 
FROM COHORT 12)  
 
Evaluation
1 
Screening/Baseline 
Treatment Cycle 1 
Treatment Cycle 2 
Subsequent 
cycles
21 
End of 
treatment 
(EOT)
22  
Follow-up 
period
23 
D-15 to D1 
D1
2 D2 D3 D4 D8
25 D14
25 
D1
2 
(D15) 
D2 D8
25 D14
25 
D1
2 
(D15) 
30 days  
(+/-5 days) 
after last IP 
administration 
>30 Days 
Informed 
Consent/Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography/Medical/Surgical 
and Disease History
3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination
4 
X 
X 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
 
Weight/Height (height at 
baseline only) 
X 
X 
 
 
 
 
X 
X 
 
 
X 
X 
X 
 
Vital Signs
5 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chest X-ray, Spirometry, 
Diffusion Capacity
6 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Performance Status 
(Karnofsky) 
X 
X 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
 
Serumȕ2-microglobulin 
X 
 
 
 
 
 
X 
 
 
 
X 
X (end of even-
numbered cycles) 
X 
 
Immunoglobulins: IgG, IgA, 
IgM 
X 
 
 
 
 
 
X 
 
 
 
X 
X (end of even-
numbered cycles) 
X 
 
Disease Assessment
7 
† (baseline within 28 days) 
X† 
 
 
 
 
 
 
 
 
 
X 
X (end of even-
numbered cycles) 
X 
 
Pregnancy Test
8 
‡ (baseline within 7 days) 
X‡ 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
 




Amended Clinical Trial Protocol 14  
22-Jul-2020 
SAR650984-TED10893-isatuximab 
Version number: 1 
Property of the sanofi-aventis group - strictly confidential 
Page 46 
Evaluation
1 
Screening/Baseline 
Treatment Cycle 1 
Treatment Cycle 2 
Subsequent 
cycles
21 
End of 
treatment 
(EOT)
22  
Follow-up 
period
23 
D-15 to D1 
D1
2 D2 D3 D4 D8
25 D14
25 
D1
2 
(D15) 
D2 D8
25 D14
25 
D1
2 
(D15) 
30 days  
(+/-5 days) 
after last IP 
administration 
>30 Days 
AE/SAE Assessment 
Continuously throughout the study period 
X (related AE, all 
SAEs) 
Prior/Concomitant Medication 
Continuously throughout the study period 
X (related AE, all 
SAEs) 
1. 
Evaluation: Assessments should be performed prior to IP administration unless otherwise indicated. Results should be reviewed by the Investigator prior to the administration of the next dose. A Cycle is 
14 days. 
2. 
D1: Day 1 of Cycle 1 refers to the day the patient receives the first IP administration.  Day 1 of each subsequent cycle corresponds to Day 15 (+/-1 day) of the previous cycle. Before Cycle 1, blood chemistry, 
hematology, coagulation, and urinalysis assessments not required if acceptable screening assessment is performed within 1 day prior to first IP administration; before subsequent cycles, assessments not required 
if acceptable assessment is performed on D14 of previous cycle. If necessary treatment with SAR650984 may be slightly delayed (max 7 days) for subsequent cycles following Cycle 2 Day 14 while awaiting results 
of disease assessment parameters. 
3. 
Demography: Includes age, gender and race. Medical/Surgical History: Includes relevant history of previous/associated pathologies, other than the tumor. Disease History: Includes date of initial diagnosis, 
stage and extent of the disease, previous anti-tumor therapy (type and response to), disease status at inclusion (primary refractory, refractory to last therapy, or recurrent). In addition, results of additional procedures 
(such as karyotype, FISH, etc) performed as part of standard of care to assess the current disease status may also be collected. 
4. 
Physical Examination: Consists of examination of major body systems, including neurological, digestive exam, extramedullary myeloma localizations, respiratory, hepatomegaly, splenomegaly, lymphadenopathy. 
Only clinically relevant findings will be reported in the CRF as AEs.  
5. 
Vital Signs: Blood pressure, heart rate, temperature, and respiration rate required at screening, Day 1 (just before starting infusion, middle of infusion, end of infusion, and 1, 2, 4 and 6 hours post-infusion) in each 
cycle, Day 2, Day 8 and Day 14 (Cycles 1 and 2), and as clinically indicated. The final measurements will be performed at the EOT visit. 
6. 
Chest X-ray, Spirometry, Diffusion Capacity: To be done within one week prior to IP administration for the first 2 cycles and then as clinically indicated. The final measurements will be performed at the EOT 
visit. 
7. 
Disease Assessment: To be done at screening up to 28 days prior to first IP administration. Response is assessed on the basis of clinical, laboratory, radiologic, and pathologic (ie, bone marrow) findings at the 
end of Cycle 2 to determine if patient is eligible to continue treatment. Patients continuing after Cycle 2 should be evaluated for disease status at least every 4 weeks (end of every even-numbered cycle), whenever 
disease progression is suspected (eg, symptomatic deterioration), to confirm a partial or complete response (4-6 weeks after initial documentation of response), and at the EOT visit. Bone marrow biopsy/aspiration 
as clinically indicated, radiologic imaging of plasmocytoma as clinically indicated, bone skeletal survey as clinically indicated, M-protein quantification (serum and/or 24-hr urine), serum free light chains, or urinary 
light chain levels as clinically indicated. If necessary treatment with SAR650984 may be slightly delayed (max 7 days) for subsequent cycles while awaiting results of disease assessment parameters. 
8. 
Pregnancy Tests: Women of child bearing potential must have a negative serum pregnancy test result within 7 days prior to first IP administration and at the EOT visit; negative urine pregnancy test required prior 
to each subsequent IP administration.  
9. 
Blood Chemistry:  
x 
Liver function tests: SGOT (AST), SGPT (ALT), bilirubin (total and direct), alkaline phosphatase, lactate dehydrogenase (LDH) 
x 
Renal function: sodium, potassium, chloride, bicarbonate/carbon dioxide, calcium, magnesium, phosphate, uric acid, blood urea nitrogen (BUN), serum creatinine and estimated creatinine clearance 
(Cockcroft-Gault Formula).  
x 
Other: glucose, albumin, total protein, peptide C  


Amended Clinical Trial Protocol 14  
22-Jul-2020 
SAR650984-TED10893-isatuximab 
Version number: 1 
Property of the sanofi-aventis group - strictly confidential 
Page 47 
x 
Erythrocyte sedimentation rate (ESR)  
10. Samples to be drawn immediately before the start of infusion, at the end of infusion, and 6 hours after the end of infusion.  
11. Sample to be drawn 24 hours after the end of infusion on D1.  
12. Hematology: Hemoglobin, hematocrit, RBC, WBC with differential, MCV, platelet counts, blast counts (AML/B-cell ALL). If grade 4 neutropenia, assess ANC every 2-3 days until ANC t0.5 x 109/L and at least 
weekly thereafter until ANC t1.0 x 109/L. 
13. Urinalysis: blood, protein, glucose, pH, ketones, bilirubin, leucocytes, nitrates, specific gravity.  
14. hs-CRP: To be done at Cycle 1 Day 1 prior to first IP administration, 6 and 24 hours post-infusion, Cycle 2 at 6 and 24 hours post-infusion and then at 6 hours post-infusion in each cycle. 
15. 12-Lead ECG: To be performed Day 1 (just before starting infusion, middle of infusion and end of infusion) in each cycle, Day 8 (Cycles 1 and 2) and Day 14 (Cycle 2), and as clinically indicated. The final 
measurements will be performed at the EOT visit. 
16. Holter Monitoring: To be placed on the patient 1-2 hours before starting the infusion and remain on the patient until 24 hours after the infusion (Cycles 1 and 2). 
17. SAR650984 Administration: At the start of each treatment cycle, the patient’s weight will be determined. The following clinical assessments are required: blood pressure, heart rate, temperature, and respiration 
rate required just before starting infusion, middle of infusion, end of infusion, and 1, 2 and 4 hours post-infusion in each cycle and as clinically indicated.     
18. Cytokines (TNF-Į,/-1-ȕ,/-6, IFN-Ȗ Baseline sample to be drawn prior to first IP administration at Cycle 1, then at 6 and 24 hours post-infusion (Cycle 1 and 2) and then at 6hours post-infusion in each cycle. 
Samples to be shipped directly to Singulex (Refer to lab manual).  
19. RO: See details regarding sampling times on Pharmacokinetics/Pharmacodynamics Flowchart Section 1.7. Samples to be shipped directly to Biocytex (Refer to lab manual). 
20. PK, Anti-Drug Antibodies: See details regarding sampling times on Pharmacokinetics/Pharmacodynamics Flowchart Section 1.7. Samples to be shipped to Covance (Refer to lab manual). 
21. Subsequent Cycles: After completing two cycles, patients may receive additional administrations of SAR650984. 
22. End of Treatment (EOT): Assessments to be performed 30 days (+/-5 days) after last IP administration. 
23. Follow-up Period: Patients will be followed beyond 30 days for IP-related AE, SAEs (regardless of relationship to study treatment) and/or unresolved toxicity. PK and ADA samples required 60 days (+/-5 days) 
after last IP administration. At 60 days, if patient is positive for ADA or the sample is inconclusive, additional ADA and PK samples are required every 30 days (±5 days) until sample is interpretable or negative. All 
IP-related AEs and all SAEs (regardless of relationship to study treatment) to be followed until ADA sample is negative. 
24. If disease assessment bone marrow biopsy/aspiration required at screening is completed within 14 days prior to IP administration, RO in bone marrow can be measured at that time. 
25. Day 8 and Day 14 +/-1 day 
 






Amended Clinical Trial Protocol 14  
22-Jul-2020 
SAR650984-TED10893-isatuximab 
Version number: 1 
Property of the sanofi-aventis group - strictly confidential 
Page 50 
Evaluation1 
Screening
/Baseline 
Cycle 1-32 
Subsequent cycles2, 3 
End of treatment 
(EOT)  
Post treatment 
Follow-up period 
D-21 to 
D1 
D12 
(±3 days) 
D15 
(±3 days) 
D1 
(±3 days) 
D15 
(±3 days) 
Up to 30 days after 
last IP admin 
At 60 days (±5 days) 
after last IP 
admin45 
Every 3 months 
(±14 days) after 
last IP admin 
Skeletal survey, CT/MRI scan41 
X 
 
 
 
 
X 
 
X39 
SAR650984 Administration: 
3 mg/kg Q2W or 10 mg/kg Q2W42 
 
X 
X 
X 
X 
 
 
 
SAR650984 Administration: 
10 mg/kg Q2W for C1-2 then 10 mg/kg Q4W
 42 
 
X 
C1, C2 only 
X 
 
 
 
 
AE/SAE Assessment43 
Continuously throughout study period 
X (related AE only) 
Prior/Concomitant Medication 
Continuously throughout study period 
X (related AE only) 
New anticancer therapy 
 
X 
X 
X 
Survival Status44 
 
X 
X 
X 
1. 
Evaluation: Assessments should be performed prior to IP administration unless otherwise indicated. 
2. 
Cycle: A cycle is 28 days. The D1 ±3 day window applies to Cycle 2 and 3 only. 
3. 
Subsequent Cycles: Patients on the Q4W schedule are only required to attend the D1 visit. 
4. 
Demography: Includes age, gender and race. Medical/Surgical History: Includes relevant history of previous/associated pathologies, other than multiple myeloma. Disease History: Includes date of initial 
diagnosis, stage and extent of the disease, previous anti-tumor therapy (type, duration and response to), disease status at inclusion (refractory to last therapy, or recurrent). In addition, results of additional 
procedures (such as karyotype, FISH, etc) performed as part of standard of care to assess the current disease status may also be collected. 
5. 
Physical Examination: Consists of examination of major body systems, including neurological, digestive exam, plasmacytoma assessment, respiratory, hepatomegaly, splenomegaly, lymphadenopathy. Only 
clinically relevant findings will be reported in the electronic case report form (eCRF) as AEs. 
6. 
Weight/Height: Height is required at baseline only. Weight is required at screening, prior to starting infusion in each cycle and at the EOT visit. 
7. 
Vital Signs: Blood pressure, heart rate, temperature, and respiration rate required at screening, D1 and D15 (just before starting infusion, middle of infusion, end of infusion) in each cycle and as clinically 
indicated. The final measurements will be performed at the EOT visit. 
8. 
ePRO (electronic Patient-Reported Outcomes EORTC QLQ-C30 and MY20): To be completed by the patient at the center prior to discussing with them their health/disease status, before the administration of 
study drug, and if possible prior to other study-related procedures on D1 of every cycle and at the EOT visit. 
9. 
ePRO (EQ-5D): To be completed by the patient at the center prior to discussing with them their health/disease status, before the administration of study drug, and if possible prior to other study-related 
procedures on D1 Cycle 1 then D1 of every 3rd cycle starting Cycle 4 (ie, C4, C7, C10, etc.) and at the EOT visit. 
10. 12-Lead ECG: To be performed at screening and then as clinically indicated. 
11. Chest X-ray: To be performed at screening and then as clinically indicated. 
12. Pregnancy Test: Women of child bearing potential must have a negative serum pregnancy test result within 7 days prior to first IP administration and at the EOT visit. 
13. Includes HBsAg, anti-HBsAb, and anti-HBcAb (total and IgM) and HBV DNA in case of positive anti-HBsAg (see Section 6.8). Once at any time if HBV status unknown before treatment started and to be repeated 
if clinically indicated for patients still under treatment at the time of amended protocol 14. 
14. Central Labs: Refer to lab manual for sample collection and shipping information. 


Amended Clinical Trial Protocol 14  
22-Jul-2020 
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15. Blood Chemistry: To be done at screening, on D1 and D15 of every cycle prior to pre-medication and IP administration, 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, blood urea nitrogen (BUN), serum creatinine and estimated creatinine clearance (Cockcroft-Gault Formula), glucose, albumin and total protein. 
16. Hematology: To be done at screening, on D1 and D15 of every cycle prior to pre-medication and IP administration, at the EOT visit and as clinically indicated. Hematology includes: Hemoglobin, hematocrit, 
RBC, WBC with differential, MCV and platelet counts. If grade 4 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. 
17. Blood chemistry and hematology assessments are not required to be repeated prior to D1 Cycle 1 if the screening labs were performed within 3 days prior to first IP administration. 
18. Coagulation: To be done at screening and then as clinically indicated. Coagulation includes: Prothombin time (PT) or international normalized ration (INR) and activated partial thromboplastin time (PTT). 
19. Urinalysis: To be done at screening and then as clinically indicated. Urinalysis includes: blood, protein, glucose, pH, ketones, bilirubin, leucocytes, nitrates and specific gravity. 
20. Cytokines (TNF-į, IL-1-Ȗ, IL-6, IFN-ȗ: Baseline sample to be drawn prior to first IP administration on D1 of Cycle 1. 
21. SAR650984 Safety labs: Should a SAR650984 infusion reaction of Grade 2 occur, additional blood sampling during the AE is required for analysis of cytokines, markers of complement activation (C3, C4, 
CH50), serum tryptase and blood chemistry. 
22. Serum Ȗ2-microglobulin and Immunoglobulins (IgG, IgA, IgM, IgD and IgE): To be performed at screening, prior to each IP administration on D1 of every cycle (starting C2) and at the EOT visit. 
23. Pharmacokinetics (PK): Refer to Pharmacokinetics/Pharmacodynamics Flowchart (Section 1.8). 
24. ADA (Anti-Drug Antibodies): To be performed on D1 of every cycle prior to each IP administration, D15 of Cycle 1, at the EOT visit and at 60 days (±5 days) after last IP administration. At 60 days, if patient is 
positive for ADA or the sample is inconclusive, additional ADA and PK samples are required every 30 days (±5 days) until sample is interpretable or negative. 
25. Bone marrow biopsy/aspirate for CD38 RD: To be performed at screening. 
26. Bone marrow biopsy/aspirate for FISH: To be performed at screening. 
27. Bone marrow biopsy/aspirate for genomics/CD38 mRNA: To be performed at screening and at the EOT visit for patients with PD. 
28. Bone marrow biopsy/aspirate for immune phenotyping: To be performed at screening. 
29. Bone marrow biopsy/aspirate for CD38 RO: To be performed at screening, on D1 of Cycle 2 prior to IP administration and at the EOT visit. CD38 RO will only be performed on patients in Stage 1 enrolled at 
selected sites trained in the CD38 RO assay. 
30. Bone marrow biopsy/aspirate for MRD assessment: To be performed at screening and time of CR confirmation. 
31. Blood sample for soluble CD38: To be performed on D1 of Cycle 1 prior to IP administration, D1 of Cycle 3 prior to IP administration and at the EOT visit for patients with PD. 
32. Blood sample for immune phenotyping: To be performed on D1 of Cycle 1 prior to IP administration, D1 of Cycle 3 prior to IP administration and at the EOT visit. 
33. Blood sample for immune genetic determinants: To be performed on D1 of Cycle 1 prior to IP administration. 
34. Blood sample for optional pharmacogenetic sample: To be collected on D1 of Cycle 1 prior to IP administration for patients enrolled in Stage 2 only. 
35. Disease assessment: At screening, all lab assessments to be performed within 7 days prior to first IP administration and all radiologic assessments to be performed within 21 days prior to first IP administration. 
Local lab results for M-protein and sFLC to be used to determine eligibility criteria. Response is assessed on the basis of clinical and laboratory findings on D1 of every cycle (starting C2, prior to IP 
administration), whenever disease progression is suspected (eg, symptomatic deterioration) and at the EOT visit. 
36. Serum M-Protein: To be performed at screening, D1 of every cycle (starting C2, prior to IP administration) and at the EOT visit. Screening sample should be split for local (to determine eligibility) and central (for 
baseline response) lab analysis. 
37. Serum free light chains (sFLC): To be performed at screening, D1 of every cycle (starting C2, prior to IP administration) and at the EOT visit. Screening sample should be split for local (to determine eligibility) 
and central (for baseline response) lab analysis. 
38. Urine M-Protein (24-hr urine): To be performed at screening, D1 of every cycle (starting C2, prior to IP administration) and at the EOT visit. 
39. Disease assessments during follow-up period are only required for patients who have discontinued study treatment for reasons other than disease progression and have not yet started treatment with another anti-
cancer therapy. Patients will be followed every month for progression during this period. Disease assessments required every month include evaluation of serum M-protein, serum free light chains and urine M-
protein. A bone marrow, skeletal survey and CT/MRI are only required if clinically indicated to confirm response or progression according to IMWG criteria. Disease assessments not required once patient starts 
treatment with another anti-cancer therapy. 
40. Bone marrow (biopsy/aspiration): To be performed at screening, to confirm a sCR, CR, disease progression, at the EOT visit and as clinically indicated. 


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41. Skeletal survey (including skull, all long bones, pelvis and chest) and CT/MRI scan: Skeletal survey and CT/MRI to be performed at screening on all patients. Repeat skeletal surveys are only required as 
clinically indicated or to confirm response or progression according to the IMWG criteria. If a plasmacytoma is present at study entry, repeat radiologic assessment (CT or MRI) is required at least every 2 cycles 
(C3, C5, C7 etc) to evaluate/confirm response. Imaging may be performed more frequently as clinically indicated to confirm response or progression according to IMWG criteria. All imaging will be sent to a 
central imaging lab. 
42. SAR650984 Administration: At the start of each treatment cycle, the patient’s weight will be determined. 
43. AE/SAE assessment: All AEs, including events 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. After the 30 day follow-up all ongoing related AEs and SAE (regardless of relationship) and new related non-serious AEs and SAEs are to be followed to resolution or 
stabilization. For patients who have a positive ADA sample, all IP-related AEs to be followed to resolution or stabilization. 
44. Survival status: Patients will also be followed for survival every 3 months from the date of last IP administration until death. 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 obtained immediately. For subsequent survival follow-up, the patient should be contacted 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. 
45. Applicable when ADA where collected at 60 days after last IP administration. 


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1.14 
STUDY FLOWCHART FOR PHASE 2, STAGE 1B  
 
Evaluation1 
Screening/ 
Baseline 
Cycle 12 
Subsequent cycles 2, 3 
End of 
treatment 
(EOT)  
Post treatment 
Follow-up period38 
D-21 to D1 
D1 
D8 
D15 
D22 
D1 
(D1 Cn=  
D29 Cn-1) 
D15 
Up to 
30 days 
after last 
IP admin 
At 60 days  
(±5 days) 
after last IP 
admin44 
Every 
3 months 
(±14 days) 
after last 
IP admin 
Informed Consent/Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Patient randomization (Stage 1 only)/ 
registration 
X 
 
 
 
 
 
 
 
 
 
Demography, Medical/Surgical and Disease 
History4 
X 
 
 
 
 
 
 
 
 
 
Physical Examination5 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Weight/Height6 
X 
X 
(weight 
only) 
X 
(weight 
only) 
X 
(weight 
only) 
X 
(weight 
only) 
X 
(weight only) 
X 
(weight only) 
X 
(weight 
only) 
 
 
Vital Signs7 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Performance Status (Karnofsky in Stage 1) 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ePRO: QLQ-C30/ MY208 
 
X 
 
 
 
 X 
 
X 
 
 
ePRO: EQ-5D9 
 
X 
 
 
 
 Every 3 cycles 
(ie, C4, C7, etc) 
 
X 
 
 
12-Lead ECG10 
X 
 
 
 
 
 
 
 
 
 
Chest X-ray11 
X 
 
 
 
 
 
 
 
 
 
Laboratory Assessments: 
Pregnancy Test12 
X  
 
 
 
 
X 
 
X 
 
 
Hepatitis B virus (HBV) serology 
 
X13 
 
 
 
Laboratory Assessment: central labs14 
Blood Chemistry15 
X 
X17 
X 
X 
X 
X 
X 
X 
 
 


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Evaluation1 
Screening/ 
Baseline 
Cycle 12 
Subsequent cycles 2, 3 
End of 
treatment 
(EOT)  
Post treatment 
Follow-up period38 
D-21 to D1 
D1 
D8 
D15 
D22 
D1 
(D1 Cn=  
D29 Cn-1) 
D15 
Up to 
30 days 
after last 
IP admin 
At 60 days  
(±5 days) 
after last IP 
admin44 
Every 
3 months 
(±14 days) 
after last 
IP admin 
Hematology16 
X 
X17 
X 
X 
X 
X 
X 
X 
 
 
Coagulation18 
X 
 
 
 
 
 
 
 
 
 
Urinalysis19 
X 
 
 
 
 
 
 
 
 
 
Cytokines20TNF-Į, IL-1-ȕ, IL-6, IFN-Ȗ)  
 
X 
 
 
 
 
 
 
 
 
SAR650984 Safety Labs21 
 
X 
X 
X 
X 
X 
X 
 
 
 
Serum ȕ2-microglobulin22 
X 
 
 
 
 
X 
 
X 
 
 
Immunoglobulins: IgG, IgA, IgM22 
X 
 
 
 
 
X 
 
X 
 
 
PK23 
 
X 
X 
X 
X 
X 
X 
X 
 
 
ADA24 
 
X 
 
X 
 
X 
 
X 
X 
 
PD/Exploratory studies: Central Labs14 
Bone marrow for:CD38 RD25 
 
X 
 
 
 
 
 
 
 
 
 
FISH26 
X 
 
 
 
 
 
 
 
 
 
Genomics27 
X 
 
 
 
 
 
 
X 
 
 
Immune phenotyping(Bone marrow)28 
X 
 
 
 
 
 
 
 
 
 
CD38 RO29 
 (Stage 1,selected sites only) 
X 
 
 
 
 
C2 only 
 
X 
 
 
MRD assessment30 
X 
 
 
 
 
 
 
 
 
 
Blood for: 
Soluble CD3831 
 
 
X  
 
 
 
 
 
C3 only 
 
 
X 
 
 


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Evaluation1 
Screening/ 
Baseline 
Cycle 12 
Subsequent cycles 2, 3 
End of 
treatment 
(EOT)  
Post treatment 
Follow-up period38 
D-21 to D1 
D1 
D8 
D15 
D22 
D1 
(D1 Cn=  
D29 Cn-1) 
D15 
Up to 
30 days 
after last 
IP admin 
At 60 days  
(±5 days) 
after last IP 
admin44 
Every 
3 months 
(±14 days) 
after last 
IP admin 
Immune phenotyping(Blood)32 
 
X 
 
 
 
C3 only 
 
X 
 
 
Immune genetic determinants33 
 
X 
 
 
 
 
 
 
 
 
Disease Assessment 34 
Central 
Lab14 
Serum M-Protein35 
X 
 
 
 
 
X 
 
X 
 
X38 
sFLC36 
X 
 
 
 
 
X 
 
X 
 
X38 
Urine M-Protein (24-hr urine) 37 
X 
 
 
 
 
X 
 
X 
 
X38 
Bone Marrow for disease assessment39 
X 
 
 
 
 
 
 
X 
 
X38 
Skeletal survey, CT/MRI scan40 
X 
 
 
 
 
 
 
X 
 
X38 
SAR650984 Administration: 
STAGE 1b: 
20 mg/kg QW for C1, then Q2W 41 
 
X 
X 
X 
X 
X 
X 
 
 
 
AE/SAE Assessment42 
 
 
Continuously throughout study period 
X (related AE only, all SAEs) 
Prior/Concomitant Medication 
 
 
Continuously throughout study period 
X (related AE only, all SAEs) 
New anticancer therapy 
 
 
 
X 
X 
X 
Survival Status43 
 
 
 
X 
X 
X 
1. 
Evaluation: Assessments should be performed prior to IP administration unless otherwise indicated. 
2. 
Cycle: A cycle is 28 days. 
3. 
Subsequent Cycles: Patients on the Q4W schedule are only required to attend the D1 visit. 
4. 
Demography: Includes age, gender and race. Medical/Surgical History: Includes relevant history of previous/associated pathologies, other than multiple myeloma; smoking status, respiratory function 
history will be checked. Disease History: Includes date of initial diagnosis, stage of the disease, previous anti-tumor therapy (drug names, reason for discontinuation, duration and response to), disease 
status at inclusion (refractory to last therapy, or relapse). In addition, results of additional procedures (such as karyotype, FISH, etc) performed as part of standard of care at the site to assess the current 
disease status may also be collected.  
5. 
Physical Examination: Consists of examination of major body systems, including neurological, digestive exam, plasmacytoma assessment, respiratory, hepatomegaly, splenomegaly, lymphadenopathy. 
Only clinically relevant findings will be reported in the electronic case report form (eCRF) as AEs. Before cycle1 physical examination should be performed within 7 days before study treatment 


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administration and repeated within 3 days before administration if abnormal. For further cycles, assessment can be performed the day of the infusion (before infusion the day of study treatment 
administration or the day before) 
6. 
Weight/Height: Height is required at baseline only. Weight is required at screening, prior to starting infusion in each cycle and at the EOT visit. 
7. 
Vital Signs: Blood pressure, heart rate, temperature, and respiration rate. For Phase 1 Stage 1, vital signs are required at screening, before starting infusion, middle of infusion, end of infusion on D1, D8, D15 
and D22 of Cycle 1 and D1 and D15 of each subsequent cycle. The final measurements will be performed at the EOT visit 
8. 
ePRO (electronic Patient-Reported Outcomes EORTC QLQ-C30 and MY20): To be completed by the patient at the center prior to discussing with them their health/disease status, before the 
administration of study drug, and if possible prior to other study-related procedures on D1 of every cycle and at the EOT visit. 
9. 
ePRO (EQ-5D): To be completed by the patient at the center prior to discussing with them their health/disease status, before the administration of study drug, and if possible prior to other study-related 
procedures on D1 Cycle 1 then D1 of every 3rd cycle starting Cycle 4 (ie, C4, C7, C10, etc) and at the EOT visit. 
10. 12-Lead ECG: To be performed at screening and then as clinically indicated. 
11. Chest X-ray: To be performed at screening and then as clinically indicated. 
12. Pregnancy Test: Women of child bearing potential must have a negative serum pregnancy test result within 7 days prior to first IP administration and at the EOT visit.  
13.  Includes HBsAg, anti-HBsAb, and anti-HBcAb (total and IgM) and HBV DNA in case of positive anti-HBsAg (see Section 6.8). Once at any time if HBV status unknown before treatment started and to be 
repeated if clinically indicated for patients still under treatment at the time of amended protocol 14. 
14. Central Labs: Refer to lab manual for sample collection and shipping information. Samples for all the parameters listed in the flowchart will be sent to a central laboratory. When indicated in the flow chart, 
blood samples for hematology, biochemistry and disease assessment tests (see footnote 34) will be split for central and local laboratory evaluations. For efficacy laboratory tests (eg, serum and urine M- 
protein, sFLC) and for safety laboratory data during the study treatment period, local results will be used for the decision to treat or not the patient at the site level. For statistical analysis, central laboratory 
results will be used. All local laboratory tests done for safety or efficacy purposes will be reported in the e-CRF. 
15. Blood Chemistry: To be done at screening, then prior to pre-medication and IP administration on D1, D8, D15 and D22 of Cycle 1 and on D1 and D15 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, ionized calcium and corrected serum calcium, magnesium, phosphate, uric acid, blood urea nitrogen (BUN), serum creatinine and estimated creatinine clearance (Cockcroft-Gault Formula), fasting 
glucose, albumin and total protein.  
16. Hematology: To be done at screening, then prior to pre-medication and IP administration on D1, D8, D15 and D22 of Cycle 1 and D1 and D15 of every subsequent cycle, at the EOT visit and as clinically 
indicated. Hematology includes: Hemoglobin, hematocrit, RBC, WBC with differential, MCV and platelet counts. If grade 4 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. 
17. Blood chemistry and hematology: assessments are required to be performed within 7 days prior to first IP administration, to be repeated within 3 days of first dose if abnormal. Both local and central 
assessment will be performed, but local laboratory results for hematology and biochemistry will be used for safety management and the decision to treat or not the patient at C1D1 and each subsequent 
administration. 
18. Coagulation: To be done at screening and then as clinically indicated. Coagulation includes: Prothombin time (PT) or international normalized ration (INR) and activated partial thromboplastin time (PTT). 
19. Urinalysis: To be done at screening and then as clinically indicated. Urinalysis includes: blood, protein, glucose, pH, ketones, bilirubin, leucocytes, nitrates and specific gravity. 
20. Cytokines (TNF-į IL-1-Ȗ, IL-4, IL-6, IFN-ȗ): Baseline sample to be drawn prior to first IP administration on D1 of Cycle 1. 
21. SAR650984 Safety labs: Should a SAR650984 infusion reaction of Grade 2 occur, additional blood sampling during the AE is required for analysis of cytokines, markers of complement activation (C3, C4, 
CH50), serum tryptase and markers of potential Tumor Lysis Syndrome (TLS) (uric acid, lactate dehydrogenase [LDH], BUN/creatinine, Potassium, Sodium and calcium) 
22. Serum Ȗ2-microglobulin and Immunoglobulins (IgG, IgA, IgM, IgD and IgE): To be performed at screening, prior to each IP administration on D1 of every cycle (starting C2) and at the EOT visit. 
23. Pharmacokinetics (PK): Refer to Pharmacokinetics/Pharmacodynamics Flowchart (Section 1.8). 
24. ADA (Anti-Drug Antibodies): To be performed on D1 of every cycle prior to each IP administration, D15 of Cycle 1, at the EOT visit and at 60 days (±5 days) after last IP administration. At 60 days, if 
patient is positive for ADA or the sample is inconclusive, additional ADA and PK samples are required every 30 days (±5 days) until sample is interpretable or negative. 
25. Bone marrow biopsy/aspirate for CD38 RD: To be performed at screening. 
26. Bone marrow biopsy/aspirate for FISH: To be performed at screening. 
27. Bone marrow biopsy/aspirate for genomics/CD38 mRNA: To be performed at screening and at the EOT visit in patients who have responded to the study treatment but subsequently develop 
progressive disease.  


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28. Bone marrow biopsy/aspirate for immune phenotyping: To be performed at screening. 
29. Bone marrow biopsy/aspirate for CD38 RO: To be performed at screening, on D1 of Cycle 2 prior to IP administration and at the EOT visit. CD38 RO will only be performed on patients in Stage 1 
enrolled at selected sites trained in the CD38 RO assay. 
30. Bone marrow biopsy/aspirate for MRD assessment: To be performed at screening and at CR confirmation. 
31. Blood sample for soluble CD38: to be performed on D1 of Cycle 1 prior to IP administration, D1 of Cycle 3 prior to IP administration and at the EOT visit for patients with PD.  
32. Blood sample for immune phenotyping: To be performed on D1 of Cycle 1 prior to IP administration, D1 of Cycle 3 prior to IP administration and at the EOT visit. 
33. Blood sample for immune genetic determinants: To be performed on D1 of Cycle 1 prior to IP administration. 
34. Disease assessment: All lab assessments for M-protein and sFLC to be performed at screening (within 21 days prior to first IP administration) for eligibility and within 7 days prior to first IP administration and all 
radiologic and bone marrow assessments to be performed within 21 days prior to first IP administration.Response to study treatment is assessed on the basis of clinical and laboratory findings on D1 of every 
cycle (starting C2, prior to IP administration), whenever disease progression is suspected (eg, symptomatic deterioration) and at the EOT visit.  
35. Serum M-Protein: To be performed at screening, D1 of every cycle and at the EOT visit. Samples should be split for local and central lab analysis. (for eligibility, treatment decision and analysis - see foot note 
13 and 16).  
36. Serum free light chains (sFLC): To be performed at screening, D1 of every cycle and at the EOT visit. Samples should be split for local and central lab analysis. For eligibity, treatment decision and 
analysis - see foot note 13 and 16. 
37. Urine M-Protein (24-hr urine): to be performed at screening, D1 of every cycle and at the EOT visit.  
38. Disease assessments during follow-up period are only required for patients who have discontinued study treatment for reasons other than disease progression and have not yet started treatment with 
another anti-cancer therapy. Patients will be followed every month for progression during this period. Disease assessments required every month include evaluation of serum M-protein, serum free light chains 
and urine M-protein. A bone marrow, skeletal survey and CT/MRI are only required if clinically indicated to confirm response or progression according to IMWG criteria. Disease assessments not required 
once patient starts treatment with another anti-cancer therapy 
39. Bone marrow (biopsy/aspiration): To be performed at screening, to confirm a sCR, CR, (and to confirm disease progression in Phase 1 Stage 1 only), at the EOT visit and as clinically indicated. 
40. Skeletal survey (including skull, all long bones, pelvis and chest) and appropriate PET-CT/MRI scan to be performed at screening on all patients. Repeated skeletal surveys are only required as 
clinically indicated or to assess/confirm response or progression according to the IMWG criteria. If a plasmacytoma is present at study entry, a repeat radiologic assessment (PET-CT or MRI) is required every 
2 cycles (C3, C5, C7 etc) and when clinically indicated (eg, suspicion of progression, confirmation of CR)) and to confirm a response according to the IMWG criteria (Appendix E). All imaging will be sent to the 
central imaging lab. The same method should be used throughout the study. 
41. SAR650984 Administration: At the start of each treatment cycle, the patient’s weight will be determined. 
42. AE/SAE assessment: All AEs, including events 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. After the 30 day follow-up all ongoing related and new related non-serious AEs and new SAEs regardless of relationship are to be followed to resolution or stabilization. For 
patients who have a positive ADA sample, all IP-related AEs and all SAEs (regardless of relationship to study treatment) to be followed to resolution or stabilization until ADA sample is negative. 
43. Survival status: Patients will also be followed for survival every 3 months from the date of last IP administration until death. 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 obtained immediately. For subsequent survival follow-up, the patient should be contacted 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. 
44. Applicable when ADA where collected at 60 days after last IP administration.  


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1.15 
STUDY FLOWCHART FOR PHASE 2, STAGE 2  
 
Evaluation1 
Screening/ 
Baseline 
Cycle 12 
Subsequent cycles2 
End of 
treatment 
(EOT)  
Post treatment 
Follow-up period42 
D-21 to D1 
D1 
D8 
D15 
D22 
D1(±3 days) 
D15 
(±3 days) 
Up to 
30 days 
after last IP 
admin 
At 60 days  
(±5 days) 
after last IP 
admin43 
Every 
3 months 
(±14 days) 
after last 
IP admin 
Informed Consent/Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Patient randomization registration3 
X 
 
 
 
 
 
 
 
 
 
Demography, Medical/Surgical and Disease History4 
X 
 
 
 
 
 
 
 
 
 
Physical Examination5 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Weight/Height6 
X 
X 
(weight 
only) 
X 
(weight 
only) 
X 
(weight 
only) 
X 
(weight 
only) 
X 
(weight only) 
X 
(weight 
only) 
X 
(weight only) 
 
 
Vital Signs7 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG Performance Status  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-Lead ECG8 
X 
 
 
 
 
 
 
 
 
 
Chest X-ray9 
X 
 
 
 
 
 
 
 
 
 
Hepatitis B virus (HBV) serology 
 
X10 
 
 
 
Local Laboratory Assessments 
Blood type, Complete blood phenotyping and antibody 
screening11 
X 
 
 
 
 
C2D1 only) 
 
 
 
 
Blood Chemistry12 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology13 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Coagulation14 
X 
 
 
 
 
 
 
 
 
 
Urinalysis15 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test16 
X  
 
 
 
 
X 
 
X 
X 
X 
Markers of potential TLS17 
 
If clinically indicated 
 
 
 


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Evaluation1 
Screening/ 
Baseline 
Cycle 12 
Subsequent cycles2 
End of 
treatment 
(EOT)  
Post treatment 
Follow-up period42 
D-21 to D1 
D1 
D8 
D15 
D22 
D1(±3 days) 
D15 
(±3 days) 
Up to 
30 days 
after last IP 
admin 
At 60 days  
(±5 days) 
after last IP 
admin43 
Every 
3 months 
(±14 days) 
after last 
IP admin 
Central Laboratory Assessment 
Serum ȕ2-microglobulin18 
X 
 
 
 
 
 
 
 
 
 
PK19 
 
X 
X 
X 
X 
X 
X 
X 
 
 
ADA20 
 
X 
 
X 
 
X 
 
X 
X 
 
PD/Exploratory studies: Central Labs 21 
 
FISH (Bone Marrow aspiration) 22 
X 
 
 
 
 
 
 
 
 
 
Genomics (Bone marrow) 23 
X 
 
 
 
 
 
 
X 
 
 
Immune phenotyping (bone marrow aspirate) 24 
X 
 
 
 
 
 
 
 
 
 
MRD assessment (Bone marrow aspirate) 25 
X 
 
 
 
 
 
 
 
 
 
Immune phenotyping (Blood) 26 
 
X 
 
 
 
C3 only 
 
X 
 
 
Immune genetic determinants (Blood) 27 
 
X 
 
 
 
 
 
 
 
 
Adaptive immune response (humoral and cellular 
response) (Blood) 28 
 
X 
 
 
 
C2, C4, C7,C10 
only 
 
X 
 
 
Adaptive immune response (including TCR repertoire) 
(Blood)29 
 
X 
 
 
 
C3 and C5  
 
 
 
 
Laboratory Disease Assessment30 
 
Central 
and Local 
Labs29 
Serum M-Protein31 
X 
X 
 
 
 
X 
 
X 
 
X42 
Urine M-Protein (24-hr urine)32 
X 
X 
 
 
 
X 
 
X 
 
X42 
sFLC33 
X 
X 
 
 
 
X 
 
X 
 
X42 
Immunoglobulins: IgG, IgA, IgM, IgD 
and IgE34 
X 
X 
 
 
 
X 
 
X 
 
 
Bone Marrow for disease assessment35 
X 
 
 
 
 
 
 
X 
 
X42 


Amended Clinical Trial Protocol 14  
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Evaluation1 
Screening/ 
Baseline 
Cycle 12 
Subsequent cycles2 
End of 
treatment 
(EOT)  
Post treatment 
Follow-up period42 
D-21 to D1 
D1 
D8 
D15 
D22 
D1(±3 days) 
D15 
(±3 days) 
Up to 
30 days 
after last IP 
admin 
At 60 days  
(±5 days) 
after last IP 
admin43 
Every 
3 months 
(±14 days) 
after last 
IP admin 
Skeletal survey, low dose whole body CT scan36 
X 
 
 
 
 
 
 
X 
 
X42 
PET-CT/MRI for plasmacytoma37 
X 
 
 
 
 
 
 
X 
 
X42 
Treatment 
 
SAR650984 infusion38 
 
X 
X 
X 
X 
X 
X 
 
 
 
Dexamethasone (Isadex arm only)39 
 
X 
X 
X 
X 
D1 and D8 
D15 and 
D22 
 
 
 
AE/SAE Assessment40 
Continuously throughout study period 
X (related AE only, all SAEs) 
Prior/Concomitant Medication41 
Continuously throughout study period 
X (related AE only, all SAEs) 
New anticancer therapy 
 
 
 
X 
X42 
X42 
Survival Status42 
 
 
 
X 
X42 
X42 
1. 
Evaluation: Assessments should be performed prior to IP administration unless otherwise indicated. 
2. 
Cycle: A cycle is 28 days.  
3. 
Randomization: To take place once the consented patient has completed all the necessary screening procedures and is deemed eligible (based on myeloma specific results from central laboratory and 
hematology/biochemistry local laboratory results) for study entry by the investigator or designee. All eligible patients must be randomized by contacting IVRS. Efforts should be done to start treatment within 
3 working days even if a maximum up to 5 working days can be allowed.  
4. 
Demography: Includes age, gender and race. Medical/Surgical History: Includes relevant history of previous/associated pathologies, other than multiple myeloma; smoking status, respiratory function history 
will be checked. Disease History: Includes date of initial diagnosis, stage of the disease, type of disease at diagnosis and at study entry (heavy and light chain component), previous anti-tumor therapy (drug 
names, include stem cell transplant, start and end date, reason for discontinuation, duration and best response), disease status at inclusion (refractory to last therapy, or relapsed). In addition, results of additional 
procedures (such as karyotype, FISH, etc) performed as part of standard of care at the site to assess the current disease status may also be collected. 
5. 
Physical Examination: To be performed at screening (<7 days prior to randomization), prior to study treatment administration on Day 1, Day 8, Day 15 and Day 22 of Cycle 1, Day 1 and Day 15 of each 
subsequent cycles and at the EOT visit. Consists of examination of major body systems, including neurological, digestive exam, plasmacytoma assessment, respiratory, hepatomegaly, splenomegaly, 
lymphadenopathy. Only clinically relevant findings will be reported in the electronic case report form (eCRF) as AEs.  
6. 
Weight/Height: Height is required at baseline only. Weight is required at screening, prior to starting infusion in each cycle and at the EOT visit. 
7. 
Vital Signs: include Blood pressure, heart rate, temperature, and respiration rate To be performed at screening (<7 days prior to randomization), before starting infusion, middle of infusion, end of infusion on Day 
1, Day 8, Day 15 and Day 22 of Cycle 1, before starting infusion on Day 1 and Day 15 of each subsequent cycles and at the EOT visit..  
8. 
12-Lead ECG: To be performed at screening and then as clinically indicated. 


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9. 
Chest X-ray: To be performed at screening and then as clinically indicated. Screening chest X-ray is for determination of eligibility only and not to be submitted as part of the independent radiographic review, 
unless clinically indicated as per the Investigator. 
10. Includes HBsAg, anti-HBsAb, and anti-HBcAb (total and IgM) and HBV DNA in case of positive anti-HBsAg (see Section 6.8). Once at any time if HBV status unknown before treatment started and to be repeated 
if clinically indicated for patients still under treatment at the time of amended protocol 14. 
11. Blood type, Complete blood phenotyping and antibody screening: Antibody screening test: Blood typing and complete blood phenotyping (C,c; E,e; Kell. Kidd; Duffy; S,s is recommended, if not available 
follow site’s standard) if not already done, and antibody screening (Indirect Coombs Test, Indirect Antiglobulin Test [IAT]) to be obtained 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 a next blood sampling. Results of IAT will be recorded in eCRF. Antibody screen information made before any blood transfusion and 
blood transfusions are to be recorded in the eCRF if performed during the study treatment. Transfusions are to be recorded in the eCRF. A blood type card will be provided to the patient indicating he (she) is 
receiving an anti-CD38 treatment and the site will notify its blood bank that the patient is receiving an anti-CD38 treatment (see Appendix K). 
12. Blood Chemistry: To be done at screening, and to be repeated if it is not within 7 days prior to first IP administration, then prior to pre-medication and IP administration on D1, D8, D15 and D22 of Cycle 1 and 
on D1 and D15 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, ionized calcium and corrected serum calcium, magnesium, phosphate, uric acid, blood urea nitrogen (BUN), serum creatinine and 
estimated creatinine clearance (Cockcroft-Gault Formula), fasting glucose, albumin and total protein. The estimated Glomerular Filtration Rate will be calculated according the Modification of diet in Renal 
Disease (MDRD) equation (see Appendix B) 
13. Hematology: To be done at screening, and to be repeated if it is not within 7 days prior to first IP administration, then prior to pre-medication and IP administration on D1, D8, D15 and D22 of Cycle 1 and D1 and 
D15 of every subsequent cycle, at the EOT visit and as clinically indicated. Hematology includes: Hemoglobin, hematocrit, RBC, WBC with differential, MCV and platelet counts. If grade 4 neutropenia, assess 
ANC every 2-3 days until ANC t 0.5 x 109/L and at least weekly thereafter until ANC t1.0 x 109/L. 
14. Coagulation: To be done at screening and then as clinically indicated. Coagulation includes: Prothrombin time (PT) or international normalized ration (INR) and activated partial thromboplastin time (PTT). 
15. Urinalysis: To be done at screening and then as clinically indicated. Urinalysis includes: blood, protein, glucose, pH, ketones, bilirubin, leucocytes, nitrates and specific gravity.  
16. Pregnancy Test: Women of child bearing potential must have a negative serum pregnancy test result within 7 days prior to first IP administration, serum or urine pregnancy test using a threshold of 20mlU/hCG 
sensitivity test will be done at D1 of each cycle, at the EOT visit and monthly for 5 months after the last administration of SAR650984. 
17. Tumor Lysis Syndrome (TLS) markers: to be done in case of suspicion of TLS (uric acid, creatinine, potassium, phosphate, calcium and corrected calcium) and LDH. 
18. 6HUXPȖ-microglobulin: To be performed at screening. 
19. Pharmacokinetics (PK): Refer to Pharmacokinetics/Pharmacodynamics Flowchart (Section 1.8).  
20. ADA (Anti-Drug Antibodies): Refer to Pharmacokinetics/Pharmacodynamics Flowchart (Section 1.8). ADA samples to be done up to Cycle 10 included. After Cycle 10, no ADA samples. If ADA + at Cycle 10, 
one additional sampling time for ADA evaluation should be collected 3 months later. For patients with less than 10 cycles will have ADA sample at EOT visit and if positive should have one additional sample in 3 
months. For patients with less than 10 cycles at the cut-off date, both PK and ADA samples collection will be stopped from the cut-off date. If last ADA before cut-off date is positive, one additional sampling time 
for ADA evaluation should be collected 3 months later. No further ADA will be sampled, even if this 3-month sample is positive. 
21. Central Lab: Refer to laboratory manual for sample collection and shipping information. 
22. Bone marrow aspirate for FISH: To be performed at screening. 
23. Bone marrow aspirate for genomics/CD38 mRNA: To be performed at screening  
24. Bone marrow aspirate for immune phenotyping: To be performed at screening. 
25. Bone marrow aspirate for MRD assessment: To be performed at screening and at CR confirmation. 
26. Blood sample for immune phenotyping: To be performed on D1 of Cycle 1 prior to IP administration, D1 of Cycle 3 prior to IP administration and at the EOT visit.  
27. Blood sample for immune genetic determinants: To be performed on D1 of Cycle 1 prior to IP administration. 
28. Blood sample for adaptive immune response (humoral and cellular response): To be performed on D1 of Cycle 1 prior to IP administration, D1 of Cycle 2 prior to IP administration, D1 of Cycle 4 prior to IP 
administration, D1 of Cycle 7 prior to IP administration, D1 of Cycle 10 prior to IP administration and in disease progression patients at EOT to assess humoral and cellular immune responses.. Humoral response 
will be assessed in all patients. Cellular response will be assessed in patients at selected sites. 
29. Blood sample for adaptive immune response (TCR repertoire assessment): To be performed on D1 of Cycle 1 prior to IP administration, D1 of Cycle 3 prior to IP administration and D1 of Cycle 5 prior to IP 
administration 


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30. Laboratory Disease assessment: (central and local 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) or lab-dependent 
decisions needed for patient treatment had to be made before the availability of central lab results. All lab assessments to be performed again prior first study treatment administration on Cycle 1 Day 1 and 
response evaluation will be calculated compared to Cycle 1 Day 1 assessments. An additional serum sample will be collected at all time-points to evaluate the potential interference of isatuximab in 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. Efficacy analyses will be done according to IRC assessment, which will use central laboratory data. 
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 CR) to be performed monthly (central and 
local laboratory) during the follow-up period until progression. 
31. Serum M-Protein immunoelectrophoresis (SPEP) and immunofixation: To be performed at screening and again at Cycle 1 Day 1 prior to study treatment administration, then at Day 1 (-1 day) of every 
subsequent cycle prior to study treatment administration, and at the EOT visit. After C1D1 immunofixation to be done if SPEP is negative 
32. Urine M-Protein (24-hour urine) immunoelectrophoresis (UPEP) and immunofixation: To be performed at screening, Cycle 1 Day 1 and Day 1 of every subsequent cycle and to be completed prior to study 
treatment administration and at the EOT visit. If urine M-protein is negative at baseline and Cycle 1 Day 1, this assessment is to be repeated every 3 cycles only (Cycle 4, Cycle 7, Cycle 10, etc) and to confirm 
CR on blood labs. After Cycle 1 Day 1, immunofixation to be done if UPEP is negative in patients whose disease is evaluable in urine. 
33. Serum free light chains (sFLC, quantification and ratio involved/non-involved): To be performed at screening, Cycle 1 Day 1, and Day 1 of every subsequent cycle (central lab analysis to be triggered if M 
protein is undetectable and immunofixation negative). 
34. Immunoglobulins (IgG, IgA, IgM, IgD and IgE): To be performed at screening, Cycle 1 Day 1 and Day 1 of every subsequent cycle prior to study treatment administration and at the EOT visit (IgD or E only if 
the heavy chain component of the disease is known to be E or D). 
35. Bone marrow for disease assessment (biopsy/aspiration): To be performed at screening, to confirm a sCR, CR, (and to confirm disease progression), at the EOT visit and as clinically indicated.  
36. 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. The same modality (skeletal survey or low-dose whole-body CT) should be used throughout the study for each individual patient. All imaging to be sent for central 
review 
37. Extramedullary disease (plasmacytoma) assessment (including bone plasmacytoma): If known extramedullary disease at baseline, PET-CT scan or MRI is to be done at baseline and to be repeated every 
12 weeks (±1 week), and if clinically indicated. If suspected extramedullary disease (plasmacytoma) at baseline, PET-CT/MRI to be done at baseline to centrally confirm its presence and in case of confirmation 
to be repeated every 12 weeks (±1 week) and if clinically indicated. To be done in case of suspicion of progression or if clinically indicated in a patient with no previous positive image for extramedullary disease. 
The same modality (PET-CT or MRI) should be used throughout the study for each individual patient. All imaging to be sent for central review. 
38. SAR650984 Administration: At the start of each treatment cycle, the patient’s weight will be determined.  
39. Dexamethasone: If the patient is in Isa/Dex arm of the study, starting Cycle 2, patient will take dexamethasone at home and record dosing information in the home diary. 
40. AE/SAE assessment: All AEs, including events 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. After the 30 day follow-up all ongoing related and new related non-serious AEs and new SAEs regardless of relationship are to be followed to resolution or stabilization. All IP-
related AEs and all SAEs (regardless of relationship to study treatment) to be followed to resolution or stabilization. 
41. Prior medications (which are not prior anti-myeloma therapy) administered within 21 days prior to randomization will be collected.  
42. Follow-up: Patients who discontinue study treatment due to PD: follow-up visit will be done every 3 months from the date of last study treatment administration until death: AEs according to footnote 40 (at EOT 
and 60 days [±5 days] after last study treatment administration), second primary malignancy, further anti-myeloma therapy, and survival status will be collected. Every effort will be made to follow all patients. If 
survival follow-up is missed and is not obtained at the time of the scheduled interval, it should be retrieved immediately. For subsequent survival follow-up, the patient 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 any effort should be done to schedule follow-up visit at clinical center.  
Patients who discontinue the study treatment without PD will be followed every month (at EOT and 60 days [±5 days] after last study treatment administration), second primary malignancy, laboratory disease 
assessment (local and central laboratory), radiological assessment every 12 weeks (±1 week) in case of extramedullary disease (plasmacytoma) at baseline until confirmation of PD (even for patients who would 
initiate further anti-myeloma therapy without PD). After PD patient will be followed every 3 months as described just above. 
43. Applicable when ADA where collected at 60 days after last IP administration.  


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1.16 
STUDY PK FLOWCHART FOR PHASE 2 STAGE 2  
 
Study Phase 
Cycle 1 
Cycle 2-3 
Cycle 4 
Subsequent 
Cycles 
EOT 
Follow-up 
Day 
D1 
D8 
D15 
D22 
D1 
D15 
D1 
D15 
D1 
D15 
30 days 
after last 
study 
treatment 
admin 
(±5 days) 
60 days 
after last 
study 
treatment 
admin 
(±5 days)f 
Monthly 
(±5 days) for 
approximately 
12 months 
Time (decimal hours) 
0ha 
Start 
Infusion 
EOIb 
EOI 
+1hc 
0ha 
Start 
Infusion 
0ha 
Start 
Infusion 
EOIb 
0ha 
Start 
Infusion 
0ha 
Start 
Infusion 
EOIb 
0ha 
Start 
Infusion 
0ha  
Start 
Infusion 
EOIb 
EOI 
+1hc 
0ha 
Start 
Infusion 
0ha 
Start 
Infusion 
0ha 
Start 
Infusion 
 
 
 
Indicative clock time 8 am 
12 
pm 1 pm 8 am 
8 am 
12 
pm 
8 am 
8 am 
12 
pm 
8 am 
8 am 
12 
pm 1 pm 8 am 
8 am 
8 am 
8 am 
8 am 
8 am 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAR650984 (IV 
infusion) 
x------ ----x 
 
x 
x------ ----x 
x 
x------ 
----x 
x 
x------ 
----x 
 
x 
x 
x 
 
 
 
Pharmacokineticsd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAR650984 
P00 
P01 P02 
P03 
P04 
P05 
P06 
P00 
P01 
P02 
P00 
P01 P02 
P03 
P00a 
P01a 
PF0e 
 
 
Pharmacodynamicsd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA (Anti-Drug 
Antibody) 
(Immunogenicity) 
P00a 
 
 
 
P01a 
 
 
P00a 
 
 
P00a 
 
 
 
P00a 
 
PF0e 
PF1e 
PFxe 
EOI = End of Infusion; ADA = Anti-Drug Antibody (immunogenicity); P = Plasma; Y = Bone Marrow;  
* 1 Cycle = 28 days 
a Sample collected just before IP administration. Sample to be collected up to and including C10. If a patient does not complete 10 cycles, EOT sample should be collected. 
b Sample collected just before actual end of infusion (EOI). A time window of [-10 min; +10 min] around the actual end of infusion will be allowed for end of infusion sample.  
c Sample collected 1 hour after the actual end of infusion 
d Refer to laboratory manual for sample collection, processing and shipping 
e For patients with less than 10 cycles should have ADA sample at EOT visit and if positive should have one additional sample in 3 months. For patients with less than 10 cycles at the cut-off date, both PK and ADA 
samples collection will be stopped from the cut-off date. If last ADA before cut-off date is positive, one additional sampling time for ADA evaluation should be collected 3 months later. No further ADA will be 
sampled, even if this 3-month sample is positive 
f 
Applicable when ADA where collected at 60 days after last IP administration. 


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2 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 14 ....................................................................................1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES .....................................................................2 
1 
FLOWCHARTS................................................................................................................... 23 
1.1 
DIAGRAM 1: PHASE 1 ACCELERATED DOSE ESCALATION PHASE - METHODOLOGY
 ............................................................................................................................................ 23 
1.2 
DIAGRAM 2: PHASE 1 BASIC DOSE ESCALATION PHASE - METHODOLOGY ........... 24 
1.3 
DIAGRAM 3: PHASE 2 STUDY DESIGN ........................................................................... 25 
1.4 
PHARMACOKINETICS/PHARMACODYNAMICS FLOWCHART PHASE 1 
ACCELERATED PHASE .................................................................................................... 26 
1.5 
PHARMACOKINETICS/PHARMACODYNAMICS FLOWCHART PHASE 1 BASIC PHASE 
(SAR650984 ADMINISTRATION EVERY 2 WEEKS - COHORTS 6-10) .......................... 27 
1.6 
PHARMACOKINETICS/PHARMACODYNAMICS FLOWCHART PHASE 1 BASIC PHASE 
(SAR650984 ADMINISTRATION EVERY WEEK - FROM COHORT 11) .......................... 28 
1.7 
PHARMACOKINETICS/PHARMACODYNAMICS FLOWCHART PHASE 1 BASIC PHASE 
(SAR650984 ADMINISTRATION EVERY 2 WEEKS - FROM COHORT 12) .................... 29 
1.8 
PHARMACOKINETICS/PHARMACODYNAMICS FLOWCHART PHASE 2 ..................... 30 
1.9 
STUDY FLOWCHART FOR PHASE 1 ACCELERATED DOSE ESCALATION PHASE ... 32 
1.10 
STUDY FLOWCHART FOR PHASE 1 BASIC DOSE ESCALATION PHASE (SAR650984 
ADMINISTRATION EVERY 2 WEEKS - FOR COHORTS 6-10) ....................................... 36 
1.11 
STUDY FLOWCHART FOR PHASE 1 BASIC DOSE ESCALATION PHASE (SAR650984 
ADMINISTRATION EVERY WEEK - FROM COHORT 11)................................................ 40 
1.12 
STUDY FLOWCHART FOR PHASE 1 BASIC DOSE ESCALATION PHASE (SAR650984 
ADMINISTRATION EVERY 2 WEEKS - FROM COHORT 12) .......................................... 44 
1.13 
STUDY FLOWCHART FOR PHASE 2, STAGE 1A ........................................................... 48 
1.14 
STUDY FLOWCHART FOR PHASE 2, STAGE 1B ........................................................... 53 
1.15 
STUDY FLOWCHART FOR PHASE 2, STAGE 2 .............................................................. 58 
1.16 
STUDY PK FLOWCHART FOR PHASE 2 STAGE 2 ......................................................... 63 
2 
TABLE OF CONTENTS ..................................................................................................... 64 
3 
LIST OF ABBREVIATIONS ............................................................................................... 73 


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4 
INTRODUCTION AND RATIONALE.................................................................................. 75 
4.1 
INTRODUCTION................................................................................................................. 75 
4.2 
MULTIPLE MYELOMA (MM) .............................................................................................. 75 
4.3 
ACUTE MYELOGENOUS LEUKEMIA (AML) .................................................................... 77 
4.4 
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) ................................................................... 77 
4.5 
NON- HODGKIN’S LYMPHOMA (NHL).............................................................................. 78 
4.6 
ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) ................................................................... 79 
4.7 
COMPOUND DESCRIPTION ............................................................................................. 79 
4.7.1 
Chemical name and structure .................................................................................................. 79 
4.7.2 
Dosage form, route of administration, and dosing regimen (frequency and duration) ....... 80 
4.7.3 
Pharmacology ..................................................................................................................... 81 
4.7.4 
Toxicology ........................................................................................................................... 81 
4.7.5 
Metabolism and pharmacokinetics in animal ...................................................................... 82 
4.7.6 
Clinical experience .............................................................................................................. 82 
4.8 
RATIONALE ........................................................................................................................ 82 
4.8.1 
Study rationale .................................................................................................................... 82 
4.8.2 
Design rationale .................................................................................................................. 82 
4.8.3 
Phase 1 dose, regimen, and treatment duration rationale .................................................. 85 
4.8.4 
Phase 2 dose selection rationale ........................................................................................ 85 
5 
STUDY OBJECTIVES ........................................................................................................ 89 
5.1 
PRIMARY ............................................................................................................................ 89 
5.2 
SECONDARY ..................................................................................................................... 89 
5.3 
EXPLORATORY ................................................................................................................. 90 
6 
STUDY DESIGN ................................................................................................................. 91 
6.1 
DESCRIPTION OF THE PROTOCOL – PHASE 1 PART .................................................. 91 
6.1.1 
Starting dose and dose escalation design .......................................................................... 91 
6.1.1.1 
Accelerated dose escalation step ....................................................................................... 91 
6.1.1.2 
Basic dose escalation phase .............................................................................................. 92 
6.1.2 
Maximum administered dose (MAD)/Maximum tolerated dose (MTD)/Recommended 
Phase 2 dose (RP2D) ......................................................................................................... 93 
6.1.3 
Phase 1 expansion cohorts ................................................................................................. 94 
6.2 
DESCRIPTION OF THE PROTOCOL - PHASE 2 PART ................................................... 94 


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6.3 
RETREATMENT OF PATIENTS ........................................................................................ 95 
6.4 
DOSE DELAYS/MODIFICATIONS ..................................................................................... 96 
6.5 
GUIDELINES FOR THE MANAGEMENT OF POTENTIAL HYPERSENSITIVITY 
REACTIONS ....................................................................................................................... 97 
6.6 
GUIDELINES FOR THE MANAGEMENT OF POTENTIAL TUMOR LYSIS SYNDROME 99 
6.7 
GUIDELINES FOR THE MANAGEMENT OF POTENTIAL ADVERSE EVENTS DUE TO 
DEXAMETHASONE ......................................................................................................... 100 
6.8 
GUIDANCE IN CASE OF HEPATITIS B REACTIVATION OCCURRING UNDER STUDY 
TREATMENT .................................................................................................................... 101 
6.9 
DURATION OF STUDY PARTICIPATION ....................................................................... 101 
6.9.1 
Duration of study participation for each patient ................................................................ 101 
6.9.2 
Determination of end of clinical trial (all patients) ............................................................. 102 
6.9.3 
Interim analysis ................................................................................................................. 102 
6.9.4 
Phase 1 Study Committee ................................................................................................ 103 
6.9.5 
Phase 2 Study Committees .............................................................................................. 103 
7 
SELECTION OF PATIENTS ............................................................................................. 105 
7.1 
NUMBER OF PATIENTS .................................................................................................. 105 
7.2 
PHASE 1 INCLUSION CRITERIA .................................................................................... 105 
7.3 
PHASE 1 EXCLUSION CRITERIA ................................................................................... 106 
7.4 
PHASE 2 (STAGE 1 AND STAGE 2) INCLUSION CRITERIA ......................................... 107 
7.5 
PHASE 2 (STAGE 1 AND STAGE 2) EXCLUSION CRITERIA ....................................... 108 
8 
TREATMENTS .................................................................................................................. 111 
8.1 
INVESTIGATIONAL PRODUCT ....................................................................................... 111 
8.1.1 
Pharmaceutical form ......................................................................................................... 111 
8.1.1.1 
Formulation for Phase 1 and Phase 2 Stage 1 ................................................................. 111 
8.1.1.2 
Formulation for Phase 2 Stage 1 and 2 ............................................................................ 111 
8.1.2 
Dose of drug per administration ........................................................................................ 111 
8.1.3 
Duration of treatment: ....................................................................................................... 113 
8.1.4 
Dilution method ................................................................................................................. 113 
8.1.5 
Stability under light ............................................................................................................ 113 
8.1.6 
Dexamethasone (investigational product for patients randomized in the ISAdex 
arm - Phase 2 Stage 2 only) ............................................................................................. 114 
8.1.6.1 
Availability ......................................................................................................................... 114 
8.1.6.2 
Accountability .................................................................................................................... 114 


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8.1.6.3 
Administration ................................................................................................................... 114 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT .......................................................... 114 
8.2.1 
Premedication ................................................................................................................... 114 
8.3 
PACKAGING AND LABELING ......................................................................................... 115 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ................................. 115 
8.5 
STORAGE CONDITIONS ................................................................................................. 116 
8.6 
RESPONSIBILITIES ......................................................................................................... 116 
8.7 
RETRIEVAL OF TREATMENTS AND/OR DESTRUCTION ............................................ 117 
8.8 
CONCOMITANT TREATMENT ........................................................................................ 117 
8.9 
POST-INVESTIGATIONAL PRODUCT ............................................................................ 118 
8.10 
TREATMENT ACCOUNTABILITY AND COMPLIANCE .................................................. 118 
8.11 
CONTRACEPTIVE MEASURES ...................................................................................... 118 
9 
ASSESSMENT OF INVESTIGATIONAL PRODUCT ...................................................... 120 
9.1 
SAFETY ............................................................................................................................ 120 
9.1.1 
Dose limiting toxicities (DLTs) 激 Phase 1 part only ........................................................... 120 
9.1.2 
Adverse events ................................................................................................................. 121 
9.1.3 
Laboratory measurements ................................................................................................ 121 
9.1.3.1 
Phase 1 laboratory assessments ...................................................................................... 121 
9.1.3.2 
Phase 2 laboratory assessments ...................................................................................... 121 
9.1.4 
Physical examinations ...................................................................................................... 122 
9.1.5 
Vital signs .......................................................................................................................... 122 
9.1.6 
ECG .................................................................................................................................. 122 
9.1.7 
Other Clinical assessments .............................................................................................. 122 
9.2 
EFFICACY ........................................................................................................................ 122 
9.2.1 
Phase 1 criteria for response ............................................................................................ 122 
9.2.2 
Phase 2 primary endpoint ................................................................................................. 123 
9.2.3 
Phase 2 secondary endpoints ........................................................................................... 123 
9.2.3.1 
Secondary efficacy endpoints: .......................................................................................... 123 
9.2.3.2 
Electronic patient reported outcomes (Phase 2 Stage 1a and 1b only) ........................... 124 
9.3 
PHARMACOKINETIC EVALUATION ............................................................................... 125 
9.3.1 
Phase 1 pharmacokinetic evaluations .............................................................................. 125 
9.3.2 
Phase 2 pharmacokinetic evaluations .............................................................................. 126 
9.3.3 
Sampling time and sample blood volume for Phase 1 and Phase 2 ................................ 126 


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9.3.4 
PK handling procedure ..................................................................................................... 126 
9.4 
IMMUNE RESPONSE ...................................................................................................... 127 
9.5 
PHARMACODYNAMIC ASSESSMENT ........................................................................... 127 
9.6 
PHASE 2 EXPLORATORY BIOMARKER STUDIES ....................................................... 127 
10 
PATIENT SAFETY............................................................................................................ 130 
10.1 
SAFETY ENDPOINTS ASSESSED IN THIS TRIAL ........................................................ 130 
10.2 
SAFETY INSTRUCTIONS ................................................................................................ 130 
10.3 
ADVERSE EVENTS MONITORING ................................................................................. 130 
10.4 
DEFINITIONS OF ADVERSE EVENT (AE) AND SERIOUS ADVERSE EVENT (SAE) .. 130 
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ............. 131 
10.5.1 
Adverse events ................................................................................................................. 131 
10.5.2 
Serious adverse events .................................................................................................... 132 
10.5.3 
Follow-up ........................................................................................................................... 132 
10.5.4 
Treatment discontinuation due to non-serious adverse event .......................................... 132 
10.6 
ADVERSE EVENT OF SPECIAL INTEREST (AESI) ....................................................... 133 
10.7 
PREGNANCY ................................................................................................................... 134 
10.8 
OVERDOSE ...................................................................................................................... 134 
10.9 
OBLIGATIONS OF SANOFI-AVENTIS ............................................................................ 134 
11 
HANDLING OF PATIENT TEMPORARY AND DEFINITIVE TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION ......................... 135 
11.1 
TEMPORARY TREATMENT DISCONTINUATION WITH INVESTIGATIONAL PRODUCT
 .......................................................................................................................................... 135 
11.2 
DEFINITIVE TREATMENT DISCONTINUATION WITH INVESTIGATIONAL PRODUCT(S)
 .......................................................................................................................................... 135 
11.2.1 
List of criteria for definitive treatment discontinuation ....................................................... 135 
11.2.2 
Handling of patients after definitive treatment discontinuation ......................................... 135 
11.3 
PROCEDURE FOR WITHDRAWAL OF PATIENTS FROM STUDY FOLLOW-UP 
SCHEDULE ....................................................................................................................... 136 
11.4 
CONSEQUENCE .............................................................................................................. 136 
12 
STUDY PROCEDURES ................................................................................................... 137 
12.1 
PHASE 1 VISIT SCHEDULE ............................................................................................ 137 


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12.1.1 
Pretreatment evaluation (screening/baseline) .................................................................. 137 
12.1.2 
Assessments for patients with an every 2 week administration (Cohorts 1-10) ............... 138 
12.1.2.1 Before the first investigational product administration and prior to IP administration at each 
cycle (within 1 day before) ................................................................................................ 138 
12.1.2.2 During the treatment period (Cycles 1 and 2) ................................................................... 139 
12.1.2.3 During the treatment period (subsequent cycles) ............................................................. 141 
12.1.3 
Assessments for patients with an every week administration (from Cohort 11) ............... 141 
12.1.3.1 Before the first investigational product administration and prior to IP administration at each 
cycle (within 1 day before) ................................................................................................ 141 
12.1.3.2 During the treatment period (Cycles 1, 2 and 3) ............................................................... 142 
12.1.3.3 During the treatment period (subsequent cycles) ............................................................. 143 
12.1.4 
Assessments for patients with an every 2 week administration (from Cohort 12) ............ 144 
12.1.4.1 Before the first investigational product administration and prior to IP administration at each 
cycle (within 1 day before) ................................................................................................ 144 
12.1.4.2 During the treatment period (Cycles 1 and 2) ................................................................... 145 
12.1.4.3 During the treatment period (subsequent cycles) ............................................................. 146 
12.1.5 
During the treatment period (all cycles, all cohorts).......................................................... 147 
12.1.6 
End of treatment visit (to be performed at least 30 days (+/-5 days) after the last 
investigational product administration) ............................................................................. 147 
12.1.7 
Follow-up period (>30 days after last IP administration) .................................................. 147 
12.2 
PHASE 2 VISIT SCHEDULE ............................................................................................ 148 
12.2.1 
Pretreatment evaluation (screening/baseline) .................................................................. 148 
12.2.2 
Randomization/registration ............................................................................................... 150 
12.2.3 
Cycle 1-3 evaluations ........................................................................................................ 150 
12.2.4 
During treatment period (subsequent cycles) ................................................................... 154 
12.2.5 
End of treatment visit (to be performed up to 30 days after the last study treatment 
administration)................................................................................................................... 156 
12.2.6 
Follow-up period at 60 days (±5 days) after last study treatment administration ............. 157 
12.2.7 
Post 60 day follow-up period ............................................................................................. 157 
12.3 
DATA COLLECTION AFTER FINAL ANALYSIS CUTOFF DATE ................................... 158 
13 
STATISTICAL CONSIDERATIONS ................................................................................. 160 
13.1 
DETERMINATION OF SAMPLE SIZE.............................................................................. 160 
13.2 
PATIENT DESCRIPTION ................................................................................................. 161 
13.2.1 
Disposition of patients ....................................................................................................... 161 
13.2.2 
Protocol deviations ............................................................................................................ 161 
13.3 
ANALYSIS POPULATIONS .............................................................................................. 161 
13.3.1 
All treated/safety population .............................................................................................. 161 
13.3.2 
Patients evaluable for DLT assessment ........................................................................... 161 


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13.3.3 
Pharmacokinetic population .............................................................................................. 162 
13.3.4 
Pharmacodynamic population ........................................................................................... 162 
13.3.5 
PRO population ................................................................................................................. 162 
13.4 
STATISTICAL METHODS ................................................................................................ 162 
13.4.1 
Demographics and baseline characteristics ..................................................................... 162 
13.4.2 
Extent of investigational product exposure ....................................................................... 162 
13.4.3 
Prior/concomitant medication/therapy .............................................................................. 163 
13.4.4 
Analysis of efficacy endpoints ........................................................................................... 164 
13.4.4.1 Efficacy endpoints for Phase 1 part of the study .............................................................. 164 
13.4.4.2 Analysis of primary efficacy endpoint for Phase 2 part of the study ................................. 164 
13.4.4.3 Analysis of secondary efficacy endpoint for Phase 2 part of the study ............................ 164 
13.4.5 
Analysis of patient reported outcomes (Phase 2 Stage 1 only) ........................................ 165 
13.4.6 
Analyses of safety data ..................................................................................................... 165 
13.4.6.1 Dose-limiting toxicities ...................................................................................................... 165 
13.4.6.2 Analyses of adverse events .............................................................................................. 165 
13.4.6.3 Deaths ............................................................................................................................... 167 
13.4.6.4 Clinical laboratory evaluations .......................................................................................... 167 
13.4.6.5 Vital signs .......................................................................................................................... 167 
13.4.6.6 Analyses of other safety variables .................................................................................... 167 
13.4.7 
Analyses of pharmacokinetic variables ............................................................................. 167 
13.4.8 
Analysis of anti-drug antibody ........................................................................................... 168 
13.4.9 
Analysis of pharmacodynamic variables ........................................................................... 169 
13.5 
INTERIM ANALYSIS ......................................................................................................... 169 
14 
ETHICAL AND REGULATORY STANDARDS ................................................................ 170 
14.1 
ETHICAL PRINCIPLES .................................................................................................... 170 
14.2 
LAWS AND REGULATIONS ............................................................................................ 170 
14.3 
INFORMED CONSENT .................................................................................................... 170 
14.4 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) . 170 
15 
STUDY MONITORING ..................................................................................................... 172 
15.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) .......................................................... 172 
15.2 
RESPONSIBILITIES OF THE SPONSOR ........................................................................ 172 
15.3 
SOURCE DOCUMENT REQUIREMENTS ....................................................................... 173 
15.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST ......................................................................................................................... 173 
15.5 
USE OF COMPUTERIZED SYSTEMS............................................................................. 173 


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16 
ADMINISTRATIVES RULES ............................................................................................ 174 
16.1 
CURRICULUM VITAE ...................................................................................................... 174 
16.2 
RECORD RETENTION IN STUDY SITES (S) ................................................................. 174 
16.3 
CONFIDENTIALITY .......................................................................................................... 174 
16.4 
PROPERTY RIGHTS ........................................................................................................ 175 
16.5 
DATA PROTECTION ........................................................................................................ 175 
16.6 
INSURANCE COMPENSATION ....................................................................................... 175 
16.7 
SANOFI-AVENTIS AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ........ 175 
16.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE ............................................................................................................................... 176 
16.9 
DECIDED BY SANOFI-AVENTIS IN THE FOLLOWING CASES: ................................... 176 
16.10 
DECIDED BY THE INVESTIGATOR ................................................................................ 176 
16.11 
CLINICAL TRIAL RESULTS ............................................................................................. 177 
16.12 
PUBLICATIONS AND COMMUNICATIONS .................................................................... 177 
17 
CLINICAL TRIAL PROTOCOL AMENDMENTS ............................................................. 178 
18 
BIBLIOGRAPHIC REFERENCES .................................................................................... 179 
19 
APPENDICES ................................................................................................................... 184 
APPENDIX A 
NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA FOR 
ADVERSE EVENTS ......................................................................................................... 184 
APPENDIX B 
KARNOFSKY/ECOG PERFORMANCE STATUS EVALUATION AND CREATININE 
CLEARANCE CALCULATION FORMULA ....................................................................... 185 
APPENDIX C 
DEFINITION OF LINE OF THERAPY AND REFRACTORY MYELOMA .............. 186 
APPENDIX D 
PHASE 1 RESPONSE CRITERIA ......................................................................... 187 
APPENDIX E 
PHASE 2 RESPONSE CRITERIA .......................................................................... 198 
APPENDIX F 
STAGING CRITERIA .............................................................................................. 202 
APPENDIX G 
PRO QUESTIONNAIRES QLQ-C30 AND MY20 ................................................... 206 
APPENDIX H 
PRO QUESTIONNAIRE EQ-5D ............................................................................. 210 
APPENDIX I 
SUMMARY OF PK/PD HANDLING PROCEDURES AND BIOANALYTICAL 
METHOD ........................................................................................................................... 212 


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APPENDIX J 
CD38 BLOOD TEST INTERFERENCE GUIDELINE AABB ................................... 213 
APPENDIX K 
SUMMARY OF HANDLING PROCEDURES FOR EXPLORATORY BIOMARKER 
ANALYSIS IN PHASE 2 STAGE 2 ................................................................................... 217 
APPENDIX L 
PROTOCOL AMENDMENT HISTORY ................................................................... 218 
  


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3 
LIST OF ABBREVIATIONS  
 
ADCC 
AE 
antibody-dependent cell mediated cytotoxicity 
adverse event  
AESI 
adverse event of special interest  
ALT (SGPT) 
alanine aminotransferase (or serum glutamate-pyruvate transferase) 
ALL 
acute lymphoblastic leukemia 
AML 
acute myelogenous/myeloid leukemia 
AP 
alkaline phosphatase 
ASCT 
autologous stem cell transplantation 
AST (SGOT) 
aspartate aminotransferase (or serum glutamate-oxaloacetate transferase) 
AUC 
area under the time concentration curve 
BUN 
blood urea nitrogen 
C 
CBR 
CDC 
cycle 
clinical benefit rate 
complement-dependent cytotoxicity  
Ceoi 
concentration at end of infusion 
CHOP 
cyclophosphamide/doxorubicin/vincristine/prednisone 
CL 
clearance 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum concentration 
CR 
complete remission 
CRF 
case report form  
CSF 
colony-stimulating factor 
CTCAE 
CTLS 
Common Terminology Criteria for Adverse Events 
Clinical Tumor Lysis Syndrome 
DRF 
Discrepancy Resolution Form  
D 
day 
DL 
dose level 
DLTs 
DMC 
DOR 
dose limiting toxicities 
Data Monitoring Committee 
duration of response 
ECOG 
FcGR 
FLC 
eGFR 
Eastern Cooperative Oncology Group 
Fc fragment of IgG receptor 
free light chains 
estimated Glomerular Filtration Rate 
G-CSF 
granulocyte colony stimulating factor 
GVHD 
Graft versus host disease 
GMCSF 
Granulocyte-monocyte colony stimulating factor 
H 
HLA 
HBcAb 
HBsAb 
HBsAg 
HBV 
HRQOL 
Hour 
human leukocyte antigen 
hepatitis B core antibody 
hepatitis B surface antibody 
hepatitis B surface antigen 
hepatitis B virus 
health-related quality of life  


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IEC 
IMiD 
Independent Ethics Committee 
Immunomodulatory drug 
INR 
International Normalized Ratio 
IP 
investigational product  
IRB 
Institutional Review Board  
IV 
IVRS 
IWRS 
KIR 
LTLS 
intravenous 
interactive voice response system 
interactive web response system 
killer cell immunoglobulin–like receptor 
Laboratory Tumor Lysis Syndrome 
LDH 
lactate dehydrogenase 
MAD 
maximum administered dose 
Min 
MR 
MRD 
minute 
minimal response 
minimal residual disease 
MM 
Multiple myeloma 
MTD 
maximum tolerated dose 
NCI 
NHL 
NIMP 
OS 
National Cancer Institute 
Non-Hodgkin’s lymphoma  
Non-investigational medicinal product 
overall survival 
ORR 
overall response rate 
PD 
PFS 
pharmacodynamics 
progression free survival 
PK 
pharmacokinetics 
PO 
per os 
PR 
partial remission 
PTT 
QW 
Q2W 
Q4W 
RD 
RO 
partial thromboplastin time 
every week 
every 2 weeks 
every 4 weeks 
receptor density 
receptor occupancy 
SAE 
serious adverse event  
SD  
selected dose    
t1/2 
half-life 
TEAE 
treatment-emergent adverse event 
ULN 
VGPR 
upper limit of normal 
very good partial response 
WBC 
white blood cell 
 


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4 
INTRODUCTION AND RATIONALE  
4.1 
INTRODUCTION  
SAR650984 is a naked humanized IgG1 monoclonal antibody directed against CD38, a receptor 
antigen expressed on hematopoietic cells. CD38 is involved in the homeostasis of the 
hematopoietic compartment as a modulator of cell survival and differentiation. It is both an 
enzyme, able to catalyze the formation of nucleotide metabolites involved in calcium signaling, 
and a receptor, which induces cell signaling through interaction with other receptors at the surface 
of the cell. CD38 antigen is expressed in a number of hematological malignancies from 
B-lymphocyte, T-lymphocyte and myeloid origin. The monoclonal antibody SAR650984 has 
3 modes of action to kill target cells: 
1. Antibody-dependent cell mediated cytotoxicity (ADCC). 
2. Complement-dependent cytotoxicity (CDC). 
3. Pro-apoptotic activity. 
In preclinical tumor models in mice, it was active as a single agent and in combination with 
reference treatments, on several CD38-positive tumors in multiple hematological malignancies, 
including multiple myeloma, non-Hodgkin’s-lymphoma and leukemia. 
Moreover, of clinical importance is that CD38 was identified as a negative prognostic marker in 
some hematological malignancies. As a consequence, SAR650984 has the potential to treat a 
variety of hematological indications:  
x Multiple myeloma (MM), with nearly all patients being CD38+. 
x Acute myeloid leukemia (AML) with 58% CD38+ patients. 
x Chronic lymphocytic leukemia (CLL) for which 20%-25% of CD38+ patients have been 
associated with an aggressive prognosis. 
x Non-Hodgkin’s lymphoma (NHL) with 30%-80% CD38+ patients depending on the 
subtype. 
x Acute lymphocytic leukemia (ALL) with 90%-100% CD38+ patients. 
4.2 
MULTIPLE MYELOMA (MM)  
Multiple myeloma is a malignant plasma cell disease that is characterized by clonal proliferation 
of plasma cells in the bone marrow 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]) (6). It is a disease predominantly associated with advancing age 
with more than 80% of patients aged 60 years or older and a median age of onset around 68 years; 
only about 2% of cases are diagnosed in individuals under the age of 40 (8). 
Patients with MM can experience bone pain, bone fractures, fatigue, anaemia, infections, 
hypercalcaemia and kidney problems (9). The disease course for multiple myeloma varies with 


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the aggressiveness of the disease and related prognostic factors. Median survival is approximately 
3 years; however, some patients can live longer than 10 years (10). Treatment options and 
survival are based on the patient’s disease status. Patients presenting with symptomatic active 
disease in good physical health will receive initial therapy with autologous stem cell 
transplantation (ASCT). To achieve cytoreduction of the disease before collecting stem cells, 
induction chemotherapy is administered. Induction treatment regimens include dexamethasone 
alone, thalidomide plus dexamethasone, and vincristine, Adriamycin® (doxorubicin), and 
dexamethasone (VAD; or modifications to this regimen); however, the later 2 regimens are 
associated with higher toxicity (9). Newer treatments with Velcade® (bortezomib) alone, 
bortezomib combinations, and Revlimid® (lenalidomide) plus dexamethasone show some promise 
as induction therapy, and these agent demonstrate higher response rates and lower toxicity 
(10, 11). 
The current aim of MM therapy is to control 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, melphalan plus prednisone 
or VAD) can be reinstituted for relapsed/refractory disease if the disease relapsed more than  
6 months after the last therapy ended. The patients for whom stem cells were cryopreserved early 
in the disease course, and who are transplant candidates, can benefit from ASCT as salvage 
therapy (10, 11). Subsequent treatment decisions are based on whether the patient experiences an 
indolent or aggressive relapse. Patients with relapsed disease may continue taking 1 drug or 
treatment regimen as maintenance therapy until relapse or toxicity. 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 and carfilzomib) and immune modulatory agents  
(eg, lenalidomide and pomalidomide). 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 therapy transplant, chemotherapy, proteasome inhibitors, and immune modulatory agents. 
Despite the dramatic improvement in patient outcomes, MM remains an incurable disease. Thus, 
the treatment of patients who have received at least three 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. 
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 suggests that this antigen may be a useful target for the in vivo depletion of tumor 
cells while sparing normal cells (12). 


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4.3 
ACUTE MYELOGENOUS LEUKEMIA (AML)  
Acute myelogenous leukaemia (AML) is considered to be one of the most common types of adult 
acute leukemias worldwide. There are approximately 12 000 new cases annually in the US and 
10,000 in Europe. AML is a stem cell disorders characterized by uncontrolled proliferation and 
accumulation of non-functional clonal hematopoietic cells called myeloblasts and impaired 
production of normal hematopoiesis leading to neutropenia, thrombocytopenia, anemia and/or 
hyperleucocytosis. Occasionally, blasts may invade different tissues, including the liver, spleen, 
skin, lymph nodes, bone, gingival and central nervous system. Despite diagnostic and therapeutic 
improvements over the last decade, the outcome of patients with AML remains poor, with a 
5-year survival rate of 20%-30% for patients <60 years and less than 10% for older patients  
(13, 14). 
Much of the search for new agents focuses on tumor targeted therapies, which may not only 
maximize the antitumor efficacy, but also significantly reduce the toxicity on normal tissues. 
Gemtuzumab ozogamicin (Mylotarg®), is a humanized anti-CD33 monoclonal antibody 
conjugated to a cytotoxic antibiotic, calicheamycin. Mylotarg obtained an accelerated approval 
from the FDA as single agent therapy for patients with CD33 positive AML in first relapse who 
are 60 years of age or older and who are not considered candidates for other cytotoxic 
chemotherapy. In these patients Mylotarg single agent induced 26% responses (CR + CRp) (15). 
The main toxicities were severe, long myelosupression (neutropenia, thrombocytopenia), 
hypersensitivity reactions and hepatotoxicity. Mylotarg is not approved in Europe. 
4.4 
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)  
Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in the Unites States (US) 
and European Union (EU) accounting for 25% of adult leukemias. Over two-thirds of patients 
with CLL are older than 60 years and the incidence steadily increases in individuals over 50 years 
of age. The disease has a very diverse natural history and patients with lymphocytosis have a 
median survival greater than 10 years whereas patients with evidence of bone marrow failure 
manifested by anemia or thrombocytopenia have a median survival of 2 years or less (16). 
Treatment is commonly reserved for symptomatic patients, since no treatment has yet shown to be 
curative nor is there objective evidence that a specific treatment prolongs survival. The NCI 
sponsored CLL Working Group proposed the following indications for initiating treatment: 
1) weight loss of more than 10% over the preceding 6 months; 2) extreme fatigue attributable to 
progressive disease; 3) fever or night sweats without evidence of infection; 4) worsening anemia 
(Rai Stage III) or thrombocytopenia (Rai Stage IV); 5) massive lymphadenopathy (>10 cm) or 
rapidly progressive lymphocytosis (lymphocyte doubling time <6 months); or 6) prolymphocytic 
or Richter’s transformation (17) 
Three purine analogues are currently used in CLL: fludarabine, pentostatin, and cladribine. 
Fludarabine remains by far the best-studied compound of the three in CLL. Fludarabine 
monotherapy produces superior overall response (OR) rates compared with other treatment 
regimens containing alkylating agents or corticosteroids. (18, 19, 20). In three Phase 3 studies in 
treatment-naïve CLL patients, fludarabine induced more remissions and more complete 


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remissions (CR) (7%-40%) than other conventional chemotherapies, such as CHOP 
(cyclophosphamide, doxorubicin, vincristine, prednisone), CAP (cyclophosphamide, doxorubicin, 
prednisone), or chlorambucil. Despite the superior efficacy of fludarabine, only a trend for longer 
overall survival could be observed, and this trend was not statistically significant. (20, 21, 22). 
Rituximab, an anti-CD20 monoclonal antibody, as a single agent is less active in CLL than in 
follicular lymphoma, unless very high doses are used. (23, 24, 25). Combinations of rituximab 
with chemotherapy have proven to be very efficacious therapies for CLL. There is preclinical 
evidence for synergy between rituximab and fludarabine (25). The majority of rituximab 
combination studies in CLL have focused on combinations with fludarabine or fludarabine-based 
regimens. 
Alemtuzumab is a recombinant, fully humanized, monoclonal antibody against the CD52 antigen. 
Monotherapy with alemtuzumab has produced response rates of 33% to 53%, with a median 
duration of response ranging from 8.7 to 15.4 months, in patients with advanced CLL who were 
previously treated with alkylating agents and had failed or relapsed after second-line 
fludarabinetherapy. (26, 27, 28). In addition, alemtuzumab has proven effective even in patients 
with poor prognostic factors, including high-risk genetic markers such as deletions of 
chromosome 11 or 17 and p53 mutations. (29, 30). 
Expression of CD38 has been reported to be important in predicting prognosis in B-cell chronic 
lymphocytic leukemia (B-CLL). B-CLL patients with high levels of CD38 expression, defined as 
greater than or equal to 30% of neoplastic lymphocytes expressing CD38, had a significantly 
poorer OS than those with low levels of CD38 expression (31). An antibody that target the 
malignant CD38 + cells in B-CLL patient might offer a therapeutic benefit in this high risk 
population. 
4.5 
NON- HODGKIN’S LYMPHOMA (NHL)  
Non-Hodgkin’s lymphoma is the 10th most frequent cancer worldwide (32). Approximately 
301 000 new cases diagnosed each year, and approximately 171 800 deaths each year due to 
non-Hodgkin’s lymphoma are reported worldwide. Diffuse Large B-cell Lymphoman (DLBCL) 
represents almost 30% of all cases of non-Hodgkin’s lymphoma (NHL). Follicular lymphoma 
(FL) is the second most frequent lymphoma subtype worldwide, representing approximately 
15%-20% of all NHL cases. The cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) 
regimen is associated with durable remissions in approximately 35% of patients with DLBCL (33) 
and improved clinical outcome in the majority of patients with FL (34). The addition of rituximab 
to the CHOP regimen (R-CHOP) was associated with superior overall survival compared to 
CHOP alone in randomized clinical trials of young and elderly patients with DLBCL (35, 36, 37) 
and in another randomized clinical trial in patients with advanced-stage FL (38). 
In the Feugier et al study (36) where long term results are reported, the median event free survival 
was 3.8 years versus 1.1 years in elderly patients with B-cell lymphoma treated with R-CHOP 
compared to CHOP alone, and the 5 year overall survival (OS) was 58% versus 45%. However, 
even if recent treatments increase durable remission and improved OS survival, novel agents and 
therapeutic strategies are still needed for the treatment of this disease. 


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4.6 
ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)  
ALL is a heterogeneous malignant neoplasm of the lymphoid precursors with distinct 
morphologic, cytogenetics, and molecular entities, some of which have important clinical 
implication. ALL represents less than 1% of adult cancers, but it represents 25% of all childhood 
cancers (39). 
Decisions regarding treatment modalities for adults with ALL have become increasingly 
dependent upon patient and disease-specific characteristics. Immunophenotype, cytogenetics, and 
molecular evaluation are needed for predicting prognosis and for selecting the best therapeutic 
choice for patients (40) 
Historically, the standard induction treatment of adult ALL generally includes a glucocorticoid, 
vincristine, and an anthracycline. However, progress has been made in moving towards more age-
specific and biologically driven treatment. Agents directed at gene mutations, signal transduction 
pathways, and specific cell surface antigens are providing the future platform for new treatment 
modalities based on specificity versus intensity. While 3-year survival estimates over the last 
decade for all adults with ALL range from 30% to 40%, recent studies using age and biologically 
risk adapted approaches suggest that significant improvements in survival may be achieved. The 
use of kinase inhibitors such as imatinib in Philadelphia + ALL is one such example of leukemia-
adapted therapy (39). 
MAb therapy also represents a promising treatment approach in ALL. The target specificity, 
different mechanisms of action and side effect profile compared to chemotherapy make mAbs an 
attractive adjunct to standard chemotherapy. ALL blast cells express a variety of specific antigens 
such as CD20, CD19, CD22, CD33, CD52 (41) and CD38 (42) that may serve as targets for 
treatment with mAbs. Rituximab, a CD20 specific mAb, has been successfully integrated in 
therapy of mature B-ALL with survival rates increased above 80% with the combination of short 
intensive chemotherapy and rituximab. The combination of hyper-CVAD regimen with rituximab 
in B-precursor ALL was feasible, and a favorable outcome of CD20+ ALL was reported. Studies 
with alemtuzumab, a CD52 specific mAb, are also ongoing in a number of different settings (41). 
4.7 
COMPOUND DESCRIPTION  
SAR650984 is the humanized version of mu38SB19, a murine anti-CD38 antibody, raised by 
immunizing mice with a murine pre-B cell overexpressing cell surface human CD38. The 
humanized version bears the constant regions of human IgG1 and displays the same affinity for 
CD38 as the murine version. SAR650984 selectively binds to human CD38 with an affinity of 
2 x 10-10 M. 
4.7.1  Chemical name and structure   
SAR650984 is a naked humanized IgG1 derived-monoclonal antibody (mAb) binding selectively 
the human CD38 membrane protein. SAR650984 is expressed in Chinese Hamster Ovarian 
(CHO) cell line. 


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INN:
isatuximab
CAS registry 
number
Not available
Laboratory 
code number:
SAR650984  
Synonymous 
names
hu38SB19 
Schematic 
representation:
Molecular 
mass:
SAR650984 is a humanized IgG1 mAb with a molecular weight of 
approximately 150 kDa (glycosylated form). 
The SAR650984 protein structure is comprised of two kappa light chains 
each with molecular weight of approximately 23 kDa and two IgG1 heavy 
chains each with a molecular weight of approximately 49 kDa 
(deglycosylated form) linked through disulfide bridges. Each light chain 
consists of 215 amino acid residues and each heavy chain consists of 
451 amino acid residues.
4.7.2
Dosage form, route of administration, and dosing regimen (frequency and duration)  
SAR650984 will be supplied for parenteral administration as a sterile, non-pyrogenic, injectable, 
solution for infusion. A refrigerated (2°C-8°C) 5 mg/mL solution (C1P1F1) for infusion is 
intended for Phase 1 and 2 clinical studies. A new refrigerated (2°C-8°C) 20 mg/mL solution
(C1P2F2) for infusion was first introduced in TED14154 study and will be used in the Phase 2 
Stage 2 of TED10893 study (Section 8.1.1), and may be for patients who are still on study 
treatment after cutoff date of Phase 2 Stage 1. 


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4.7.3 Pharmacology  
SAR650984 targets CD38, an antigen expressed in hematological malignancies and represents a 
new treatment entity displaying, in vitro, three key biological properties: ADCC, CDC and 
apoptosis. SAR650984 demonstrated in vivo antitumor activity as a single agent and in 
combination with reference treatments on several CD38-positive tumor models. In addition, 
SAR650984 demonstrated antitumor activity against primary patient cells ex vivo supporting its 
clinical evaluation in CD38+ multiple myeloma, non-Hodgkin’s lymphoma and leukemia patients. 
4.7.4 Toxicology  
Several techniques and in vitro assays were used to identify a relevant animal species. CD38 
sequence analysis between the human and other animal species showed that only the CD38 
sequence from Chimpanzee, Rhesus monkey, and Cynomolgus monkey displayed a percentage of 
identity with human CD38 sequence >92%. As a result, SAR650984 binding affinity was 
evaluated in 4 monkey species (baboon, Cynomolgus monkey, Rhesus and African green 
monkey) but demonstrated no binding. Moreover, IHC cross-reactivity studies conducted with 
SAR650984 on tissues from 13 animal species (mouse, rat, hamster, Guinea pig, rabbit, ferret, 
minipig, dog, Cynomolgus monkey, Rhesus monkey, marmoset, baboon and Chimpanzee) 
identified the Chimpanzee as the only species with a similar SAR650984 tissue binding pattern as 
observed in human tissues. However, due to ethical considerations, traditional toxicology studies 
cannot be conducted in the Chimpanzee.  
Two monkey surrogate antibodies (ch38SB25 and chOKT10) were generated and investigated to 
potentially collect nonclinical safety information. Both surrogate antibodies bound Cynomolgus 
monkey CD38+ cells with affinities similar to that of SAR650984 to human CD38+ cells. 
However, ch38SB25 and chOKT10 demonstrated differences in tissue cross-reactivity (namely 
the vascular staining observed in multiple tissues of monkeys and not in human) and absence of 
pro-apoptotic activity in human tumor cell lines. As a result, toxicology findings in preclinical 
studies with these antibodies would be of very limited predictive value for safety evaluation of 
SAR650984 in human. 
In vitro assays using SAR650984 on normal human PBMCs did not demonstrate any significant 
effects on cytokine release, cellular activation, or depletion (despite some induction of apoptosis 
in purified NK cells in 2 of 3 donors tested). However, it cannot be excluded that in a clinical 
setting SAR650984 could modulate cell survival, differentiation of both lymphoid and myeloid 
cells, and cytokine release in cancer patients. Therefore, appropriate monitoring of patients will be 
conducted in the clinical study. 
In conclusion, given the absence of a relevant animal species for in vivo toxicity studies and the 
absence of a true surrogate antibody with complete pharmacological activity, single and/or 
repeated-dose in vivo toxicology studies in primates with SAR650984 or with the available 
surrogate antibodies were not expected to provide the necessary information to determine a safe 
starting dose for this FIM study nor to identify potential target organs for toxicity in human. 
Therefore, the Sponsor has selected the starting dose of 0.0001 mg/kg for the FIM study in 
patients based on the Minimal Anticipated Biological Effect Level (MABEL) approach using 
10% of the theoretical occupancy (on normal B and T lymphocytes) (see Section 4.7.3). 


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4.7.5 Metabolism and pharmacokinetics in animal  
Not applicable and not determined. 
4.7.6 Clinical experience  
Please refer to the Investigator Brochure for details on the clinical experience to date. 
4.8 
RATIONALE  
4.8.1 Study rationale  
The CD38 antigen is expressed in a number of hematological malignancies of B-lymphocyte, 
T-lymphocyte and myeloid origin. Moreover, CD38 was identified as a negative prognostic 
marker of clinical importance in some hematological malignancies. As a consequence, 
monoclonal antibodies to CD38 have the potential to treat a variety of hematological indications 
including MM, B-cell NHL, CLL, AML and B-cell ALL. 
SAR650984 has shown promising activity in MM patients in the Phase 1 dose escalation part of 
this study. Therefore, the study has been amended to include a Phase 2 part in order to further 
evaluate the efficacy and safety of SAR650984 as a single agent or in combination with 
dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma. 
4.8.2 Design rationale  
Phase 1 
Modified methodology published by Eisenhauer (43) has been chosen for selecting the number of 
patients by dose level (DL) and the dose escalation plan, according to the dose limiting 
toxicity(ies) (DLTs) observed. 
The rationale of the dose escalation scheme is to rapidly increase the dose when no related 
adverse events (AEs) are reported in order to minimize the number of patients treated at 
sub-therapeutic doses. The general approach is to begin with an accelerated dose escalation phase 
when no treatment-emergent, drug-related non-KHPDWRORJLFDO$(V*UDGH$(LQFOXGLQJIHYHU
are observed (with exception of Grade 1 nausea, vomiting, diarrhea, fatigue, asthenia, anorexia, 
anemia, alkaline phosphatase (AP) elevation, or local [injection site] reactions. In the event of a 
Grade 1 or higher treatment-emergent, IP related non-hematological AE including fever, the 
cohort will be expanded to 3 patients and a semi-log escalation will be used between 2 DLs for all 
future doses. All successive cohorts will then include 3 patients per DL. A Grade 2 or higher 
treatment-emergent, IP related nausea, vomiting, diarrhea, fatigue, asthenia, anorexia, anemia, AP 
elevation and local (injection site) reactions will result in an expansion of that cohort to 3 patients 
and all successive cohorts will include 3 patients and to switch to semi-log dose escalation. In the 
event that a potential DLT (as defined in Section 9.1.1) is reported during this accelerated dose 
escalation scheme, up to 6 patients will be assessed at this DL. If less than 2 out of 6 patients 
experienced an IP related DLT at this DL, the dose escalation will proceed with 3 patients per DL 


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and with semi-log dose escalation. When a DLT considered related to IP is observed in a patient, 
all patients who are still receiving drug whatever the DL shall be monitored for evidence of a 
similar sub-toxic effect in the same organ system. 
As a principle, in this study, any AE will be considered as potentially IP related in absence of 
clear evidence to the contrary. The causal relationship of potential DLTs or other AEs will be 
reviewed by the Study Committee (for the Phase 1 part) and by the Data Monitoring Committee 
(for the Phase 2 part), as well as by competent authorities, as appropriate. 
During the Phase 1 part, patients who begin treatment at the same DL will be considered a cohort. 
As part of Amendment 6, additional cohorts have been included to the Phase 1 part to evaluate 
additional dose levels and administration schedules. PK analysis suggests a nonlinear receptor 
mediated clearance at lower doses and a relatively short half-life between 8 to 18 days at the 
5 mg/kg dose Q2W. Given this data, increasing the dosing frequency to every week (QW) to 
attain a steady state concentration closer to the mouse tumor growth inhibition model effective 
concentration of 129 ug/mL is desirable. In addition, increasing the dose to 20 mg/kg Q2W may 
also achieve the desired steady state concentration. A 20 mg/kg loading dose may hasten the time 
to reach this desired concentration earlier rather than waiting for steady state with the 10 mg/kg 
QW. Of note, based on updated pharmacokinetic characterization of isatuximab in 2019, the 
plasma half-life has been re-estimated to 28 days. 
In order to establish a recommended Phase 2 dose (RP2D) and schedule for further studies, 
Cohorts 11 (10 mg/kg every week) and 12 (20 mg/kg every 2 weeks) will be evaluated in parallel 
since they have a similar monthly dose intensity. These cohorts will accrue 3 patients each. An 
additional 3 patients will be accrued to each of these cohorts if less than 2 out of the initial 
3 patients experience an IP related DLT. An additional 6 patients (up to 12 patients per cohort) 
may be accrued if required, in order to establish a recommended dose and schedule. Cohorts 11 
(10 mg/kg every week) and 12 (20 mg/kg every 2 weeks) will be restricted to patients with 
relapsed/refractory MM who have failed prior therapy with an immunomodulatory drug (IMiD) 
and proteasome inhibitor (as defined in Section 7.2).  
After completion of Cohort 12, in order to further define the recommended dose for future studies, 
two expansion cohorts are planned to assess the safety and preliminary disease response in 
specific MM populations (1) standard risk MM patients and (2) high risk MM patients (optional, 
as defined in Section 7.2). Each expansion cohort will accrue up to 18 patients each. In November 
2013, the dose selected for the expansion cohorts was 10 mg/kg based on the analysis of safety, 
efficacy and PK data of Cohorts 1-12. 
In June 2014, PK analysis of patients enrolled in the standard risk expansion cohort showed that 
some patients treated at 10 mg/kg Q2W presented biphasic elimination profiles. These data 
suggest that SAR650984 exhibits nonlinear pharmacokinetics with target-mediated clearance 
dominating the elimination phase at low concentrations (10-ȝJP/ZKLFKOHDGs to low 
exposure and high interpatient variability at this dose and schedule. In order to overcome the 
mediated clearance disposition and reach the desired higher concentration, 20 mg/kg QW will be 
evaluated in Cohort 13. Cohort 13 was opened for enrollment following approved by the Study 
Committee and before the implementation of Amendment 10.  


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Phase 2 
As part of Protocol Amendment 8, the Phase 2 part of the study was added to evaluate the efficacy 
and safety of SAR650984 as a single agent in patients with relapsed or relapsed/refractory MM.  
Stage 1 
x Stage 1a: 
The Stage 1a part is to commence after the Phase 1 standard risk expansion cohort has 
completed enrollment.  
Since responses were seen at different dose levels starting from 1 mg/kg Q2W 
(Section 4.8.4) Stage 1a was designed to further evaluate the activity and safety of 
SAR650984 at the following dose/schedules: 
- 
Arm 1: 3 mg/kg Q2W (every 2 weeks (Day 1 and 15 of each 28-day cycle)). 
- 
Arm 2: 10 mg/kg Q2W (Day 1 and 15 of each 28-day cycle). 
- 
Arm 3: 10 mg/kg Q2W for 2 cycles (Day 1 and 15 of Cycle 1 and 2), then 10 mg/kg 
Q4W (every 4 weeks (Day 1 of each 28-day cycle)). 
x Stage 1b: 
As part of Amendment 10, Stage 1b (Arm 4) has been included to evaluate a 20 mg/kg 
QW for 1 cycle, followed by 20 mg/kg Q2W. This arm has been added following the 
analysis of the PK data of patients in the standard risk cohort (see Phase 1 section above). 
Since Stage 1b has been added after enrollment has started into Stage 1a, enrollment in 
Stage 1b will commence after completion of Cohort 13 (6 evaluable patients followed for 
safety for at least 4 weeks) and enrollment into Stage 1a is completed, whichever is last. 
- 
Arm 42: 20 mg/kg QW for 1 cycle (Day 1, 8, 15 and 22 of Cycle 1), then 20 mg/kg 
Q2W (Day 1 and 15 of each 28-day cycle) 
Stage 2 
Phase 2 Stage 2 will further evaluate the activity and safety of SAR650984 at the dose and 
schedule selected from Stage 1a and 1b, alone or in combination with dexamethasone. Although 
the objective of the study is not to compare the efficacy and safety of the ISA and ISAdex arms, 
patients in Stage 2 will be randomly assigned in 1 of the 2 arms using an Interactive Voice 
Response System (IVRS) to not introduce any bias in the enrollment of the patients in the 2 arms. 
 
2 The planned dose for arm 4 is 20 mg/kg, however during the Phase 1, if 20 mg/kg QW is the MAD then a 
lower dose (such as 15 mg/kg QW) would be evaluated in this arm. 


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4.8.3 Phase 1 dose, regimen, and treatment duration rationale  
In this FIM study, the starting dose of 0.0001 mg/kg was selected based on 10% of the theoretical 
CD38 receptor occupancy on normal B and T lymphocytes as part of MABEL (The “Minimal 
Anticipated Biological Effect Level”) approach. 
x The calculation of MABEL is an integrated approach (EMEA guidance 
http://www.emea.europa.eu/pdfs/human/swp/2836707enfin.pdf) using all in vitro and in 
vivo information available from pharmacokinetic/pharmacodynamic (PK/PD) data.  
SAR650984 activity is linked to 3 mechanisms of action: ADCC, CDC and apoptosis activities. 
Therefore, each component of SAR650984 activity as well as receptor occupancy was studied to 
evaluate individual MABEL, using different test systems. In the in vitro models, the MABEL was 
defined as the effective concentrations that induced 20% of the maximal effect (EC20 values). In 
the in vivo model, the MABEL was defined by the trough concentration at steady-state at the 
lowest active dose.  
The MABEL based on the concentration observed on in vitro most sensitive model (eg, ADCC) 
leads to an extremely low dose in patients (0.000005 mg/kg) and <0.5% of receptor occupancy.  
Considering that: 
x There was no cytokine release from PBMC up to 10 μg/mL (equivalent to 0.20 mg/kg in 
humans) of SAR650984 concentration, which is the concentration corresponding to in 
vivo MABEL. 
x There was no effect of SAR650984 on PBMC proliferation up to 10 μg/mL (0.20 mg/kg). 
x The high in vitro ADCC activity of SAR650984 might not be representative of the 
physiological condition, since normal serum levels of IgG1 have been shown to compete 
for access of immune effector cells. 
x The monitoring of CD38 receptor occupancy on normal cells can be used as a tool for 
safety monitoring during dose escalation. 
The recommended starting dose is based on 10% of the predicted CD38 receptor occupancy 
measured from normal cells. This dose is 2000 fold less than the predicted human dose of 
0.2 mg/kg (lowest in vivo active dose based on animal model) demonstrating no significant in 
vitro effect on normal PBMC cytokine production, apoptosis and proliferation. 
Further dose escalation in the clinic may be guided by higher levels of receptor occupancy. 
4.8.4 Phase 2 dose selection rationale  
A total of 45 patients were treated with SAR650984 in the Phase 1 dose escalation phase 
(Cohorts 1-12) of the study. SAR650984 has shown a favorable safety profile in hematological 
malignancies. Evaluation of PK parameters using both non-compartmental and individual 
modeling approaches show that there is a high variability of exposure and CL within a given dose 
level and SAR650984 has a non linear PK behavior with dose increases. CL was demonstrated to 


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decrease as doses were increased with lowest change occurring between 10 and 20 mg/kg (a 
5% decrease). Evaluation of CD38 RO reached the Emax for the highest dose levels (10 mg/kg 
Q2W, 10 mg/kg QW and 20 mg/kg Q2W). Please refer to the SAR650984 Investigator Brochure 
for additional details of the safety, PK and PD observed in the Phase 1 part of the study. 
At the time of Amendment 8, analysis of the safety, PK and CD38 RO data demonstrated there 
was no significant difference between these dose levels, therefore 10 mg/kg Q2W was selected as 
the RP2D for the Phase 1 expansion cohorts. Clinical activity has been observed at dose levels 
 mg/kg Q2W in the Phase 1 part of the study. 
Stage 1a (Amendment 8): 
In order to further confirm the dose and schedule for future studies, Stage 1a of the Phase 2 part of 
the study will evaluate the 10 mg/kg Q2W alongside 3 mg/kg. The dose levels were selected 
based on PK and RO analyses which demonstrated high variability at the 3 mg/kg level but more 
constant clearance and RO at the 10 mg/kg level. In addition, a schedule of 10 mg/kg Q2W for  
8 weeks (2 cycles) followed by 10 mg/kg every 4 weeks (Q4W) will also be evaluated. This 
alternative schedule was selected based on PK simulations which demonstrated that SAR650984 
trough concentrations would be above 129 μg/mL (the concentration required to maintain for 
tumor eradiation in mice) after administering 10 mg/kg Q2W for 8 weeks. Thereafter, an 
administration of 10 mg/kg Q4W could be sufficient to maintain SAR650984 above this threshold 
concentration. 
Stage 1b (Amendment 10): 
After Amendment 8 was implemented, analysis of the PK parameters in patients in the 10 mg/kg 
Q2W standard risk expansion cohort demonstrated a high level of variability in exposure and 
nonlinear clearance suggesting that a higher dose and more intense “loading” schedule may be 
required to reach the desired steady state faster. Therefore, in Amendment 10, Stage 1b was 
included to evaluate a 20 mg/kg QW for 1 cycle, then 20 mg/kg Q2W dose schedule. The 
selection of the dose and schedule was based upon PK simulations.  
The dose and schedule for Stage 2 will be determined based on response rate along with safety, 
PK, PD, and overall efficacy reported for Stage 1a and 1b (see Section 13.5). 
Stage 2 (Amendment#11) 
From July 2014 to April 2015, a total of 97 patients were treated in Stage 1 of TED10893 study at 
doses ranging from 3 mg/kg to 20 mg/kg at four different doses and/or schedules of 
administration. As planned in the protocol (see Section 13.5), an interim analysis of efficacy, 
safety, PK and PD data of the Phase 2 Stage 1 part was performed to define the dose of 
SAR650984 to be used in Phase 2 6WDJH$VXPPDU\RIWKHPRVWIUHTXHQW7($(VRI
patients) is presented in Table 1. Overall, SAR650984 appeared to be well tolerated at all dose 
OHYHOVWHVWHG$WGRVHV mg/kg, preliminary data show no difference in terms of type, incidence 
and severity of TEAEs. Infusion associated reactions occurred in approximately half of patients 
and were of Grade 1/2 for all patients except for 2 patients treated at 10 mg/kg Q2W. 


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Preliminary efficacy data show a dose response effect between the 3 mg/kg Q2W (ORR <10%) 
and the doses 10 mg/kg (ORR LQDOODUPV$WGRVHV mg/kg, response rate was 
ranging from 20% to 29%, without clear dose response between the 10 mg/kg and the 20 mg/kg 
arms. 
A preliminary PK/PD analysis to evaluate the relationship between ORR and PK parameters was 
performed using generalized additive model with pooled Phase 1 and Phase 2 Stage 1 data. This 
analysis showed that Ctrough at Week 4 (CT4W) was a significant predictor of tumor response. The 
probability of response to treatment increases as CT4W increases up to a plateau. This plateau 
was reached for CT4W values following a weekly administration at 20 mg/kg, indicating that 
frequent administration together with a high dose in the first cycle is needed to optimize the 
response (4 weekly administrations at 20 mg/kg). In addition, modeling and simulations of 
exposure-response to SAR650984 based on M-protein concentration-time profile would induce a 
higher response to treatment in term of reduction in M-protein at 8 or 12 weeks following 
20 mg/kg QW for 4 weeks followed 20 mg/kg Q2W compared to lower doses (ie, 10 mg/kg QW 
for 4 weeks followed 10 mg/kg Q2W). 
Taking the PK/PD analysis together, 20 mg/kg weekly (QW) for 1 cycle followed by 20 mg/kg 
every 2 weeks (Q2W) would allow an optimal response to treatment. 
Therefore, based on safety, efficacy and PK/PD modeling and simulation, the selected dose and 
schedule of administrations for Stage 2 are: 20 mg/kg weekly (QW) for 1 cycle (4-week 
treatment) followed by 20 mg/kg every 2 weeks (Q2W) for subsequent cycles. 
Table 1 - TED10893 - Phase 2 (Stage 1): Summary of the most frequent TEAEs by system 
organ class and preferred term regardless relationship to study treatment - All treated 
population (preliminary results)  
 
 
3mg/kg Q2W 
(N=23) 
 
 
10mg/kg Q2W 
(N=24) 
 
 
10mg/kg 
Q2W/Q4W 
(N=25) 
 
 
20mg/kg 
QW/Q2W 
(N=25) 
 
Primary SOC 
Preferred Term 
All Grades 
Grade >=3 
All 
Grades 
Grade >=3 
All 
Grades 
Grade >=3 
All 
Grades 
Grade >=3 
Any TEAEs 
22 (95.7%) 
16 
(69.6%) 
24 (100%) 
18 
(75.0%) 
25 
(100%) 
14 
(56.0%) 
25 
(100%) 
12 (48.0%) 
 
 
 
 
 
 
 
 
 
Infections and infestations 
12 (52.2%) 
7 (30.4%) 
14 
(58.3%) 
7 (29.2%) 
15 
(60.0%) 
2 (8.0%) 
12 
(48.0%) 
4 (16.0%) 
Upper respiratory tract 
infection 
5 (21.7%) 
2 (8.7%) 
4 (16.7%) 
0
 
 
7 (28.0%) 
0
 
 
3 
(12.0%) 
0 
 
 
 
 
 
 
 
 
 
 
Blood and lymphatic system 
disorders 
10 (43.5%) 
9 (39.1%) 
3 (12.5%) 
3 (12.5%) 
6 (24.0%) 
6 (24.0%) 
10 
(40.0%) 
6 (24.0%) 
Anaemia 
9 (39.1%) 
8 (34.8%) 
1 (4.2%) 
1 (4.2%) 
5 (20.0%) 
5 (20.0%) 
7 
(28.0%) 
4 (16.0%) 
Thrombocytopenia 
4 (17.4%) 
4 (17.4%) 
0
 
 
0
 
 
0
 
 
0
 
 
8 
(32.0%) 
5 (20.0%) 
 
 
 
 
 
 
 
 
 
Metabolism and nutrition 
disorders 
10 (43.5%) 
4 (17.4%) 
10 
(41.7%) 
3 (12.5%) 
6 (24.0%) 
1 (4.0%) 
7 
(28.0%) 
3 (12.0%) 
 
 
 
 
 
 
 
 
 


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3mg/kg Q2W 
(N=23) 
 
 
10mg/kg Q2W 
(N=24) 
 
 
10mg/kg 
Q2W/Q4W 
(N=25) 
 
 
20mg/kg 
QW/Q2W 
(N=25) 
 
Primary SOC 
Preferred Term 
All Grades 
Grade >=3 
All 
Grades 
Grade >=3 
All 
Grades 
Grade >=3 
All 
Grades 
Grade >=3 
Nervous system disorders 
8 (34.8%) 
1 (4.3%) 
10 
(41.7%) 
2 (8.3%) 
11 
(44.0%) 
0
 
 
8 
(32.0%) 
1 (4.0%) 
Headache 
4 (17.4%) 
0
 
 
3 (12.5%) 
0
 
 
8 (32.0%) 
0
 
 
4 
(16.0%) 
0 
 
 
 
 
 
 
 
 
 
 
Respiratory, thoracic and 
mediastinal disorders 
13 (56.5%) 
4 (17.4%) 
15 
(62.5%) 
3 (12.5%) 
18 
(72.0%) 
1 (4.0%) 
19 
(76.0%) 
1 (4.0%) 
Dyspnoea 
7 (30.4%) 
1 (4.3%) 
5 (20.8%) 
1 (4.2%) 
7 (28.0%) 
1 (4.0%) 
7 
(28.0%) 
0 
 
Cough 
3 (13.0%) 
1 (4.3%) 
8 (33.3%) 
0
 
 
5 (20.0%) 
0
 
 
9 
(36.0%) 
0 
 
 
 
 
 
 
 
 
 
 
Gastrointestinal disorders 
14 (60.9%) 
2 (8.7%) 
11 
(45.8%) 
0
 
 
18 
(72.0%) 
2 (8.0%) 
11 
(44.0%) 
1 (4.0%) 
Nausea 
7 (30.4%) 
0
 
 
8 (33.3%) 
0
 
 
11 
(44.0%) 
0
 
 
6 
(24.0%) 
0 
 
Diarrhoea 
5 (21.7%) 
0
 
 
5 (20.8%) 
0
 
 
8 (32.0%) 
1 (4.0%) 
5 
(20.0%) 
0 
 
Vomiting 
1 (4.3%) 
0
 
 
3 (12.5%) 
0
 
 
7 (28.0%) 
0
 
 
6 
(24.0%) 
0 
 
Constipation 
7 (30.4%) 
0
 
 
2 (8.3%) 
0
 
 
2 (8.0%) 
0
 
 
1 (4.0%) 
0 
 
 
 
 
 
 
 
 
 
 
Musculoskeletal and 
connective tissue disorders 
10 (43.5%) 
2 (8.7%) 
15 
(62.5%) 
3 (12.5%) 
10 
(40.0%) 
2 (8.0%) 
10 
(40.0%) 
2 (8.0%) 
Back pain 
3 (13.0%) 
1 (4.3%) 
7 (29.2%) 
2 (8.3%) 
3 (12.0%) 
1 (4.0%) 
5 
(20.0%) 
1 (4.0%) 
 
 
 
 
 
 
 
 
 
General disorders and 
administration site conditions 
16 (69.6%) 
3 (13.0%) 
16 
(66.7%) 
0
 
 
17 
(68.0%) 
2 (8.0%) 
16 
(64.0%) 
1 (4.0%) 
Fatigue 
5 (21.7%) 
0
 
 
5 (20.8%) 
0
 
 
11 
(44.0%) 
0
 
 
8 
(32.0%) 
0 
 
Chills 
4 (17.4%) 
0
 
 
5 (20.8%) 
0
 
 
7 (28.0%) 
0
 
 
3 
(12.0%) 
0 
 
Chest discomfort 
1 (4.3%) 
0
 
 
4 (16.7%) 
0
 
 
3 (12.0%) 
0
 
 
6 
(24.0%) 
0 
 
 
 
 
 
 
 
 
 
 
Investigations 
8 (34.8%) 
6 (26.1%) 
4 (16.7%) 
1 (4.2%) 
7 (28.0%) 
3 (12.0%) 
7 
(28.0%) 
1 (4.0%) 
 
 
 
 
 
 
 
 
 
Injury, poisoning and 
procedural complications 
10 (43.5%) 
0
 
 
15 
(62.5%) 
2 (8.3%) 
17 
(68.0%) 
2 (8.0%) 
16 
(64.0%) 
1 (4.0%) 
Infusion related reaction 
9 (39.1%) 
0
 
 
11 
(45.8%) 
2 (8.3%) 
13 
(52.0%) 
0
 
 
14 
(56.0%) 
0 
 
Extracted from : PGM=DEVOPS/SAR650984/TED10893_P2S1/DWG_2015_02/REPORT/PGM/ae_teae_socpt5_cr_s_t.sas 
                           OUT=REPORT/OUTPUT/ae_teae_socpt5_cr_s_t_i.rtf (18NOV2015 - 17:00) 


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5 
 STUDY OBJECTIVES   
5.1 
PRIMARY  
Phase 1 
x To determine the maximum tolerated dose (MTD)/maximum administered dose (MAD) of 
SAR650984 according to the investigational product (IP) related dose-limiting toxicities 
(DLTs) observed in patients with CD38+-selected hematological malignancies. 
Phase 2 
x In Phase 2 Stage 1: To evaluate the activity of single agent SAR650984 at different 
doses/schedules and to select dose and regimen for Phase 2 Stage 2.  
x In Phase 2 Stage 2: To further evaluate the activity in terms of overall response rate (ORR) 
of SAR650984 at the selected dose/schedule from Stage 1, as single agent (ISA arm) and 
in combination with dexamethasone (ISAdex arm) in patients with relapsed or 
relapsed/refractory multiple myeloma. 
5.2 
SECONDARY  
Phase 1 
x To characterize the global safety profile including cumulative toxicities.  
x To evaluate the pharmacokinetic profile of SAR650984 in the proposed dosing 
schedule(s).  
x To assess the pharmacodynamics, immune response, and preliminary disease response. 
Phase 2 Stage 1 
To evaluate the followings objectives for SAR650984 as single agent: 
x Safety. 
x Efficacy as measured by: 
- 
Duration of response (DOR). 
- 
Clinical benefit rate (CBR). 
- 
Progression free survival (PFS). 
- 
Overall survival (OS). 
x Patient-reported changes in health-related quality of life, symptoms of multiple myeloma 
and generic health status. 
x Pharmacokinetic profile of SAR650984. 
x Immunogenicity of SAR650984. 


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x Investigate the relationship between CD38 receptor density and CD38 receptor occupancy 
(Stage 1 only) on multiple myeloma cells and parameters of clinical response. 
Phase 2 Stage 2 
To evaluate the followings objectives in each arm (Isa and ISAdex): 
x Safety. 
x Efficacy as measured by: 
- 
Duration of response (DOR). 
- 
Clinical benefit rate (CBR). 
- 
Progression free survival (PFS). 
- 
Overall survival (OS). 
x Pharmacokinetic profile of SAR650984. 
x Immunogenicity of SAR650984. 
5.3 
EXPLORATORY  
Phase 2 
x To assess minimal residual disease (MRD) in patients achieving a CR and correlate with 
clinical outcome. 
x To investigate the relationship between tumor cell CD38 mRNA, multiple myeloma 
molecular subtype (as defined by marker expression, cytogenetics, and/or genomics) and 
parameters of clinical response. 
x To investigate the relationship of soluble CD38 and parameters of PK and clinical 
response (Stage 1 only). 
x To investigate the relationship between immune genetic determinants, immune phenotype 
adaptive immune response and parameters of clinical response. 


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6 
STUDY DESIGN  
This is an open-label, international multi-center study conducted in 2 parts (Phase 1 and Phase 2). 
6.1 
DESCRIPTION OF THE PROTOCOL – PHASE 1 PART  
The Phase 1 part is a dose escalation study of SAR650984 administered as single agent as an 
intravenous (IV) infusion every week or every 2 weeks to adult patients with selected CD38+ 
hematological malignancies that have progressed on or after standard therapy for which there is 
no effective standard therapy, or for which the patient is not suitable for standard therapy at the 
discretion of the treating physician. 
In the Phase 1 part, a cycle is 14 days. 
6.1.1 Starting dose and dose escalation design  
The Phase 1 starting dose selection and dose escalation design are described in Diagrams 
Section 1.1 and Section 1.2. 
The dose escalation decision will be based on the IP related DLTs observed in C1 +C2 of each 
DL. However, cumulative toxicities observed on subsequent administrations should also be 
considered for the dose escalation process and the dose selection decision. 
The administration of SAR650984 will start at the 0.0001 mg/kg dose (representing 10% of 
theoretical CD38 receptor occupancy (RO) on normal B and T lymphocytes).  
Two dose escalation schemes will be used based upon AEs observed during the first two cycles of 
treatment (4 weeks). In this FIM study, potential DLTs are defined in Section 9.1.1. 
6.1.1.1 Accelerated dose escalation step  
One patient per DL unless Grade 1 or higher IP related non-hematological toxicity, and log dose 
escalation between DLs until 0.1 mg/kg (representing the dose with minimal antitumor activity in 
an animal model) unless the MAD reached.  
Cohort 1: 0.0001 mg/kg, 
Cohort 2: 0.001 mg/kg, 
Cohort 3: 0.01 mg/kg, 
Cohort 4: 0.03 mg/kg, 
Cohort 5: 0.1 mg/kg, 
x Patient(s) will receive two administrations (cycles) of SAR650984 (at 2 week interval) 
followed by a 2 week post-second dose administration observation period. The data 
obtained from this 4-week period will be used for acute safety monitoring and to make 
decisions regarding cohort expansion and/or dose escalation for the next cohort.  


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x PK and CD38 receptor occupancy data will be collected and may also be used for dose 
escalation decisions. 
x After completing two cycles, patients may be considered for additional administrations of 
SAR650984 (at the same DL) every 2 weeks upon Investigator’s decision provided that 
this dosing regimen is considered safe. Patients can continue treatment until unacceptable 
toxicity, disease progression, death, withdrawal of consent, Investigator’s decision and/or 
availability of study drug. Additional PK, safety and disease response will be assessed. 
x In the event of a Grade 1 or higher treatment-emergent, IP related non-hematological 
toxicity including fever, the cohort will be expanded to 3 patients and a semi-log 
escalation will be used between DLs for all future doses. All successive cohorts will then 
include 3 patients per DL. In addition, in the event of a Grade 2 or higher treatment-
emergent nausea, vomiting, diarrhea, fatigue, asthenia, anorexia, AP elevation or local 
(injection site) reaction, the cohort will be expanded to 3 patients with a switch to semi-log 
dose escalation. All successive cohorts will also include 3 patients. In the event that a 
potential DLT is reported during the accelerated dose escalation scheme, up to 6 patients 
will be assessed at this DL. If <2 out of 6 patients experienced an IP related DLT at this 
DL, the dose escalation will proceed with 3 patients per DL. If >2 out of 6 patients 
experience an IP related DLT MAD reached and dose escalation is stopped. 
A Study Committee will be set up, including at least the Principal Investigator(s) and Clinical 
Study Director from sanofi-aventis. When needed, ad hoc members will be included. Upon 
completion of enrollment in each cohort, Study Committee will review collected data and will 
make the decision to continue the enrollment in a subsequent DL cohort. 
6.1.1.2 Basic dose escalation phase  
Successive patient cohorts will include at least 3 evaluable patients if no potential DLT is 
reported, or up to 6 evaluable patients if a potential DLT is experienced by 1 of the first 3 patients, 
and semi-log dose escalation between DLs. In each cohort, at least 7 days must pass after dosing 
the first patient before dosing the second patient. 
Cohort 6: 0.3 mg/kg every 2 weeks, 
Cohort 7: 1 mg/kg every 2 weeks, 
Cohort 8: 3 mg/kg every 2 weeks, 
Cohort 9: 5 mg/kg every 2 weeks, 
Cohort 10: 10 mg/kg every 2 weeks, 
Cohort 11: 10 mg/kg every week, 
Cohort 12: 20 mg/kg every 2 weeks, 
Cohort 13: 20 mg/kg every week, 
x Patients in cohorts 6-10 and 12 will initially receive two administrations of SAR650984 
(at a 2 week interval) followed by a 2-week post-second dose administration observation 
period. Patients in Cohort 11 and 13 will initially receive four administrations of 


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SAR650984 (at a 1 week interval) followed by a 1-week post-fourth dose administration 
observation period. The data obtained from this 4-week period will be used for acute 
safety monitoring. PK and CD38 receptor occupancy data will be collected and may be 
used to make the dose escalation decision for the next cohort.  
x After completing two cycles, patient(s) may continue to receive additional administrations 
of SAR650984 (at the same DL and schedule). If this dosing regimen is considered safe, 
patients can continue treatment until unacceptable toxicity, disease progression, death, 
withdrawal of consent, Investigator’s decision and/or availability of study drug. Additional 
PK, safety and disease response will be assessed. 
x Cohorts 11, 12 and 13 will initially accrue 3 patients each. Cohorts 11 and 12 will be 
evaluated in parallel since they have similar monthly dose intensity. An additional 
3 patients will be accrued to each of these cohorts if 1 out of the initial 3 patients 
experience an IP related DLT. An additional 6 patients (up to 12 patients per cohort) may 
be accrued if required, in order to establish a recommended dose and schedule. 
Patients enrolled in Cohort 13 will follow the every week schedule detailed in Section 1.6 (PK/PD 
Flowchart) and Section 1.11 (Study Flowchart) corresponding to Cohort 11 visit schedules. 
x Additional (optional) cohort(s) beyond Cohort 13 may be evaluated (such as 15 mg/kg 
every week, evaluation of a loading dose followed by a weekly or every 2-week schedule, 
or evaluation of intermediate doses such as 7.5 mg/kg every week or 15 mg/kg every  
2 weeks), however, the decision to proceed to these optional cohort(s) will be discussed 
with the Study Committee and based on the totality of safety and PK data. 
A Study Committee will be set up, including at least the Principal Investigator(s) and Clinical 
Study Director from sanofi-aventis. When needed, ad hoc members will be added. Upon 
completion of enrollment in each cohort, Study Committee will review collected data and will 
make the decision to continue the enrollment in a subsequent DL cohort. 
Dose escalation will stop when the MAD is reached. MAD is defined below in Section 6.1.2. 
6.1.2 Maximum administered dose (MAD)/Maximum tolerated dose (MTD)/Recommended 
Phase 2 dose (RP2D)  
The MAD is defined in Section 6.1.1.1 of this protocol. 
The MTD is defined as the highest DL at which no more than 1 patient of a maximum of 
6 patients experienced an IP related DLT. Usually, the MTD is one DL below the MAD. The 
RP2D is defined as the dose selected for the Phase 1 expansion cohort. The Study Committee will 
review the overall safety and PK/PD data observed up to and including Cohort 12 and will decide 
the dose and schedule for the Phase 1 expansion cohort.  
Although the dose escalation process is guided by the safety evaluation any time after treatment, 
cumulative toxicities observed in subsequent administrations should also be considered for the 
dose escalation and dose selection decisions (ie, smaller increases in dose, expansion of a given 
DL, intermediate DL), upon agreement between the Investigator and sanofi-aventis. 


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6.1.3 Phase 1 expansion cohorts  
Once the MTD or RP2D has been established based on Cohorts 1-12, the decision to proceed to 
the standard risk and high risk cohorts will be based on the overall safety and PK observed during 
dose escalation. 
Two MM specific expansion cohorts are planned: 
x Standard risk cohort (as defined in Section 7.2) 
x (Optional) High risk cohort(as defined in Section 7.2) 
Up to 18 additional patients per cohort (for a total accrual of 36 patients) will be accrued to further 
evaluate the safety, tolerability, PK and disease response at the selected SAR650984 dose and 
schedule. Patients enrolled in the expansion cohorts will follow the every 2 week schedule 
detailed in Section 1.7 (PK/PD Flowchart) and Section 1.12 (Study Flowchart) corresponding to 
Cohort 12 visit schedules.  
6.2 
DESCRIPTION OF THE PROTOCOL - PHASE 2 PART  
The Phase 2 part is to commence after the Phase 1standard risk cohort has completed enrollment 
and will evaluate the efficacy and safety of SAR650984 as a single agent, in patients with 
multiple myeloma who have previously received an IMiD and a proteasome inhibitor and have 
relapsed or relapsed/refractory disease. In the Phase 2 part, a cycle is 28 days. The Phase 2 study 
will be conducted in 3 stages; Stage 1a dose finding to evaluate 3 dose levels, Stage 1b dose 
finding to evaluate 1 dose level and Stage 2 expansion to evaluate the selected Stage 1 dose: 
x Stage 1a will determine the dose and schedule of single agent SAR650984 by evaluating 
the activity and safety of SAR650984 at 3 dose levels: 
- 
Arm 1: 3 mg/kg Q2W (Day 1 and 15 of each 28-day cycle). 
- 
Arm 2: 10 mg/kg Q2W (Day 1 and 15 of each 28-day cycle). 
- 
Arm 3: 10 mg/kg Q2W for 2 cycles (Day 1 and 15 of Cycle1 and 2), then 10 mg/kg 
Q4W (every 4 weeks (Day 1 of each 28-day cycle)). 
Patients in Stage 1a will be randomly assigned to one of 3 treatment arms (Arm 1, 2 or 3), in a 
1:1:1 ratio using an Interactive Voice Response System/Interactive Web Response System 
(IVRS/IWRS). Randomization will be stratified according to the patients prior multiple myeloma 
therapy; Stratum 1: prior treatment with pomalidomide and/or carfilzomib, Stratum 2: no prior 
treatment with pomalidomide and/or carfilzomib. 
x Stage 1b will commence after Cohort 13 has completed the DLT-observation period and 
enrollment in Stage 1a is completed, whichever is last. The following dose/schedule will 
be evaluated if fewer than 1/3 or 2/6 patients experiences a DLT in Cohort 13: 
- 
Arm 43: 20 mg/kg QW for 1 cycle (Day 1, 8, 15 and 22 of Cycle 1), then 20 mg/kg 
Q2W (Day 1 and 15 of each 28-day cycle). 
 
3 The planned dose for arm 4 is 20 mg/kg, however during the Phase 1, if 20 mg/kg QW is the MAD then a 
lower dose (such as 15 mg/kg QW) would be evaluated in this arm. 


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x Stage 2 will further evaluate the activity and safety of SAR650984 alone or in combination 
with dexamethasone.  
In Phase 2 Stage 2, patients will be randomly assigned to one of the 2 treatment arms in a 2:1 ratio 
using an IVRS/IWRS. Enrollment will stop when the targeted number of patients is reached in 
both arms. 
SAR650984 dose and schedule for Phase 2 Stage 2 is selected from the interim analysis of 
Phase 2 Stage 1a and 1b (see Section 13.5) is: 20mg/kg QW for 4 IV infusions followed by 
20 mg/kg Q2W (in both arms). This dose was determined based on response rate along with 
safety, PK, PD and overall efficacy from Phase 1 and Stage 1a and b (see Section 13.5). For 
patients in ISAdex arm, dexamethasone will be administered at the dose of 40mg/day (20mg/day 
IRU75 y.o patients) on Days 1, 8, 15, 22 of each cycle. Dexamethasone will be administered as 
IV or PO. As part of the pre-medication, dexamethasone will be administered before the 
SAR650984 infusion.  
The Phase 2 Stage 2 part of the TED10893 will be initiated after completion of the dose escalation 
and dose expansion parts of TED14154 study aiming to evaluate the C1P2F2 formulation in 
patients with multiple myeloma and that preliminary safety and PK data are supporting the use of 
the C1P2F2 formulation in the Phase 2 Stage 2 part of the TED10893 study.  
In addition, the data monitoring committee (DMC) will review preliminary safety data on the 
first 12 patients treated in the Phase 2 Stage 2 part of TED10893 with a cut-off date 1 month 
follow-up after randomization of the 12th patient. 
For all stages of the Phase 2 part, the primary efficacy endpoint is overall response rate defined as 
the proportion of patients with  
x Stringent complete response (sCR),  
x Complete response (CR), 
x Very good partial response (VGPR), 
x Partial response (PR), 
x Using the International Myeloma Working Group (IMWG) Uniform Response Criteria (1) 
in Stage 1 and the updated IMWG Response Criteria (2) in Stage 2. 
6.3 
RETREATMENT OF PATIENTS  
In case of AEs, the patient must have recovered to JUDGHRUWR his (her) baseline status before 
being considered for the next administration of SAR650984. In case of clear clinical benefit a 
patient can continue the study treatment at the same DL until disease progression, unacceptable 
toxicity or patient’s decision. 


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6.4 
DOSE DELAYS/MODIFICATIONS  
In Phase 1 part: 
A dose delay of up to 2 weeks is permitted in order for a patient to recover to their baseline status 
(see Section 6.3) or to accommodate scheduling issues (eg, holidays, weather, etc). In case of a 
delay greater than 2 weeks due to an AE the patient will be withdrawn from the treatment as per 
study committee decision. Exceptions allowed by the study committee should be considered only 
for patients with clear objective clinical benefit. 
Individual patients may be considered for treatment at a higher dose or different schedule than 
they were originally assigned. In order for a patient to be treated at a higher dose or different 
schedule, the patient must have tolerated the original dose or schedule for at least 12 weeks. In 
addition, the new dose level or schedule with which the patient is to be treated, must be a dose or 
schedule that has previously been determined to be safe. During the Phase 1 part, all intra-patient 
dose and schedule modifications will be discussed on a case-by-case basis and agreed between 
Sanofi and the Study Committee. 
In Phase 2 Stage 1 part: 
During the Phase 2 Stage 1 part only, all patients who have progressive disease while on treatment 
may be considered for treatment at a higher dose level (not to exceed 20 mg/kg on a 
Q2Wschedule). To be considered for a dose increase, the patient must have tolerated their original 
dose or schedule for at least 1 cycle. 
During the Stage 1a part, patients treated at the 3 mg/kg dose level may be considered for 
treatment at a higher dose level (10 mg/kg or 20 mg/kg Q2W schedule). In order for a patient to 
be treated at the higher dose, the patient must have tolerated the 3 mg/kg dose for at least  
12 weeks.  
All intra-patient dose and schedule modifications will be discussed on a case-by-case basis and 
agreed between Sanofi and the treating Investigator. 
In Phase 2 Stage 2 part: 
No dose reduction is authorized for SAR650984. Dexamethasone dose reduction is planned in 
case of toxicity (see Table 7). 
If a patient experiences several toxicities and there are conflicting recommendations, the most 
conservative dose adjustment recommended (dose reduction/omission appropriate to the most 
severe toxicity) should be followed. Once a dose has been decreased, intra-patient re-escalation 
back to the previous dose level is not permitted.  
Cycle delay up to 14 days is allowed. If administration within 14 days following the planned date 
is not possible the patient will discontinue the study treatment. Exceptions can be considered only 
for patients with clear objective clinical benefit and after the discussion between investigator and 
sponsor. 


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SAR650984 infusion/dexamethasone administration delay up to 3 days within a cycle is allowed. 
If administration within cycle cannot be done within the 3 days following the planned date, 
SAR650984 infusion (at Cycle 1 only)/dexamethasone administration may be omitted, in which 
case, the Cycle 1 should be increased to 5 weeks to allow 4 of SAR650893 administration if 
possible. 
No more than 2 dose reductions of dexamethasone and no more than 2 SAR650984 consecutive 
infusions omitted per patient are permitted. 
In ISA arm, the patient will be withdrawn from the study treatment in case of SAR650984 
discontinuation. In ISAdex arm, if one drug is prematurely discontinued, patient may continue 
other study treatment until disease progression, unacceptable toxicity, cut-off date or willingness 
to stop (whichever comes first). 
6.5 
GUIDELINES FOR THE MANAGEMENT OF POTENTIAL HYPERSENSITIVITY 
REACTIONS  
Patient(s) should routinely receive premedications prior to SAR650984 infusion as detailed in 
Section 8.2.1 to reduce the risk and severity of hypersensitivity reactions commonly observed 
with monoclonal antibodies. Infusion associated reactions (IARs) are defined as related adverse 
events typically with onset within 24 hours from the start of the infusion. Please refer to the 
current edition of the IB for IARs manifestations reported in patients treated with isatuximab. 
General guidelines for the management of IARs (excluding Phase 2 Stage 2) are provided in 
Table 2.  
Table 2 - Infusion associated reactions management (excluding Phase 2 Stage 2)  
Symptom severity 
Intervention recommendation 
Mild 
Grade 1 NCI CTCAE v. 4.03 eg, transient 
flushing or rash, drug fever <38°C 
(<100.4°F) 
Continuation of SAR650984 infusion is per the judgment of the Investigator 
following close direct monitoring of the patient’s clinical status. SAR650984 
infusion may be stopped at any time if deemed necessary. If stopped, 
SAR650984 infusion may be resumed* only after patient recovery with slower 
infusion rate and with continued close monitoring. If the infusion is stopped, 
patients may receive additional premedication with IV diphenhydramine 25 mg IV 
(or equivalent) and/or IV methylprednisolone 100 mg (or equivalent) as needed. 
Moderate 
Grade 2 NCI CTCAE v. 4.03 eg, cutaneous 
reaction, pruritus, flushing, rash, dyspnea, 
tachycardia, hypotension, anxiety, 
headache, myalgia, edema, nausea 
Stop SAR650984 infusion; 
Give additional premedication with IV diphenhydramine 25 mg IV (or equivalent) 
and/ or IV methylprednisolone 100 mg (or equivalent) as needed. SAR650984 
may be resumed* only after patient recovery, with slower infusion rate and with 
close monitoring 
Severe 
Grade 3 NCI CTCAE v. 4.03 
eg, symptomatic bronchospasm, generalized 
XUWLFDULDV\VWROLF%3 mm Hg, 
angioedema, anaphylaxis 
Stop SAR650984 infusion; 
Give additional premedication with diphenhydramine 25 mg IV (or equivalent) 
and/ or IV methylprednisolone 100 mg (or equivalent) and/or epinephrine as 
needed. 
Definitive treatment discontinuation 
*The infusion should be completed within 7.5 hours (C1P1F1) or 16 hours (C1P2F2) from the end of infusion preparation or a new infusion 
should be prepared with the remaining dose to be administered the same day. 


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Patients who experience Grade 1 or Grade 2 IAR(s) may subsequently resume SAR650984 
infusion under close monitoring and supportive care as needed. Patients may receive additional 
premedication per the judgment of the Investigator. Additional recommended premedications are: 
dyphenhydramine 25 mg IV (or equivalent) and methylprednisolone 100 mg IV (or equivalent). 
These patients must be informed of the potential risk of recurrent allergic reactions.  
2QFHD*UDGH,$5KDVLPSURYHGWR*UDGHWKHLQIXVLRQPD\EHrestarted at one half the 
original infusion rates. If symptoms do not recur after 30 minutes, the infusion rate may be 
increased in 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour.  
Patients with Grade 3 or 4 SAR650984 IAR must have SAR650984 permanently discontinued 
and appropriate supportive therapy should be administered. The infusion reaction and the therapy 
administered must be documented in the CRF. 
Grade 3 and Grade 4 IARs must be reported as AESIs (see Section 10.6). Study personnel should 
consult the Medical Monitor for further guidance regarding re treatment of patients with infusion 
reactions and regarding issues of premedication management (eg, alternative medications for 
patients allergic or intolerant to premedication agents) or to determine if locally used equivalent 
medications are acceptable. 
In Phase 2 Stage 2 part updated general guidelines on IAR management are provided in Table 3. 
Infusion associated reactions (IARs) NCI CTCAE v. 4.03 term are defined as adverse events 
related to SAR650984 typically with onset within 24 hours from the start of the infusion. 
Table 3 - IAR management (2) (Phase 2 Stage 2)  
NCICTCAE v. 4.03 criteria definition 
Intervention recommendation 
Mild Grade 1 
Infusion interruption or intervention not 
indicated 
Continuation of SAR650984 infusion is per the judgment of the Investigator 
following close direct monitoring of the patient’s clinical status. SAR650984 
infusion may be stopped at any time if deemed necessary. If stopped, IAR 
will be classified as a 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 hrs) 
Stop SAR650984 infusion. Give additional premedication with IV 
diphenhydramine 25 mg IV (or equivalent) and/or IV methylprednisolone 
100 mg (or equivalent) as needed. SAR650984 may be resumeda only after 
patient recovery, with slower infusion rate and with close monitoring. Blood 
samples for additional safety labs will be collected. 
Severe 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 SAR650984 infusion. Give additional premedication with 
diphenhydramine 25 mg IV (or equivalent) 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 
a The infusion should be completed within 16hours (C1P2F2) from the end of infusion preparation or a new infusion should be prepared 
with the remaining dose to be administered the same day. 


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6.6 
GUIDELINES FOR THE MANAGEMENT OF POTENTIAL TUMOR LYSIS SYNDROME  
General guidelines for the management of the tumor lysis syndrome are provided in Table 4. 
Table 4 - Tumor lysis syndrome management (excluding Phase 2 Stage 2)  
Symptom 
Recommended action 
Laboratory Tumor Lysis Syndrome (LTLS): 
x 
2 simultaneous abnormalities within 3 days prior 
to and up to 7 days after start of treatment. 
x 
Uric acid !PJG/!ȝPRO/. 
x 
Potassium >6.0 mmol/L. 
x 
Phosphorus >4.5 mg/dL (>1.5 mmol/L). 
x 
Corrected calcium <7.0 mg/dL (<1.75 mmol/L) 
orionized calcium <1.12 mg/dL (<0.3 mmol/L). 
x 
Clinical Tumor Lysis Syndrome (CTLS): meeting 
criteria for LTLS in addition to one of the following 
complications 
x 
Elevated creatinine. 
x 
Seizures. 
x 
Dysrhythmia. 
Hold SAR650984 until all serum chemistries have resolved 
Ensure normal hydration; correct laboratory abnormalities, fluid 
overload, electrolyte or acide-based deviations 
Monitor for CTLS complications including renal function  
Reinstitute SAR650984 at full doses after resolution  
In Phase 2 Stage 2 part updated general guidelines on TLS management are provided in Table 5 
(44) 
Table 5 - Tumor lysis syndrome management (2) (Phase 2 Stage 2)  
Symptom 
Recommended action 
Laboratory TLS (LTLS) 
VLPXOWDQHRXV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) 
Clinical TLS: LTLS in addition to one of the following complications 
x 
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/hr for 6 hr. 
x 
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. 
x 
Dysrhythmias probably or definitely caused by 
hyperkaliemia. 
Omit IMP 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 IMP at full doses after resolution  
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). 


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6.7 
GUIDELINES FOR THE MANAGEMENT OF POTENTIAL ADVERSE EVENTS 
DUE TO DEXAMETHASONE  
For patients randomized in the ISAdex arm, dose reductions levels and instructions for 
management of toxicities related to dexamethasone are provided in Table 6 and Table 7, 
respectively. 
Table 6 - Dose reduction steps for dexamethasone  
Starting dose of 
dexamethasone 
(IV/PO) 
Days 1, 8, 15, and 22 
1ST  
Dose reduction 
2ND  
Dose reduction 
3RD  
Dose reduction 
40 mga/20 mgb 
24 mga/12 mgb 
16 mga/8 mgb 
Discontinue dexamethasone 
a in patients <75 y.o. 
b in patients \R. 
Table 7 - Dexamethasone adverse events management  
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 
> Grade 3 (requiring hospitalization 
or surgery) 
Omit dexamethasone until symptoms adequately controlled. 
Restart and decrease one dose level of current dose along with 
concurrent therapy with H2 blockers, sucralfate, or omeprazole. 
If symptoms persist despite above measures, discontinue 
dexamethasone and do not resume. 
Acute pancreatitis 
Discontinue dexamethasone and do not resume. 
Cardiovascular 
Edema 
Diuretics as needed, and decrease dexamethasone dose by 
1 dose level; if edema persists despite above measures, 
decrease dose another dose level. 
Discontinue dexamethasone and do not resume if symptoms 
persist despite second reduction. 
> Grade 3 (limiting function 
and unresponsive to therapy or 
anasarca) 
Neurology 
Confusion or Mood alteration 
> Grade 2 (interfering with function 
+/- interfering with activities of daily 
living) 
Omit dexamethasone until symptoms resolve. Restart with 
one dose level reduction. If symptoms persist despite above 
measures, discontinue dexamethasone and do not resume. 
Musculoskeletal 
Muscle weakness 
> Grade 2 (symptomatic and 
interfering with function +/- 
interfering with activities of daily 
living 
Decrease dexamethasone by one dose level. If weakness 
persists despite above measures decrease dose by one level. 
Discontinue dexamethasone and do not resume if symptoms 
persist. 
Metabolic 
Hyperglycemia 
> Grade 3 or higher 
Treatment with insulin or oral hypoglycemics as needed. If 
uncontrolled despite above measures, decrease dose by one 
dose level until levels are satisfactory. 


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'RVHUHGXFWLRQIRUSHUVLVWHQW*UDGHRU*UDGH$(VEHOLHYHGWREHUHlated to dexamethasone 
and not listed above are permitted. The AE must be documented in the eCRF. More aggressive 
dose reductions for lower grade adverse reaction than those listed above must first be discussed 
with the Clinical Study Director. If dexamethasone is discontinued due to toxicities, and if the 
patient is benefiting from treatment, SAR650984 can be continued as single agent until 
progression at the Investigator’s discretion and in consultation with the Clinical Study Director. 
6.8 
GUIDANCE IN CASE OF HEPATITIS B REACTIVATION OCCURRING UNDER STUDY 
TREATMENT  
Patient still on treatment at the time of amended protocol 14 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 
(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. 
6.9 
DURATION OF STUDY PARTICIPATION  
6.9.1 Duration of study participation for each patient  
For the Phase 1 part, study duration for an individual patient will include a screening period for up 
to 2 weeks, up to 4 weeks of SAR650984 administration (weekly or Q2W) unless discontinued 
earlier due to safety or disease progression, followed by a minimum of 30 days following the last 
use of study drug or more than 30 days in case of unresolved IP related AE, or up to initiation of 
another anticancer treatment. Patients with SD, or objective response (CR, PR) and no DLT at the 
end of 4 weeks of SAR650984 dosing maybe considered for continued treatment as long as 
clinical benefit is possible, or until PD or other reasons for discontinuation (see Section 11.2). 
Patients will be followed for a minimum of 30 days following the last use of study drug or more 
than 30 days in case of unresolved IP related AE, or up to initiation of another anticancer 
treatment. In addition, PK and ADA sample are required at 60 days after last IP administration 
and then, in the case of a positive ADA sample, every 30 days until the sample is negative. 
For the Phase 2 part, the study duration for an individual patient will include a screening period 
for up to 3 weeks prior to the first administration of IP, then a treatment period and a follow-up 
period. Following the screening period, eligible patients will receive SAR650984 at their assigned 
dose and schedule. Treatment will continue until disease progression, unacceptable adverse 


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reactions or other reasons for discontinuation (see Section 11.2). Patients with documented 
disease progression at the end of treatment visit will receive follow-up visits at 30, 60 and 90 days 
after the last dose (in Phase 2 Stage 1 part) and in Phase 2 Stage 2 part, at 60 days after the last 
dose of study treatment (isatuximab or dexamethasone, whichever comes last), then will be 
followed every 3 months until death or cutoff date, whichever comes first. However, female 
patients of childbearing potential will have the serum pregnancy test every month for 5 months 
after the last administration of SAR650984. Patients without documented disease progression at 
the end of treatment visit and have not yet started treatment with another anti-cancer therapy will 
receive follow-up visits every month until initiation of another anti-cancer therapy, progression, 
death or cutoff date, whichever comes first. However, female patients of childbearing potential 
will have the serum pregnancy test every month for 5 months after the last administration of 
SAR650984. For all patients, any IP-related adverse events and all serious adverse events 
(regardless of their causal 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 serious adverse events related to study treatment will be 
collected and followed until resolution or stabilization.  
6.9.2 Determination of end of clinical trial (all patients)  
For the Phase 1 part, the final analysis cutoff date for primary statistical analysis will be 4 months 
after the date of the first dose of the last patient. Patients still on treatment at time of the cutoff 
date and who still continue benefiting from treatment with SAR650984 will have the option to 
continue treatment under this protocol (see Section 12.3).  
For the Phase 2 Stage 1 part, the cutoff date for the primary analysis of ORR and for the 
secondary analysis will be 12 months after the date of the first dose of the last patient.  
For Phase 2 Stage 2, the cutoff date for the primary analysis of ORR is 4 months after the date of 
the first dose of the last patient. Final analysis cutoff date for the updated analysis of ORR and 
final analysis of secondary endpoints is 12 months after the date of the first dose of the last 
patient. 
Patients that are still on treatment at time of the final analysis cutoff date and continue benefiting 
from treatment with SAR650984 will have the option to continue treatment under this protocol 
(Section 12.3). 
At the cut-off date, patients in follow-up will be discontinued from the study unless there are 
ongoing related adverse events or ongoing serious adverse events 30 days after last study 
treatment administration whatever the relationship to study treatment. 
6.9.3 Interim analysis  
Refer to Section 13.4.8. 


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6.9.4 Phase 1 Study Committee  
A Study Committee will be set up to include at least the Principal Investigator and the 
sanofi-aventis Monitoring Team members. Decisions to initiate or continue the enrollment in 
subsequent cohorts will be taken after the appropriate data are collected and reviewed by the 
Study Committee. For this purpose, bi-weekly teleconferences will be held between Investigators 
and the sanofi-aventis Monitoring Team. A tracking form with all TEAEs (with their severity) 
will be distributed and jointly reviewed at each teleconference. Before escalating SAR650984 
dose to the next DL, the TEAEs and especially the reported potential DLTs will be reviewed in 
order to determine their relationship to the IP. Dose escalation or dose decrease decisions will be 
based on the assessment of IP related DLTs, in agreement within the Study Committee. Any of 
these decisions will be documented in writing, communicated to all investigators in a timely 
manner and submitted to the Competent Health Authorities, as appropriate. As part of the study 
committee meeting, any AE that meets the protocol definition of a DLT will be identified and 
appropriate decisions implemented. Prompt communication with the FDA will occur when needed 
to determine the relevance of the event not being considered as a DLT based on the full protocol 
definitions.  
6.9.5 Phase 2 Study Committees  
Executive Steering Committee (ESC) (Phase 2 Stage 1 only): The ESC will include the Study 
Chairman, the designated main Investigators and Sponsor representatives. They will be 
responsible for: 
x Supervising the progress of the trial toward its overall objectives. 
x Reviewing relevant information that may affect the study conduct at regular intervals. 
x Discussing the implementation of the recommendations of the independent DMC. 
Detailed guidelines regarding the structure, function and decision-making mechanisms for this 
committee are described in the DMC charter. 
Data Monitoring Committee (DMC): The DMC will be comprised of 3 independent experts. They 
will be responsible for: 
x Reviewing the conduct of the study. 
x Reviewing the safety data. 
x Reviewing the efficacy and safety results from the Stage 1 analysis. 
x Reviewing early safety data from the first 12 patients treated in the Phase 2 Stage 2 part of 
the study. 
x Advising the sponsor and the ESC on potential modifications or communications that may 
be necessary to ensure patient safety or to protect the scientific integrity of the trial. 
In the above capacities, the DMC is advisory to the Sponsor. Detailed guidelines regarding the 
structure, function and decision-making mechanisms for this committee are described in the DMC 
charter.  


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Independent Adjudication Committee (IAC): The IAC will be comprised of independent Multiple 
Myeloma experts. They will be responsible for: 
x Determine presence or absence of plasmacytomas and bone lesions at baseline. 
x Objectively assessing clinical response as defined by the IMWG response criteria on an 
on-going basis in order to independently evaluate the drug effect of SAR650984 on 
disease status. 
x The IAC will determine response using: 
- 
Serum and urine M-protein, free light chains (FLC), bone marrow biopsy/aspirate and 
corrected calcium. 
- 
Radiologic results for bone lesions and plasmacytoma assessment. 
Detailed guidelines regarding the structure, function and decision-making mechanisms for this 
committee are described in the IAC charter. 


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7 
SELECTION OF PATIENTS  
7.1 
NUMBER OF PATIENTS  
Phase 1: It is anticipated that approximately 85 patients will be required to establish the MTD and 
the preliminary safety of SAR650984. 
Phase 2: Approximately 96 patients (24 patients per arm) will be enrolled in Stage 1a and 1b of 
the study. 
Approximately 160 patients will be enrolled in Stage 2 of the study. 
7.2 
PHASE 1 INCLUSION CRITERIA  
I 01. A. For dose escalation Cohorts 1 to 10 and the Cohort 10 expansion: Patients with 
confirmed selected CD38+ hematological malignancies (as outlined below) who have 
progressed on or after standard therapy or for whom there is no effective standard therapy 
(refractory/relapsed patients). 
x Multiple myeloma (MM) patients with measurable M-protein (serum and/or 24-hr urine, 
or serum free light chains). 
x Acute myeloid leukemia (AML) patients, all types except M3 based on FAB classification 
x Chronic lymphocytic leukemia (CLL) patients. 
x B-cell non-Hodgkin’s lymphoma (NHL) patients. For lymphoma patients at least 
1 measurable lesion should be present. 
x Acute lymphoblastic leukemia (ALL) patients. 
B. For dose escalation Cohorts 11, 12 and 13 (and additional optional cohorts):  
Patients with relapsed/refractory MM with measurable M-protein (serum M-protein 
of >0.5 g/dL and/or urine M-protein of >200 mg (24-hr urine)) or elevated serum free light 
chains (FLC >10 mg/dL with abnormal FLC ratio) who have progressed on or after 
standard therapy that includes an IMiD and a proteasome inhibitor. 
For the standard risk expansion cohort: Patients with relapsed/refractory MM with 
measurable M-protein (serum M-protein of >0.5 g/dL and/or urine M-protein of  
>200 mg (24-hr urine)) or elevated serum free light chains (FLC >10 mg/dL with 
abnormal FLC ratio) who meet the following criteria: 
x have progressed on or after at least 2 prior lines of standard therapy that includes an IMiD 
and a proteasome inhibitor 
For the high risk expansion cohort: Patients with relapsed/refractory MM with 
measurable M-protein (serum M-protein of >0.5 g/dL and/or urine M-protein of >200 mg 
(24-hr urine) or elevated serum free light chains (FLC >10 mg/dL with abnormal FLC 
ratio) who have progressed on or after standard therapy that includes an IMiD and a 
proteasome inhibitor and who meet one of the following criteria: 


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x have relapsed within 6 months of autologous transplantation 
x have 17p deletion, t (4, 14), t (14, 16), t (14, 20) or >3 copies of 1q21 
x have a high-risk gene expression profiling (GEP) signature (if available) 
I 02. Signed written informed consent. 
7.3 
PHASE 1 EXCLUSION CRITERIA  
E 01. No previous treatment with any anti-CD38 is allowed 
E 02. Patient less than 18 years old 
E 03. Karnofsky performance status <60 
E 04. Poor bone marrow reserve as defined by absolute neutrophils count <1.0 x 109/L or 
hemoglobin <9.0 g/dL or platelets <50 x 109/L 
E 05. Poor organ function as defined by one of the following: 
x Liver function tests 
- 
(AST, ALT, AP, bilirubin >2.5 x upper limit of normal [ULN] if no liver 
metastasis; >5 x ULN if liver metastases 
- 
>5 x ULN AP if bone involvement 
x Serum creatinine >2 x ULN (>3 x ULN for multiple myeloma 
E 06. Received any investigational drug within 30 days or 5 half-lives of the investigational 
drug, whichever is longer 
E 07. Prior anticancer therapy (chemotherapy, targeted agents, radiotherapy, immunotherapy) 
within 21 days except for alkylating agents (eg, Melphalan) 28 days will be required. 
Hydroxyurea may be used up to 24 hours prior to the first drug infusion and leukophoresis 
may be used up to 1 week prior to the first drug infusion 
E 08. Known intolerance to infused protein products, sucrose, histidine, polysorbate 80 or known 
hypersensitivity to any of the components of study therapy that is not amenable to 
pre-medication with steroids and H2 blockers 
E 09. Allogeneic bone marrow transplant or an allogeneic peripheral blood stem cell transplant 
within 1 year prior to study entry or evidence of GVHD requiring >10 mg prednisone. 
Patients having undergone ASCT(s) may be included in the study. For AML patients, prior 
allogeneic stem cell transplantation or donor lymphocytes infusion within 3 months 
preceding the first dose of SAR650984 
E 10. Any serious active disease (including clinically significant infection that is chronic, 
recurrent, or active) or co-morbid condition, which, in the opinion of the Investigator, 
could interfere with the safety, the compliance with the study or with the interpretation of 
the results 


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E 11. Any other severe underlying medical conditions including presence of laboratory 
abnormalities, which could impair the ability to participate in the study or the 
interpretation of its results 
E 12. Concomitant or prior malignancy (other than the one under study) except adequately 
treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, 
or other cancer for which the subject has been disease-IUHHIRU\HDUV 
E 13. Concurrent treatment with other anti-cancer therapy not specified in the protocol 
E 14. Central nervous system (CNS) metastatic disease 
E 15. Pregnant or breast-feeding women 
E 16. Female patients of childbearing potential and male subjects with female partners of 
childbearing potential who are not willing to avoid pregnancy by using an adequate 
method of contraception (2 barrier method or 1 barrier method with a spermicide or 
intrauterine device for 2 weeks prior to screening, during and 5 months after the last dose 
of trial medication). Adequate methods of contraception are provided as examples. Other 
acceptable and effective methods of birth control are also permitted (eg, abstinence). 
E 17. Known HIV seropositivity, AIDS, hepatitis C or active hepatitis B infection 
E 18. Autoimmune disease (eg, inflammatory bowel disease such as Crohn’s disease, systemic 
lupus or multiple sclerosis) 
E 19. No resolution of all specific toxicities (excluding alopecia) related to any prior anti-cancer 
WKHUDS\WR*UDGHDFFRUGLQJWRWKH1&,&7&$(Y4.03 
E 20. Any of the following within 6 months prior to enrollment: myocardial infarction, 
severe/unstable angina, or coronary/peripheral artery bypass graft surgery, clinically 
symptomatic and uncontrolled cardiovascular disease, or clinically significant cardiac 
arrhythmias (Grade 3-4) 
E 21. Mental condition rendering the patient unable to understand the nature, scope and possible 
consequences of the study. Patient unlikely to comply with protocol eg, uncooperative 
attitude, inability to return for follow up visits, and unlikelihood of completing the study 
7.4 
PHASE 2 (STAGE 1 AND STAGE 2) INCLUSION CRITERIA  
I 01. Patients must have a known diagnosis of multiple myeloma with evidence of measurable 
disease, as defined below: 
- 
Serum M-SURWHLQJG/JG/LQFDVHRI,J$GLVHDVH in Stage 2), or urine 
M-SURWHLQPJKRXUV 
OR 
- 
in the absence of measurable m-protein, serum immunoglobulin free light chain  
PJG/DQGDEQRUPDOVHUXPLPPXQRJOREXOLQNDSSDODPEGDIUHHOLJKWFKDLQUDWLR
(<0.26 or >1.65). 
I 02. Patients PXVWKDYHUHFHLYHGSULRUWUHDWPHQWZLWKDQ,0L'IRUF\FOHVRUmonths of 
WUHDWPHQWDQGDSURWHDVRPHLQKLELWRUIRUF\FOHVRUPRQWKVRIWUHDWPHQW. 


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I 03. Patients must have received at least three prior lines of therapy (as defined in Appendix C) 
for multiple myeloma. Induction therapy and stem cell transplant (± maintenance) will be 
considered as one line 
OR 
Patients whose disease is double refractory to an IMiD and a PI. For patients who have 
received more than one type of IMiD and PI, their disease must be refractory to the most 
recent one. 
Refractory disease is defined as a disease that is progressive while being on treatment, or 
progressive within 60 days of the last administration of these therapies or never reached at 
least a MR with those drugs 
I 04. Patients must have achieved an MR or better to at least one prior line of therapy.  
I 05. 3DWLHQWVPXVWKDYHUHFHLYHGDQDON\ODWLQJDJHQWF\FOHVRUPRQWKVHLWKHUDORQHRULQ
combination with other MM treatments (history of stem cell transplant is acceptable). 
Treatment with high-dose melphalan for stem cell transplantation meets this requirement.  
I 06. Patients must have evidence of disease progression on or after the most recent prior 
regimen based on IMWG criteria ((2) and Appendix E) (Phase 2 Stage 2) 
I 07. Signed written informed consent and be willing and able to complete all study-related 
procedures, including completion of patient-reported endpoints 
7.5 
PHASE 2 (STAGE 1 AND STAGE 2) EXCLUSION CRITERIA  
E 01. Patients less than 18 years old. 
E 02. Patients with multiple myeloma IgM subtype. 
E 03. Previous treatment with any anti-CD38 therapy. 
E 04. Patients with concurrent plasma cell leukemia. 
E 05. Patients with known or suspected amyloidosis. 
E 06. Patients treated with approved or investigative anticancer therapeutic agents, excluding 
dexamethasone in Phase 2 Stage 2 but including steroid therapy (eg, 
prednisone >10 mg/day orally or equivalent for more than 7 consecutive days except for 
inhalation corticosteroids and patients being treated for adrenal insufficiency/replacement 
therapy), within 3 weeks or within five drug half-lives (t1/2) prior to first dose, whichever 
time is greater. 
E 07. Patients treated with systemic radiation therapy within 4 weeks prior to first dose or 
localized radiation therapy within 1 week prior to first dose. 
E 08. Patients who have had major surgery within 3 weeks prior to first dose. 
E 09. Prior autologous stem cell transplant within 12 weeks of the first dose of study treatment 
and/ or prior allogeneic transplant within 1 year or has evidence of active graft versus host 
disease (GVHD) requiring >10 mg prednisone daily. 
E 10. Patients with a life expectancy of less than three months. 


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E 11. Karnofsky performance status <60.  
In Stage 2 part patient with ECOG Performance status >2. 
E 12. Patients with laboratory values of: 
a) Total bilirubin  x upper limit of normal (excluding congenital conjugation 
disorders (Gilberts) with direct bilirubin <2 x upper limit of normal. 
b) AST or AL7 x upper limit of normal. 
c) Phase 2 Stage 1: Calculated or measured creatinine clearance <30 mL/minute (using 
Cockcroft and Gault formula [(140 - age) x mass (kg) / (72 x creatinine mg/dL)], 
multiply result by 0.85 if female).  
Phase 2 Stage 2: serum creatinine >2xULN and/or estimated Glomerular Filtration 
Rate calculated according the Modification of diet in Renal Disease (MDRD) equation 
<15mL/min/1.73m2, (see formula in Appendix B), and/or on renal dialysis. 
d) Absolute neutrophil count  000/mm3 (use of colony-stimulating factors to achieve 
these counts is allowed). 
e) Hemoglobin <8.0 g/dL (patients may receive red blood cell transfusion or receive 
supportive care such as erythropoietin and darbepoetin in accordance with institutional 
guidelines). 
f) 3ODWHOHWFRXQWPP3 (patients should be platelet transfusion independent for  
2 weeks prior to screening lab values). 
E 13. No resolution of all specific toxicities (excluding alopecia) related to any prior anti-cancer 
therapy to Grade  according to the NCI CTC AE v.4.03. 
E 14. Patients with concurrent POEMS syndrome (polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein, and skin changes). 
E 15. Patients with congestive heart failure (New York Heart Association class III to IV), 
symptomatic ischemia, conduction abnormalities uncontrolled by conventional 
intervention, or myocardial infarction in the 6 months prior to first dose. 
E 16. Patients with active infection requiring systemic antibiotics, antivirals or antifungals within 
2 weeks prior to first dose (except when used for chronic prophylaxis). 
E 17. Known intolerance to infused protein products, sucrose, histidine, polysorbate 80 or known 
hypersensitivity to any of the components of study therapy that is not amenable to  
pre-medication with steroids and H2 blockers. 
E 18. Patients with known HIV. 
E 19. Patients with active hepatitis B, or C infection. 
E 20. Patients diagnosed or treated for a malignancy within the past 3 years except: 
a) adequately treated basal cell or squamous cell skin cancer, or 
b) carcinoma in situ of the cervix, or 
c) prostate cancer with < Gleason Grade 6 and stable PSA.  


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E 21. Patients with myelodysplastic syndrome (MDS). 
E 22. Patients with significant neuropathy (*UDGHZLWKSDLQRU Grade 3) within 2 weeks prior 
to first dose. 
E 23. Any clinically significant medical or psychiatric disease or condition that, in the 
Investigator's opinion, may interfere with protocol adherence, the ability to complete 
patient-reported measures or the ability to give informed consent. 
E 24. Female patients of childbearing potential and male patients with female partners of 
childbearing potential who are not willing to avoid pregnancy by using an adequate 
method of contraception (2-barrier method or 1 barrier method with a spermicide or 
intrauterine device for 2 weeks prior to screening, during and 5 months after the last dose 
of trial medication) and/or who are unwilling or unable to be tested for pregnancy monthly 
for 5 months after the last administration of SAR650984. Adequate methods of 
contraception are provided as examples. Other acceptable and effective methods of birth 
control are also permitted (eg, abstinence). 
E 25. Female patients who are pregnant or breast feeding. 
E 26. (Phase 2 Stage 2) Patient is the Investigator or any Sub-investigator, research assistant, 
pharmacist, study coordinator, other staff or relative thereof directly involved in the 
conduct of the protocol. 


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8 
TREATMENTS  
8.1 
INVESTIGATIONAL PRODUCT  
8.1.1 Pharmaceutical form  
8.1.1.1 Formulation for Phase 1 and Phase 2 Stage 1  
The C1P1F1 drug product is presented as a concentrate for solution for infusion in vials 
containing 5 mg/mL (100 mg/20 mL) SAR650984 in 10 mM histidine, 10 % (w/v) sucrose, 
0.005 % (w/v) polysorbate 80, pH 6.5 buffer. For administration to patients, the appropriate 
volume of SAR650984 will be diluted in an infusion bag of 0.9% sodium chloride solution. The 
final infusion volume corresponding to the dose of SAR650984 will be administered for period of 
time that will depend on dose administered and will be based on protein amount given per hour. 
8.1.1.2 Formulation for Phase 2 Stage 1 and 2  
The C1P2F2 drug product is presented as a concentrate for solution for infusion in vials 
containing 20 mg/mL (500 mg/25 mL) SAR650984 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, non-pyrogenic, 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 SAR650984 P2F2. The fill volume has been established to ensure removal 
of 25 mL. 
For administration to patients, the appropriate volume of SAR650984 will be diluted in an 
infusion bag of 0.9% sodium chloride solution. The final infusion volume corresponding to the 
dose of SAR650984 will be administered for period of time that will depend on dose administered 
and will be based on protein amount given per hour. 
For those patients that are still on treatment after study cutoff date in Phase 2 Stage 1, they may be 
switched from C1P1F1 to C1P2F2. 
For more details, please see the Investigator’s brochure. 
8.1.2 Dose of drug per administration  
During Phase 1 SAR650984 will be administered by IV infusion every week or once every 
two weeks (Q2W) as determined by the assigned cohort in 14-day cycles. 
During Phase 2 SAR650984 will be administered by IV infusion at the assigned dose and 
schedule (see Section 6.2) in 28-day cycles.  


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For both Phase 1 and Phase 2 parts, the dose administered should be calculated using actual body 
weight as measured at each cycle. 
The rate of infusion for each of the planned dose levels in the Phase 1 is as follows: 
0.0001 mg/kg ---------------------------- 0.042 mg/hr for a total of 3 mL 
0.001 mg/kg ----------------------------- 0.42 mg/hr for a total of 3 mL 
0.01 mg/kg ------------------------------- 1.4 mg/hr 
0.03 mg/kg ------------------------------- 4.2 mg/hr 
0.1 mg/kg -------------------------------- 7 mg/hr 
0.3 mg/kg  ------------------------------- 10.5 mg/hr 
1 mg/kg  ---------------------------------- 17.5 mg/hr 
3 mg/kg ---------------------------------- 52.5 mg/hr 
5 mg/kg ---------------------------------- 87.5 mg/hr 
10 mg/kg --------------------------------- 175 mg/hr 
20 mg/kg --------------------------------- 250 mg/hr 
First infusion: initiate infusion at a rate noted above. In the absence of infusion reaction, increase 
infusion rate by 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour. 
Subsequent infusions: initiate infusion at a rate noted above. In the absence of infusion reaction, 
increase rate by 100 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour. 
During Phase 2, the rate of infusion will be at 175 mg/hr and will follow the first and subsequent 
infusion rate increases as detailed above. 
In Phase 2 Stage 2:  
The rate of infusion for SAR650984 at 20 mg/kg is as follows: 
First infusion: initiate infusion at a rate of 175 mg/hour. In the absence of infusion reaction after  
1 hour of infusion, increase infusion rate by 50 mg/hour increments every 30 minutes, to a 
maximum of 400 mg/hour. 
Subsequent infusions: initiate infusion at a rate of 175mg/hour. In the absence of infusion reaction 
after 1 hour of infusion, increase rate by 100 mg/hour increments every 30 minutes, to a 
maximum of 400 mg/hour. 
In case of IAR of Grade WKHDGPLQLVWUDWLRQVKRXOGEHLQWHUUXSWHGLQFDVHRI,$5RIGrade 
SAR650984 should be permanently discontinued (see Table 3). Once the event has improved to 
*UDGHWKHLQIXVLRQPD\EHUHstarted at one half the initial infusion rates. If symptoms do not 
recur after 30 minutes, the infusion rate may be increased in 50 mg/hour increments every  
30 minutes, to a maximum of 400 mg/hour. 


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8.1.3 Duration of treatment:  
Phase 1: Patient(s) in Cohorts 1 to 10 and 12 will receive administrations of SAR650984 at 
2-week intervals. Patients in Cohort 11 and 13 will receive administration of SAR650984 at 
1-week intervals. 
Patients enrolled in the Phase 1 expansion cohorts (standard risk or the optional high risk cohorts) 
will receive SAR650984 at 10 mg/kg Q2W for continued treatment as long as clinical benefit is 
possible, or until PD or for other reasons (see Section 11.2). 
Phase 2: Patients will receive administrations of SAR650984 at the assigned dose and schedule 
(or modified dose and schedule, see Section 6.4) for continued treatment as long as clinical 
benefit is possible, or until PD or for other reasons (see Section 11.2). 
8.1.4 Dilution method  
The SAR650984 concentrate for solution for infusion will be diluted in an infusion bag with 
0.9% sodium chloride solution to achieve the appropriate drug concentration for infusion. 
The low doses 0.0001 and 0.001 mg/kg will require serial dilution to achieve the necessary drug 
concentration for infusion. For all other doses, a single dilution will be sufficient.  
Due to the low volume (3 mL) of administration, the 0.0001 and 0.001 mg/kg doses will be 
administrated by extemporaneous injection of bolus by syringe.  
For all other doses, infusion via a central line is preferred if available according to the rate of 
infusion detailed above. Patients with local intolerance after peripheral IV infusion should receive 
next dose(s) using a central line. The final infusion volume corresponding to the dose of 
SAR650984 will be administered by IV infusion for the period of time that will depend on dose 
administered and on the protein amount administered per hour (detailed above). 
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. 
A 0.2μm in-line filter is required for administration from the second dose (0.001 mg/kg). 
Therefore for IV infusion, an IV tubing administration set with a 0.20-micron in-line filter will be 
used for infusion; if an in-line filter is unavailable, a 0.20-micron filter unit may be attached to the 
administration set before administration. 
Detail instruction for dilution of the SAR650984 concentrate for solution for infusion is provided 
in a Pharmacy Manual.  
8.1.5 Stability under light  
No protection from light is required for storage in the infusion bags. 


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8.1.6 Dexamethasone (investigational product for patients randomized in the ISAdex 
arm - Phase 2 Stage 2 only)  
8.1.6.1 Availability  
Dexamethasone 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. 
8.1.6.2 Accountability  
A patient diary will be used to document all oral dexamethasone drug administration. 
8.1.6.3 Administration  
Dexamethasone, being part of both backbone treatment regimen and SAR650984 premedication, 
will be administered orally (PO) or and by intravenous infusion (IV) as follows: 
x Patients of <75 year-old: 40 mg on D1, D8, D15, D22 of each cycle 
x 3DWLHQWVRI\HDU-old: 20 mg on D1, D8, D15, D22 of each cycle 
On days of SAR650984 administration, dexamethasone will be given before the SAR650984 
infusion (see Section 8.2.1). 
For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, oral dexamethasone may be supplied at the site 
or from the PI/site/Sponsor to the participant via a Sponsor-approved courier company where 
allowed by local regulations and agreed upon by the participant during the time the measures are 
applied. 
For dexamethasone dose adjustment, see Section 6.4 and Section 6.7. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT  
8.2.1 Premedication  
In Phase 1 and Phase 2 Stage 1: 
Patient(s) should routinely receive premedications prior to SAR650984 infusion to reduce the risk 
and severity of hypersensitivity reactions commonly observed with monoclonal antibodies. The 
recommended premedication agents are: diphenhydramine 25-50 mg IV (or equivalent), 
methylprednisolone 100 mg IV (or equivalent), ranitidine 50 mg IV (or equivalent) and 
acetaminophen 650-1000 mg po 15-30 minutes (but no longer than 60 minutes) prior to 


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SAR650984 infusion. General guidelines for the management of the infusion associated reactions 
are provided in Table 1. If an infusion associated reaction is observed, patients must also be 
informed of the potential risk of recurrent allergic reactions.  
For the Phase 2 part, patients who do not experience an infusion associated reaction during the 
first 4 SAR650984 infusions may have the need for subsequent pre-medication reconsidered at the 
investigator’s discretion in consultation with the sponsor to avoid unnecessary sedation. 
In Phase 2 Stage 2: 
Before each administration of SAR650984, all patients will receive prophylaxis for infusion 
associated reaction.  
In ISA arm: The recommended premedication agents are: diphenhydramine 25-50 mg IV (or 
equivalent), methylprednisolone 100 mg IV (or equivalent), ranitidine 50 mg IV (or equivalent) 
and acetaminophen 650-1000 mg PO. The pre medication will be administered at least 15 to 
30 minutes (but no longer than 60 minutes) prior to SAR650984 infusion. 
In ISAdex arm, on the day of SAR650984 infusion, a total of 40 mg (or 20 mg for patients 
 years old) of dexamethasone will be administered as part of the pre-medication and the 
combination treatment. 
The order of premedication administration is the following:  
x When dexamethasone is administered orally: dexamethasone, acetaminophen, ranitidine, 
and then diphenhydramine. 
x When dexamethasone/methylprednisolone is administered IV, acetaminophen, ranitidine, 
diphenhydramine and then dexamethasone/methylprednisolone. 
x Patients who do not experience an infusion associated reaction in 4 consecutive 
SAR650984 infusions may have the need for subsequent pre-medication reconsidered at 
the investigator’s discretion inconsultation with the sponsor to avoid unnessary sedation. 
8.3 
PACKAGING AND LABELING  
The investigational product is packaged in 25 mL glass vials fitted with elastomeric closure for 
C1P1F1 and is packaged in 30 mL glass vials fitted with elastomeric closure for Phase 2 Stage 2 
C1P2F2.  
The content of the labeling is in accordance with the local regulatory specifications and 
requirements. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP  
In Phase 1, there is no randomization. 


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In Phase 2, after each patient has completed the necessary screening visit procedures and is 
deemed eligible for study enrolment by the investigator, the study site will contact the 
IVRS/IWRS, to allow for patient randomization or registration for Stage 1a and Stages 1b and 2, 
respectively. 
For Stage 1a, patients will be classified into 1 of 2 strata according to their prior multiple 
myeloma therapy: 
x Stratum 1: Prior treatment with pomalidomide and/or carfilzomib. 
x Stratum 2: No prior treatment with pomalidomide and/or carfilzomib. 
Within each stratum, patients will be randomized to Stage 1a in a 1:1:1 ratio into one of the  
3 treatment arms (Arm 1, 2 or 3). The patient randomization list will be generated by the 
IVRS/IWRS according to the randomization scheme provided by the study biostatistician. 
Enrollment in Stage 1b will start after completion of Cohort 13 and enrollment in Stage 1a is 
completed, whichever is last.  
Stage 2 will be initiated after the interim analysis of Stage 1. Patients will be registered and 
randomized using an Interactive Voice Response System/Interactive Web Response System 
(IVRS/IWRS).  
8.5 
STORAGE CONDITIONS  
The Investigational product is stored at +2°C to +8°C. Storage of Investigational Product should 
be in a secure area with restricted access.  
Details of the storage conditions for the diluted solution is provided in the Pharmacy Manual.  
8.6 
RESPONSIBILITIES  
The Investigator, the Hospital Pharmacist, or other personnel allowed to store and dispense 
Investigational Product will be responsible for ensuring that the Investigational Product used in 
the clinical trial is securely maintained as specified by sanofi-aventis and in accordance with the 
applicable regulatory requirements. 
All Investigational Product shall 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. 
A potential defect in the quality of Investigational Product may be subject to initiation by 
sanofi-aventis of a recall procedure. In this case, the Investigator will be responsible for promptly 
addressing any request made by sanofi-aventis, in order to recall Investigational Product and 
eliminate potential hazards. 


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Under no circumstances will the Investigator supply Investigational Product to a third party, allow 
the Investigational Product to be used other than as directed by this Clinical Trial Protocol, or 
dispose of Investigational Product in any other manner. 
8.7 
RETRIEVAL OF TREATMENTS AND/OR DESTRUCTION  
All used treatments of SAR650984 will be destroyed at the study site after an accurate 
accountability has been performed and signed by the Investigator (or the pharmacist).  
All unused IPs may be retrieved by sanofi-aventis. A detailed treatment log form of the returned 
Investigational Product will be established with the Investigator (or the pharmacist) and 
countersigned by the Investigator and the Monitoring Team. 
The Investigator will not destroy the unused Investigational Product unless sanofi-aventis 
provides written authorization. 
A potential defect in the quality of Investigational Product may be subject to initiation by 
sanofi-aventis of a recall procedure. In this case, the Investigator will be responsible for promptly 
addressing any request made by sanofi-aventis, in order to recall Investigational Product and 
eliminate potential hazards. 
8.8 
CONCOMITANT TREATMENT  
All treatments being taken by the patient 7 days prior to registration onto the study, 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 the type, dose and route of administration must be 
documented on the appropriate pages of the CRF or e-CRF. 
Concomitant medications should be kept to a minimum during the study. However, 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 or in the 
e-CRF: 
x Palliative radiotherapy may be given for control of pain for palliative intents. Sanofi-
aventis should be notified to obtain prior approval prior to treatment if palliative 
radiotherapy is being considered, and prior to resuming therapy on the study. 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 and radiological assessments of the tumor. If 
the only evaluable lesions are to be irradiated, the patient will stop the study treatment. 
The irradiated area cannot be used as a parameter for response assessment.  
x Supportive treatment as medically indicated for the patient’s well-being may be prescribed 
at the Investigator’s discretion. Every medication or treatment taken by the patient during 
the trial and the reason for its administration must be recorded on the CRF. 


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The following concomitant treatments are not permitted during this study: 
x Concurrent treatment with other investigational drugs. 
x Concurrent treatment with any other anticancer therapy not specified in this protocol, 
including immunotherapy, hormonal therapy, targeted therapy, steroid therapy or 
biological therapies. 
x During the Phase 1 part, prophylactic use of hematopoietic growth factors (eg, G-CSF, 
GM-CSF, erythropoietin) during the first cycle. Prophylactic use of hematopoietic growth 
factors during the Phase 2 part is permitted. 
8.9 
POST-INVESTIGATIONAL PRODUCT  
As per the discretion of the Investigator. 
8.10 
TREATMENT ACCOUNTABILITY AND COMPLIANCE  
Administration of the Investigational Product will be supervised by the Investigator or 
sub-investigator. 
The person responsible for drug dispensing is required to maintain adequate records of the IP. 
These records (eg, drug movement form) include the date the IP is received from sanofi-aventis, 
dispensed for patient and destroyed or returned to sanofi-aventis. The packaging batch number 
(PR Nr) on the vial must be recorded on the drug accountability form. 
The person responsible for drug administration to the patient will record precisely the date and the 
time of the drug administration. 
8.11 
CONTRACEPTIVE MEASURES  
Females of child bearing potential or male subjects with female partners of childbearing potential 
shall be required to use effective contraceptive methods (double barrier method, intrauterine 
device, oral contraception or abstinence) starting 2 weeks before first IMP administration, while 
on therapy and for 5 months following the last dose of IMP. A woman is considered of 
childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post- 
menopausal unless permanently sterile. The following highly effective methods of contraception 
are accepted: 
x Established use of oral, intravaginal, or transdermal combined (estrogen and progestogen 
containing) hormonal contraception associated with inhibition of ovulation. 
x Established use of oral, injectable, or implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation. 
x Placement of an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS). 


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x Barrier methods of contraception: male condom with either cap, diaphragm or sponge with 
spermicide (double barrier methods). The use of double barrier methods should always be 
supplemented with the use of a spermicide. Female condom and male condom should not 
be used together. 
x Male sterilization (provided that the partner is the sole sexual partner of the patient and 
that the sterilized partner has received medical assessment of the surgical success.) 
x Sexual abstinence. 


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9 
ASSESSMENT OF INVESTIGATIONAL PRODUCT  
9.1 
SAFETY  
The primary objective of the Phase 1 part is to establish, based on IP related DLTs, the MTD or 
RP2D of SAR650984 when administered as an intravenous infusion every week or every 2 weeks 
to patients with advanced hematologic malignancies known to be refractory to standard available 
therapies or for which no standard therapy exists. A secondary objective of the Phase 2 part is to 
evaluate the safety of SAR650984 when administered as an intravenous infusion to patients with 
relapsed or relapsed/refractory multiple myeloma. The safety profile will be assessed from the 
findings of physical examination (preferably by the same physician), laboratory tests, etc, and will 
be based on incidence, severity (as graded by the NCI CTCAE v. 4.03), and cumulative nature of 
AEs as defined in Section 10.4. 
The NCI CTC AE v 4.03 (45) can be accessed through the NCI website at 
http://ctep.info.nih.gov/reporting/ctc.html (45). 
9.1.1 Dose limiting toxicities (DLTs) 澡 Phase 1 part only  
For the purposes of dose escalation and determination of the MTD/RP2D, only DLTs that occur 
during the first 28 days (Cycle 1 and Cycle 2) of treatment will be considered for decisions 
regarding dose escalation. 
DLTs are defined as any Grade 3 or higher non-hematological toxicity (with the exception of 
allergic reaction/hypersensitivity), Grade 4 neutropenia and/or Grade 4 thrombocytopenia lasting 
longer than 5 days, attributed to SAR650984 and as defined by the NCI-CTCAE v.4.03.  
Any other toxicity that the Investigator and the sponsor deem to be dose limiting, regardless of the 
grade, may also be considered as DLT. 
Before escalating SAR650984 dose to the next DL, all safety data, and especially the reported 
potential DLTs will be reviewed to determine their relationship to the IP. Dose escalation or dose 
decrease decisions will be based on the assessment of IP related DLTs by the Safety Committee.  
'RVHHVFDODWLRQZLOOEHVWRSSHGLILQXSWRSDWLHQWVRISDWLHQWVH[SHULHQFHGDQ,3
related DLT observed during the first two cycles of treatment (4 weeks), according to the 
definition of MAD. 
In case of existing usable prophylactic and/or curative treatment for a dose limiting non-
hematologic AE (eg: diarrhea, hypersensitivity, nausea-vomiting, hyperglycemia), this treatment 
may be evaluated in an additional cohort of up to 6 patients treated at the same DL. Further dose 
escalation could be allowed if <33% of patients in this additional cohort experience DLT when 
receiving the prophylactic/corrective therapy. These prophylactic/corrective therapies will be 
systematically implemented in further DLs. In addition, in the expansion cohort at MTD, 
cumulative toxicities will be specifically detected, in order to confirm the feasibility of the MTD 
selected in the dose escalation step.  


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Although the dose escalation process is guided by the safety evaluation during the first two cycles 
of treatment, cumulative toxicities observed in subsequent administrations should also be 
considered for the dose escalation and the dose selection decisions (ie, smaller increases in dose, 
expansion of a given DL, intermediate DL), upon agreement within the Study Committee. 
9.1.2 Adverse events  
Safety profile will be based on incidence, severity (as graded by the NCI CTC AE v. 4.03), and 
cumulative nature of treatment-emergent AEs (TEAEs). TEAEs are defined as AEs that develop 
or worsen during the on-treatment period. For this study, the on-treatment period will be defined 
as the period from the time of first dose of IP to at least 30 days after last administration of the IP. 
Each patient will be assessed preferably by the same physician for AEs and according to the NCI 
CTC AE v. 4.03 classifications. 
The NCI CTC AE v. 4.03 may be accessed through the NCI website at 
http://ctep.info.nih.gov/reporting/ctc.html (45). 
9.1.3 Laboratory measurements  
9.1.3.1 Phase 1 laboratory assessments  
Blood chemistry, hematology, coagulation, urinalysis, cytokines and CRP will be performed at 
screening, during treatment and at the EOT visit (see Section 12.1 for assessment timings).  
Blood Chemistry: SGOT (AST), SGPT (ALT), bilirubin (total and direct), alkaline phosphatase 
(AP), lactate dehydrogenase (LDH), sodium, potassium, chloride, bicarbonate/carbon dioxide, 
calcium, magnesium, phosphate, uric acid, blood urea nitrogen (BUN), serum creatinine and 
estimated creatinine clearance, glucose, albumin, total protein, peptide C, erythrocyte 
sedimentation rate (ESR) 
Hematology: hemoglobin, hematocrit, RBC, WBC with differential, MCV, platelet count 
Coagulation: PT/INR, PTT 
Urinalysis: blood, protein, glucose, pH, ketones, bilirubin, leucocytes, nitrates, specific gravity  
Cytokines: Tumor necrosis factor alpha (TNF-Į,/-6, IL-1B, IFN-Ȗ 
Hs/CRP  
9.1.3.2 Phase 2 laboratory assessments  
Blood chemistry, hematology, coagulation, urinalysis and cytokines will be performed at 
screening, during treatment and at the EOT visit (see Section 12.2 for assessment timings).  


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Blood Chemistry: SGOT (AST), SGPT (ALT), bilirubin (total and direct), AP, lactate 
dehydrogenase (LDH), sodium, potassium, chloride, bicarbonate/carbon dioxide, calcium, 
corrected serum calcium, magnesium, phosphate, uric acid, blood urea nitrogen (BUN), serum 
creatinine and estimated creatinine clearance, glucose, albumin and total protein 
Hematology: hemoglobin, hematocrit, RBC, WBC with differential, MCV, platelet count 
Coagulation: PT/INR, PTT 
Urinalysis: blood, protein, glucose, pH, ketones, bilirubin, leucocytes, nitrates, specific gravity 
Cytokines: Tumor necrosis factor alpha (TNF-Į,/-6, IL-1B, IFN-Ȗ 
Safety labs: 6KRXOGD6$5LQIXVLRQUHDFWLRQRI*UDGH2 occur, additional blood sampling 
during the AE is required for analysis of cytokines, markers of complement activation (C3, C4, 
CH50), serum tryptase and blood chemistry (Phase 1 and Phase 2 Stage 1 only) 
9.1.4 Physical examinations  
Please refer to Section 12.2 for assessment timings. Physical examination consists of examination 
of major body systems, plasmacytoma assessment, respiratory, hepatomegaly, splenomegaly, 
lymphadenopathy. 
9.1.5 Vital signs  
Please refer to Section 12 for assessment timings. Vital signs consist of examination of blood 
pressure, heart rate, temperature, and respiration rate. 
9.1.6 ECG  
Please refer to Section 12 for assessment timings of the 12-lead ECG. 
9.1.7 Other Clinical assessments  
x Karnofsky performance status evaluation for Phase 1 and Phase 2 Stage 1, ECOG 
Performance status for Phase 2 Stage 2 part. 
x Results of additional procedures (such as karyotype, FISH, etc) performed as part of 
standard of care to assess the current disease status may also be collected. 
9.2 
EFFICACY  
9.2.1 Phase 1 criteria for response  
Please refer to Appendix D for the response criteria for each disease type (MM, AML, CLL, NHL 
and ALL). 


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9.2.2 Phase 2 primary endpoint  
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) based on responses 
as assessed by the Independent Adjudication Committee (IAC) using the International Myeloma 
Working Group (IMWG) Uniform Response Criteria (Stage 1[(1)] , Stage 2 [(2)] see Appendix E) 
Response evaluation will include: 
x M-protein quantification (serum and 24-hr urine) 
x Serum free light chain levels 
x Bone marrow biopsy/aspiration 
x PET-CT or MRI or CT scan of plasmacytoma 
x Bone skeletal survey or low dose whole body CT scan 
x Corrected serum calcium 
In the Stage 2 SDUWUHVSRQVHHYDOXDWLRQZLOOEHSHUIRUPHGRQDPRQWKO\EDVLV5HVSRQVHV PR) 
and progression should be confirmed on 2 consecutive biology (serum and/or urine M protein) 
disease assessments according to study flow-chart. Confirmation of response or progression will 
be performed within 4 weeks (to confirm response or progressive disease, two discrete samplers 
are required: testing cannot be based upon the splitting of a single sample). Progression based on 
images does not need to be confirmed.  
In case of plasmacytoma at baseline, response assessment will include radiological every 2 cycles 
until progression. 
9.2.3 Phase 2 secondary endpoints  
9.2.3.1 Secondary efficacy endpoints:  
x DOR: defined as the time from the date of the first IAC determined response to the date of 
subsequent IAC determined PD or death, whichever happens earlier. In the absence of the 
confirmation of subsequent IAC determined disease progression or death before the 
analysis cut-off date, the DOR will be censored at the date of the last valid assessment, the 
analysis cut-off date or date of initiation of new anticancer treatment, whichever is earlier. 
'25LVGHWHUPLQHGRQO\IRUSDWLHQWVZKRKDYHDFKLHYHGDUHVSRQVHRI PR. DOR will not 
be calculated for patients that do not achieve a response.  
x CBR: defined as the proportion of patients with sCR, CR, VGPR, PR or MR according to 
IMWG criteria, as determined by the IAC. 
x PFS: defined as the time interval from the date of first study treatment administration to 
the date of the first IAC-assessed disease progression or the date of death due to any cause, 
whichever comes first. In the absence of disease progression or death before the analysis 
cut-off date, or the date of initiation of new anticancer treatment, PFS will be censored at 
the date of the last valid assessment performed before the cut-off date or the date of 
initiation of new anticancer treatment, whichever is earlier. 


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x OS: defined as the time interval from the date of first study treatment administration to 
death from any cause. In the absence of the confirmation of death before the analysis cut-
off date, OS will be censored at the last date the patient is known to be alive or at the study 
cut-off date, whichever is earlier. 
9.2.3.2 Electronic patient reported outcomes (Phase 2 Stage 1a and 1b only)  
Health-related quality of life (HRQOL) and symptoms of multiple myeloma will be obtained 
through the use of the European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire (EORTC QLQ-C30) and its myeloma-specific module (MY-20). Generic 
health status will be measured through the use of the EQ-5D. These will be captured electronically 
throughout the study.  
The EORTC-QLQ-C30 and QLQ-MY20 as well as the EQ-5D (Appendix G, Appendix H) that 
will be completed by the patients in the Phase 2 part, as specified in the study flowchart 
(Section 1.13). These HRQOL and health status measures must be completed through the 
electronic format before other assessments are performed or study drug is administered, or before 
any information regarding current health or state of disease has been communicated to the patient. 
The EORTC QLQ-C30 and QLQ-MY20 questionnaires will be completed on Day 1 Cycle 1 then 
D1 of every cycle and at the EOT visit. The EQ-5D questionnaire will be completed on Day 1 
Cycle 1 then D1 of every 3rd cycle starting Cycle 4 (ie, Cycle 4, 7, 10, etc) and at the EOT visit. 
x The EORTC QLQ-30 is a cancer-specific instrument that contains 30 questions and 
provides a multi-dimensional assessment of HRQOL. The validity and reliability of the 
EORTC-QLQ-C30 has been established in various types of cancers, including multiple 
myeloma (46, 47). The QLQ-C30 is composed of both multi-item scales and single-item 
measures. These include five functional scales (physical functioning, role functioning, 
emotional functioning, cognitive functioning, and social functioning), three symptom 
scales (fatigue, nausea and vomiting, and pain), a Global Health Status (GHS)/quality of 
life scale, and six 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 high score for a functional scale/GHS represents a high/healthy level of 
functioning/QOL, but a high score for a symptom scale/item represents a high level of 
symptomatology/problems. The time recall period for this instrument is 1 week. 
x The QLQ-MY20 multiple myeloma module (20-items; (48) has 4 independent subscales, 
2 functional subscales (body image, future perspective), and 2 symptoms scales (disease 
symptoms and side-effects of treatment). This will be administered following, yet in 
conjunction with the EORTC QLQ-C30. 
These are reliable and valid measures of HRQOL in patients with cancer and takes about 
15 minutes to administer. The instruments consist of a total of 50 items and have been validated 
and used in many countries. 
x Generic health status will be assessed via the EQ-5D (49) The EuroQol EQ-5D  
(Appendix H) provides a simple descriptive profile and an overall numeric estimate of 
health utility/health status which can be used for both clinical and economic evaluations of 
health care. It is validated for use in a wide range of health conditions and treatments. 


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EQ-5D essentially consists of 2 pages - the EQ-5D descriptive system and the Visual 
Analogue Scale VAS. The EQ-5D descriptive system comprises 5 items: mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression. Each item has 3 levels: 
no problem, some problems, and severe problems. The Visual Analogue Scale (VAS) 
records the respondent's self-rated health on a vertical visual analogue scale. The VAS 
'thermometer' has endpoints of 100 (Best imaginable health state) at the top and 0 (Worst 
imaginable health state) at the bottom. This information can be used as a quantitative 
measure of health outcome as judged by the individual respondents. The questionnaire is 
self-administered and takes about 5 minutes to complete. The 5 dimensional 3-level 
system will be converted into a single index utility score: values for the 243 theoretically 
possible health states defined by the EuroQol classification are calculated using a 
regression model (49). 
The minimum value for the single index utility score (UK based) is -0.594, which corresponds to 
a level 3 (severe problems) for mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression. The maximum value for this index is 1.0, which corresponds to a full health 
(level 1 (no problem) for mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression). 
9.3 
PHARMACOKINETIC EVALUATION  
The following PK parameters will be calculated with PKDMS software (Pharsight), using non-
compartmental methods from plasma of SAR650984 concentrations obtained after single dose 
administration and/or using population PK modeling after repeated dose administration (Phase 2). 
The parameters will include, but may not be limited to the following: 
x Maximum observed concentration (Cmax). 
x Concentrations just before drug infusion (Ctrough). 
x AUC over the dosing interval (AUC1week or AUC2week). 
9.3.1 Phase 1 pharmacokinetic evaluations  
During the Accelerated Phase, PK samples will be collected prior to, during, and after 
administration of Cycle 1 Day 1, then on Days 2, 3, and 8, and on Cycle 2 prior to and after drug 
administration on Day 1, then on Days 2, 3, 8, and 14 and at the end of study. 
During Basic Phase (Cohorts 6-10), PK samples will be collected prior, during and after 
administration on Cycle 1, Day 1, then on Days 2, 3, and 8, then on Day 1 (prior to drug 
administration) of subsequent cycles, at the end of study and at 60 days after last IP 
administration. If a patient is positive or inconclusive for ADA at 60 days, additional ADA and 
PK samples will be collected at 90 days after the last drug administration and then every 30 days 
until the patient has a negative ADA sample. 
During Basic Phase (with an every week administration of SAR650984, from Cohort 11), PK 
samples will be collected prior, during and after administration on Day 1, then on Days 2, 3, 4 and 


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8 of Cycle 1 and Cycle 3, then Day 1 and Day 8 (prior to drug administration) on Cycle 2 and all 
other cycles, at the end of study and at 60 days after last IP administration. If a patient is positive 
or inconclusive for ADA at 60 days, additional ADA and PK samples will be collected at 90 days 
after the last drug administration and then every 30 days until the patient has a negative ADA 
sample. 
During Basic Phase (with an every 2 week administration of SAR650984, from Cohort 12), PK 
samples will be collected prior, during and after administration on Day 1 Cycle 1, 2 and, then on 
Days 2, 3, 4, and 8, then on Day 1 (prior to drug administration) of subsequent cycles, at the end 
of study and at 60 days after last IP administration. If a patient is positive or inconclusive for 
ADA at 60 days, additional ADA and PK samples will be collected at 90 days after the last drug 
administration and then every 30 days until the patient has a negative ADA sample. 
9.3.2 Phase 2 pharmacokinetic evaluations  
During the Phase 2 part, PK samples will be collected as detailed in Section 1.8 and Section 1.16.  
Blood concentrations of SAR950894 will be used for population PK analysis by non-linear mixed 
effects modeling. Additional details of the analysis plan and the results could 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 patho-physiologic 
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. PK estimates 
will then be investigated as prognostic factors for clinical outcome including safety and efficacy 
endpoints, if possible. 
9.3.3 Sampling time and sample blood volume for Phase 1 and Phase 2  
It is of utmost importance to collect all blood samples at the specified times and according to the 
specifications. 
Samples missed or lost, for any reason should be recorded. Actual times of blood collection 
should be recorded in the CRF. The days of sampling, the times of drug administration should 
also be precisely recorded. 
The sampling times for blood collection can be found in the PK Flowcharts (For Phase 1: 
Section 1.4, Section 1.5, Section 1.6, Section 1.7 and for Phase 2: Section 1.8 and Section 1.16). 
Details of the sampled blood volume during Cycle 1 and further cycles, as appropriate are 
summarized in Appendix I. 
9.3.4 PK handling procedure  
Detailed in the laboratory manual and summarized in Appendix I. 


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9.4 
IMMUNE RESPONSE  
Human anti-drug antibodies to SAR650984 will be assessed throughout the Phase 1 and Phase 2 
parts of the study. Blood samples will be collected for ADA detection according to the flowcharts 
(see Section 1). 
Phase 1: In case of positivity or inconclusive sample at 60 days post last IP administration, 
additional assessment of ADA will be performed at 90 days and then every 30 days until sample 
is negative. 
Phase 2 Stage 1: In case of positivity or inconclusive sample at 60 days post last IP 
administration, additional assessment of ADA will be performed at 90 days and then every  
30 days until sample is negative. 
Phase 2 Stage 2: In case of positivity of the last sample, one additional sample should be assessed 
in 3 months. No additional samples will be performed. 
Special procedures for storage and shipping of samples are described in detail in the laboratory 
manual. 
9.5 
PHARMACODYNAMIC ASSESSMENT  
For the Phase 1 part, CD38 receptor occupancy (RO) and receptor density (RD) will be assessed 
from bone marrow aspirates at the time points detailed in Section 1.8. 
For the Phase 2 part (Stages 1a and 1b only), CD38 RD from baseline bone marrow aspirates will 
be correlated with parameters of clinical response, including overall response rate, clinical benefit 
rate, duration of response, PFS and/or OS. 
For the Phase 2, Stages 1a and 1b parts only, CD38 RO will be assessed from bone marrow 
aspirates at the time points detailed in Section 1.8. 
9.6 
PHASE 2 EXPLORATORY BIOMARKER STUDIES  
Exploratory biomarker handling procedures detailed in the laboratory manual and summarized in 
Appendix K. 
Bone marrow and blood samples will be collected and analyzed for the following purposes: 
x Myeloma cell CD38 mRNA levels from baseline bone marrow aspirates will be correlated 
with parameters of clinical response. 
x Correlation of minimal residual disease (MRD) in bone marrow samples from patients 
achieving a CR with parameters of clinical response will be assessed by flow cytometry 
and/or sequencing. Traditional methods to measure MRD include multiparametric flow 
cytometry. More recently next generation sequencing to amplify and sequence 
immunoglobulin gene segments present in myeloma clone has also been used as a 
quantitative method for MRD detection. Bone marrow samples will be collected at CR 
confirmation. 


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x Chromosomal abnormalities such as del17p, t (4; 14), t (14; 16), 1q gain and 1p deletion; 
have been associated with poor prognosis and high risk in multiple myeloma (50, 51, 52). 
Baseline bone marrow samples will be collected for FISH analyses. In addition, results of 
local FISH/cytogenetic tests performed the most recently prior to patient enrollment may 
also be collected through report or access to data. 
x For genomics studies, DNA and/or RNA will be isolated from multiple myeloma cells and 
sequenced to identify somatic mutations present only in the myeloma cells (not in the 
patient's germline, or heritable genome). Sequencing studies may include whole exome or 
whole genome sequencing (for DNA), or whole transcriptome sequencing to quantify gene 
expression or identify expressed gene fusions, mutations or other tumor-specific 
transcripts. A source of normal DNA (non-tumor DNA), from blood leukocytes may also 
be sequenced. For the purposes of myeloma genomics, the normal (non-tumor) DNA 
sequence will be used only as a reference genome for the identification of myeloma-
specific somatic mutations in a given patient. The normal (non-tumor) DNA sequence will 
not be used to determine risk or prognosis of multiple myeloma or other malignancies, or 
used in any other disease-specific research unless explicitly granted by separate 
pharmacogenetic consent.  
x Sequencing will also be performed at EOT with tumor DNA in patients who have 
responded to the study treatment but subsequently develop progressive disease to identify 
acquired mutations that may elucidate potential resistance mechanism.Genomics analyses 
will be performed only in Phase 2 Stage 1 only.  
x Correlation of immune genetic determinants (FcȖ5 genes, HLA and KIR genotypes) 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. Blood 
samples collected on D1 of Cycle 1 will be used for this analysis. 
x Correlation of adaptive immune response (TCR repertoire profiling) with parameters of 
clinical response. Blood samples collected on D1 of Cycle 1, D1 of Cycle 3 and on D1 of 
Cycle 5 will be used for this analysis. In addition, humoral (antibody) and cellular (T cell) 
response to a panel of multiple myeloma-related tumor antigenes following isatuximab 
administration will be assessed and correlated with clinical response. Blood samples will 
be collected on Day 1 of Cycles 1, 2, 4, 7, 10 and in disease progression patients at EOT. 
Cellular response analysis will be performed in patients who have positive humoral 
response. These analyses will be performed in Phase 2 Stage 2 only. 
x Correlation of immune phenotype in bone marrow and/or peripheral blood with 
parameters of clinical response. Immune cell populations including B-cell, T-cell and 
NK-cell subsets will be characterized by multiparametric flow cytometry based on the 
expression of cell surface markers. The proportion of cells positive for a given marker or 
set of markers (eg, regulatory T cells [Tregs]) will be correlated with response to 
SAR650984. Bone marrow aspirate collected at baseline and blood samples collected at 
D1 of Cycle 1, D1 of Cycle 3 and EOT will be used for this analysis. 
x Soluble CD38 level will be correlated with parameters of PK and clinical response. In 
Phase 2 Stage 1, blood samples collected at D1 Cycle 1, D1 of Cycle 3, and EOT in 
disease progression patients will be used for soluble CD38 analysis.  


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x Additional molecular analysis, not specified in the protocol but related to the drug action 
and/or effect of SAR650984, may be conducted on remaining samples pending evolving 
literature.  


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10 
PATIENT SAFETY  
10.1 
SAFETY ENDPOINTS ASSESSED IN THIS TRIAL  
The NCI CTCAE v.4.03 will be used in this study to grade clinical and laboratory AEs.  
The safety profile will be based on incidence, severity, and cumulative nature of TEAEs. TEAEs 
are defined as AEs that develop or worsen in grade or become serious during the on-treatment 
period. 
Adverse events encountered before the start of SAR650984 treatment will be summarized 
separately. Adverse events will be coded to a “Lower Level Term (LLT)”, “Preferred Term (PT)”, 
“High Level Term (HLT)”, “High Group Level Term (HGLT)” and associated primary “System 
Organ Class (SOC)” using MedDRA (Medical Dictionary for Regulatory Activities). AEs will be 
summarized with respect to the type, frequency, severity, seriousness, and relatedness. Laboratory 
abnormalities will be assessed according to the NCI CTCAE v.4.03. 
Please also refer to Section 9.1. 
10.2 
SAFETY INSTRUCTIONS  
The safety of the patients in this clinical trial is primarily dependent on the clinical Investigators’ 
monitoring and assessment of their patients. For hypersensitivity reactions, please refer to 
Section 6.5. 
10.3 
ADVERSE EVENTS MONITORING  
All AEs will be managed and reported in compliance with all applicable regulations, and included 
in the final clinical study report. 
10.4 
DEFINITIONS OF ADVERSE EVENT (AE) AND SERIOUS ADVERSE EVENT (SAE)  
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
A SAE is any untoward medical occurrence that at any dose: 
x Results in death or; 
x 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. 


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x Requires inpatient hospitalization or prolongation of existing hospitalization or; 
x Results in persistent or significant disability/incapacity or; 
x Is a congenital anomaly/birth defect; 
x 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 
intervention to prevent one of the other outcomes listed in the definition above. 
Note: Examples of such events are intensive treatment in an emergency room or at home for 
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that does not result in hospitalization, or development of drug dependency or drug abuse. 
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING  
10.5.1 Adverse events  
All AEs regardless of seriousness or causal relationship to the Investigational Product, spanning 
from the signature of the informed consent form (ie, occurring during the wash out period even in 
the absence of any administration of IP), up to the last visit planned in the protocol (ie, up to  
30 days after the last IP administration), are to be recorded on the corresponding page(s) included 
in the Case Report Form. 
All IP-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 during the follow-up 
period until resolution or stabilization. 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms (with 
the exception of IARs for which a main diagnosis IAR and individual symptoms should be 
reported).The Investigator should specify the date of onset, intensity, action taken with respect to 
Investigational Product, 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 Investigational Product. 
Laboratory, vital signs or ECG abnormalities are to be recorded as Adverse Events only if they 
lead to treatment discontinuation and/or modification of treatment administration (delay, 
reduction, omission) or fulfill a seriousness criterion and/or are defined as an Adverse Event of 
Special Interest (AESI) (see Section 10.6). 


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10.5.2 Serious adverse events  
In the case of a Serious Adverse Event, an AESI, a pregnancy report or an overdose, the 
Investigator must immediately: 
x ENTER (within 24 hours) the information related to the Serious Adverse Event in the 
appropriate screens of the e-CRF; the system will automatically send the notification to the 
Monitoring Team after approval of the Investigator within the e-CRF or after a standard 
delay. 
x 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. 
x When cohorts of more than one patient begin accruing, the monitoring team will notify the 
study investigators of the occurrence of DLTs and SAEs within 24 hours. 
x All further data updates should be recorded in the e-CRF as appropriate within 1 working 
day of knowledge. In addition, every effort should be made to further document each 
Serious Adverse Event that is fatal or life threatening within the week (7 days) following 
initial notification. 
x A back-up plan is used (using paper flow) when the e-CRF system does not work. 
10.5.3 Follow-up  
x The Investigator should take all appropriate measures to ensure the safety of the patients, 
notably he/she should follow up the outcome of any AEs (clinical signs, laboratory values 
or other, etc) until the return to normal or consolidation of the patient's condition; 
x In case of any Serious Adverse Event, the patient must be followed up until clinical 
recovery is complete and laboratory results have returned to normal, or until outcome has 
been stabilized. This may imply that follow-up may continue after the patient has left the 
Clinical Trial and that additional investigations may be requested by the Monitoring Team; 
x In case of any Serious or Non Serious Adverse Event brought to the attention of the 
Investigator at any time after cessation of Investigational Product and considered by 
him/her to be caused by the Investigational Product with a reasonable possibility, this 
should be reported to the Monitoring Team. 
x Follow-up information for any events entered in the pharmacovigilance database will be 
entered in the pharmacovigilance database at any time irrespective of the clinical database 
lock. GPE may also request follow-up on Individual Case Safety Reports received for 
entry in the pharmacovigilance database. 
10.5.4 Treatment discontinuation due to non-serious adverse event  
In the case of a treatment discontinuation due to a non-Serious Adverse Event: 


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x ENTER (within 24 hours) the information related to treatment discontinuation due to a 
non-Serious Adverse Event in the appropriate screens of the e-CRF (AE with the box 
"action taken with IP" ticked “permanently discontinued,” together with the end of 
treatment form with reason that should be ticked “Adverse Event”); the system will 
automatically send the notification to the Monitoring Team after approval of the 
Investigator within the e-CRF or after a standard delay. 
10.6 
ADVERSE EVENT OF SPECIAL INTEREST (AESI)  
An AESI is an AE (serious or non-serious) of scientific and medical concern specific to 
SAR650984, for which ongoing monitoring and rapid communication by the Investigator to 
sanofi-aventis is required (see Section 10.5). Such adverse events may require further 
investigation in order to characterize and understand them. Adverse events of special interest may 
be added or removed during a study by protocol amendment.  
The following adverse events are considered AESIs: 
x Acute infusion associated reactions  Grade 3 (IARs; “please refer to the current edition of 
the IB for IARs manifestations reported in patients treaded with isatuximab”). An IAR is 
an adverse event related to SAR650984 with onset within 24 hours from the start of the 
infusion. A main diagnosis and individual symptoms should be reported in the eCRF as 
AESIs in order to well characterize IARs. 
x During Phase 1, all protocol-defined potential or IP related DLTs (as defined in  
Section 9.1.1) are considered AESIs, and as such, the Investigators will be required to 
report them to the Sponsor within 24 hours of the Investigator becoming aware of the 
adverse event. The Investigator will attach the DLT-specific CRF page to the DLT/AESI 
form. 
When cohorts of more than one patient begin accruing, the monitoring team will notify the study 
investigators of the occurrence of DLTs and SAEs within 24 hours. 
x 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). In the event of pregnancy in a female 
participant, treatment with the IP should be discontinued.  
Follow-up of the pregnancy in a female patient or in a female partner of a male participant is 
mandatory until the outcome has been determined (see Section 10.7). 
- 
Symptomatic overdose (serious or non-serious) of IP/Non-Investigational medinical 
product (NIMP) An overdose (accidental or intentional) with the IMP/NIMP is an 
event suspected by the Investigator or spontaneously notified by the patient (not based 
on systematic pills count) and defined as at least 30% above the intended administered 
dose. 
- 
Of note, asymptomatic overdose has to be reported as a standard AE. 


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10.7 
PREGNANCY  
x Pregnancy of a female subject entered in a study (as well as pregnancy occurring in a 
female partner of a male subject 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. 
x In the event of pregnancy in a female subject, Investigational Product should be 
discontinued and sanofi-aventis Monitoring Team should be informed immediately (within 
24 hours), even if the event does not fulfill a seriousness criterion, using the AE form 
together with the SAE complementary form to be sent to the representative of the 
Monitoring Team whose name, address and fax number appear on page 2 of the clinical 
trial protocol. 
x Follow-up of the pregnancy is mandatory until the outcome has been determined. 
10.8 
OVERDOSE  
In case of accidental or intentional overdose (at least 30% above the intended administered dose at 
each cycle expressed in unit per body weight) with the IP, 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 e-CRF. 
10.9 
OBLIGATIONS OF SANOFI-AVENTIS  
During the course of the study, sanofi-aventis will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the IP according to applicable regulations and 
as appropriate, to the Authorities, Independent Ethic Committes (IECs) /Institional Review 
Boards (IRBs) as appropriate and to the Investigators. 
All AEs not listed as expected events in the Investigator’s Brochure will be considered as 
unexpected. 
Sanofi-aventis will report all safety observations made during the conduct of the trial in the CSR. 


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11 
HANDLING OF PATIENT TEMPORARY AND DEFINITIVE 
TREATMENT DISCONTINUATION AND OF PATIENT STUDY 
DISCONTINUATION  
The Investigational Product should be continued whenever possible in accordance with the 
Investigator’s judgment and patient consent. In case the IP is stopped, it should be determined if 
the stop can be made temporarily; permanent IP discontinuation should be a last resort. Any IP 
discontinuation should be fully documented in the CRF. In any case, the patient should remain in 
the study as long as possible. 
Pregnancy will lead to definitive treatment discontinuation in all cases. 
11.1 
TEMPORARY TREATMENT DISCONTINUATION WITH INVESTIGATIONAL PRODUCT  
From oncology perspectives, temporary treatment discontinuation may correspond to “retreatment 
of patients” and “dose-delays/modifications:” Section 6.3 and Section 6.4. 
11.2 
DEFINITIVE TREATMENT DISCONTINUATION WITH INVESTIGATIONAL 
PRODUCT(S)  
The patients may withdraw from treatment with Investigational Product 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 for discontinuation and this should be documented in the 
CRF. 
11.2.1 List of criteria for definitive treatment discontinuation  
Investigational Product should be discontinued in any of the following cases: 
x Unacceptable AE. 
x Disease progression. 
x Poor compliance to the study protocol. 
x Study termination. 
x Patients lost to follow up will also be considered permanently discontinued, as of the time 
of their last IP administration. 
11.2.2 Handling of patients after definitive treatment discontinuation  
Patients will be followed up according to the study procedures as specified in this protocol up to 
the study cut-off date, or up to recovery or stabilization of a study drug related AE or SAE 
(regardless of casual relationship to study drug) which has been followed-up, whichever comes 
last. 


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If possible, and after the permanent discontinuation of treatment, the patients will be assessed 
using the procedure normally planned for the last dosing day with the Investigational Product 
including a PK sample, if appropriate. 
All definitive treatment discontinuation should be recorded by the Investigator in the appropriate 
pages when considered as confirmed. 
Patients who have been withdrawn from the study cannot be re-included in the study. 
11.3 
PROCEDURE FOR WITHDRAWAL OF PATIENTS FROM STUDY FOLLOW-UP 
SCHEDULE  
The patients may withdraw from the study follow-up schedule, before study completion if they 
decide to do so, at any time and irrespective of the reason: 
x All study withdrawals should be recorded by the Investigator in the appropriate CRF pages 
or screens of the e-CRF and in the patient’s medical records when considered as confirmed 
(at least date of and reason for withdraw). 
x If possible, the patients are assessed using the procedure normally planned for the end-of-
study visit including a PK sample, if appropriate (or according to other procedures to be 
specified here such as follow-up phase). 
The Investigator should make every effort to recontact the patient, to identify the reason why 
he/she failed to attend the visit, 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). 
11.4 
CONSEQUENCE  
Patients treated with isatuximab who have been withdrawn from the study treatment cannot be 
reincluded in the study. Their inclusion and treatment number must not be re-used.  
In the Phase 1 part patients who withdraw from the study treatment may be replaced if considered 
to be appropriate by the Study Committee. 
In the Phase 2 part, only screened patients who did not meet the study inclusion/exclusion criteria 
and were not treated will be replaced. 


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12 
STUDY PROCEDURES  
12.1 
PHASE 1 VISIT SCHEDULE  
During the course of the study, all patients entering the study must be evaluated according to the 
schedules outlined in the Study Flowcharts and described below. The results of the evaluation will 
be recorded in the e-CRF pages until the patients are not followed anymore. After the 
screening/baseline visit, all the patients eligible and included in the study will have a visit on site 
as detailed below. A complete visit will be performed at End of Treatment (30 days (+/-5 days) 
after last IP administration). The patients will be followed beyond 30 days until recovery or 
consolidation of any IP related AE. Additionally, PK and ADA samples are required (60 days) 
(+/-5 days) after last IP administration). In the Phase 1 part, a cycle is 14 days. 
12.1.1 Pretreatment evaluation (screening/baseline)  
The pretreatment examinations are to be performed within 15 days (unless specified otherwise) 
prior to the first IP administration. The informed consent must be signed by the patient before any 
procedure specific to the study is performed. 
x History and Clinical Examination:  
- 
Medical/Surgical History: includes relevant history of previous/associated pathologies, 
other than the tumor.  
- 
Disease History: includes date of initial diagnosis, stage and extent of the disease, 
previous anti-tumor therapy (type and response to), disease status at inclusion (primary 
refractory, refractory to last therapy, or recurrent), results of additional procedures 
(such as karyotype, FISH, etc). 
- 
Prior anti-cancer therapies and Concomitant Medications. 
- 
Physical Examination: consists of examination of major body systems, including 
neurological, digestive exam, extramedullary myeloma localizations, respiratory, 
hepatomegaly, splenomegaly, lymphadenopathy. 
- 
Weight and Height. 
- 
Vital Signs: includes blood pressure, heart rate, temperature, and respiration rate. 
- 
Performance Status (Karnofsky). 
x Laboratory Assessments: 
- 
CD38 Expression (for Cohorts 1-10): Archival samples may be used. If no archival 
sample, will be assessed at screening by flow cytometry and/or immunohistochemistry 
using malignant cells from peripheral blood, bone marrow and/or lymph node tissue 
depending on the disease type. When feasible, bone marrow and tissue samples will be 
obtained by Fine Needle Aspiration (FNA).  
- 
6HUXPȕ-microglobulin (CLL, MM only). 
- 
Immunoglobulins: IgG, IgA, IgM (MM only).  


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- 
Pregnancy Test: women of child bearing potential must have a negative serum 
pregnancy test result within 7 days prior to first IP administration. 
- 
Blood Chemistry: SGOT (AST), SGPT (ALT), bilirubin (total and direct), alkaline 
phosphatase (AP), lactate dehydrogenase (LDH), sodium, potassium, chloride, 
bicarbonate/carbon dioxide, calcium, magnesium, phosphate, uric acid, blood urea 
nitrogen (BUN), serum creatinine and estimated creatinine clearance, glucose, 
albumin, total protein, peptide C, Erythrocyte sedimentation rate (ESR). 
- 
Hematology: hemoglobin, hematocrit, RBC, WBC with differential, MCV, platelet 
count, blast counts (B-cell ALL/AML). 
- 
Coagulation: PT/INR, PTT. 
- 
Urinalysis: blood, protein, glucose, pH, ketones, bilirubin, leucocytes, nitrates, specific 
gravity. 
x Disease Assessment: (Up to 28 days prior to first IP administration): 
- 
MM: Bone marrow biopsy/aspiration as clinically indicated, radiologic imaging of 
plasmocytoma as clinically indicated, bone skeletal survey as clinically indicated,  
M-protein quantification (serum and/or 24-hr urine), serum free light chain levels, or 
urinary light chain levels as clinically indicated. 
- 
B-cell NHL: Bone marrow biopsy/aspiration as clinically indicated, lymph node 
biopsy as clinically indicated, radiologic tumor assessment (by X-ray, computed 
tomography [CT] scan, PET scan or magnetic resonance imaging [MRI]; ultrasound is 
not sufficient). 
- 
B-cell ALL: Bone marrow biopsy/aspiration as clinically indicated, blood count with 
differential including blast count. 
- 
AML: Bone marrow biopsy/aspiration as clinically indicated, blood count with 
differential including blast count. 
- 
CLL: Clinical examination, bone marrow biopsy/aspiration as clinically indicated, 
lymph node biopsy as clinically indicated, blood count with differential. 
Patients who meet all the inclusion criteria, and none of the exclusion criteria, will be eligible for 
inclusion in the study. Each patient will receive an incremental identification number 
corresponding to his/her order of enrollment in the study. 
12.1.2 Assessments for patients with an every 2 week administration (Cohorts 1-10)  
12.1.2.1 Before the first investigational product administration and prior to IP 
administration at each cycle (within 1 day before)  
The same parameters as performed at screening/baseline will be performed for each of the 
required evaluations. The evaluations below are to be performed prior to first IP administration. 
x Clinical Examination: includes physical examination, weight, vital signs, and performance 
status. 


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x Chest X-ray, Spirometry, Diffusion Capacity (can be performed within one week prior to 
IP administration for the first 2 cycles and then as clinically indicated) 
x Laboratory Assessments: 
- 
Pregnancy Test: a negative urine pregnancy test result required prior to IP 
administration at each cycle. 
- 
Blood Chemistry including blood glucose measurement. 
- 
Hematology. 
- 
PSA, Pituitary Hormone Levels (GH, FSH/LH, ACTH, TSH). 
- 
Coagulation. 
- 
Urinalysis. 
- 
hs-CRP. 
- 
Cytokines (TNF-Į,/-1-ȕ,/-6, IFN-Ȗ%DVHOLQHVDPSOHWREHGUDZQSULRUWRILUVW,3
administration at Cycle 1). 
- 
PK/RO/ADA: (see Pharmacokinetics/Pharmacodynamics Accelerated/Basic 
Flowcharts) (RO at Cycles 1 and 2 only). 
x 12-Lead ECG: Baseline to be performed just before starting infusion and as clinically 
indicated throughout the study. Will be reviewed by central cardiologist. 
x Holter Monitoring: To be placed on the patient 1-2 hours before starting the infusion and 
remain on the patient until 24 hours after the infusion (Cycles 1 and 2); to detect 
atrio-ventricular conduction abnormalities, other potential ventricular arrhythmias, QTc. 
Will be reviewed by central cardiologist.  
12.1.2.2 During the treatment period (Cycles 1 and 2)  
(Day 1) 
x SAR650984 Administration 
x Vital Signs: middle of infusion (basic phase), end of infusion, and 1, 2, 4, and 6 hours 
post-infusion.  
x ECG: to be performed just before starting infusion, middle of infusion (Basic Phase), and 
end of infusion. 
x Laboratory Assessments: 
- 
hs-CRP: 6 hours post-infusion 
- 
Cytokines: 6 hours post-infusion 
- 
PK/RO: (see Pharmacokinetics/Pharmacodynamics Accelerated/Basic Flowcharts) 
- 
Blood Chemistry: end of infusion, 6 hours post-infusion 


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(Day 2)  
x Vital Signs: 24 hours post-infusion  
x Laboratory Assessments: 
- 
hs-CRP: 24 hours post-infusion. 
- 
Cytokines: 24 hours post-infusion. 
- 
PK/RO: (see Pharmacokinetics/Pharmacodynamics Accelerated Flowchart). 
- 
Blood Chemistry: 24 hours post-infusion. 
x Holter Monitoring: Will be removed 24 hours after the infusion 
(Day 3)  
x Laboratory Assessments: 
- 
PK/RO/ADA: (see Pharmacokinetics/Pharmacodynamics Accelerated/Basic 
Flowcharts) (Cycle 1); PK/RO: (see Pharmacokinetics/Pharmacodynamics Accelerated 
Flowchart) (Cycle 2). 
(Day 8)  
x Clinical Examination: includes physical examination, vital signs, and performance status  
x Laboratory Assessments: 
- 
Blood Chemistry 
- 
Hematology  
- 
Coagulation 
- 
Urinalysis 
- 
PK: (see Pharmacokinetics/Pharmacodynamics Accelerated/Basic Flowcharts) 
x 12-Lead ECG 
(Day 14)  
x Clinical Examination: includes physical examination, weight, vital signs, and performance 
status. 
x Laboratory Assessments: 
- 
Serum ȕ-microglobulin (CLL, MM only). 
- 
Immunoglobulins: IgG, IgA, IgM (MM only).  
- 
Pregnancy Test: urine (Cycle 2). 
- 
Blood Chemistry. 
- 
Hematology. 
- 
PSA, Pituitary Hormone Levels (GH, FSH/LH, ACTH, TSH): (Cycle 2). 


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- 
Coagulation. 
- 
Urinalysis. 
- 
hs-CRP (Cycle 2). 
- 
PK/RO/ADA: (see Pharmacokinetics/Pharmacodynamics Accelerated/Basic 
Flowcharts) (Cycle 2). 
x 12-Lead ECG: (Cycle 2). 
x Disease Assessment: Response is assessed on the basis of clinical, laboratory, radiologic, 
and pathologic (ie, bone marrow) findings at the end of Cycle 2, to determine if patient is 
eligible to continue treatment.  
12.1.2.3 During the treatment period (subsequent cycles)  
Patients continuing after Cycle 2 will have evaluations performed as per Section 12.1.2.2 (prior to 
IP administration), Day 1, Day 2, and Day 8 (for weekly administration only) above. 
The below assessments will be done every 4 weeks (end of even-numbered cycles) 
x Laboratory Assessments: 
- 
6HUXPȕ-microglobulin (CLL, MM only). 
- 
Immunoglobulins: IgG, IgA, IgM (MM only).  
x Disease Assessment: Patients continuing after Cycle 2 should be evaluated for disease 
status at least every 4 weeks (even-numbered cycles), whenever disease progression is 
suspected (eg, symptomatic deterioration), to confirm a partial or complete response  
(4-6 weeks after initial documentation of response), and at the End of Treatment visit. 
12.1.3 Assessments for patients with an every week administration (from Cohort 11)  
12.1.3.1 Before the first investigational product administration and prior to IP 
administration at each cycle (within 1 day before)   
The same parameters as performed at screening/baseline will be performed for each of the 
required evaluations. The evaluations below are to be performed prior to first IP administration on 
Day 1 and Day 8. 
x Clinical Examination: includes physical examination, weight (Day 1 only), vital signs, and 
performance status. 
x Chest X-ray, Spirometry, Diffusion Capacity (Day 1 only, can be performed within one 
week prior to IP administration for the first 2 cycles and then as clinically indicated) 
x Laboratory Assessments: 
- 
Pregnancy Test: a negative urine pregnancy test result required prior to IP 
administration on Day 1 at each cycle. 


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- 
Blood Chemistry including blood glucose measurement. 
- 
Hematology. 
- 
PSA, Pituitary Hormone Levels (GH, FSH/LH, ACTH, TSH) (Day 1 only). 
- 
Coagulation. 
- 
Urinalysis. 
- 
hs-CR. 
- 
Cytokines (TNF-Į,/-1-ȕ, IL-6, IFN-Ȗ%DVHOLQHVDPSOHWREHGUDZQSULRUWRILUVW,3
administration at Cycle 1). 
PK/RO/ADA: (see Pharmacokinetics/Pharmacodynamics Flowcharts Section 1.6, Cycle 1 and 
2 only) 
x 12-Lead ECG: Baseline to be performed just before starting infusion and as clinically 
indicated throughout the study. Will be reviewed by central cardiologist. 
x Holter Monitoring: To be placed on the patient 1-2 hours before starting the infusion and 
remain on the patient until 24 hours after the infusion (Cycles 1 and 2); to detect 
atrio-ventricular conduction abnormalities, other potential ventricular arrhythmias, QTc. 
Will be reviewed by central cardiologist. 
12.1.3.2 During the treatment period (Cycles 1, 2 and 3)  
(Day 1 and Day 8) 
x SAR650984 Administration 
x Vital Signs: middle of infusion, end of infusion, and 1, 2, 4, and 6 hours post-infusion.  
x ECG: to be performed just before starting infusion, middle of infusion, and end of 
infusion. 
x Laboratory Assessments: 
- 
hs-CRP: 6 hours post-infusion 
- 
Cytokines: 6 hours post-infusion 
PK: (see Pharmacokinetics/Pharmacodynamics Flowcharts Section 1.6, Cycle 1 and 3 only) 
- 
Blood Chemistry: end of infusion, 6 hours post-infusion 
(Day 2)  
x Vital Signs: 24 hours post-infusion (Cycle 1 and 2 only) 
x Laboratory Assessments: 
- 
hs-CRP: 24 hours post-infusion (Cycle 1 and 2 only) 
- 
Cytokines: 24 hours post-infusion (Cycle 1 and 2 only) 


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PK: (see Pharmacokinetics/Pharmacodynamics Flowchart Section 1.6, Cycle 1 and 3 only) 
- 
Blood Chemistry: 24 hours post-infusion (Cycle 1 and 2 only) 
x Holter Monitoring: Will be removed 24 hours after the infusion (Cycle 1 and 2 only) 
(Day 3, Cycle 1 and 3 only) 
x Laboratory Assessments: 
PK/ADA: (see Pharmacokinetics/Pharmacodynamics Flowcharts Section 1.6) 
(Day 4, Cycle 1 and 3 only) 
x Laboratory Assessments: 
- 
PK: (see Pharmacokinetics/Pharmacodynamics Flowcharts Section 1.6) 
(Day 14, Cycle 1 and 2 only)  
x Clinical Examination: includes physical examination, weight, vital signs, and performance 
status. 
x Laboratory Assessments: 
- 
6HUXPȕ-microglobulin. 
- 
Immunoglobulins: IgG, IgA, IgM. 
- 
Pregnancy Test: urine (Cycle 2). 
- 
Blood Chemistry. 
- 
Hematology. 
- 
PSA, Pituitary Hormone Levels (GH, FSH/LH, ACTH, TSH): (Cycle 2). 
- 
Coagulation.  
- 
Urinalysis. 
- 
RO: (see Pharmacokinetics/Pharmacodynamics Flowcharts Section 1.6) (Cycle 2). 
x 12-Lead ECG: (Cycle 2). 
x Disease Assessment: Response is assessed on the basis of clinical, laboratory, radiologic, 
and pathologic (ie, bone marrow) findings at the end of Cycle 2, to determine if patient is 
eligible to continue treatment.  
12.1.3.3 During the treatment period (subsequent cycles)  
Patients continuing after Cycle 2 will have evaluations performed as per Section 12.1.3.2 (prior to 
IP administration) Day 1 and Day 8 above. 
The below assessments will be done every 4 weeks (end of even-numbered cycles) 
x Laboratory Assessments: 
- 
6HUXPȕ-microglobulin. 


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- 
Immunoglobulins: IgG, IgA, IgM. 
Disease Assessment: Patients continuing after Cycle 2 should be evaluated for disease status at 
least every 4 weeks (even-numbered cycles), whenever disease progression is suspected  
(eg, symptomatic deterioration), to confirm a partial or complete response (4-6 weeks after initial 
documentation of response), and at the End of Treatment visit. 
12.1.4 Assessments for patients with an every 2 week administration (from Cohort 12)  
12.1.4.1 
Before the first investigational product administration and prior to IP 
administration at each cycle (within 1 day before)  
The same parameters as performed at screening/baseline will be performed for each of the 
required evaluations. The evaluations below are to be performed prior to first IP administration. 
x Clinical Examination: includes physical examination, weight, vital signs, and performance 
status. 
x Chest X-ray, Spirometry, Diffusion Capacity (can be performed within one week prior to 
IP administration for the first 2 cycles and then as clinically indicated) 
x Laboratory Assessments: 
- 
Pregnancy Test: a negative urine pregnancy test result required prior to IP 
administration at each cycle. 
- 
Blood Chemistry including blood glucose measurement. 
- 
Hematology. 
- 
PSA, Pituitary Hormone Levels (GH, FSH/LH, ACTH, TSH). 
- 
Coagulation.  
- 
Urinalysis.  
- 
hs-CRP. 
- 
Cytokines (TNF-Į,/-1-ȕ,/-6, IFN-Ȗ%DVHOLQHVDPSOHWREHGUDZQSULRUWRILUVW,3
administration at Cycle 1). 
- 
PK/RO/ADA: (see Pharmacokinetics/Pharmacodynamics Flowcharts Section 1.7, 
Cycle 1 and 2 only). 
x 12-Lead ECG: Baseline to be performed just before starting infusion and as clinically 
indicated throughout the study. Will be reviewed by central cardiologist. 
x Holter Monitoring: To be placed on the patient 1-2 hours before starting the infusion and 
remain on the patient until 24 hours after the infusion (Cycles 1 and 2); to detect 
atrio-ventricular conduction abnormalities, other potential ventricular arrhythmias, QTc. 
Will be reviewed by central cardiologist.  


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12.1.4.2 
During the treatment period (Cycles 1 and 2)  
(Day 1) 
x SAR650984 Administration 
x Vital Signs: middle of infusion, end of infusion, and 1, 2, 4, and 6 hours post-infusion.  
x ECG: to be performed just before starting infusion, middle of infusion, and end of 
infusion. 
x Laboratory Assessments: 
- 
hs-CRP: 6 hours post-infusion. 
- 
Cytokines: 6 hours post-infusion. 
PK: (see Pharmacokinetics/Pharmacodynamics Flowcharts Section 1.7) 
- 
Blood Chemistry: end of infusion, 6 hours post-infusion. 
(Day 2)  
x Vital Signs: 24 hours post-infusion.  
x Laboratory Assessments: 
- 
hs-CRP: 24 hours post-infusion. 
- 
Cytokines: 24 hours post-infusion. 
PK: (see Pharmacokinetics/Pharmacodynamics Flowcharts Section 1.7) 
- 
Blood Chemistry: 24 hours post-infusion. 
x Holter Monitoring: Will be removed 24 hours after the infusion 
(Day 3, Cycle 1 only)  
x Laboratory Assessments: 
PK/ADA: (see Pharmacokinetics/Pharmacodynamics Flowcharts Section 1.7) 
(Day 4, Cycle 1 only) 
x Laboratory Assessments: 
PK: (see Pharmacokinetics/Pharmacodynamics Flowcharts Section 1.7) 
(Day 8)  
x Clinical Examination: includes physical examination, vital signs, and performance status  
x Laboratory Assessments: 
- 
Blood Chemistry. 
- 
Hematology. 
- 
Coagulation. 


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- 
Urinalysis. 
PK: (see Pharmacokinetics/Pharmacodynamics Flowcharts Section 1.7, Cycle 1 only) 
x 12-Lead ECG. 
(Day 14)  
x Clinical Examination: includes physical examination, weight, vital signs, and performance 
status. 
x Laboratory Assessments: 
- 
6HUXPȕ-microglobulin. 
- 
Immunoglobulins: IgG, IgA, IgM. 
- 
Pregnancy Test: urine (Cycle 2). 
- 
Blood Chemistry. 
- 
Hematology. 
- 
PSA, Pituitary Hormone Levels (GH, FSH/LH, ACTH, TSH): (Cycle 2). 
- 
Coagulation. 
- 
Urinalysis. 
- 
RO: (see Pharmacokinetics/Pharmacodynamics Flowcharts Section 1.7) (Cycle 2). 
x 12-Lead ECG: (Cycle 2). 
x Disease Assessment: Response is assessed on the basis of clinical, laboratory, radiologic, 
and pathologic (ie, bone marrow) findings at the end of Cycle 2, to determine if patient is 
eligible to continue treatment.  
12.1.4.3 During the treatment period (subsequent cycles)  
Patients continuing after Cycle 2 will have evaluations performed as per Section 12.1.4.1 (prior to 
IP administration) and Day 1 above. 
The below assessments will be done every 4 weeks (end of even-numbered cycles) 
x Laboratory Assessments: 
- 
6HUXPȕ-microglobulin.  
- 
Immunoglobulins: IgG, IgA, IgM.  
x Disease Assessment: Patients continuing after Cycle 2 should be evaluated for disease 
status at least every 4 weeks (even-numbered cycles), whenever disease progression is 
suspected (eg, symptomatic deterioration), to confirm a partial or complete response 
(4-6 weeks after initial documentation of response), and at the End of Treatment visit. 


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12.1.5 During the treatment period (all cycles, all cohorts)  
x AE/SAE Assessment. 
x Concomitant Medication. 
12.1.6 End of treatment visit (to be performed at least 30 days (+/-5 days) after the last 
investigational product administration)  
x Clinical examination: includes physical examination, weight, vital signs, and performance 
status. 
x Chest X-ray, Spirometry, Diffusion Capacity 
x Laboratory Assessments: 
- 
6HUXPȕ-microglobulin (CLL, MM only). 
- 
Immunoglobulins: IgG, IgA, IgM (MM only).  
- 
Pregnancy Test: serum. 
- 
Blood Chemistry. 
- 
Hematology. 
- 
PSA, Pituitary Hormone Levels (GH, FSH/LH, ACTH, TSH). 
- 
Coagulation. 
- 
Urinalysis. 
- 
hs-CRP.  
- 
PK/RO/ADA: (see Pharmacokinetics/Pharmacodynamics Accelerated/Basic 
Flowcharts). 
x 12-lead ECG. 
x Disease Assessment. 
x AE/SAE Assessment. 
x Concomitant Medication. 
12.1.7 Follow-up period (>30 days after last IP administration)  
x Laboratory Assessment: 
- 
PK/ADA: (60 days (+/-5 days) after last IP administration and then if sample is 
positive or inconclusive, every 30 days (+/-5 days) until sample is negative). 
x AE/SAE Assessment: (if IP-related AE and/or unresolved toxicity). 
x Concomitant Medication: (if IP-related AE and/or unresolved toxicity). 


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12.2 
PHASE 2 VISIT SCHEDULE  
During the course of the study, all patients entering the study must be evaluated according to the 
schedules outlined in the Study Flowchart (Section 1.13,Section 1.14 and Section 1.15 ) and 
described below. The results of the evaluation will be recorded in the eCRF pages until the 
patients are not followed anymore. In the Phase 2 part, a cycle is 28 days. 
12.2.1 Pretreatment evaluation (screening/baseline)  
The pretreatment examinations are to be performed within 21 days (unless specified otherwise) 
prior to the first IP administration. The informed consent must be signed by the patient before any 
procedure specific to the study is performed. 
x History and Physical Examination: 
- 
Demography: Includes age, gender and race. 
- 
Medical/Surgical History: includes relevant history of previous/associated pathologies, 
other than multiple myeloma. Respiratory function history will be checked. 
- 
Disease History: includes date of initial diagnosis, stage and disease sybtype, previous 
anti-tumor therapy (drug names, reason for discontinuation, duration and response to), 
results of additional procedures (such as karyotype, FISH, etc). 
- 
Prior medications 
- 
Physical Examination: consists of examination of major body systems, including 
neurological, digestive exam, plasmacytoma assessment, respiratory, hepatomegaly, 
splenomegaly, lymphadenopathy 
- 
Weight and Height 
- 
Vital Signs: includes blood pressure, heart rate, temperature, and respiration rate 
- 
Performance Status (Karnofsky) in Phase 1 and Phase 2 Stage 1 and ECOG 
Performance status in Phase 2 Stage 2) 
x AE/SAE assessment 
x 12-Lead ECG 
x Chest X-ray 
x Laboratory Assessments: 
- 
Pregnancy Test: women of child bearing potential must have a negative serum 
pregnancy test result within 7 days prior to first IP administration. 
- 
Blood Chemistry: SGOT (AST), SGPT (ALT), bilirubin (total and direct), alkaline 
phosphatase (AP), lactate dehydrogenase (LDH), sodium, potassium, chloride, 
bicarbonate/carbon dioxide, ionized calcium and corrected serum calcium, magnesium, 
phosphate, uric acid, blood urea nitrogen (BUN), serum creatinine and estimated 
creatinine clearance (using Cockcroft and Gault formula [(140 - age) x mass (kg) /  
(72 x creatinine mg/dL)], multiply result by 0.85 if female), glucose, albumin and total 


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protein. In Stage 2 the estimated Glomerular Filtration Rate will be calculated 
according the Modification of diet in Renal Disease (MDRD) equation  
(see Appendix B). 
- 
Hematology: hemoglobin, hematocrit, RBC, WBC with differential, MCV, platelet 
count. 
- 
Blood type (if not already done), complete blood phenotyping (C,c; E,e; Kell. Kidd; 
Duffy; S,s) and antibody screening (Indirect Coombs test, Indirect Antiglobulin Test 
(IAT)) only to be obtained prior C1D1 administration (blood type card will be kept by 
the patient with the study card). Antibody screen information made before any blood 
transfusion and blood transfusions are to be recorded in the eCRF if performed during 
the study treatment. 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. 
- 
A blood type card will be provided to the patient indicating he (she) is receiving an 
anti-CD38 treatment and the site will notify its blood bank that the patient is receiving 
an anti-CD38 treatment (see Appendix K). 
- 
Coagulation: PT/INR, PTT. 
- 
Urinalysis: blood, protein, glucose, pH, ketones, bilirubin, leucocytes, nitrates, specific 
gravity. 
- 
6HUXPȕ-microglobulin 
x Disease Assessment: (all lab assessments to be performed within 7 days in Stage 1 part 
and all radiologic assessments to be performed within 21 days prior to first IP 
administration. Local lab results for M-protein and sFLC to be used to determine 
eligibility criteria.) 
 
M-protein quantification (serum and 24-hr urine to be completed prior to dosing), 
including sub-types IgG, IgA, IgM, IgD and IgE; an additional blood sample will be 
collected to test M protein with an assay without interference of the SAR650984 
antibody. 
 
Serum free light chain levels. 
 
Bone marrow biopsy/aspiration. 
- 
Radiologic imaging (PET-CTscan or MRI scan) of plasmacytoma. For 
Stage 2 - patients with known lesions at baseline. 
- 
Skeletal survey (X-ray; including skull, all long bones, pelvis and chest) or low dose 
whole body CT scan. 
For Stage 2: at screening, disease assessment procedures should be performed within 21 days 
prior to first IP administration. Local lab results for M-protein and sFLC will be used to determine 
eligibility criteria. All disease and laboratory assessments should be repeated prior of first dose 
(see flowchart in Section 1.14 and Section 1.15). 
x PD/Exploratory Studies: 
- 
Bone marrow biopsy/aspiration for CD38 RD (Stage 1 patient only). 


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- 
Bone marrow aspirate for FISH. 
- 
Bone marrow aspirate for genomics/CD38 Mrna. 
- 
Bone marrow aspirate for immune phenotyping. 
- 
Bone marrow biopsy/aspirate for CD38 RO (Stage 1 patients only). 
- 
Bone marrow aspirate for MRD assessment. 
12.2.2 Randomization/registration  
Patients, who meet all the inclusion criteria, and none of the exclusion criteria, will be eligible for 
inclusion in the study. Each patient will be registered via an IVRS/IWRS and receive an 
incremental identification number corresponding to his/her order of enrollment in the study. In 
addition, all Stage 1a and Stage 2 eligible patients will be randomized by the IVRS/IWRS to a 
treatment arm (see Section 8.4). In Stage 1b eligible patients will be enrolled.  
12.2.3 Cycle 1-3 evaluations  
The same parameters as performed at screening/baseline will be performed for each of the 
required evaluations unless specified in the flowchart and in the following sections. 
Day 1 
The evaluations below are to be performed prior to first IP administration on Day 1 of Cycle 1-3 
unless otherwise indicated. 
x ePROs: QLQ-C30, MY20 (performed prior to any assessments) (Stage 1 only). 
x EQ-5D (performed prior to any assessments, Cycle 1 only) (Stage 1 only). 
x Physical Examination: consists of examination of major body systems, including 
neurological, digestive exam, plasmacytoma assessment, respiratory, hepatomegaly, 
splenomegaly, lymphadenopathy. 
x Weight. 
x Vital Signs. 
x Performance Status (Karnofsky in Phase 1 and Phase 2 Stage 1 and ECOG Performance 
status in Phase 2 Stage 2). 
x AE/SAE assessment. 
x Concomitant medications. 
x Laboratory Assessments: 
- 
Blood Chemistry (Required prior to pre-medication and IP administration on D1, D8, 
D15 and D22 of Cycle 1 and D1 and D15 of every subsequent cycle). 
- 
Hematology (Required prior to pre-medication and IP administration on D1, D8, D15 
and D22 of Cycle 1 and D1 and D15 of every subsequent cycle). 


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- 
If not performed during screening and prior to C1D1: Blood type (if not already done), 
complete blood phenotyping (C,c; E,e; Kell. Kidd; Duffy; S,s is recommended, if not 
available follow site's standard)and antibody screening (Indirect Coombs test, Indirect 
Antiglobulin Test (IAT)) only to be obtained prior C1D1 administration (blood type 
card will be kept by the patient with the study card). Antibody screen information 
made before any blood transfusion and blood transfusions are to be recorded in the 
eCRF if performed during the study treatment.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. 
- 
Indirect Antiglobulin Test (IAT) to be obtained prior C2D1 administration . Antibody 
screen information made before any blood transfusion and blood transfusions are to be 
recorded in the eCRF if performed during the study treatment.  
- 
Cytokines (Cycle 1 only)  
- 
Safety labs (if *UDGH2 infusion reaction) (Stage 1 only) 
- 
6HUXPȕ-microglobulin (Cycle 2 and 3 only) 
- 
PK/ADA (Day 1) (refer to Section 1.8 and Section 1.16) Samples will be collected up 
to and including C10. 
- 
Serum or urine Pregnancy test (except Cycle 1 if done within 7 days). 
x Disease Assessment: 
- 
M-protein quantification (serum and 24-hr urine to be completed prior to dosing 
including IgG, IgA, IgM, IgD and IgE) (In Stage 2: Required prior to pre-medication 
and IP administration on D1 of Cycle 1 and D1 of every subsequent cycle). In Stage 2: 
an additional blood sample will be collected to test M protein with an assay without 
interference of the SAR650984 antibody). 
- 
Serum free light chain levels (Required prior to pre-medication and IP administration 
on D1, D8, D15 and D22 of Cycle 1 and D1 of every subsequent cycle). 
- 
Bone marrow biopsy/aspiration (only required to confirm a sCR, CR or PD). 
- 
Radiologic imaging: skeletal survey and/or PET-CT scan or MRI scan to confirm 
response or in case of suspicion of progression according to IMWG criteria and/or 
when clinically indicated, or in case of plasmocytoma at baseline to be performed 
every 2 cycles.  
x PD/Exploratory Studies: 
- 
Bone marrow biopsy/aspirate for CD38 RO (Stage 1 patients only, Cycle 2 only). 
- 
Bone marrow aspirate sample for MRD assessment (only at CR confirmation). 
- 
Blood sample for soluble CD38 (Stage 1 only: Cycle 1 and 3 only). 
- 
Blood sample for immune phenotyping (Cycle 1 and 3 only). 
- 
Blood sample for immune genetic determinants (Cycle 1 only). 


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- 
Blood sample for adaptive immune response - T cell repertoire (Stage 2: Cycle 1 and 3 
only). 
- 
Blood sample for adaptive immune response - humoral and cellular response (Stage 2: 
Cycle 1 and 2 only).  
Samples for all the parameters listed in the flowchart (Section 1.14 and Section 1.15) and in the 
corresponding footnotes will be sent to a central laboratory. At each time point, blood samples 
will be split for central and local laboratory evaluations.  
Administration of SAR650984 
The evaluations below are to be performed during and after IP administration: 
x Vital Signs: middle of infusion and end of infusion 
x Laboratory Assessments: 
- 
PK (Cycle 1 only refer to Section 1.8 and Section 1.16) 
Day 8 (Cycle 1 only for patients on a QW schedule). 
The evaluations below are to be performed prior to IP administration on Day 8 of Cycles 1 only. 
x Physical Examination: consists of examination of major body systems, including 
neurological, digestive exam, plasmacytoma assessment, respiratory, hepatomegaly, 
splenomegaly, lymphadenopathy. 
x Weight. 
x Vital Signs. 
x Performance Status (Karnofsky in Phase 1 and Phase 2 Stage 1 and ECOG Performance 
status in Stage 2). 
x AE/SAE Assessment. 
x Concomitant Medication. 
x Laboratory Assessments: 
- 
Blood Chemistry (Required prior to pre-medication and IP administration). 
- 
Hematology (Required prior to pre-medication and IP administration). 
- 
PK(Cycle 1 only refer to Section 1.8 and Section 1.16) 
Administration of SAR650984 on Day 8 of Cycle 1 for patients on the QW schedule. 
The evaluations below are to be performed during and after IP administration. 
x Vital Signs: middle of infusion and end of infusion 
x Laboratory Assessments: 
- 
6DIHW\ODEVLI Grade 2 infusion reaction) (Stage 1 only). 


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Day 15 
The evaluations below are to be performed prior to IP administration on Day 15 of Cycles 1-3 
unless otherwise indicated. 
x Physical Examination: consists of examination of major body systems, including 
neurological, digestive exam, plasmacytoma assessment, respiratory, hepatomegaly, 
splenomegaly, lymphadenopathy. 
x Weight. 
x Vital Signs. 
x Performance Status (Karnofsky in Phase 1 and Phase 2 Stage 1 and ECOG Performance 
status in Stage 2). 
x AE/SAE Assessment. 
x Concomitant Medication. 
x Laboratory Assessments: 
- 
Blood Chemistry (Required prior to pre-medication and IP administration) 
- 
Hematology (Required prior to pre-medication and IP administration) 
- 
PK/ADA (refer to Section 1.8 and Section 1.16) 
Administration of SAR650984 on Day 15 of Cycle 1 and 2 for all patients. 
Administration of SAR650984 on Day 15 of Cycle 3 for patients remaining on the Q2W schedule.  
The evaluations below are to be performed during and after IP administration. 
x Vital Signs: middle of infusion and end of infusion 
x Laboratory Assessments: 
- 
PK (Cycle 1 only refer to Section 1.8). 
- 
6DIHW\ODEVLI Grade 2 infusion reaction) (Stage 1 only). 
Day 22 (Cycle 1 only for patients on a QW schedule). 
The evaluations below are to be performed prior to IP administration on Day 22 of Cycles 1 only. 
x Physical Examination: consists of examination of major body systems, including 
neurological, digestive exam, plasmacytoma assessment, respiratory, hepatomegaly, 
splenomegaly, lymphadenopathy. 
x Weight. 
x Vital Signs. 
x Performance Status (Karnofsky in Phase 1 and Phase 2 Stage 1 and ECOG Performance 
status in Stage 2). 


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x AE/SAE Assessment. 
x Concomitant Medication. 
x Laboratory Assessments: 
- 
Blood Chemistry (Required prior to pre-medication and IP administration). 
- 
Hematology (Required prior to pre-medication and IP administration). 
Administration of SAR650984 on Day 22 of Cycle 1 for patients on the QW schedule. 
The evaluations below are to be performed during and after IP administration. 
x Vital Signs: middle of infusion and end of infusion 
x Laboratory Assessments: 
- 
6DIHW\ODEVLI Grade 2 infusion reaction) (Stage 1 only) 
- 
PK(Cycle 1 only refer to Section 1.8 and Section 1.16) 
12.2.4 During treatment period (subsequent cycles)  
Patients following the Q2W schedule: The evaluations below are to be performed prior to IP 
administration on Day 1 and Day 15 of subsequent cycles. 
Patients following the Q4W schedule: The evaluations below are to be performed prior to IP 
administration on Day 1 of every cycle. 
x ePROs: QLQ-C30, MY20 (Day 1 of every cycle, performed prior to any assessments)  
(Stage 1 only). 
x ePRO: EQ-5D (Day 1 of every 3rd cycle starting Cycle 4, performed prior to any 
assessments) (Stage 1 only). 
x Physical Examination: consists of examination of major body systems, including 
neurological, digestive exam, plasmacytoma assessment, respiratory, hepatomegaly, 
splenomegaly, lymphadenopathy. 
x Weight. 
x Vital Signs. 
x Performance Status (Karnofsky) in Phase 1 and Phase 2 Stage 1 and ECOG Performance 
status in Stage 2). 
x AE/SAE Assessment. 
x Concomitant Medication. 
x Laboratory Assessments: 
- 
Blood Chemistry (Required prior to pre-medication and IP administration on D1 and 
D15 of every subsequent cycle). 


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- 
Hematology (Required prior to pre-medication and IP administration on D1 and D15 
of every subsequent cycle). 
- 
Indirect Antiglobulin Test [IAT]) to be repeated at C2D1 if the test is not performed at 
this visit, it can be done at the next blood sampling. Antibody screen information made 
before any blood transfusion and blood transfusions are to be recorded in the eCRF if 
performed during the study treatment. 
- 
6HUXPȕ-microglobulin (Day 1 of every cycle) (Required prior to pre-medication and 
IP administration on D1of every subsequent cycle). 
- 
PK /ADA (refer to Section 1.8 and Section 1.16) Samples will be collected up to and 
including C10. 
x Disease Assessment (Day 1 of every cycle): 
- 
M-protein quantification (serum and 24-hr urine to be completed prior to dosing 
including IgG, IgA, IgM, IgD and IgE). An additional blood sample will be collected 
to perform the interference test. 
- 
Serum free light chain levels. 
- 
Bone marrow biopsy/aspiration (only required to confirm a sCR, CR or PD). 
- 
Radiologic imaging: Skeletal survey and/or PET-CTscan or MRI scan only required if 
clinically indicated or to confirm response or progression according to IMWG criteria. 
CT/MRI scan is required every 2 cycles (ie, Cycle 5, Cycle 7, etc) if a plasmacytoma 
was present at baseline.  
x Serum or urine Pregnancy test 
Samples for all the parameters listed in the flowchart (Section 1.14) and in the corresponding 
footnotes will be sent to a central laboratory. At each time point, blood samples will be split for 
central and local laboratory evaluations.  
x PD/Exploratory Studies: 
- 
Bone marrow sample for MRD assessment (only at CR confirmation). 
- 
Blood sample for adaptive immune response - T cell repertoire (Stage 2: Cycle 5 only). 
- 
Blood sample for adaptive immune response - humoral and cellular response (Stage 2: 
Day 1 of Cycles 4, 7 and 10).  
Administration of SAR650984 on Day 1 of subsequent Cycles for all patients. 
Administration of SAR650984 on Day 15 of subsequent cycles for patients on the Q2W schedule. 
The evaluations below are to be performed during and after IP administration. 
x Vital Signs: middle of infusion and end of infusion 
x Laboratory Assessments: 
- 
6DIHW\ODEVLI Grade 2 infusion reaction) (Stage 1 only) 


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- 
PK (Day 1 of Cycle 4 only, refer to Section 1.8 and Section 1.16) 
12.2.5 End of treatment visit (to be performed up to 30 days after the last study treatment 
administration)  
x ePROs: QLQ-C30, MY20, PRO: EQ-5D (performed prior to any assessments) (Stage 1 
only) 
x Clinical examination: includes physical examination, weight, vital signs, and performance 
status. 
x Laboratory Assessments: 
- 
Pregnancy Test: serum. 
- 
Blood Chemistry. 
- 
Hematology. 
- 
6HUXPȕ-microglobulin. 
- 
PK/ADA (refer to Section 1.8 and Section 1.16). Only to be collected if the patient has 
not completed 10 cycles or if the last ADA was positive and will collect one additional 
sample in 3 months. 
x Exploratory Studies: 
- 
Bone marrow biopsy/aspiration for genomics (only patients who have responded to the 
study treatment but subsequently develop progressive disease, in Stage 1 only). 
- 
Blood sample for soluble CD38 (only patients with progressive disease, in Stage 1 
only). 
- 
Blood sample for immune phenotyping. 
- 
Blood sample for adaptive immune response - humoral and cellular response (in 
disease progression patients, Stage 2 only).  
x Disease Assessment 
 
M-protein quantification (serum and/or 24-hr urine to be completed prior to study 
treatment dosing, including IgG, IgA, IgM, IgD and IgE); an additional blood sample 
will be collected to test M protein with an assay without interference of the 
SAR650984 antibody. 
- 
Serum free light chain levels. 
- 
Radiologic imaging (PET-CT or MRI scan) of plasmacytoma (only required if 
plasmacytoma present at baseline or developed during treatment period). 
 
Skeletal survey (X-ray) or low dose whole body CT scan (only required if bone lesion 
present at baseline or developed during treatment period). 
Samples for all the parameters listed in the flowchart (Section 1.14) and in the corresponding 
footnotes will be sent to a central laboratory. At each time point, blood samples will be split for 
central and local laboratory evaluations. 


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x AE/SAE Assessment. 
x Concomitant Medication. 
x New anticancer treatment. 
x Survival status. 
12.2.6 Follow-up period at 60 days (±5 days) after last study treatment administration  
x Disease Assessment (only for patients who have discontinued study treatment for reasons 
other than disease progression). Radiologic imaging and bone marrow biopsy/aspiration 
are only required if clinically indicated or to confirm response or progression according to 
IMWG criteria.  
- 
M-protein quantification (serum and 24-hr urine). 
 
Serum free light chain levels. 
 
Bone marrow biopsy/aspiration. 
 
Radiologic imaging: PET-CT scan or MRI scan of plasmacytoma and skeletal survey 
(plain X-ray) or low dose whole body scan. 
x Pregnancy Test: serum monthly. 
x AE/SAE Assessment: all AEs related to study treatment and all SAEs regardless of study 
treatment ongoing 30 days after last study treatment administration (SAR650984 or 
dexamethasone, whichever comes last) and all new AEs related to study treatment (serious 
or not) occurring after 30 days will be collected and followed until recovery or 
stabilization. 
Concomitant Medication (all AEs related to study treatment and all SAEs regardless of study 
treatment ongoing 30 days after last study treatment administration (SAR650984 or 
dexamethasone, whichever comes last) and all new AEs related to study treatment (serious or not) 
occurring after 30 days will be collected and followed until recovery or stabilization.) 
x New anticancer therapy. 
x Survival status. 
12.2.7 Post 60 day follow-up period  
For patients who have discontinued study treatment for reasons other than disease progression and 
have not yet started treatment with another anti-cancer therapy, follow-up visits will be performed 
every month until the patient has disease progression or the patient initiates a new anticancer 
therapy. At this point, patients will be followed every 3 months (±14 days) after the last study 
treatment administration. 
For patients who discontinued study treatment for disease progression, assessments will be 
performed every 3 months (±14 days) after last study treatment administration unless otherwise 
specified. 


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x Laboratory Assessment: 
- 
ADA: only if patient is positive at the last sample. Patient should have a sample  
3 months later. No further ADA will be sampled, even if this 3-month sample is 
positive. 
x Disease Assessment (only for patients who have discontinued study treatment for reasons 
other than disease progression and have not yet started treatment with another anti-cancer 
therapy). Laboratory disease assessments are required every month (±7 days) after last 
study treatment administrations. Radiologic imaging and bone marrow biopsy/aspiration 
are required if clinically indicated or to confirm response or progression according to 
IMWG criteria. Disease assessments not required once patient starts treatment with 
another anti-cancer therapy. 
 
M-protein quantification (serum and 24-hr urine). 
- 
Serum free light chain levels.  
- 
Bone marrow biopsy/aspiration. 
- 
Radiologic imaging: PET-CT scan or MRI scan of plasmacytoma and skeletal survey 
(plain X-ray) or low dose whole body CT scan only for patients who discontinued for 
other reason than PD. 
The following information will be collected at each follow-up visit:  
x Pregnancy Test: serum monthly for 5 months after the last administration of SAR650984. 
x AE/SAE Assessment: All AEs related to study treatment and all SAEs regardless of study 
treatment ongoing 30 days after last study treatment administration (SAR650984 or 
dexamethasone, whichever comes last) and all new AEs related to study treatment  
(serious or not) occurring after 30 days will be collected and followed until recovery or 
stabilization. 
x Concomitant Medication (if IP-related AE, new SAE and/or unresolved toxicity). 
x New anticancer therapy. 
x Survival status. 
12.3 
DATA COLLECTION AFTER FINAL ANALYSIS CUTOFF DATE  
For patients still receiving SAR650984 at time of the final analysis cutoff date, treatment with 
SAR650984 may be continued according to investigator judgment on benefit/risk, until disease 
progression, unacceptable toxicity or patient refusal. After treatment discontinuation, patients will 
be followed for a minimum of 30 days following the last use of study drug. 
Procedures and data collection for patients still receiving SAR650984 at the time of the final 
analysis cutoff date will be as follows: 


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x Laboratory Assessment: 
- 
ADA: if last ADA before cut-off date is positive, one additional sampling time for 
ADA evaluation should be collected 3 months later. No further ADA will be sampled, 
even if this 3-month sample is positive. 
- 
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. 
x Study treatment administration (SAR650984 and dexamethasone). 
x Pregnancy Test: serum monthly for 5 months after the last administration of SAR650984. 
x Pre-medication will be given as indicated but will not be collected in eCRF (Stage 2 only). 
x Ongoing related AE(s) and ongoing SAE(s), up to stabilization or resolution. 
x New SAE(s) regardless of relationship with study treatments, new related AE(s). 
x End of treatment reason upon SAR650984 discontinuation. 
Patients with ongoing related AE(s) and ongoing SAE(s) after treatment discontinuation will be 
followed until stabilization (stabilization defined as no change for 3 months) or resolution of the 
AE/SAE. All relevant laboratory results and medications given for SAE will be captured in the 
SAE complimentary form in the eCRF 


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13 
STATISTICAL CONSIDERATIONS  
13.1 
DETERMINATION OF SAMPLE SIZE  
Phase1 part: 
The Phase 1 part of this study aims to establish the MTD of SAR650984 according to DLTs 
observed. 
Cohorts of 3 to 6 patients will be screened and treated at each DL during the basic dose escalation 
phase. The number of DLs examined and the emerging SAR650984 related toxicities will 
determine the sample size.  
Up to 18 patients will be enrolled in the standard risk and up to 18 patients in the high risk 
expansion cohorts may be enrolled and treated at the RP2D. 
It is anticipated that up to approximately 85 patients in total will be enrolled to this part of the 
study. 
Phase 2 part: 
Stage1: 
Although Stage 1b has been added in protocol amendment 10 and will start enrollment after 
completion of accrual in Stage 1a (ie, patients will not be randomized between the  
4 doses/schedules tested), sample size for Stage 1 will be calculated considering Stage 1a and 1b 
as a whole with 4 arms. 
Stage 1 of the Phase 2 portion of the study is based on a selection design (7). Such a design is 
used to maximize the probability of selecting the best of the four SAR650984 doses tested during 
Stage 1 using ORR as endpoint. No statistically significant difference between the four treatment 
arms is required to select a recommended Stage 2 dose. 
A total of 96 patients (24 patients by arm) will provide at least 80% probability to select the best 
SAR650984 dose assuming an ORR of 10% in the 3 mg/kg arm and assuming the difference in 
ORR between the best dose and the 3 mg/kg arm is at least 15%. 
Stage 2:  
SAR650984 arm: 105 patients need to be randomized and treated in the SAR650984 arm (ISA 
arm). Given an assumed true ORR of 28WKHQXOOK\SRWKHVLV25515% will be rejected using 
an exact binominal test at a one-sided alpha of 0.025 with 90% power, if the observed ORR is 
greater than or equal to 22.9% (24 responders).  
SAR650984+dexamethasone arm: 55 patients need to be randomized and treated in the 
SAR650984+dexamethasone arm. Given an assumed true ORR of 33%, the null hypothesis ORR 


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ZLOOEHUHMHFWHGXVLQJDQH[DFWELQRPLQDOWHVWDWDRQH-sided alpha of 0.025 with 
85% power, if the observed ORR is greater than or equal to 27.3% (15 responders). 
For the Phase 2 Stage 2, the sample size calculation was performed using nQuery Advisor 
7.0 software. 
13.2 
PATIENT DESCRIPTION  
13.2.1 Disposition of patients  
The number of screened patients as well as the number and percentage of patients included in the 
analysis populations defined in Section 13.3 will be provided. Reasons for treatment 
discontinuation will be summarized using the all treated/safety population. 
13.2.2 Protocol deviations  
All critical or major deviations potentially impacting evaluation of the MTD (Phase 1 only) 
efficacy analyses, as well as drug-dispensing irregularities and other major or critical deviations 
will be summarized in tables giving numbers and percentages of patients with deviations. 
13.3 
ANALYSIS POPULATIONS  
13.3.1 All treated/safety population  
For both Phase 1 and Phase 2 parts of the study, the all treated/safety population will include all 
patients who have given their informed consent and who have received at least one dose  
(even incomplete) of SAR650984. 
For Stage 2, patients who received dexamethasone in addition to isatuximab (excluding when 
given as part of premedication) will be included in the ISAdex arm. 
This population is the primary population for the analyses of efficacy and safety parameters.  
All analyses using this population will be based on the treatment actually received. 
13.3.2 Patients evaluable for DLT assessment  
The DLT evaluable population is only applicable to the Phase 1 part of the study. 
The evaluable for DLT population is the subset of patients from the all treated population with a 
DLT assessment at the end of Cycle 2. In practice, a “Dose Limiting toxicities” form should have 
been filled in at the end of Cycle 2. This includes patients followed up to the end of the evaluation 
period or patients having experienced a DLT validated by the study committee. If there are 
missing or incomplete data that influence the evaluation of DLT, the patient will not be evaluable 
for DLT, except if a DLT is documented during Cycle 1 or 2. Patients excluded from this 
population will be replaced. 


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13.3.3 Pharmacokinetic population  
The PK analysis will be performed on the all treated/safety population who have a PK parameter. 
13.3.4 Pharmacodynamic population  
The pharmacodynamic analysis will be performed on the all treated/safety population who have 
evaluable pharmacodynamic data. 
13.3.5 PRO population  
There will be no population flag for PRO. PRO endpoints will be analyzed using patients from the 
all treated population who have a baseline assessment and/or an on-treatment assessment, 
depending on the analysis being performed (Phase 2 – Stage 1 only). 
13.4 
STATISTICAL METHODS  
The statistical methods defined in this section will be used for the analysis of the data from the 
Phase 1 and Phase 2 portion of the study, unless otherwise specified. Data from Phase 1 and each 
stage of the Phase 2 will be analyzed and reported separately (see Section 6.9.2). In particular, 
data from Stage 1a and Stage 1b will be presented in the same set of tables. Summary tables will 
be presented by dose levels/arm (when appropriate) and overall, unless otherwise noted. 
Unless otherwise specified, analyses will be descriptive and performed based on the all treated 
population. 
Continuous data will be summarized using number of available data, mean, SD, median, 
minimum, and maximum. Categorical and ordinal data will be summarized using number and 
percentage of patients.  
13.4.1 Demographics and baseline characteristics  
The following standard demographic and baseline characteristics (including age, race, gender, 
Karnofsky/ECOG performance status), medical history, cancer diagnosis will be collected at 
baseline and described.  
13.4.2 Extent of investigational product exposure  
The extent of investigational product exposure will be assessed and summarized by DL within the 
all treated population.  
The dose information will be assessed by the following variables: 
1. Duration of study treatment exposure: is defined depending on the isatuximab 
administration schedule as follows: 
- 
If treatment is discontinued at a cycle with QW isatuximab administration: [date of last 
dose of isatuximab + 7 days – date of first dose of isatuximab] / 7. 


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- 
If treatment is discontinued at a cycle with Q2W isatuximab administration: [date of 
last dose of isatuximab + 14 days – date of first dose of isatuximab] / 7. 
2. Cumulative dose: The cumulative dose is the sum of all doses from first dose to last 
SAR650984 administration. 
3. Actual dose intensity (ADI): defined as the cumulative dose divided by the number of 
weeks on study. 
4. 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. 
5. Dose reduction and reason for dose reduction. 
6. Dose delays: A cycle is deemed to have been delayed if start date of the current cycle – 
14 (for Phase 1 part) or 28 (for the Phase 2 part) – start date of previous cycle >2 days. 
7. Dose interruption. 
Similar analyses will be performed for dexamethasone exposure (ISAdex arm, Phase 2 Stage 2). 
Dose information variables will be summarized descriptively (N, Mean, SD, Median, Q1:Q3, Min, 
and Max). Analyses will be performed based, on one hand, on the number of patients and, on the 
other hand, on the number of cycles. 
13.4.3 Prior/concomitant medication/therapy  
The following parameters regarding prior anticancer will be summarized for patients with MM: 
x Prior anticancer treatments: number of prior lines, main anticancer treatments, time from 
completion of last line of treatment to first SAR650984 administration (months), best 
response to last line, duration of last line of therapy  
x Prior transplant: number (%) of patients with transplant, type of transplant, number of 
transplant by patient 
x Prior surgery: number (%) of patients with any prior surgery related to cancer, type of 
surgery and time from last surgery to first SAR650984 administration (months) 
x Prior radiotherapy: number (%) of patients with any prior radiotherapy related to cancer, 
intent, location and time from last radiotherapy to first study treatment infusion (months). 
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the ATC class (anatomic category) and the first three digits of the 
ATC class (therapeutic category). All ATC codes corresponding to a medication will be 
summarized patients will be counted once in each ATC categories (anatomic or therapeutic) 
linked to the medication.  
Medications of specific interest such as antibiotics and hematopoietic growth factors (G-CSF, 
GM-CSF and erythropoietin or red blood cells transfusion) will be summarized and listed by DL. 


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Further treatment of interest for the analysis and given to the patient after withdrawal from IP will 
be listed. 
13.4.4 Analysis of efficacy endpoints  
All efficacy analyses will be performed using the all treated/safety population. 
13.4.4.1 Efficacy endpoints for Phase 1 part of the study  
The following efficacy endpoints will be analyzed for Phase 1 study: 
x Overall response rate (ORR). 
x Duration of response defined as the time from initial response to the first documented 
tumor progression. 
ORR and duration of response will be listed along with relevant patient/disease characteristics. In 
addition, ORR and duration of response will be summarized with descriptive statistics and 
95% confidence interval (for ORR only) for patients with MM. 
13.4.4.2 Analysis of primary efficacy endpoint for Phase 2 part of the study  
The data cut for the primary analysis of ORR will be 4 months and 12 months for Stage 1 and 
Stage 2 respectively after the last enrolled patient receives first study treatment. ORR will be 
summarized with descriptive statistics. A 95% two-sided confidence interval will be computed 
using Clopper-Pearson method. For Stage 2, the null hypothesis that the true response rate (ORR) 
is <15% will be tested for each arm using a one-sided exact binomial test with a significance level 
of 0.025. 
Secondary/Exploratory analyses of primary efficacy endpoint (eg, analysis of patients with high-
risk cytogenetics) will be detailed in the statistical analysis plan. 
13.4.4.3 Analysis of secondary efficacy endpoint for Phase 2 part of the study  
x CBR: the CBR will be analyzed using the same method as the primary efficacy analysis of 
ORR.  
x DOR: Kaplan-Meier estimates such as median and Kaplan-Meier curves will be provided 
for DOR for patients who achieve a response (CR and PR). 
x PFS: the PFS will be analyzed using the Kaplan-Meier method. The Kaplan-Meier 
estimates of the 25th, 50th and 75th percentiles and the 95% confidence intervals of 
median will also be computed. The Kaplan-Meier curves will be plotted. The PFS will be 
analyzed based upon all treated population. 
x OS: the OS will be analyzed using the same method as PFS.  


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13.4.5 Analysis of patient reported outcomes (Phase 2 Stage 1 only)  
For each questionnaire the compliance profile over time will be summarized (number and 
percentage of forms received versus expected, and number and percentage of forms evaluable 
versus expected). 
For each EORTC QLQ-C30 and QLQ-MY20 scales a descriptive summary at each visit and 
change from baseline will be provided for each group: the five functional scales (physical 
functioning, role functioning, emotional functioning, cognitive functioning, and social 
functioning), the three symptom scales (fatigue, nausea and vomiting, and pain), the GHS/ quality 
of life scale, and the six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and 
financial difficulties) of the QLQ-C30 and the 2 functional subscales (body image, future 
perspective), and 2 symptoms scales (disease symptoms and side-effects of treatment) of the 
MY20. In addition, the proportion of patients who achieve clinically meaningful improvements on 
all scales will be reported, with the primary scales of importance being pain, fatigue, and physical 
functioning. A clinically meaningful improvement will be defined as a change from  
baseline <= -10 for the symptoms pain and fatigue and as a change from baseline >=10 for the 
physical functioning scale. Clinically meaningful improvements will be further detailed in the 
statistical analysis plan. 
The responses of each EQ-5D items will be presented by visit and group. The tables will contain 
information on the frequency and proportion of the population reporting level 1 (no problems), 
level 2 (some problems) and level 3 (extreme problems) per item. Tables will also be presented 
cross-tabulating a visit with the baseline visit. Descriptive summary statistics (size, mean, 
standard deviation, median, range) will be provided for the single index utility score and the 
visual analogue scale at each visit. Change from baseline will be also described. 
13.4.6 Analyses of safety data  
Analyses of data will be based on the all treated/safety population. 
13.4.6.1 Dose-limiting toxicities  
For the Phase 1 part of the study, DLTs will be summarized by DL. Details will be provided 
(characteristics of DLTs) by patient. 
13.4.6.2 Analyses of adverse events  
Adverse events will be assessed according to NCI-CTCAE v4.03 from the time informed consent 
is signed until at least 30 days after the last IP administration. AEs will be classified by System 
Organ Class/preferred term according to the latest available version of MedDRA dictionary. 
Definitions 
Period of observation: The observation period will be divided into three segments: pre-treatment, 
on-treatment and post-treatment. The pre-treatment period is defined as the time from when the 
patients give informed consent and the start of IP. The on-treatment period is defined as the time 


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from first dose of IP up to 30 days after the last dose of IP. The post-treatment period is defined as 
the time starting 31 days after the last dose of IP to the study closure. 
Pre-treatment AEs are defined as any AE during the pre-treatment period. 
Treatment-emergent AEs (TEAEs) are defined as AEs that developed, worsened (according to the 
Investigator’s opinion) or became serious during the on-treatment phase.  
Post-treatment AEs are defined as AEs that are reported during the post-treatment period. 
The grade and cycle will be taken into account in the summary. For patients with multiple 
occurrences of the same PT, the maximum grade is used. The denominator used for the summary 
by cycle is the total number of cycles administered in a DL. For a given PT, a patient contributes 
1 to the numerator for each cycle in which an episode occurred.  
The primary focus of AE reporting will be on TEAEs. Pre- and post-treatment AEs will be 
described separately.  
Adverse event incidence tables will present for each DL, the number (n) and percentage (%) of 
patients experiencing an AE. Multiple occurrences of the same event in the same patient will be 
counted only once in the tables within a treatment phase. The denominator for computation of 
percentages is the number of patients in the all treated population. 
Sorting within tables should ensure same presentation for the set of all AE within the observation 
period (pre, on and post treatment). For that purpose, the table of all TEAEs presented by system 
organ class (SOC), high level group terms, high level terms and preferred terms (PT) sorted by 
internationally agreed order unless otherwise specified.  
The following TEAE summaries will be generated: 
x Overview of TEAEs, summarizing number (%) of patients with any 
- 
TEAE. 
- 
Any Grade 3-4 TEAE. 
- 
Serious TEAE. 
- 
TEAE leading to death. 
- 
TEAE leading to permanent treatment discontinuation. 
The following frequency distribution of AEs (incidence tables) will be provided for the safety 
population: 
x Number (%) of patients experiencing TEAEs by primary SOCs and PT will be 
summarized by CTCAE grade (all grades and Grade 6LPLODUWDEOHVZLOOEHSUHSDUHG
for drug-related TEAEs, TEAEs leading to IMP/NIMP discontinuation, TEAEs leading to 
dose modification, serious TEAEs, AESI, IARs and AEs/SAEs occurring during the post 
treatment dosing period. 


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13.4.6.3 Deaths  
The following deaths summaries will be generated; 
x Number (%) of patients who died by study period (pre-treatment, on-treatment, post-
treatment). 
x TEAEs leading to death (death as an outcome on the AE e-CRF page as reported by the 
Investigator) and related TEAEs leading to death by primary system organ class, 
alphabetic order of high level group level terms, high level terms, and preferred terms 
showing number (%) of patients.  
A listing of deaths will be provided. 
13.4.6.4 Clinical laboratory evaluations  
For patients with multiple occurrences of the same laboratory variable during the on treatment 
period, the maximum grade (worst) per patient and/or per cycle will be used. The denominator 
used for the summary by cycle is the total number of cycles administered. For a given laboratory 
variable, a patient contributes 1 to the numerator for each cycle in which an episode occurred. An 
episode occurs during a cycle, if the date of sampling is on or after the first day of the cycle, but 
prior to the first day of the next cycle. Hematological and clinical biochemistry toxicities will be 
assessed from laboratory test parameters. Each test result will be graded by NCI-CTCA v4.03. 
The number of patients with abnormal lab tests at baseline will be presented by grade. The 
frequency of patients and/or cycles in each grade of lab tests during treatment will be summarized 
(similar analysis will be performed based on data recorded at Cycle 1). When appropriate, the 
summary table will present the frequency of patients and/or cycles with any grade of abnormal 
laboratory tests and with Grade 3-4 of abnormal laboratory tests.  
13.4.6.5 Vital signs  
The summary statistics (including mean, median, Q1, Q3, standard error, minimum and 
maximum) of all vital signs variables (raw data and changes from baseline) will be calculated for 
each visit or study endpoint (baseline, each post baseline time point, last on treatment value and/or 
worst value). Mean changes from baseline with the corresponding standard error (or boxplots) 
will be plotted over time (at same time points). 
13.4.6.6 Analyses of other safety variables  
Not applicable. 
13.4.7  Analyses of pharmacokinetic variables   
Pharmacokinetic parameters of SAR650984 will be summarized by descriptive statistics (such as 
mean, geometric mean, median, SD, SEM, CV, minimum, and maximum) under the responsibility 
of Translational Medicine and Early Development, Sanofi. 


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Individual plasma concentrations and PK parameters of SAR650984 will be tabulated with 
standard descriptive statistics. Individual and mean profiles will be presented graphically. 
The relationship between dose and exposure will be investigated, using analysis of variance. 
Analyses of pharmacodynamic/genomic population variables (as appropriate) 
Time dependence will be investigated with Ceoi (Concentration at end of infusion) and Ctrough 
(plasma concentration observed before treatment administration after repeated administration, if 
relevant) data from all cycles. 
13.4.8 Analysis of anti-drug antibody  
The observation period for ADAs will be divided into 2 periods:  
x The ADA pretreatment period will be defined as the time that informed consent is signed 
until the first study treatment administration. 
x The ADA on-study observation period will be defined as the time from the first study 
treatment administration until the end of the study. 
Patients with at least one evaluable ADA result during the ADA pretreatment period will be 
considered as evaluable at baseline. Patients with at least one evaluable ADA result during the 
ADA on-study observation period will be considered evaluable during the on-study observation 
period. 
Definitions:  
x Pre-existing ADA, defined as ADA that are present in samples drawn during the 
pretreatment period. 
x Treatment-induced ADA, defined as ADA that developed at any time during the ADA 
on-study observation period in patients without pre-existing ADA (including patients 
without pretreatment samples). 
x Treatment boosted ADA, defined as pre-existing ADA with a significant increase in the 
ADA titer during the study compared to the baseline titer.  
x ADA positive patients, defined as patients with at least one treatment-induced or 
treatment-boosted ADA positive sample at any time following the first study treatment 
administration. 
x ADA prevalence, defined as the sum of the number of patients with pre-existing ADA and 
the number of patients with treatment induced ADAs, divided by the number of evaluable 
patients. 
x ADA incidence, defined as the number of ADA positive patients divided by the number of 
evaluable patients. 
The immunogenicity for isatuximab will be assessed by summarizing the number (%) of patients 
with pre-existing ADA and ADA negative at baseline, and by summarizing the number (%) of 
ADA positive patients (including treatment-induced ADA and treatment boosted ADA) during the 
on-study observation period.  


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ADA prevalence and ADA incidence will be also described.  
The impact of positive immune response will be evaluated on efficacy, PK and safety endpoints 
when relevant. 
13.4.9 Analysis of pharmacodynamic variables  
The CD38 receptor density and receptor occupancy (Phase 1 and Phase 2 – Stage 1 parts only) 
will be summarized for the Phase 1 and Phase 2 part.  
A graph showing ORR/non-responder rate (in y-axis) by CD38 RD level (ranging from 0 to 
500,000 by increment of 1,000 in x-axis) will be provided.  
The relationship between CD38 RO and SAR650984 concentrations will be analyzed. A graph of 
CD38 RO versus SAR650984 concentration at 4 week will be provided. Another analysis will be 
performed when all patients will have been followed for at least 4 months to confirm dose 
selection. 
13.5 
INTERIM ANALYSIS  
An interim analysis of the data from Stage 1 will be performed when all patients have completed 
at least two disease assessments. This analysis will be used for the selection of the dose of 
SAR650984 to be used in Stage 2. Response rate along with safety, PK, PD, and overall efficacy 
will be used to select the dose and schedule for Stage 2. Another analysis will be performed when 
all patients will have been followed for at least 4 months to confirm dose selection. 
An interim analysis of the safety data from Phase 2 Stage 2 may be performed if enrollment is not 
completed by December 2017. No formal statistical hypothesis will be tested in this analysis. 


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14 
ETHICAL AND REGULATORY STANDARDS  
14.1 
ETHICAL PRINCIPLES  
This Clinical Trial will be conducted in accordance with the principles laid down by the 18th 
World Medical Assembly (Helsinki, 1964) and all applicable amendments laid down by the 
World Medical Assemblies and the ICH guidelines for Good Clinical Practice (GCP). 
14.2 
LAWS AND REGULATIONS  
This Clinical Trial will be conducted in compliance with all international laws and regulations, 
and national laws and regulations of the country(ies) in which the Clinical Trial is performed, as 
well as any applicable guidelines. 
14.3 
INFORMED CONSENT  
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the Patient of all 
pertinent aspects of the Clinical Trial including the written information giving approval/favorable 
opinion by the Ethics Committee (IRB/IEC). All participants should be informed to the fullest 
extent possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the Clinical Trial, the written Informed Consent Form should 
be signed, name filled in and personally dated by the patient or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion. A copy of the 
signed and dated written Informed Consent Form will be provided to the patient. 
Prior to collection of blood for pharmacogenetics, the optional pharmacogenetic informed consent 
form (written) should be signed, name filled in, and personally dated by the patient or by the 
subject’s legally acceptable representative, and by the person who conducted the informed 
consent discussion. A copy of the signed and dated written optional informed consent form will be 
provided to the subject. 
The informed consent form and the optional pharmacogenetic informed consent form used by the 
Investigator for obtaining the patient's informed consent must be reviewed and approved² by the 
Sponsor prior to submission to the appropriate ethics committee (IRB/IEC) for approval/favorable 
opinion. 
14.4 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)  
As required by local regulation, the Investigator or sanofi-aventis must submit this Clinical Trial 
Protocol to the appropriate Ethics Committee (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 Ethics Committee (IRB/IEC) composition. 


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The Clinical Trial (study number, Clinical Trial Protocol title and version number), the documents 
reviewed (Clinical Trial Protocol, Informed Consent Form, Investigator’s Brochure, Investigator’s 
CV, etc) and the date of the review should be clearly stated on the written (IRB/IEC) 
approval/favorable opinion. 
Investigational Product 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 
sanofi-aventis. 
During the Clinical Trial, any amendment or modification to the Clinical Trial Protocol should be 
submitted to the Ethics Committee (IRB/IEC) before implementation, unless the change is 
necessary to eliminate an immediate hazard to the patients, in which case the IRB/IEC should be 
informed as soon as possible. It should also be informed of any event likely to affect the safety of 
patients or the continued conduct of the Clinical Trial, in particular any change in safety. All 
updates to the Investigator’s Brochure will be sent to the Ethics Committee (IRB/IEC). 
A progress report is sent to the Ethics Committee (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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15 
STUDY MONITORING  
15.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S)  
The Investigator(s) undertake(s) to perform the Clinical Trial in accordance with this Clinical 
Trial Protocol, ICH guidelines for Good Clinical Practice and the applicable regulatory 
requirements. 
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 Case Report Form [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 
Sub-Investigators to assist in the conduct of the Clinical Trial in accordance with the Clinical 
Trial Protocol. All Sub-Investigators shall be appointed and listed in a timely manner. The 
Sub-Investigators 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. 
15.2 
RESPONSIBILITIES OF THE SPONSOR  
The Sponsor of this Clinical Trial is responsible to Health Authorities for taking all reasonable 
steps to ensure the proper conduct of the Clinical Trial Protocol as regards ethics, Clinical Trial 
Protocol compliance, and integrity and validity of the data recorded on the Case Report Forms. 
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, Serious Adverse Event 
documentation and reporting, AESI documentation and reporting ,AE documentation, 
Investigational Product allocation, patient compliance with the Investigational Product regimen, 
Investigational Product accountability, concomitant therapy use and quality of data. 


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15.3 
SOURCE DOCUMENT REQUIREMENTS  
According to the ICH guidelines for Good Clinical Practice, the Monitoring Team must check the 
Case Report Form entries against the source documents, except for the pre-identified source data 
directly recorded in the Case Report Form. The Informed Consent Form will include a statement 
by which the patient allows the Sponsor’s duly authorized personnel, the Ethics Committee 
(IRB/IEC), and the regulatory authorities to have direct access to original medical records which 
support the data on the Case Report Forms (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 rules). 
15.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST  
An electronic CRF will be used to collect the data for all enrolled patients. A separate manual will 
describe in detail the procedures for using the e-CRF. The Sponsor is responsible for ensuring that 
appropriate material is available at the investigative sites for completion of the e-CRFs or for 
providing this material, if needed. It is the responsibility of the Investigator to maintain adequate 
and accurate e-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. All e-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 will be entered in the e-CRF overwriting the initial 
information. An audit trail will allow identifying the modification.  
Data are available within the system to the sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the Sponsor after receipt of the e-CRFs 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 
e-CRF. 
15.5 
USE OF COMPUTERIZED SYSTEMS  
Computerized systems used during the different steps of the study are: 
x For data management activities: Oracle Clinical. 
x For pharmacokinetic activities: PKDMS (Pharsight). 
x For statistical activities: SAS. 
x For pharmacovigilance activities: AWARE. 
x For monitoring activities: IMPACT. 
x For medical writing activities: GRESDA/DOMASYS (Documentum). 
x For ePRO: site-based electronic tablets with internet capability. 


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16 
ADMINISTRATIVES RULES  
16.1 
CURRICULUM VITAE  
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Sub-Investigator will be provided to sanofi-aventis prior to the beginning of 
the Clinical Trial. 
16.2 
RECORD RETENTION IN STUDY SITES (S)  
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
It is recommended that the Investigator retain the study documents at least fifteen (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 sanofi-aventis 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 sanofi-aventis and the relevant records shall be transferred to a 
mutually agreed upon designee. 
16.3 
CONFIDENTIALITY  
All information disclosed or provided by sanofi-aventis (or any company/institution acting on 
their behalf), or produced during the Clinical Trial, including, but not limited to, the Clinical Trial 
Protocol, 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 sanofi-aventis. 
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 Sub-Investigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Sub-Investigators of the confidential nature of the Clinical Trial. 
The Investigator and the Sub-Investigators 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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16.4 
PROPERTY RIGHTS  
All information, documents and Investigational Product provided by sanofi-aventis or its designee 
are and remain the sole property of sanofi-aventis. 
The Investigator shall not 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 sanofi-aventis. 
Sanofi-aventis may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). Sanofi-aventis 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 Sub-Investigators shall provide all assistance 
required by sanofi-aventis, at sanofi-aventis' expense, for obtaining and defending any patent, 
including signature of legal documents. 
16.5 
DATA PROTECTION  
The patient's personal data and Investigator's personal data which may be included in the 
sanofi-aventis 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, 
sanofi-aventis shall take all appropriate measures to safeguard and prevent access to this data by 
any unauthorized third party. 
16.6 
INSURANCE COMPENSATION  
Sanofi-aventis 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 sanofi-aventis does not relieve the Investigator and the collaborators from 
maintaining their own liability insurance policy. An insurance certificate will be provided to the 
Ethics committees/IRB or Health Authorities in countries requiring this document. 
16.7 
SANOFI-AVENTIS AUDITS AND INSPECTIONS BY REGULATORY AGENCIES  
For the purpose of ensuring compliance with the Clinical Trial Protocol, Good Clinical Practice 
and applicable regulatory requirements, the Investigator should permit auditing by or on the 
behalf of sanofi-aventis and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study records 
for review, being understood that this personnel is bound by professional secrecy, and as such will 
not disclose any personal identity or personal medical information. 


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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 
sanofi-aventis and authorize sanofi-aventis to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to sanofi-aventis. 
The Investigator shall take appropriate measures required by sanofi-aventis to take corrective 
actions for all problems found during the audit or inspections. 
16.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE  
The sponsor reserves the right to discontinue this study under the conditions specified in the 
clinical trial agreement. 
16.9 
DECIDED BY SANOFI-AVENTIS IN THE FOLLOWING CASES:  
x If the information on the product leads to doubt as to the benefit/risk ratio. 
x If the Investigator has received from sanofi-aventis all Investigational Product, means and 
information necessary to perform the Clinical Trial and has not included any patient after a 
reasonable period of time mutually agreed upon. 
x In the event of breach by the Investigator of a fundamental obligation under this 
agreement, including but not limited to breach of the Clinical Trial Protocol, breach of the 
applicable laws and regulations or breach of the ICH guidelines for Good Clinical Practice 
x If the total number of patients are included earlier than expected. 
x If the study no longer meets the development needs of the compound or business needs of 
the company. 
In any case sanofi-aventis will notify the Investigator of its decision by written notice. 
16.10 DECIDED BY THE INVESTIGATOR  
The Investigator must notify (30 days’ prior notice) sanofi-aventis of his/her decision and give the 
reason in writing. 
In all cases (decided by sanofi-aventis or by the Investigator), the appropriate Ethics Committee(s) 
(IRB/IEC) and Health Authorities should be informed according to applicable regulatory 
requirements. 


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16.11 CLINICAL TRIAL RESULTS  
Sanofi-aventis will be responsible for preparing a Clinical Study Report and to provide a summary 
of study results to Investigator; 
When the data from all investigational sites have been fully analyzed by sanofi-aventis, the latter 
will communicate the results of the Clinical Trial to the Investigator(s). 
16.12 PUBLICATIONS AND COMMUNICATIONS  
As the Study is being conducted at multiple sites, sanofi-aventis agrees that, consistent with 
scientific standards, first presentation or publication of the results of the Study shall be made only 
as part of a publication of the results obtained by all sites performing the Protocol. However, if no 
multicenter publication has occurred 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 patient to the review procedure set forth herein. The Investigator shall provide 
sanofi-aventis with a copy of any such presentation or publication derived from the Study for 
review and comment at least thirty (30) days in advance of any presentation or submission for 
publication. In addition, if requested by sanofi-aventis, any presentation or submission for 
publication shall be delayed for a limited time, not to exceed ninety (90) days, to allow for filing 
of a patent application or such other measures as sanofi-aventis deems appropriate to establish and 
preserve its proprietary rights.  
The Investigator shall not use the name(s) of sanofi-aventis and/or of its employees in advertising 
or promotional material or publication without the prior written consent of sanofi-aventis. 
sanofi-aventis 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). 
Sanofi-aventis has the right at any time to publish the results of the Study. 


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17 
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 of the Clinical Trial 
Protocol without agreement by sanofi-aventis and prior review and documented 
approval/favorable opinion from the IRB/IEC of an amendment, 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 sanofi-aventis 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 
Ethics Committee (IRB/IEC) prior to its implementation, unless there are overriding safety 
reasons. 
In some instances, an amendment may require a change to the Informed Consent Form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised 
Informed Consent Form prior to implementation of the change. 


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18 
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23. Huhn D, von Schilling C, Wilhelm M, Ho A D, Hallek M, Kuse R, et al. Rituximab therapy of 
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escalation trial in chronic lymphocytic leukaemia. J Clin Oncol. 2001;19(8):2165-70. 


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25. di Gaetano N, Xiao Y, Erba E, Bassan R, Rambaldi A, Golay J, et al. Synergism between 
fludarabine and rituximab revealed in a follicular lymphoma cell line resistant to the cytotoxic 
activity of either drug alone. Br J Haematol. 2001;114(4):800-9. 
26. Österborg A, Dyer MJ, Bunjes D, Pangalis GA, Bastion Y, Catovsky D, et al. Phase II 
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leukemia. J Clin Oncol. 1997;15(4):1567-74. 
27. Rai KR, Freter CE, Mercier RJ, cooper MR, Mitchell BS, Stadtmauer EA, et al. Alemtuzumab 
in previously treated chronic lymphocytic leukemia patients who also had received 
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28. Keating MJ, Flinn I, Jain V, Binet Jacques-Louis, Hillmen Peter, Byrdet John, et al. 
Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: 
results of a large international study. Blood. 2002; 99(10):3554-61. 
29. Stilgenbauer S, Dohner H. Campath-1H-induced complete remission of chronic lymphocytic 
leukemia despite p53 gene mutation and resistance to chemotherapy. N Engl JMed. 
2002;347(6):452-3. 
30. Lozanski G, Heerema NA, Flinn IW, Smith L, Harbison J, Webb J, et al. Alemtuzumab is an 
effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood. 
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31. Chang CC, Liu CZ, Cleveland RP. Relative importance of CD38 expression over myeloid 
associated markers expression in predicting the clinical course of B-CLL patients. Leuk 
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32. Parkin D, Bray F, Ferlay J, Pisani Paola. Global Cancer Statistics, 2002. CA Cancer J Clin. 
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33. Abramson JS, Shipp MA. Advances in the biology and therapy of diffuse large B-cell 
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35. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP 
chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse 
large B-cell lymphoma. N Engl J Med. 2002;346(4):235-42. 
36. Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Fermé C, et al. Long-term 
results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell 
lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 
2005;23(18):4117-26. 


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37. Pfreundschuh M, Trumper I, Osterborg A, Pettengell R, Trneny M, Imrie K, et al. CHOP-like 
chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with 
good-prognosis diffuse large B cell lymphoma: a randomized controlled trial by the MabThera 
International Trial (MInT) Group. Lancet Oncol. 2006;7(5):379-91. 
38. Hiddemann W, Kneba M, Dreyling M,  Schmitz N, Lengfelder E, Schmits R, et al. Frontline 
therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, 
vincristine, and prednisone (CHOP) significantly improves the outcome for patients with 
advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a 
prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 
2005;106(12):3725-32. 
39. Thomas X.  Chemotherapy of acute leukemia in adults.  Expert Opin Pharmacother. 
2009;10(2):221-37. 
40. Larson S, Stock W. Progress in the treatment of adults with acute lymphoblastic leukemia. 
Curr Opin Hematol. 2008;15(4):400-7. 
41. Gökbuget N, Hoelzer D. Treatment of adult acute lymphoblastic leukemia. Hematology Am 
Soc Hematol Educ Program. 2006;133-41. 
42. Koehler M, Behm F, Hancock M, Pui C-H. Expression of Activation Antigens CD38 and 
CD71 is not clinically important in childhood acute lymphoblastic leukemia. Leukemia. 
1993;7(1):41-5. 
43. Eisenhauer EA, O’Dwyer PJ, Christian M, Humphrey JS. Phase I Clinical Trial Design in 
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44. Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 
2011;364(19):1844-54. 
45. NCI-CTC Version 4.03 reference. Available from: 
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46. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-76. 
47. Kvam K, Fayers PM, Wisloff F. Responsiveness and minimal important score differences in 
quality-of-life questionnaires: a comparison of the EORTC QLQ-C30 cancer-specific 
questionnaire to the generic utility questionnaires EQ-5D and 15D in patients with multiple 
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48. EuroQoL Group. EuroQoL-a new facility for the measurement of health-related quality of life. 
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49. Dolan P. Modeling valuations for EuroQol health states. Med Care. 1997;35(11):1095-108. 


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50. Ross F, Avet-Loiseau H, Ameye G, Gutiérrez NC, Liebisch P, O'Connor S, et al. Report from 
the European Myeloma network on interphase FISH in multiple myeloma and related 
disorders. Haematologica. 2012;97(8):1272-7. 
51. Munshi NC, Anderson KC, Bergsagel PL, Shaughnessy J, Palumbo A, Durie B, et al. 
Consensus recommendations for risk stratification in multiple myeloma: Report of the 
International Myeloma Workshop Consensus Panel 2. Blood. 2011;117(18):4696-700. 
52. Rajkumar SV. Multiple myeloma: 2012 update on diagnosis, risk-stratification and 
management. Am J Hematol. 2012;87(1):78-88. 
53. Ottmann O, Druker B, Sawyers C, Goldman J, Reiffers J, Silver RT, et al. A phase 2 study of 
imatinib in patients with relapsed or refactory Philadelphia chromosome-positive acute 
lymphoid leukemias. Blood. 2002;100(6):1965-71. 
 


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19 
APPENDICES  
Appendix A 
National Cancer Institute Common Terminology Criteria for Adverse 
Events  
Refer to NCI CTC AE v. 4.03(45) in the Study Reference Manual, or online at the following 
NCIwebsite: http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev4.pdf 
Toxicity grade should reflect the most severe degree occurring during the evaluated period, not an 
average. 
When 2 criteria are available for similar toxicities, the one resulting in the more severe grade 
should be used. 
The evaluator must attempt to discriminate between disease/treatment and related 
signs/symptoms. 
An accurate baseline prior to therapy is essential. 


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Appendix B 
Karnofsky/ECOG Performance Status Evaluation and creatinine 
clearance calculation formula  
 
Karnofsky performance status scale  
Score 
Normal; no complaints; no evidence of disease  
100 
Able to carry on normal activity; minor signs or symptoms of disease  
90 
Normal activity with effort; some signs or symptoms of disease  
80 
Cares for self; unable to carry on normal activity or to do active work  
70 
Requires occasional assistance but is able to care for most of his or her needs  
60 
Requires considerable assistance and frequent medical care  
50 
Disabled; requires special care and assistance  
40 
Severely disabled; hospitalization is indicated although death not imminent  
30 
Hospitalization necessary; very sick, active supportive treatment is necessary  
20 
Moribund; fatal processes progressing rapidly  
10 
National Cancer Institute. Cancer therapy evaluation program. Available at: http://ctep.cancer.gov/reporting/adeers.html. 
ECOG performance status scale 
Performance status 
Description 
0 
Normal, fully functional 
1 
Fatigue without significant decrease in daily activity 
2 
Fatigue with significant impairment of daily activities or bed rest <50% of waking hours 
3 
Bed rest/sitting >50% of waking hours 
4 
Bedridden or unable to care for self 
AND 
Formula creatinine clearance 
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 C 
Definition of Line of Therapy and Refractory Myeloma  
Taken from Rajkumar et al (1). 
A line of therapy is defined as one or more cycles of a planned treatment program. This may 
consist of one or more planned cycles of single-agent therapy or combination therapy, as well as a 
sequence of treatments administered in a planned manner. For example, a planned treatment 
approach of induction therapy followed by autologous stem cell transplantation, followed by 
maintenance is considered one line of therapy. A new line of therapy starts when a planned course 
of therapy is modified to include other treatment agents (alone or in combination) as a result of 
disease progression, relapse, or toxicity. A new line of therapy also starts when a planned period 
of observation off therapy is interrupted by a need for additional treatment for the disease. 
Refractory myeloma is defined as disease that is nonresponsive while on primary or salvage 
therapy, or progresses within 60 days of last therapy. Nonresponsive disease is defined as either 
failure to achieve minimal response or development of progressive disease while on therapy. 


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Appendix D 
Phase 1 Response Criteria  
EBMT Response criteria for multiple myeloma (MM) (6) 
The following response criteria for secretory multiple myeloma, developed by an international 
group of multiple myeloma and bone marrow transplant experts, is referred to as the EBMT 
criteria (6) 
Complete response (CR) 
CR requires all of the following: 
x Absence of the original M-protein in serum and urine by immunofixation, maintained for a 
minimum of 6 weeks. The presence of oligoclonal bands consistent with oligoclonal 
immune reconstitution does not exclude CR. 
x <5% plasma cells in a bone marrow aspirate and also on trephine bone biopsy if biopsy is 
performed. If absence of M-protein is sustained for 6 weeks it is not necessary to repeat 
the bone marrow. 
x No increase in size or number of lytic bone lesions (development of a compression 
fracture does not exclude response). 
x Disappearance of soft tissue plasmacytomas. 
Subjects in whom some, but not all, the criteria for CR are fulfilled are classified as PR, providing 
the remaining criteria satisfy the requirements for PR. This includes subjects in whom routine 
electrophoresis is negative but in whom immunofixation has not been performed. 
Partial response (PR) 
PR requires all of the following: 
x reduction in the level of the serum M-protein, maintained for a minimum of  
6 weeks. 
x Reduction in 24 KRXUXULQDU\OLJKWFKDLQH[FUHWLRQHLWKHUE\RUWR mg, 
maintained for a minimum of 6 weeks.  
x UHGXFWLRQLQWKHVL]HRIVRIWtissue plasmacytomas (by radiography or clinical 
examination). 
x No increase in size or number of lytic bone lesions (development of a compression 
fracture does not exclude response). 
Subjects in whom some, but not all the criteria for PR are fulfilled are classified as MR, provided 
the remaining criteria satisfy the requirements for MR. 


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Minimal response (MR) 
MR requires all of the following: 
x 25 to 49% reduction in the level of the serum M-protein maintained for a minimum of 
6 weeks. 
x 50 to 89% reduction in 24 hour urinary light chain excretion, which still exceeds 
200 mg/24 hour, maintained for a minimum of 6 weeks. 
x 25 to 49% reduction in the size of soft tissue plasmacytomas (by radiography or clinical 
examination). 
x No increase in the size or number of lytic bone lesions (development of a compression 
fracture does not exclude response). 
MR also includes subjects in whom some, but not all, the criteria for PR are fulfilled, provided the 
remaining criteria satisfy the requirements for MR. 
No change (Stable disease) 
x Not meeting the criteria of either MR or progressive disease. 
Plateau 
x Stable values (within 25% above or below value at the time response is assessed) 
maintained for at least 3 months. 
Complete response relapse 
Relapse from CR requires at least 1 of the following: 
x Reappearance of serum or urinary M-protein on immunofixation or routine 
electrophoresis, confirmed by at least 1 further investigation and excluding oligoclonal 
immune reconstitution. 
x 5% plasma cells in a bone marrow aspirate or on trephine bone biopsy. 
x Development of new lytic bone lesions or soft tissue plasmacytomas or definite increase in 
the size of residual bone lesions (development of a compression fracture does not exclude 
continued response and may not indicate progression). 
x Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.8 mmol/L) not 
attributable to any other cause. 
Progressive disease 
Progressive disease (for subjects not in CR) requires 1 or more of the following: 
x >25% increase in the level of the serum M-protein, which must also be an absolute 
increase of at least 5 g/L and confirmed by at least 1 repeated investigation. 
x >25% increase in the 24 hour urinary light chain excretion, which must also be an absolute 
increase of at least 200 mg/24 hour and confirmed by at least 1 repeated investigation. 


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x >25% increase in plasma cells in bone marrow aspirate or on trephine biopsy, which must 
also be an absolute increase of at least 10%. 
x Definite increase in the size of existing bone lesions or soft tissue plasmacytomas. 
x Development of new bone lesions or soft tissue plasmacytomas. Development of 
compression fracture does not exclude continued response and may not indicate 
progression. 
x Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.8 mmol/L) not 
attributable to any other cause. 
Response criteria for serum free light chain analysis in non-secretory multiple myeloma (MM) 
(1) 
The following response criteria are for patients who have non-secretory or oligosecretory multiple 
myeloma, developed by International Myeloma Working Group (IMWG). 
CR - In patients who lack measurable M proteins in the serum and urine being monitored using 
the FLC levels, the definition of CR requires a normalization of the FLC ratio in addition to the 
above criteria. 
VGPR - In patients who lack measurable M proteins in the serum and urine being monitored using 
the FLC levels, the definition of VGPR requires >90 percent decrease in the difference between 
involved and uninvolved free light chain levels. 
PR - In patients who lack measurable M proteins in the serum and urine being monitored using 
WKH)/&OHYHOVWKHGHILQLWLRQRI35UHTXLUHVSHUFHQWGHFUHDVHLQWKHGLIIHUHQFHEHWZHHQ
involved and uninvolved free light chain levels FLC levels. If the FLC levels were also 
unmeasurable at baseline, a 50 percent reduction in bone marrow plasma cells is acceptable as 
long as the original bone marrow contained at least 30 percent plasma cells. 
SD - Does not meet criteria for CR, VGPR, PR, or PD. 
PD - Difference in the kappa and lambda FLC (absolute increase must be >10 mg/dL). 
Response criteria for acute myelogenous leukemia (AML) (14) 
Anti-leukemia activity of SAR650984 will be evaluated as follows: 
By inclusion criteria, all patients enrolled will have evidence of AML, on the basis of peripheral 
blood count and bone marrow aspiration or biopsy. 
Response to treatment will be defined using the following criteria: 
x Complete remission (CR): Neutrophil count >1 x 109/L, platelet count >100 x 109/L, 
normal bone marrow morphology with <5% blasts and absence of extra-medullary 
localizations. Patients must be independent of transfusions. 


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x Remission with incomplete platelet recovery (CRp): As per CR but platelet count 
<100 x 109/L. 
x Partial remission (PR): Criteria for CR in the peripheral blood, but with 5% to 25% blasts 
in the bone marrow or 50% reduction in bone marrow blasts compared with 
pre-treatment values (ie, If the pretreatment bone marrow blast percentage is 50% to 
100%, the percentage of blasts must decrease to a value between 5% to 25%; if the 
pretreatment blast percentage is 20% to less than 49%, they must decrease by at least half 
to a value of more than 5%).  
x Progressive disease (PD): An increase in bone marrow blasts of more than 50% of the  
pre-treatment value and to a level >70% and/or a doubling of the percentage of peripheral 
blood blasts to a level >70%. 
x Stable disease (SD): Failure to fulfill criteria for response or progression. 
Response criteria for acute lymphoblastic leukemia (ALL) (53) 
The primary efficacy endpoint in this study is sustained hematologic response lasting at least 
4 weeks, assessed as: 
1. Complete hematologic response (CHR), defined according to conventional criteria as blast 
count below 5% in bone marrow, no blasts in peripheral blood, neutrophil count at least 
1.5 x 109/L, platelet count at least 100 x 109/L, and no evidence of extramedullary 
involvement. 
2. Complete marrow response (marrow-CR) in patients achieving a blast count of less than 
5% in bone marrow, no blasts in peripheral blood, no evidence of extramedullary 
involvement, a neutrophil count at least 1.0 x 109/L, but no platelet recovery (platelet 
count at least 20 x 109/L). 
3. Partial response, defined as fewer than 15% blasts in peripheral blood and bone marrow. 
Sustained responses are required to be observed at 2 consecutive evaluations at least 
4 weeks apart. 
Response criteria for chronic lymphocytic leukemia (CLL) (4) 
Complete remission (CR) 
CR requires all of the following criteria as assessed at least 2 months after completion of therapy: 
x Peripheral blood lymphocytes (evaluated by blood and differential count) below 4 x 109/L.  
x Absence of significant lymphadenopathy (eg, lymph nodes >1.5 cm in diameter) by 
physical examination.  
CT scan of the abdomen, pelvis, and thorax is desirable if previously abnormal. Lymph 
nodes should not be larger than 1.5 cm in diameter. 
x No hepatomegaly or splenomegaly by physical examination.  


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CT scan of the abdomen should be performed at response assessment if found to be 
abnormal before therapy or if physical examination is inconclusive at the time of 
evaluation. 
x Absence of constitutional symptoms. 
x Blood counts above the following values: 
- 
Neutrophils more than 1.5 x 109/L without need for exogenous growth factors. 
- 
Platelets more than 100 x 109/L without need for exogenous growth factors. 
- 
Hemoglobin more than 110 g/L (11.0 g/dL) without red blood cell transfusion or need 
for exogenous erythropoietin. 
x A marrow aspirate and biopsy should be performed at least 2 months after the last 
treatment and if clinical and laboratory results listed in bullet 5 above has been achieved.  
To define a CR, the marrow sample must be at least normocellular for age, with less than 
30% of nucleated cells being lymphocytes. Lymphoid nodules should be absent. If 
lymphoid nodules can be found, these nodules should be recorded as “nodular PR.” 
Immunohisto-chemistry should be performed to define whether these nodules are 
composed primarily of T cells or lymphocytes other than CLL cells or of CLL cells. If the 
marrow is hypocellular, a repeat determination should be performed after 4 weeks, or until 
peripheral blood counts have recovered. However, this time interval should not exceed 
6 months after the last treatment.  A marrow biopsy should be compared with that of 
pretreatment marrow. The use of a marrow biopsy for evaluating a CR is at the discretion 
of the physician. 
CR with incomplete marrow recovery (CRi) 
Patients who fulfill all the criteria for a CR (including the marrow examinations) but who have a 
persistent anemia or thrombocytopenia or neutropenia unrelated to CLL but related to drug 
toxicity. For the definition of this category, CRi, the marrow evaluation should be performed and 
not show any clonal infiltrate.  
Partial remission (PR) 
x A decrease in the number of blood lymphocytes by 50% or more from the value before 
therapy. 
x Reduction in lymphadenopathy (by CT scans in clinical as defined by the following: 
- 
A decrease in lymph node size by 50% or more either in the sum products of up to 
6 lymph nodes, or in the largest diameter of the enlarged lymph node(s) detected prior 
to therapy. 
- 
No increase in any lymph node, and no new enlarged lymph node. In small lymph 
nodes (2 cm), an increase of less than 25% is not considered to be significant. 
x A reduction in the noted pretreatment enlargement of the spleen or liver by 50% or more, 
as detected by CT scan  


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x The blood count should show one of the following results: 
- 
Neutrophils more than 1.5 x 109/L without need for exogenous growth factors. 
- 
Platelet counts greater than 100 x 109/L or 50% improvement over baseline without 
need for exogenous growth factors. 
- 
Hemoglobin greater than 110 g/L (11.0 g/dL) or 50% improvement over baseline 
without requiring red blood cell transfusions or exogenous erythropoietin. 
Progressive disease 
Progressive disease during or after therapy is characterized by at least one of the following: 
x Appearance of any new lesion, such as enlarged lymph nodes (>1.5 cm), splenomegaly, 
hepatomegaly, or other organ infiltrates. 
x An increase by 50% or more in greatest determined diameter of any previous site. 
x An increase in the previously noted enlargement of the liver or spleen by 50% or more or 
the de novo appearance of hepatomegaly or splenomegaly. 
x An increase in the number of blood lymphocytes by 50% or more with at least 5000 B 
lymphocytes per microliter. 
x Transformation to a more aggressive histology (eg, Richter syndrome). Whenever 
possible, this diagnosis should be established by lymph node biopsy. 
x Occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to CLL. 
x During therapy. Cytopenias may occur as a side effect of many therapies and should be 
assessed according to Table 8. (During therapy, cytopenias cannot be used to define 
disease progression)  
 


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Table 8 - Grading scale for hematologic toxicity in CLL studies  
 
x After treatment. The progression of any cytopenia (unrelated to autoimmune cytopenia), as 
documented by a decrease of Hb levels by more than 20 g/L (2 g/dL) or to less than  
100 g/L (10 g/dL), or by a decrease of platelet counts by more than 50% or to less than 
100 x 109/L, which occurs at least 3 months after treatment, defines disease progression, if 
the marrow biopsy demonstrates an infiltrate of clonal CLL cells. 
Stable disease 
Patients who have not achieved a CR or a PR, and who have not exhibited progressive disease, will 
be considered to have stable disease (which is equivalent to a nonresponse). 


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Treatment failure 
Responses that should be considered clinically beneficial include CR and PR; all others (eg, stable 
disease, nonresponse, progressive disease, or death from any cause) should be rated as a treatment 
failure. 
Response criteria for Non-Hodgkin’s lymphoma (NHL) (3) 
INTERNATIONAL WORKING GROUP RECOMMENDATIONS (3) 
Table 9 - Response definitions for clinical trials  
 
Response 
Definition 
Nodal masses 
Spleen, liver 
Bone marrow 
CR 
Disappearance of all 
evidence of disease 
(a) FDG-avid or PET positive 
prior to therapy: mass of any 
size permitted if PET 
negative 
(b) Variably FDG-avid or PET 
negative: regression to 
normal size on CT 
Not palpable, nodules 
disappeared 
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology, 
immunohistochemistry 
should be negative 
PR 
Regression of measurable 
disease and no new sites 
50% decrease in SPD of up 
to 6 largest dominant 
masses; no increase in size 
of other nodes 
(a) FDG-avid or PET positive 
prior to therapy: one or more 
PET positive at previously 
involved site 
(b) Variably FDG-avid or PET 
negative: regression on CT 
50% decrease in SPD 
of nodules (for single 
nodule in greatest 
transverse diameter); 
no increase in size of 
liver or spleen 
Irrelevant if positive 
prior to therapy; cell 
type should be 
specified 
SD 
Failure to attain CR/PR or 
PD 
(a) FDG-avid or PET positive 
prior to therapy: PET positive 
at prior sites of disease and 
no new sites on CT or PET 
(b) Variably FDG-avid or PET 
negative: no change in size 
of previous lesions on CT 
 
 
Relapsed 
disease 
or PD 
Any new lesion or 
increase by 50% of 
previously involved sites 
from nadir 
Appearance of a new 
lesion(s) >1.5 cm in any axis, 
50% increase in SPD of 
more than one node, or 50% 
increase in longest diameter 
of a previously identified 
node >1 cm in short axis. 
Lesions PET positive if FDG-
avid lymphoma or PET 
positive prior to therapy 
>50% increase from 
nadir in the SPD of any 
previous lesions 
New or recurrent 
involvement 
CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography; PR, partial 
remission; SPD, sum of the product of the diameters; SD, stable disease; PD, progressive disease. 


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Complete remission (CR) 
The designation of CR requires the following: 
1. Complete disappearance of all detectable clinical evidence of disease and disease-related 
symptoms if present before therapy.  
2a. Typically FDG-avid lymphoma: in patients with no pretreatment PET scan or when the PET 
scan was positive before therapy, a post-treatment residual mass of any size is permitted as 
long as it is PET negative.  
2b. Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a pretreatment 
PET scan, or if a pretreatment PET scan was negative, all lymph nodes and nodal masses must 
have regressed on CT to normal size (1.5 cm in their greatest transverse diameter for 
nodes >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in their long 
axis and more than 1.0 cm in their short axis before treatment must have decreased to 1.0 cm 
in their short axis after treatment.  
3. The spleen and/or liver, if considered enlarged before therapy on the basis of a physical 
examination or CT scan, should not be palpable on physical examination and should be 
considered normal size by imaging studies, and nodules related to lymphoma should 
disappear. However, determination of splenic involvement is not always reliable because a 
spleen considered normal in size may still contain lymphoma, whereas an enlarged spleen may 
reflect variations in anatomy, blood volume, the use of hematopoietic growth factors, or 
causes other than lymphoma.  
4. If the bone marrow was involved by lymphoma before treatment, the infiltrate must have 
cleared on repeat bone marrow biopsy. The biopsy sample on which this determination is 
made must be adequate (with a goal of >20 mm unilateral core). If the sample is indeterminate 
by morphology, it should be negative by immunohistochemistry. A sample that is negative by 
immunohistochemistry but that demonstrates a small population of clonal lymphocytes by 
flow cytometry will be considered a CR until data become available demonstrating a clear 
difference in patient outcome.  
CRu (CR unconfirmed) 
The use of the above definition for CR and that below for PR eliminates the category of CRu. 
Partial remission (PR) 
The designation of PR requires all of the following: 
1. At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the 
largest dominant nodes or nodal masses. These nodes or masses should be selected according 
to all of the following: they should be clearly measurable in at least 2 perpendicular 
dimensions; if possible they should be from disparate regions of the body; and they should 
include mediastinal and retroperitoneal areas of disease whenever these sites are involved.  
2. No increase should be observed in the size of other nodes, liver, or spleen.  


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3. Splenic and hepatic nodules must regress by 50% in their SPD or, for single nodules, in the 
greatest transverse diameter.  
4. With the exception of splenic and hepatic nodules, involvement of other organs is usually 
assessable and no measurable disease should be present.  
5. Bone marrow assessment is irrelevant for determination of a PR if the sample was positive 
before treatment. However, if positive, the cell type should be specified (eg, large-cell 
lymphoma or small neoplastic B cells). Patients who achieve a CR by the above criteria, but 
who have persistent morphologic bone marrow involvement will be considered partial 
responders.  
When the bone marrow was involved before therapy and a clinical CR was achieved, but with no 
bone marrow assessment after treatment, patients should be considered partial responders.  
1. No new sites of disease should be observed.  
2. Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if the PET scan 
was positive before therapy, the post-treatment PET should be positive in at least one 
previously involved site.  
3. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment 
PET scan, or if a pretreatment PET scan was negative, CT criteria should be used.  
In patients with follicular lymphoma or mantle-cell lymphoma, a PET scan is only indicated with 
one or at most two residual masses that have regressed by more than 50% on CT; those with more 
than two residual lesions are unlikely to be PET negative and should be considered partial 
responders.  
Stable disease 
Stable disease (SD) is defined as the following:  
1. A patient is considered to have SD when he or she fails to attain the criteria needed for a CR 
or PR, but does not fulfill those for progressive disease (see Relapsed Disease [after 
CR]/Progressive Disease [after PR, SD]).  
2. Typically FGD-avid lymphomas: the PET should be positive at prior sites of disease with no 
new areas of involvement on the post-treatment CT or PET.  
3. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment 
PET scan or if the pretreatment PET was negative, there must be no change in the size of the 
previous lesions on the post-treatment CT scan.  
Relapsed disease (after CR)/progressive disease (after PR, SD) 
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm regardless of the 
short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered abnormal 
if its short axis is more than 1.0. Lymph nodes 1.0 x 1.0 cm will not be considered as abnormal for 
relapse or progressive disease.  


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1. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, 
even if other lesions are decreasing in size. Increased FDG uptake in a previously unaffected 
site should only be considered relapsed or progressive disease after confirmation with other 
modalities. In patients with no prior history of pulmonary lymphoma, new lung nodules 
identified by CT are mostly benign. Thus, a therapeutic decision should not be made solely on 
the basis of the PET without histologic confirmation.  
2. At least a 50% increase from nadir in the SPD of any previously involved nodes, or in a single 
involved node, or the size of other lesions (eg, splenic or hepatic nodules). To be considered 
progressive disease, a lymph node with a diameter of the short axis of less than 1.0 cm must 
increase by 50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the long axis.  
3. At least a 50% increase in the longest diameter of any single previously identified node more 
than 1 cm in its short axis.  
4. Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was 
PET positive before therapy unless the lesion is too small to be detected with current PET 
systems (<1.5 cm in its long axis by CT). 
Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. 
For these recommendations, the spleen is considered nodal disease. Disease that is only assessable 
(eg, pleural effusions, bone lesions) will be recorded as present or absent only, unless, while an 
abnormality is still noted by imaging studies or physical examination, it is found to be 
histologically negative.  
In clinical trials where PET is unavailable to the vast majority of participants, or where PET is not 
deemed necessary or appropriate for use (eg, a trial in patients with MALT lymphoma), response 
should be assessed as above, but only using CT scans. However, residual masses should not be 
assigned CRu status, but should be considered partial responses. 


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Appendix E 
Phase 2 Response Criteria  
IMWG Uniform Response criteria for multiple myeloma (MM) (1) 
The following response criteria for secretory multiple myeloma, developed by an international 
group of multiple myeloma and bone marrow transplant experts, is referred to the IMWG 
Uniform Response Criteria. 
 


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Phase 2 Stage 2 response criteria 
Disease response will be assessed using the updated International Myeloma Working Group 
Response Criteria (IMWG) (2). A confirmation measurement for disease response and 
progression assessments is required within 4 weeks in this protocol. 
Updated International Myeloma Working Group response criteria 
 
Response 
IMWG criteria 
CR 
x 
Negative immunofixation on the serum and urine and 
x 
disappearance of any soft tissue plasmacytomas and 
x 
<5% plasma cells in bone marrow. 
x 
In patients with only FLC disease, a normal FLC ratio of 0.26-1.65 is required. 
Two consecutive assessments are needed 
sCR 
CR as defined below plus: 
x 
normal FLC ratio and 
x 
absence of clonal cells in bone marrow by immunohistochemistry or 2-4 color flow 
cytometry 
Two consecutive assessments of laboratory parameters are needed 
Immunophenotypic CR 
sCR as defined plus absence of phenotypically aberrant plasma cells (clonal) in bone marrow 
with minimum of 1 million total bone marrow cells analyzed by multiparametric flow cytometry 
(with > four colors)  
Molecular CR  
CR as defined plus negative allele-specific oligonucleotide polylmerase chain reaction 
(sensitivity 10-5) 
VGPR 
x 
Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 
x 
>90% reduction in serum M-protein plus urine M-protein level <100 mg/24 h. 
x 
In patients with only FLC disease, >90% decrease in the difference between involved 
and uninvolved FLC levels is required. 
Two consecutive assessments are needed 
PR 
x 
50% reduction of serum M-protein and reduction in 24 hours urinary M-protein 
by >90% or to <200 mg/24 h 
x 
If the serum and urine M-protein are unmeasurable,3 a >50% decrease in the 
difference between involved and uninvolved FLC levels is required in place of the M-
protein criteria 
x 
If serum and urine M-protein are not measurable, and serum free light assay is also 
not measureable, >50% reduction in plasma cells is required in place of M-protein, 
provided baseline bone marrow plasma cell percentage was >30% 
x 
In addition to the above listed criteria, if present at baseline, a >50% reduction in the 
size of soft tissue plasmacytomas is also required 
Two consecutive assessments are needed. No known evidence of progressive disease or 
new bone lesions if radiographic studies were performed  
MR 
for relapse refractory 
myeloma only 
EXW <49% reduction in serum M-protein and reduction in 24 h urine M-protein by 
50%-89%, which still excedd 200 mg/24 H. 
If present at baseline, 25%-49% reduction in size of soft tissue plasmacytomas; no increase in 
size or number of lytic bone lesions (developpement of compression fracture does not exclude 
response) 


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Response 
IMWG criteria 
Stable Disease 
x 
Not meeting criteria for CR, VGPR, PR or progressive disease 
x 
No known evidence of progressive disease or new bone lesions if radiographic studies 
were performed 
Progressive disease 
Increase of >25% from lowest response value in any one of the following: 
x 
Serum M-component (the absolute increase must be >0.5 g/dL) 4 and/or 
x 
Urine M-component (the absolute increase must be >200 mg/24 h) and/or 
x 
Only in patients without measurable serum and urine M protein, the difference 
between involved and uninvolved FLC levels. The absolute increase must 
be >10 mg/dL 
x 
Only in patients without measurable serum and urine M-protein and without 
measurable disease by FLC levels, bone marrow plasma cell percentage (absolute % 
PXVWEH 
Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in 
the size of existing bone lesions or soft tissue plasmacytomas 
x 
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be 
attributed solely to the plasma cell proliferative disorder 
Two consecutive assessments before new therapy are needed. 
Abbreviations: CR, complete response; FLC, free light chain; M, monoclonal; PD, progressive disease; PR, partial response; sCR, stringent 
complete response; SD, stable disease; VGPR, very good partial response. 
 


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Appendix F
Staging Criteria
Staging criteria for multiple myeloma (MM)
Classifications for acute myelogenous leukemia (AML)
While the FAB system is still the most commonly used, some doctors now refer to the World 
Health Organization (WHO) system of classification when diagnosing cases of AML and 
planning the most appropriate treatment. WHO Classification divides AML into broader groups 
based on factors such as genetic abnormalities and the presence of other leukemia-related blood 
disorders like myelodysplastic syndrome. These groups are as follows:  
x
AML with Recurrent Genetic Abnormalities
-
AML with translocation of certain genes between chromosomes 8 and 21.  
-
AML with translocation of certain genes between chromosomes 15 and 17.  
-
AML with inversion or translocation of certain genes on chromosome 16.  
-
AML with abnormalities of chromosome 11.  
-
Acute Promyelocytic Leukemia. 
x
AML with multilineage dysplasia (leukemia in which more than one abnormal myeloid 
cell type is involved). 
-
With prior myelodysplastic syndrome. 
-
Without prior myelodysplastic syndrome. 
x
AML with Myelodysplastic Syndrome, Therapy-Related. 
-
Alkylating agent-related - alkylating agents are a certain type of drug used in 
chemotherapy for various cancers. Examples would include drugs like altretamine. 
-
Epipodophyllotoxin-related - epipodophyllotoxins are also used in chemotherapy.  
-
Other Types. 


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x
AML Not Otherwise Categorized. 
-
AML minimally differentiated (MO).  
-
AML without maturation (M1).  
-
AML with maturation (M2).  
-
Acute myelomonocytic leukemia (M4).  
-
Acute monocytic leukemia (M5).  
-
Acute erythroid leukemia (M6).  
-
Acute megakaryocytic leukemia (M7).
-
Acute basophilic leukemia.
-
Acute panmyelosis with myelofibrosis. 
Classifications for acute lymphocytic leukemia (ALL)
The recent WHO International panel on ALL recommends that the FAB classification be 
abandoned, since the morphological classification has no clinical or prognostic relevance. It 
instead advocates the use of the immunophenotypic classification mentioned below. 
x
Acute lymphoblastic leukemia/lymphoma Synonyms:Former Fab L1/L2. 
-
Precursor B acute lymphoblastic leukemia/lymphoma. Cytogenetic subtypes. 
-
Precursor T acute lymphoblastic leukemia/lymphoma.  
x
Burkitt’s leukemia/lymphoma Synonyms:Former FAB L3. 
x
Biphenotypic acute leukemia. 
Staging criteria for chronic lymphocytic leukemia (CLL)
Modified Rai staging criteria


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Staging criteria for B-cell Non-Hodgkin’s-lymphoma (NHL) 
Staging criteria for the subjects with B-cell Non-Hodgkins’ lymphoma is provided in Table 10 
below. 
Table 10 - Ann Arbor staging of lymphoma  
 
Identification of the presence or absence of symptoms should be noted with each stage 
designation, as defined in Table 11. 


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Table 11 - Subclassification of non-Hodgkin’s lymphoma (A and B categories)  










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Appendix H 
PRO Questionnaire EQ-5D  




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Appendix I 
Summary of PK/PD handling procedures and bioanalytical method  
Table 12 - Summary of handling procedures  
 
PK 
ADA 
RO/RD 
Blood sample 
volume: 
3 mL 
3 mL 
5 mL of blood or 2 mL 
of bone marrow 
Anticoagulant 
Tube Type: 
Blood will be collected into EDTA tub 
Blood will be collected into EDTA 
tube 
Blood will be 
collected into EDTA 
tube 
Handling 
procedures: 
Blood is centrifuged at 2000 g for 
20 minutes at +4°C within 30 min of 
sampling time. 
Blood is centrifuged at 2000 g for 
20 minutes at +4°C within 30 min of 
sampling time. 
Refer to operator 
manual 
Plasma aliquot 
split: 
2 samples, 0.5 mL in aliquot 1 and the 
remaining in aliquot 2 
2 samples, 0.5 mL in aliquot 1 and 
the remaining in aliquot 2 
Refer to laboratory 
manual 
Plasma storage 
conditions: 
Polypropylene tubes with screw caps 
and frozen promptly (within 1 hour after 
collection of blood) at (-)80°C. 
Polypropylene tubes with screw caps 
and frozen promptly (within 1 hour 
after collection of blood) at (-)20°C. 
Refer to laboratory 
manual)  
Plasma shipment 
conditions: 
Dry ice  
Dry ice  
Ambient temperature 
Table 13 - Bioanalytical method for SAR650984 in plasma  
Analyte 
SAR650984 
ADA 
RO/RD 
RO/RD 
Matrix: 
Plasma 
Plasma 
Blood 
Bone marrow 
Analytical 
technique: 
ELISA 
PandA 
Flow cytometry 
Flow cytometry 
Lower limit of 
quantification: 
 0.500 ng/mL 
n.a. 
n.a. 
n.a. 
Assay volume: 
100 μL 
20 μL 
5 mL 
2 mL 
Site of 
bioanalysis: 
Sanofi R&D DSAR, 
(Alfortville, France) 
Sanofi R&D 
DSAR, (Alfortville, 
France) 
Under the responsibility of 
Sanofi R&D DSAR, 
(Alfortville, France) 
Under the responsibility of 
Sanofi R&D DSAR, 
(Alfortville, France) 
Summary of procedures for collection, handling, storage and shipment of SAR650984 specimens 
for pharmacogenetic samples: please refer to laboratory manual. 
* This list is not intended to be exhaustive 










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Appendix K 
Summary of handling procedures for exploratory biomarker 
analysis in Phase 2 Stage 2  
Table 14 - Summary of handling procedures  
 
FISH/Genomics/MRD/ 
Immune Phenotyping 
Immune 
Phenotyping 
Immune 
Genetics 
Determinants 
Adaptive Immune 
Responsea (including 
T-Cell Repertoire 
[TCR]) 
Sample volume:  
6 mL of bone marrow aspirate 
(BMA) 
4 mL of blood 
4 mL of blood 
6 mL of blood 
Tube type: 
BMA will be collected into K3 
EDTA tube 
Blood will be collected into K2 EDTA tube 
Handling procedures: 
Collect bone marrow aspirate 
(BMA) according to local 
clinical procedures.  
Fill tube completely with BMA. 
Gently invert 8-10 times.  
Do not freeze BMA.  
Sample should remain 
AMBIENT. 
Fill tube completely. Gently invert 8-10 times. 
Do not open tube.  
Do not centrifuge.  
Do not freeze sample.  
Sample should remain AMBIENT. 
Shipment conditions: 
Ambient temperature. 
Ambient temperature. 
Shipment to: 
Do not ship to Medpace 
Reference Laboratories.  
 
Please ship directly via World 
Courier on the day of 
collection to Pr. Hervé AVET-
LOISEAU (IUCT Toulouse) for 
Europe and ROW sites, or to 
Mayo Clinic (Scottsdale) for 
America sites. 
The central lab should receive 
samples within 24 hours after 
collection. 
Do not ship to Medpace Reference Laboratories.  
 
Please ship directly via World Courier on the day of collection to Pr. 
Hervé AVET-LOISEAU (IUCT Toulouse) for Europe and ROW sites, 
or to Mayo Clinic (Scottsdale) for America sites. 
The central lab should receive samples within 24 hours after 
collection. 
a In addition to TCR analysis, blood samples will be collected for Adaptive Immune Response - Humoral and Cellular response assessment. 
Refer to Laboratory Manual for complete handling procedures and shipping instructions. 


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Appendix L 
Protocol amendment history  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
before the Clinical Trial Summary. 
The reasons for amendment for all other amendments are provided below: 
1. 
Amended clinical trial protocol 01 based on Amendement 1 (16-Dec-2009) 
Reason for amendment 
To address issues raised during FDA review of the final version of the protocol: 
x Revise definition of DLT to include hematological toxicities 
x Provide a procedure to notify investigators of DLTs and SAEs within 24 hours 
x Ensure that the first 2 patients in a multiple-dose cohort do not receive study drug on the 
same day 
x Remove patients with dose delays greater than 2 weeks for an AE from study 
x Increase monitoring for glucose levels following the first 2 doses of study drug 
x Clarify definition of patients considered unsuitable for standard first-line treatment but 
suitable for treatment with study drug 
x Add assessment of vital signs 6 hours following first infusion of study drug 
2. 
Amended Clinical Trial protocol 02 based on Amendement 2 (07-Apr-2010) 
Reason for amendment 
To make the following revisions and/or corrections: 
x Update Clinical Study Director 
x Correct Clinical Trial Summary, Assessment Schedule, Disease Response Evaluation as 
follows: 6HUXPȕ-microglobulin to be performed as indicated in Study Flowcharts; Add 
AML. Include blast counts for B-cell ALL/AML patients. 
x Revise Pharmacokinetics/Pharmacodynamics Flowcharts as follows: Clarify that RO in 
blood to be performed on ALL, AML, and CLL patients only and that RO in bone marrow 
to be performed on MM patients only. Move RO in bone marrow from C1D8 to C2D14; 
Add PK, RO in blood, and ADA at C2D14 (Basic Phase). 
x Correct Pharmacokinetics/Pharmacodynamics Flowcharts as follows: Correct S = Serum 
to P = Plasma for PK and ADA; Correct ADA = Anti-Drug Antibody. 
x Revise Study Flowcharts as follows: Revise per revisions made to 
Pharmacokinetics/Pharmacodynamics Flowcharts; Clarify that archival sample may be 
used at screening for CD38 expression; Remove CD38 expression to be performed after 
screening/baseline; Add that spirometry and diffusion capacity will also be performed at 


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End of Treatment visit; Add additional parameters to be performed for urinalysis; Revise 
holter monitoring to have holter placed on the patient 2 hours before starting the infusion. 
x Correct Study Flowcharts as follows: Correct per modificatons made to 
Pharmacokinetics/Pharmacodynamics Flowcharts; Correct respirometer to spirometry. 
x Revise/Correct Section 12 Study Procedures to reflect changes made to Study Flowcharts. 
x Clarify regarding secondary endpoint(s) for PK samples. 
x Revised Appendix C to reflect Central Labs. 
x Minor edits for consistency in formatting. 
3. 
Amended Clinical Trial protocol 03 based on Amendement 3 (11-Oct-2010) 
Reason for amendment 
To make the following revisions and/or corrections: 
x Revise study design to include intra-patient dose escalation. 
x Revise main selection criteria to exclude patients with platelets <50 x 109/L for all 
indications. 
x Clarify IP dilution and rate of infusion for patients. 
x Revise Study Flowcharts as follows: Clarify CXR, Diffusion Capacity and Spirometry can 
be completed within one week prior to IP administration; Clarify timing of Day 1 RO bone 
marrow for multiple myeloma patients; Clarify that Day 1 RO bone marrow can be 
combined with disease assessment bone marrow if completed within 7 days of IP 
administration; Clarify that bone marrow for RO in multiple myeloma patients is optional 
for Cohorts 1-3. 
x Minor edits for consistency in formatting. 
4. 
Amended Clinical Trial protocol 04 based on Amendement 4 (05-Jan-2011) 
Reason for amendment 
To make the following revisions and/or corrections: 
x Revise study design to remove intra-patient dose escalation. 
x Clarify main selection criteria for multiple myeloma to include patients with free light 
chain disease. 
x Revise main selection criteria to exclude patients with platelets <50 x 109/L for all 
indications. 
x Clarify IP dilution and rate of infusion for patients. 
x Revise Study Flowcharts as follows: Clarify CXR, Diffusion Capacity and Spirometry can 
be completed within one week prior to IP administration; Clarify multiple myeloma 
disease assessment parameters; Clarify timing of Day 1 RO bone marrow for multiple 


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myeloma patients; Clarify that Day 1 RO bone marrow can be combined with disease 
assessment bone marrow if completed within 7 days of IP administration; Clarify that 
bone marrow for RO in multiple myeloma patients is optional for Cohorts 1-3. 
x Minor edits for consistency in formatting. 
x Cover Page: Removed the Protocol amendment 1, 2, 3 titles to be compliant with current 
template standards. 
5. 
Amended Clinical Trial protocol 05 based on Amendement 5 (10-Sep-2012) 
Reason for amendment 
x 
Change to the DLT definition 
In section(s): Clinical Trial Summary and 9.1.1 
Rationale: to modify DLT definition to remove Grade 2 or higher allergic 
reaction/hypersensitivity attributed to SAR650984 
x 
Change to the study flowchart for basic dose escalation 
In section(s): 1.6 
Rationale: to modify acceptable timing of subsequent cycles following Cycle 2, to add +/-1 day 
window for Day 8 and Day 14 evaluations, and to modify timing of screening bone marrow 
biopsy/aspiration receptor occupancy assessment 
x 
Change to guidelines for management of hypersensitivity reactions 
In section(s): 6.7  
Rationale: clarify management of hypersensitivity reactions in the setting of routine pre-
medication with dexamethasone and diphenhydramine 
x 
Change to dose of drug per administration 
In section(s): 8.1.2 
Rationale: clarify that actual body weight as measured at each cycle should be used for dose 
calculation 
x 
Institute routine pre-medication with dexamethasone and diphenhydramine 
In section(s): 8.1.5 
Rationale: institute routine pre-medication for observed mild hypersensitivity reaction prophylaxis 
x 
Clarify disease assessment parameters 
In section(s): 1.6 and 12.2 


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Rationale: clarify that selection of disease assessment parameter is based on clinical indication 
and judgment of investigator 
x 
Clarify timing of safety evaluations to be performed including laboratory 
assessments and EKG 
In section(s): 12.3 and 12.4 
Rationale: clarify timing of safety evaluations to be consistent with study flowcharts 
x 
Clarify response criteria for non-secretory multiple myeloma 
In section(s): Appendix D 
Rationale: clarify response criteria for serum free light chain analysis for patients who have non-
secretory multiple myeloma, as developed by the International Myeloma Working Group 
(IMWG) 
In addition, other minor changes are listed in the description of changes (next section). 
6. 
Amended Clinical Trial protocol 06 based on Amendement 6 (05-Apr-2013) 
Reason for amendment 
x Addition of dose escalation and expansion cohorts 
In section(s): tabulated clinical trial summary, sections 1.2, 1.4, 1.5, 1.6, 1.9, 1.10, 4.8.2, 6.1, 
6.2.2, 6.3, 6.6, 6.8, 8.1.2, 8.1.3, 9.1, 9.2, 9.3.2, 12.1, 12.4, 12.5 and 13.1 of the protocol 
Rationale: 
- 
Analysis of PK data up to Cohort 9 (5 mg/kg, every 2 weeks) and modeling of the 10 
mg/kg every 2 weeks PK data indicates a higher steady state concentration is required 
to sustain the desired concentration anticipated for tumor elimination (based on 
preclinical data). Therefore, 2 dose escalation cohorts have been included to additional 
dose levels and schedules. Cohort 11 will evaluate 10 mg/kg every week and Cohort 
12 will evaluate 20 mg/kg every 2 weeks. 
- 
One expansion cohort and one optional expansion cohort have been added to fully 
evaluate the MTD or effective dose in multiple myeloma patients, the target population 
for future studies. The 2 expansion cohorts are defined as patients with (1) standard 
risk multiple myeloma and (2) an optional high risk multiple myeloma. 
- 
The protocol has been updated through to reflect the study is now evaluating an every 
week and every 2 week schedule. 
x Change to the inclusion/Exclusion criteria 
In section(s): tabulated clinical trial summary, sections 7.2 & 7.3 of the protocol 


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Rationale: 
- 
I01. was updated to define the multiple myeloma population that will be eligible for 
Cohorts 11, 12 and the standard risk and high risk expansion cohorts. 
- 
E09. was clarified to exclude patients who have had an allogenic transplant within 1 
year or have active graft versus host disease. 
x Addition of new rate of infusion information  
In section(s): tabulated clinical trial summary, section 8.1.2 of the protocol 
Rationale: 
- 
Information on the rate of infusion for the 20 mg/kg dose level was added. 
x Change to the assessment schedule 
In section(s): tabulated clinical trial summary, sections 1.4, 1.5, 1.6, 1.9, 1.10, 9.2, 9.3.2, 12.3, 
12.4, 12.5 of the protocol 
Rationale: 
- 
A new assessment schedule for the weekly administration was introduced. 
- 
A new assessment schedule for the every 2 week administration starting from chort 12 
was introduced. 
- 
The assessment schedule for the every 2 week administration (Cohorts 1-10) was 
updated to allow the C2D1 PK sample to be taken predose and to clarify the chest X-
ray, spirometry and diffusion capacity assessments can be performed within one week 
prior to IP administration in each cycle. 
In addition, other administrative corrections and clarifications were made. All changes are listed 
in the description of changes (next section). 
7. 
Amended Clinical Trial protocol 07 based on Amendement 7 (13-Aug-2013) 
Reason for amendment 
x Change to the Exclusion criteria 
In section(s): tabulated clinical trial summary, sections 7.3 of the protocol 
Rationale: 
- 
E016. were clarified/added in order to better define required contraception. 
x Change Clinical Study Director 
In section(s): Names and Addresses 
Rationale: 
- 
Change in study personnel for this study 


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8. 
Amended Clinical Trial protocol 08 based on Amendement 8 (19-Mar-2014) 
Reason for amendment 
x Additional of the Phase 2 part to the protocol 
Sections that were amended or added: title page, tabulated clinical trial summary, 1.3, 1.8, 1.13, 
4.7, 4.8, 5.1, 5.2, 6.2, 6.4, 6.6, 6.7, 7.1, 7.4, 7.5, 8.1, 8.3, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 10.6, 11.4, 
12.2, 12.3, 13.1, 13.2, 13.3, 13.4, 13.5, 15.5, 18, Appendix C, Appendix E, Appendix G, 
Appendix H, Appendix I 
Rationale: the Phase 2 part of the study was added to evaluate the efficacy of SAR650984 in 
patients with relapsed and/or refractory multiple myeloma. The Phase 2 part is to commence after 
the standard risk expansion cohort has completed enrollment. The addition of the Phase 2 part will 
allow for a seamless enrollment of patients to the study once the standard risk expansion cohort 
has completed enrollment. 
x Change to dose modification guidance 
In section(s): 6.4 
Rationale: To enable patients in the Phase 1 part of the study to be considered for intra-patient 
dose modifications if they have received treatment for at least 12 weeks on current dose level and 
they have no SAR-related AE > Grade 1. 
x Change to the frequency of Chest X-ray, Spirometry, Diffusion Capacity 
In section(s): 1.9, 1.10, 1.11, 12.1.2.1, 12.1.3.1, 12.1.4.1 
Rationale: To reduce the frequency of chest X-ray, spriometry and diffusion capacity for patients, 
these assessments are only required during the first 2 cycles and then as clinically indicated.  
In addition, other minor changes are listed in the description of changes (next section). 
9. 
Amended Clinical Trial protocol 09 based on Amendement 9 (08-Apr-2014) 
Reason for amendment 
x Change to the Exclusion criteria 
In section(s): tabulated clinical trial summary, Sections 7.3 & 7.5 of the protocol 
Rationale: Phase 1 E08 and Phase 2 E17 exclusion criteria were modified to include known 
intolerance to histidine or known hypersensitivity to any components of the study therapy to 
ensure the exclusion criteria corresponds to the excipients listed in the investigator brochure.  
x Include a time window for collection of PK samples 
In Section(s): 1.8 of the protocol 


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Rationale: to provide a time window for collection of PK samples. 
In addition, other minor changes are listed in the description of changes (next section). 
10. 
Amended Clinical Trial protocol 10 based on Amendement 10 (22-Aug-2014) 
Reason for amendment 
x Addition of Cohort 13 to the Phase 1 part of the study 
In section(s): tabulated clinical trial summary, Sections 4.8.2 and 6.1.1.2 
Rationale: addition of Cohort 13 was added to enable evaluation of the 20 mg/kg every week 
(QW) dose level. 
x Addition of Stage 1b to the Phase 2 part of the study 
In section(s): tabulated clinical trial summary, PK/PD Flowchart 1.8, Study Flowchart 1.14, 
Sections 4.8.2, 4.8.4, 6.2, 6.7.5, 12.2, 13.1, 13.4, 13.5 
Rationale: addition of Stage 1b was added to the Phase 2 part of the protocol following additional 
PK analysis of the dose escalation and expansion cohorts. The updated analysis of PK parameters 
of patients in the 10 mg/kg every 2 weeks (Q2W) dose escalation and standard risk expansion 
cohorts demonstrated a high level of variability in exposure and nonlinear clearance. These data 
suggest that SAR650984 exhibits nonlinear pharmacokinetics with target-mediated clearance 
dominating the elimination phase at low concentrations (10-ȝJP/ZKLFKOHDGVWRORZ
exposure and high inter-patient variability at 10 mg/kg Q2W. In order to overcome the mediated 
clearance disposition and reach the desired higher concentration, a higher dose and more intense 
‘loading’ schedule may be required. Based on PK modeling and simulation a dose of 20 mg/kg 
QW for Cycle 1 then Q2W thereafter was selected for further evaluation in Arm 4 (Stage 1b). 
Enrollment into arm 4 will commence once safety has been established in Cohort 13 of the Phase 
1 part of the study. 
x Addition of MRD and tumor cell CD38 mRNA to exploratory endpoints 
In section(s): tabulated clinical trial summary, Study Flowcharts 1.13, 1.14, Sections 5.3, 9.6 and 
12.2 
Rationale: the minimal residual disease (MRD) assessment was not included when the Phase 2 
part was originally added to TED10893, however since Amendment 9 was issued the 
methodology to evaluate this important exploratory endpoint has been defined. It is being 
included to fully evaluate the depth of response in patients who achieve a complete response (CR) 
and determine if any minimal residual disease exists in these patients. For this assessment, a 
sample of the bone marrow aspirate collected for routine disease assessment will be used. In 
addition, an existing exploratory endpoint has been further clarified to specifically state tumor cell 
CD38 mRNA will be evaluated and correlated with clinical response. This protocol clarification 
does not result in any additional blood or bone marrow samples for the CD38 mRNA analysis. 
x Addition of optional pharmacogenetic sample 


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In section(s): Study Flowcharts 1.13, 1.14, Sections 9.6 and 12.2 
Rationale: an optional pharmacogenetic sample has been included in the Stage 2 part of the study. 
This sample will be collected on day 1 Cycle 1 only from patients who have signed the optional 
pharmacogenetic informed consent. 
x Change to dose modification guidance 
In section(s): Section 6.4 
Rationale: to enable all patients in the Phase 2 part of the study to be considered for treatment at a 
higher dose level if they have disease progression while on study treatment. To be considered, 
patients must have been able to tolerate their original dose or schedule for at least 1 cycle and all 
modifications will be discussed on a case-by-case basis between Sanofi and the treating 
investigator. 
x Clarification of the Adverse Event of Special Interest and overdose definition 
In section(s): Sections 10.6, 10.8, and Appendix J 
Rationale: the definition of AESI has been clarified and updated based on the ongoing safety 
review. In addition, 2 tables have been included in the Appendix to provide guidance on the 
symptoms and diagnosis typical of an infusion associated reaction. Clarification was also 
provided to the definition of an overdose to harmonize with the new AESI definition. 
x Clarification of the high risk cohort definition 
In section(s): tabulated clinical trial summary and Section 7.1 
Rationale: to clarify the prior therapy inclusion requirements for the high risk cohort. These 
requirements are stated as general requirements for all patients enrolled into expansion cohorts 
(which include the high risk cohort); however, this clarifies specifically for the high risk. 
x Addition of refractory definition 
In section(s): Section 7.4 and Appendix C 
Rationale: to provide a clear definition of refractory disease according to the IMWG guidance. 
x Clarification of AEs and SAEs during the follow-up period 
In section(s): tabulated clinical trial summary, Study Flowcharts 1.10, 1.11, 1.12, Sections 10.5.1 
and 11.2.2 
Rationale: clarification and harmonization within the protocol that all IP-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 during the follow-up period until resolution or stabilization. 
x Clarification of assessments required during the follow-up period 
In section(s): footnotes of Study Flowchart 1.13, 1.14, Section 6.7.1 and 12.2 


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Rationale: clarification and harmonization within the protocol of those assessments that are 
required at 60 days and post-60 days after last IP administration. 
x Clarification on the guidelines for managing potential hypersensitivity reactions and 
potential tumor lysis syndrome 
In section(s): Sections 6.5 and 6.6 
Rationale: to harmonize with updated AESI language the guidance on managing potential 
hypersensitivity. The guidance on managing potential tumor lists syndrome (TLS) has been 
further clarified to define laboratory TLS and clinical TLS. 
x Update to Immunoglobulins to be assessed  
In section(s): Study Flowcharts 1.13, 1.14, and Section 12.2 
Rationale: IgD and IgE were added to the panel of immunoglobulins to be assessed during the 
Phase 2 part of the study. 
x Clarification to the PK parameters to be assessed  
In section(s): tabulated clinical trial summary and Section 9.3 
Rationale: clarification of the PK software being used and parameters that are being assessed. 
In addition, other minor changes are listed in the description of changes (next section). 
11. 
Amended Clinical Trial protocol 11 based on Amendement 11 (22-Apr-2016) 
Reason for amendment 
x To introduce the concentrated formulation of SAR650984/isatuximab that will be 
used in Phase 2 stage2 
In sections: tabulated clinical trial summary, 4.7.1, 4.7.2, 8.1.1, 8.1.2 and 8.3. 
Changes: characteristics of the new formulation of SAR650984 are added. 
Rationale: The SAR650984 process and formulation (abbreviated C1P1F1 for cell 1, 
process 1, formulation 1) used in TED10893 Phase 1 and Phase 2 Stage 1 was adequate to 
supply these studies but larger scale production is required for TED10893 Phase 2 Stage 2 
and phase 3 studies. Thus, a new drug product C1P2F2 (cell line 1, process 2, 
formulation 2) from the same cell line, a different process, a different manufacture site has 
being developed and is currently being evaluated in a Phase 1 safety study (TED14154) 
conducted in patients with multiple myeloma (MM). A preliminary safety analysis of the 
TED14154 study will be performed when all patients from dose escalation phase and dose 
expansion phase of the study will have completed at least one cycle of treatment. 
The Phase 2 Stage 2 part of the TED10893 study will be initiated only if the results from 
the preliminary analysis of safety and PK data are supporting the use of the C1P2F2. 


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Then all the patients enrolled in the Phase 2 Stage 2 part will be treated with C1P2F2, 
while ongoing patients in Phase 2 Stage 1 part will continue to receive C1P1F1. The study 
Investigators will be informed of the results from preliminary safety analysis of the 
TED14154 trial before treating any patients with C1P2F2 formulation in TED10893. 
In addition, the data monitoring committee (DMC) will review preliminary safety data of 
the first 12 patients treated in the Phase 2 Stage 2 with a cut-off date 1 month after first 
dose of the last patient. 
x To provide the dose and schedule of administration of SAR650984 for the Phase 2 
Stage 2 part of the study 
In sections: 4.8.2, 4.8.4, and 6.2. 
Changes: clinical and pharmacokinetic data supporting the dose and schedule of 
SAR650984 administration are described. 
Rationale: As planned in the protocol, an interim analysis of efficacy, safety and 
pharmacokinetic (PK) data from the Phase 2 Stage 1 part of the TED10893 study was 
performed in September 2015 to define the dose and schedule to be used in Phase 2 Stage 
2. Based on this analysis including also PK/PD modelling and simulation detailed in 
updated section 4.8.4, the following dose and the schedule of administration were selected 
for the Phase 2 Stage 2: 20 mg/kg every week for 4 infusions followed by 20 mg/kg every 
2 weeks. 
In section: 6.4 
Changes: The definitions of dose delay, dose modifications and dose omission are clarified 
Rationale: dose delay, dose modifications and dose omission definitions are added for 
Phase 2 Stage 2 part in order to allow harmonization across project studies and to fix the 
rules for the data analysis. 
x To introduce the evaluation of SAR650984 alone (ISA) or in combination with 
dexamethasone (ISAdex) in Phase 2 Stage 2 and to clarify the route of administration 
of dexamethasone. 
In sections: Tabulated summary, flow chart1.14, 4.8.4, 5, 6.2, 6.7, 8.2, 8.5, and 12.2 
Changes: In Phase 2 Stage 2, an isatuximab in combination with dexamethasone arm is 
added. In ISAdex arm, dexamethasone being part of isatuximab premedication and of the 
combination regimen, will be given IV or PO at the discretion of the investigator, on 
days 1, 8, 15 and 22 of each cycle. Doses will be adapted according patient age. Dose 
modifications are planned in case of adverse events related to dexamethasone. In ISA arm, 
steroids premedication will be given IV or PO at the discretion of the investigator and will 
still follow the rules as indicated in the protocol. 


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Rationale: dexamethasone has been used as monotherapy at a high dose, and more 
frequently at a lower dose in combination with other therapeutic agents for multiple 
myeloma treatment, including cytotoxic agents (cyclophosphamide, melphalan), 
proteasome inhibitor (Velcade®/bortezomib, carfilzomib, ixazomib), IMiD (thalidomide, 
lenalidomide, pomalidomide), HDAC inhibitor (panobinostat) and monoclonal antibody 
(elotuzumab). It has been demonstrated that the addition of dexamethasone onto a variety 
of regimens significantly increase the clinical activity, with adding limited toxicities. For 
example, in a heavily pre-treated RRMM population, pomalidomide alone achieved an 
over response rate of 7.4%, and adding dexamethasone increased overall response rate to 
29.2%. As another example, for patients with relapsed multiple myeloma who failed to 
responding to Velcade® monotherapy (defined as progression after 2 cycles of treatment or 
stable disease after 4 cycles of treatment), adding dexamethasone onto Velcade® achieved 
18% of response rate (minimal response or better). Therefore, a second arm is added in 
Stage 2 to evaluate the activity of isatuximab in combination with dexamethasone. Patients 
in Stage 2 will be randomized to either isatuximab or to isatuximab + dexamethasone arm 
using a 2:1 randomization ratio. 
x To update the inclusion/exclusion criteria for the Phase 2 Stage 2 part of the study 
In section(s): tabulated clinical trial summary and section 7.4, 7.5. 
Changes: Clarification of inclusion criteria for Phase 2 Stage 2. Criteria for progressive 
disease and refractory disease are also detailed. 
Rationale: Inclusion criteria are modified to include clarification on patients status at study 
entry. 
In section(s): tabulated clinical trial summary and in section 7.5. 
Changes: a few exclusion criteria are adjusted for Phase 2 Stage 2. 
Rationale: For sake of clarity and to update few criteria according to the most recent 
reference 
x To add a section on Contraceptive measures and to add additional serum pregnancy 
tests during the study period 
In section: flow chart 1.14, and in section 12.2 
Changes: serum pregnancy tests are added at the beginning of each cycle 
Rationale: to comply with European Guidance 
In section: 8.11 
Changes: Contraceptive measures is added 


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Rationale: to comply with European Guidance, a new section on “contraceptive measures” 
has been added. 
x To update the assessment of the Investigational Product 
In sections: 6.5 and 6.6 
Changes: Table 3 and table 5 are added with updated general guidelines to be implemented 
for Infusion Associated Reactions and Tumor Lysis Syndrome, respectively. 
Rationale: to harmonize these general guidelines across the ongoing studies 
In section: 9.3 
Changes: Pharmacokinetic evaluation in Phase 2 Stage 2 part of the study is updated. 
Rationale: Sparse sampling has been implemented in Phase 2 to perform population PK 
analysis with pool data from Phase 1 and 2. 
In sections: Tabulated summary, 1.14 (Study Flowchart), footnotes 33-44, 9.6 and 12.2 
Changes: Phase 2 exploratory biomarker studies is changed for Phase 2 Stage 2 of the study 
Rationale: Based on recent publications, poor prognosis has been associated with several 
chromosomal abnormalities detected by FISH method. Additional tests will be performed 
to detect these abnormalities in Stage 2. 
According to clinical data (ASH 2015), increased adaptive immune responses contribute to 
Daratumumab’s efficacy in MM patients. Analysis of adaptive responses including the 
quantification of the T-cell receptor genetic variability (TCR) will be performed in blood 
at C1D1, C3D1 and C5D1 and correlated with clinical response in Stage 2. 
x To update the disease assessment procedures and IMWG criteria 
In sections: 1.14 (Study Flowchart) and footnotes 26, 34, 37, 40 and 12.2 
Changes: the disease assessment procedures are detailed for Phase 2 Stage 2 
Rationale: to ensure an accurate and homogeneous evaluation of the efficacy of isatuximab 
in the selected population 
x To change the statistical part for Phase 2 Stage 2 part of the study 
In sections: tabulated clinical trial summary and 1.3, 7.1, 13.1 
Changes: The sample size calculation has been revised. 


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Rationale: Assumptions for sample size calculations are adjusted to account for changes in 
inclusion criteria for Stage 2 and Stage 1 interim analysis results. Sample size calculation 
for the isatuximab + dexamethasone arm is also added. 
x To change appendices B and E and to add Appendix K 
Changes: The modification of Diet in Renal Disease (MDRD) equation for creatinine 
clearance calculation is added for Phase 2 Stage 2 part for consistency across the studies. 
The IMWG criteria table is updated. 
The appendix K is added to provide the Investigators with the background information and 
guidance regarding anti-CD38 interference with serologic testing. 
Rationale: Appendices B and E are updated to keep consistency across the study protocol 
for Phase 2 Stage 2 part including the changes described above. 
CD38 monoclonal antibodies can result in interference with blood bank serologic tests and 
thereby cause delays in issuing Red Blood Cell (RBC) units to patients receiving these 
agents. The AABB Clinical Transfusion Medicine Committee has developed a bulletin 
(# 16-02) to provide background information and guidance to members regarding anti-
CD38 interference with serologic testing. This bulletin is attached in the Appendix K. In 
addition, the patients treated in the study will receive a blood type card indicating the 
treatment with a CD38 agent and the study site will notify its blood bank that the patient is 
receiving an anti-CD38 treatment. 
x Finally, other additional minor changes and edits will be included in this amendment 
for the sake of clarity 
12. 
Amended Clinical Trial protocol 12 based on Amendement 12 (12-Jul-2017) 
Reason for amendment 
x To add a potential interim analysis for Phase 2 Stage 2 
x In section(s): clinical trial summary and section 13.5 of the protocol 
Rationale: an interim analysis of the safety data from Phase 2 Stage 2 may be performed if the 
enrollment is not completed by December 2017. No formal statistical hypothesis will be tested in 
this analysis. 
x To change the exclusion criteria #12 for the Phase 2 Stage 2  
In section(s): tabulated Clinical Trial Summary, section 7.5 of the protocol 
Rationale: preliminary PK analyses shown that creatinine clearance is not a significant covariate 
on linear Clearance and volume of distribution from central compartment. To allow more 
heterogeneous population included in the study to better reflect multiple myeloma patient 
population, creatinine clearance exclusion criteria lowered from eGFR <30 mL/min/1.73 m2 to 
<15 mL/min/1.73 m2 


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x To add Phase 2 exploratory study objectives: adaptive immune response 
x In section(s): Clinical Trial Summary and sections 1.15, 5.3, 9.6, 12.2.3, 12.2.4 and 12.2.5 
of the protocol 
x Rationale: the additional blood samples to be collected at baseline and post treatment for 
humoral and cellular response to further understand of the potential mechanism of action. 
x To remove exploratory blood sample: soluble CD38 and optional pharmacogenetic in 
Phase 2 Stage 2 
x In section(s): Clinical Trial Summary and sections 1.14 and 12.2.3 of the protocol 
Rationale: These two analyses are to be removed from the protocol due to restricted total blood 
collection volume after inclusion of the new humoral and cellular immune response tests, which 
are deemed more important. PGx samples were for banking purpose only. 
x To remove the bone marrow sample for CD38 receptor density (RD) and receptor 
occupancy (RO) in Phase 2 Stage 2: 
In section(s): Clinical trial summary (endpoints and other evaluations), sections 1.8, 9.5, 1.15 and 
12.2.1 of the protocol. 
Rationale: The CD38 RD data have been collected in the TED10893 Phase 1, Phase 2 Stage 1. 
Although there was a trend of higher response rate in patients with higher CD38 RD, the 
correlation was not significant.  
x To remove central laboratory tests for blood chemistry, hematology, coagulation and 
urinalysis in Phase 2 Stage 2 
x In section(s): section 1.14 of the protocol 
Rationale: To reduce the blood volume to be drawn for each assessment, and the operation 
procedure, safety laboratory assessment include for hematology, biochemistry and coagulation 
will be done locally at investigator’s site only for Phase 2 Stage 2.  
x Removal of specific safety labs including cytokines, serum tryptase and markers of 
complement activation when a Grade 2 or higher Infusion Associated Reaction 
occurs in Phase 2 Stage 2 
x In section(s): Clinical Trial Summary and section 1.14 of the protocol 
x Rational: preliminary analysis in Phase 1 and Phase 2 Stage 1 did not show a clear 
evidence of cytokine linked with IAR.  
x To remove the ePRO in Phase 2 Stage 2 secondary endpoints 
x In section(s): Clinical Trial summary, sections 1.14, 5.2, 9.2.3.2, 12.2.3, 12.2.4, 12.2.5 and 
13.4.5 of the protocol 
x Rationale: Without a comparator arm, it is not expected to have a meaningful data 
concluded from patient reported outcome; therefore ePRO is to be removed in Phase 2 


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Stage 2 to avoid extra effort required for this assessment from sponsor, investigator and 
patient. 
x To change Dexamethasone from NIMP to IMP 
x In section(s): Clinical Trial summary, section 8.0 of the protocol 
x Rationale: requested by Austrian regulatory. 
x To add complete blood type, complete blood phenotyping and antibody screening 
tests at baseline and antibody test after study treatment in Phase 2 Stage 2 
In section(s): sections 1.15, 12.2.1 and 12.2.3 of the protocol 
Rationale: it has been reported, treatment with anti-CD38 mAb can have potential interference 
with various blood bank serologic tests. Therefore, tests will be done before and after treatment 
with isatuximab to assess the potential interference.  
x To add the possibility to switch the drug product for patients enrolled in Phase 2 
Stage 1 that are continued isatuximab treatment  
In section(s): tabulated Clinical Trial Summary (Investigational product(s)), sections 4.7.2 and 
8.1.1.2 of the protocol 
Rationale: The drug product used in Phase 2 Stage 1 was C1P1F1. The new drug product C1P2F2 
has been studied in the TED14154 and the clinical safety and activity are similar to what was 
observed with C1P1F1. C1P2F2 is now used in ongoing and all new studies. Patients enrolled in 
TED10893 Phase 2 Stage 1 and are still receiving study treatment may be switched from C1P1F1 
to C1P2F2 due to the drug availability.  
x To clarify the data collection for patients that are still on treatment after the final 
analysis cut-off date  
In section(s): tabulated Clinical Trial Summary, section 12.3 of the protocol 
Rationale: Data to be collected for patients continuing study treatment after the cut-off date for 
final analysis required clarifications.  
x To update PK and ADA sampling schedule 
In section(s): tabulated Clinical Trial Summary, section 1.8, 1.15, 12.2.3, 12.2.4, 12.2.5, 12.2.6 
and 12.2.7 of the protocol 
Rationale: Based the PK and ADA profile, PK and ADA Sampling beyond Cycle 10 will not 
provide additional information. 
x Update the definition of Infusion Associated Reactions as Adverse Event of Special 
Interest  
x In section(s): sections 6.5 and 10.6 of the protocol 


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x Rational: With the information that has been learned from Phase 1 and Phase 2 Stage 1, 
Grade 1 and Grade 2 Infusion Associated Reactions are no longer needed for an expedited 
report, to reduce the work load of Investigator’s site and sponsor. 
x To clarify the supply of Dexamethasone 
x In section: 8.1.6.1 
x Rationale: Clarification on the supply of Dexamethasone when commercial supplies are 
not available Dexamethasone will be re-labeled by Sponsor before supplies are provided to 
the study sites. 
x To add Flowchart 1.15 
x In section(s): Flowchart 1.15 
x Rationale: Flowchart 1.15 will be devoted to Phase 2 Stage 2 for a better clarity and easier 
to follow.  
x Updating Pharmacokinetic parameters in Phase 2 secondary endpoints  
x In sections: Clinical trial summary  
x Rationale: To fit the wording to a modelling approach, that will be on isatuximab 
concentrations obtained during Phase 2 Stage 2, instead of a Non-Compartmental 
Analysis, to provide individual PK parameters. 
x Clarify the end time of 24 hour urine 
x In sections: 1.14, 1.15, 12.2.1, 12.2.3, 12.2.4 and 12.2.5 
x Rationale: To provide clarity to the sites when the completion of the 24 hour urine for 
disease assessment must be completed. 
x Clarify dose delays/modifications 
x In section(s): 6.4 
x Rational: It was not clear about dose delays/modifications window and allowances.  
x To clarify when premedication can be reconsidered 
x In section: 8.2.2 
x Rational: To provide clarity to the Investigators when to reconsider the need for pre-
medications.  
x Clarify the definition of study treatment exposure in statistical analysis 
x In section: 13.4.2 
x Rational: To provide clarity of the assessment in the duration of study treatment exposure. 
x To clarify analysis of anti-drug antibody 
x In section(s): 13.4.8 
x Rational: To provide specific detail in the ADA analysis  


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x To delete Appendix J: Definitions of Infusion Associated Reactions (IAR) 
x In section(s): Appendix  
x Rationale most up-to-date information has been provided in the last version (2017 edition 
8) and will be updated with each version of IB. To avoid the need of revision in the study 
protocol, the definition of IAR will be cross-referenced to the most recent edition of IB.  
x To add Appendix K 
x In section(s): Appendix K 
x Rationale: provide instruction for the sample handling/process of exploratory biomarkers. 
x Editorial corrections 
x In sections(s):  
x Rationale: For better clarity and correct some editorial errors.  
13. 
Amended protocol [13] (11 June 2019) 
x This amended protocol (amendment 13) 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 
x 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, 
Section 7.3 Phase 1 Exclusion 
criteria and Section 7.5 Phase 2 
(Stage 1 AND Stage 2) Exclusion 
criteria 
E16 (Phase 1) and E24 (Phase 2) 
amended to indicate that female patients 
of child-bearing potential and male 
patients with female partners of child-
bearing potential will be required to use 
contraception for 5 months after 
discontinuation of study treatment, and 
that female patients of child-bearing 
potential in Phase 2 will require monthly 
pregnancy tests for 5 months after 
discontinuation of study treatment. 
Change from 12 weeks due to re-
estimation of isatuximab plasma half-life 
Tabulated clinical trial summary 
and 
Section 6.8.1 Duration of study 
participation for each patient 
Added that female patients of 
childbearing potential will have the serum 
pregnancy test every month for 5 months 
after the last administration of isatuximab. 
Due to re-estimation of isatuximab plasma 
half-life  
Section 4.8.2 Design rationale 
Re-estimation of isatuximab half-life of 28 
days is included. 
Due to re-estimation of isatuximab plasma 
half-life 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.11 Contraceptive 
measures 
Amended to indicate that that female 
patients of child-bearing potential and 
male patients with female partners of 
child-bearing potential will be required to 
use contraception for 5 months after 
discontinuation of study treatment. 
Change from 12 weeks due to re-
estimation of isatuximab plasma half-life 
Study flowchart for Phase 2,  
Stage 2, including footnote 15;  
Section 12.2.6 Follow-up period at 
60 days (±5 days) after last study 
treatment administration; Section 
12.2.7 Post 60 day follow-up 
period; and Section 12.3 Data 
collection after final analysis cutoff 
date 
Amended to indicate that females of 
child-bearing potential will be required to 
be tested for pregnancy every month for 
5 months after discontinuation of study 
treatment. 
Due to re-estimation of isatuximab plasma 
half-life 
 

SAP_003.pdf: 


Statistical Analysis Plan  
19-Nov-2015 
SAR650984-TED10893 (Phase 1) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN....................................................................................................................1 
TABLE OF CONTENTS..................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..........................................................................5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN.................................................................................7 
1.1 
STUDY DESIGN AND RANDOMIZATION ......................................................................................7 
1.2 
OBJECTIVES...................................................................................................................................8 
1.2.1 
Primary objectives............................................................................................................................8 
1.2.2 
Secondary objectives .......................................................................................................................8 
1.3 
DETERMINATION OF SAMPLE SIZE.............................................................................................9 
1.4 
STUDY PLAN...................................................................................................................................9 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL................................10 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN......................10 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .....................................................................11 
2.1 
ANALYSIS ENDPOINTS................................................................................................................11 
2.1.1 
Demographic and baseline characteristics ....................................................................................11 
2.1.2 
Prior or concomitant medications (other than anticancer therapies)..............................................14 
2.1.3 
Efficacy endpoints ..........................................................................................................................15 
2.1.4 
Safety endpoints.............................................................................................................................17 
2.1.4.1 
Adverse events variables ...............................................................................................................17 
2.1.4.2 
Deaths............................................................................................................................................18 
2.1.4.3 
Laboratory safety variables ............................................................................................................18 
2.1.4.4 
Vital signs variables........................................................................................................................19 
2.1.4.5 
Electrocardiogram variables...........................................................................................................19 
2.1.4.6 
Other safety endpoints ...................................................................................................................20 
2.1.5 
Pharmacokinetic variables .............................................................................................................21 
2.1.6 
Immune response ..........................................................................................................................21 
2.1.7 
Pharmacodynamic endpoints.........................................................................................................22 
2.1.8 
Quality-of-life endpoints..................................................................................................................22 
2.1.9 
Health economic endpoints............................................................................................................22 
2.1.10 
Further therapy after discontinuation of investigational medicinal product administration 
during the study..............................................................................................................................22 
(electronic 1.0)


Statistical Analysis Plan  
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2.2 
DISPOSITION OF PATIENTS .......................................................................................................22 
2.2.1 
Randomization and drug dispensing irregularities .........................................................................23 
2.3 
ANALYSIS POPULATIONS ...........................................................................................................23 
2.3.1 
All treated/safety population...........................................................................................................23 
2.3.2 
Evaluable for DLT population.........................................................................................................23 
2.3.3 
All-treated MM population ..............................................................................................................23 
2.3.4 
Pharmacokinetic population...........................................................................................................23 
2.3.5 
Pharmacodynamic population........................................................................................................24 
2.4 
STATISTICAL METHODS .............................................................................................................24 
2.4.1 
Demographics and baseline characteristics ..................................................................................24 
2.4.2 
Prior or concomitant medications (other than anticancer therapies)..............................................25 
2.4.3 
Extent of investigational medicinal product exposure ....................................................................25 
2.4.4 
Analyses of efficacy endpoints.......................................................................................................27 
2.4.5 
Analyses of safety data ..................................................................................................................27 
2.4.5.1 
Analyses of adverse events ...........................................................................................................27 
2.4.5.2 
Deaths............................................................................................................................................31 
2.4.5.3 
Analyses of laboratory variables ....................................................................................................31 
2.4.5.4 
Analyses of vital sign variables ......................................................................................................31 
2.4.5.5 
Analyses of electrocardiogram variables .......................................................................................32 
2.4.5.6 
Analyses of other safety endpoints ................................................................................................32 
2.4.6 
Analyses of pharmacokinetic, immune response and pharmacodynamic variables......................32 
2.4.6.1 
Pharmacokinetic variables .............................................................................................................32 
2.4.6.2 
Immune response ..........................................................................................................................33 
2.4.6.3 
Pharmacodynamic variables ..........................................................................................................33 
2.4.6.4 
Pharmacokinetic/pharmacodynamic analysis ................................................................................33 
2.4.7 
Analyses of quality of life/health economics variables ...................................................................34 
2.4.8 
Further therapy after discontinuation of investigational medicinal product administration 
during the study..............................................................................................................................35 
2.5 
DATA HANDLING CONVENTIONS...............................................................................................35 
2.5.1 
General conventions ......................................................................................................................35 
2.5.2 
Data handling conventions for secondary efficacy variables..........................................................35 
2.5.3 
Missing data ...................................................................................................................................35 
2.5.4 
Windows for time points.................................................................................................................36 
2.5.5 
Unscheduled visits .........................................................................................................................36 
2.5.6 
Pooling of centers for statistical analyses ......................................................................................36 
2.5.7 
Statistical technical issues .............................................................................................................36 
3 
INTERIM ANALYSIS .....................................................................................................................37 
4 
DATABASE LOCK ........................................................................................................................38 
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Statistical Analysis Plan  
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5 
SOFTWARE DOCUMENTATION..................................................................................................39 
6 
REFERENCES...............................................................................................................................40 
7 
LIST OF APPENDICES .................................................................................................................41 
(electronic 1.0)


Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
Page 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ACTH: 
adrenocorticotrophic hormone   
ADA: 
anti-drug antibodies 
ADI: 
actual dose intensity 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase  
AST: 
aspartate aminotransferase  
AT: 
all treated 
ATC: 
Anatomical Therapeutic Chemical 
BOR: 
best overall response 
CBR: 
clinical benefit rate 
Ceoi: 
concentration at end of infusion 
COPD: 
chronic obstructive pulmonary disease 
CR: 
complete response 
CTCAE: 
Common Terminology Criteria for Adverse Events 
CTLS: 
clinical tumor lysis syndrome 
CV: 
coefficient of variation 
DL: 
dose level 
DLCO: 
diffusing capacity of the lungs for carbon monoxide  
DLT: 
dose limiting toxicity 
DOR: 
duration of response 
EBMT: 
European Society for Blood and Marrow Transplantation 
EC1: 
expansion cohort 1 
EC2: 
expansion cohort 2 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group  
eCRF: 
electronic case report form 
FEV1: 
forced expiratory volume in 1 second 
FIH: 
first in human 
FLC: 
free light chain  
FSH: 
follicle-stimulating hormone  
FUD: 
follow-up duration 
GH: 
growth hormone  
HLGT: 
high-level group term 
HLT: 
high-level term 
HR: 
heart rate, high risk 
Hs-CRP: 
high-sensitivity C-reactive protein  
IAR: 
infusion associated reaction 
IFN-Ȗ: 
interferon-gamma  
IL: 
interleukin 
(electronic 1.0)


Statistical Analysis Plan  
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IMiD: 
immunomodulatory drug 
ISS: 
International Staging System 
IV: 
intravenous 
KPS: 
Karnofsky Performance Status 
LC: 
light chain 
LH: 
luteinising hormone   
LLT: 
lower-level term 
LTLS: 
laboratory tumor lysis syndrome 
MAD: 
maximum administered dose 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MM: 
multiple myeloma 
MR: 
minor response 
MTD: 
maximum tolerated dose 
NCI: 
National Cancer Institute 
NE: 
not evaluable 
ORR: 
overall response rate 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamic, progressive disease 
PI: 
proteasome inhibitors 
PK: 
pharmacokinetic  
PR: 
partial response 
PS: 
performance status 
PSA: 
prostate specific antigen  
PT: 
preferred term 
Q2W: 
every 2 weeks 
QW: 
every week 
RD: 
receptor density  
RDI: 
relative dose intensity 
RO: 
receptor occupancy 
RP2D: 
recommended Phase 2 dose 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SD: 
standard deviation, stable disease 
SEM: 
standard error of the mean 
SGOT: 
serum glutamate-oxaloacetate transferase  
SGPT: 
serum glutamate-pyruvate transferase 
SOC: 
system organ class 
TEAE: 
treatment-emergent adverse event  
TLS: 
tumor lysis syndrome 
TNF-Į: 
tumor necrosis factor alpha  
TSH: 
thyroid-stimulating hormone  
TTR: 
time to response 
WHO-DD: 
World Health Organization-Drug Dictionary  
 
(electronic 1.0)


Statistical Analysis Plan  
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SAR650984-TED10893 (Phase 1) - isatuximab 
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Property of the Sanofi Group - strictly confidential 
Page 7 
1 
OVERVIEW AND INVESTIGATIONAL PLAN 
TED10893 is the first in human (FIH) study of isatuximab (SAR650984). It is an open-label, 
international multi-center study conducted in 2 parts (Phase 1 and Phase 2).  This statistical 
analysis plan (SAP) describes the statistical methods to be used for the analyses of data collected 
during the Phase 1 part of the study. This SAP should be read in conjunction with the amended 
study protocol (Version 10, 22 August 2014) and electronic case report form (eCRF). 
1.1 
STUDY DESIGN AND RANDOMIZATION 
The Phase 1 part of TED10893 was a dose-escalation study of isatuximab administered as a single 
agent as an intravenous (IV) infusion every week (QW) or every 2 weeks (Q2W) to adult patients 
with selected CD38+ hematological malignancies that have progressed on or after standard 
therapy for which there was no effective standard therapy, or for which the patient was not 
suitable for standard therapy at the discretion of the treating physician. 
In the Phase 1 part, a cycle was 14 days.  Treatment with SAR650984 was to be continued until 
unacceptable toxicity, disease progression, death, withdrawal of consent, or Investigator’s 
decision. 
The starting dose of isatuximab was 0.0001 mg/kg (representing 10% of theoretical CD38 receptor 
occupancy (RO) on normal B and T cells). The maximum dose defined in the protocol was 
20 mg/kg administered QW. 
Dose escalation was conducted using 2 dose-escalation schemes. 
Accelerated dose escalation scheme 
In this part of the study, 1 evaluable patient was planned to be enrolled per dose level (DL). A 
log-dose escalation between DLs was used until 0.1 mg/kg or 1 of the following events was 
observed, whichever was first: 
x 
Grade 1 or higher drug-related non-hematological toxicity including fever (excluding the 
events described in the next bullet point); 
x 
Grade 2 or higher nausea, vomiting, diarrhea, fatigue, asthenia, anorexia, alkaline 
phosphatase elevation, or local (injection site) reaction. 
If 1 of the above events was observed at 1 DL, the cohort was expanded to 3 patients and further 
dose escalations were performed using the basic dose-escalation scheme. 
Basic dose escalation scheme 
During this part of the study, 3 evaluable patients were planned to be enrolled in each cohort.  
A semi-log dose escalation was used between DLs. 
(electronic 1.0)


Statistical Analysis Plan  
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Page 8 
Dose-limiting toxicities, maximum administered dose, and maximum tolerated dose 
Potential dose limiting toxicities (DLTs) were defined as any Grade 3 or higher non-hematological 
toxicity (excluding allergic reaction/hypersensitivity [as per administrative letter sent to the 
investigators on 31 August 2012]), Grade 4 neutropenia, and/or Grade 4 thrombocytopenia lasting 
longer than 5 days, attributed to isatuximab and as defined by the National Cancer Institute (NCI) 
- Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
For both schemes, the DLT observation period was defined as 2 cycles (ie, 28 days). The data 
obtained during the DLT observation period were used to make decisions regarding cohort 
expansion and/or dose escalation for the next cohort. 
In the event that a potential DLT was reported, up to 6 patients were to have been assessed at this 
DL. If <2 out of 6 patients experienced a drug-related DLT at this DL, the study was to have 
proceeded to the next dose level with 3 patients per DL (basic dose-escalation scheme). If >2 out 
of 6 patients experienced a drug-related DLT, the maximum administered dose (MAD) was 
reached and dose escalation was to have been stopped. The maximum tolerated dose (MTD) was 
defined as the highest DL at which no more than 1 patient of a maximum of 6 patients 
experienced a drug-related DLT. Usually, the MTD is one DL below the MAD. 
Expansion cohorts 
Once the MTD or the recommended Phase 2 dose (RP2D) was defined (in case the MAD was not 
reached at doses up to 20 mg/kg), a cohort expansion of 18 patients was planned in patients with 
multiple myeloma (MM) (expansion cohort 1 [EC1]). An additional expansion cohort (expansion 
cohort 2 [EC2]) also enrolled patients with high-risk (HR) MM. 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of the Phase 1 part of this study was to determine the MTD/MAD of 
isatuximab according to the drug-related DLTs observed in patients with CD38+-selected 
hematological malignancies. 
1.2.2 Secondary objectives 
Secondary objectives of the Phase 1 part of the study were: 
x 
To characterize the global safety profile including cumulative toxicities. 
x 
To evaluate the pharmacokinetic profile of isatuximab in the proposed dosing schedule(s). 
x 
To assess the pharmacodynamics, immune response, and preliminary disease response. 
(electronic 1.0)


Statistical Analysis Plan  
19-Nov-2015 
SAR650984-TED10893 (Phase 1) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 9 
1.3 
DETERMINATION OF SAMPLE SIZE 
The Phase 1 part of this study aimed to establish the MTD of isatuximab according to DLTs 
observed. 
The number of DLs examined and the emerging isatuximab related toxicities determined the 
sample size. Up to 18 patients were planned to be enrolled in each expansion cohort. It was 
anticipated that up to approximately 85 patients in total would be enrolled to this part of the study. 
1.4 
STUDY PLAN 
Safety evaluations were performed continuously throughout the study and included the following: 
x 
Adverse events (AEs) (including DLTs) evaluation. Toxicity grade were determined 
according to the NCI CTCAE version 4.03. 
x 
Laboratory tests in blood and urine 
x 
Physical examinations and vital signs 
x 
Karnofsky Performance Status (KPS) 
x 
Level of human anti-drug antibodies (ADA) 
x 
Prostate specific antigen (PSA) and pituitary hormones levels (growth hormone [GH], 
follicle-stimulating hormone [FSH]/luteinising hormone [LH], adrenocorticotrophic 
hormone [ACTH], thyroid-stimulating hormone [TSH]) 
x 
Cytokines (tumor necrosis factor alpha [TNF-Į], interleukin [IL]-1-ȕ, IL-6, 
interferon-gamma [IFN-Ȗ]), markers of complement (C3, C4, CH50), serum tryptase 
x 
Pulmonary function tests (diffusing capacity of the lungs for carbon monoxide [DLCO] 
and forced expiratory volume in 1 second [FEV1]) 
x 
Electrocardiogram (ECG) and Holter monitoring 
x 
Chest X-ray 
Disease response evaluation for patients with MM was performed every 4 weeks, unless otherwise 
stated, including: 
x 
Bone marrow biopsy/aspiration; 
x 
Radiologic imaging of plasmocytoma; 
x 
Bone skeletal survey; 
x 
M-protein quantification (serum and/or 24-hour urine), serum free light chain levels; 
x 
Serum ȕ2-microglobulin. 
(electronic 1.0)


Statistical Analysis Plan  
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Page 10 
The following additional evaluations were also performed: 
x 
Receptor density (RD) on bone marrow samples 
x 
Receptor occupancy (RO) on bone marrow samples 
Pharmacokinetic (PK) samples were collected in all patients receiving isatuximab as depicted in 
the PK study flowcharts included in the protocol. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL 
No modification of the statistical section of the protocol was made in the SAP. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
Not applicable.  This is version 1 of the SAP. 
(electronic 1.0)


Statistical Analysis Plan  
19-Nov-2015 
SAR650984-TED10893 (Phase 1) - isatuximab 
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Page 11 
2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
Unless otherwise specified, the baseline value is defined as the last available value before or on 
date of isatuximab administration. 
All baseline safety and efficacy parameters (apart from those listed below) are presented along 
with the on-treatment summary statistics in the safety and efficacy sections (Section 2.4.5 and 
Section 2.4.4). 
Demographic characteristics 
Demographic parameters include age, age by category (ie, < 65, and 65 years), gender (male, 
female), race (Caucasian/white, black, Asian/oriental, other), weight (kg), and Eastern 
Cooperative Oncology Group (ECOG) Performance Status (PS) at baseline. The correspondence 
between KPS (collected in the eCRF) and ECOG Performance Status is presented in Table 1. 
Table 1 - Performance status scales: Karnofsky & ECOG scores 
Karnofsky Status 
Karnofsky 
Grade 
ECOG 
Grade 
ECOG Status 
Normal, no complaints 
100 
0 
Fully active, able to carry on all pre-disease 
performance without restriction 
Able to carry on normal activities. Minor 
signs or symptoms of disease 
90 
1 
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, 
office work 
Normal activity with effort 
80 
1 
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, 
office work 
Care for self. Unable to carry on normal 
activity or to do active work 
70 
2 
Ambulatory and capable of all selfcare but 
unable to carry out any work activities. Up and 
about more than 50% of waking hours 
Requires occasional assistance, but able 
to care for most of his needs 
60 
2 
Ambulatory and capable of all selfcare but 
unable to carry out any work activities. Up and 
about more than 50% of waking hours 
Requires considerable assistance and 
frequent medical care 
50 
3 
Capable of only limited selfcare, confined to bed 
or chair more than 50% of waking hours 
Disabled. Requires special care and 
assistance 
40 
3 
Capable of only limited selfcare, confined to bed 
or chair more than 50% of waking hours 
(electronic 1.0)


Statistical Analysis Plan  
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Karnofsky Status 
Karnofsky 
Grade 
ECOG 
Grade 
ECOG Status 
Severly disabled. Hospitalisation indicated 
though death nonimminent 
30 
4 
Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair 
Very sick. Hospitalisation necessary. 
Active supportive treatment necessary 
20 
4 
Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair 
Moribund 
10 
4 
Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair 
Dead 
0 
5 
Dead 
Source: 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 Dec;5(6):649-55. 
Medical or surgical history 
Medical or surgical history other than the studied CD38+ hematological malignancies will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) version in effect at 
Sanofi at the time of database lock. 
Disease characteristics at diagnosis 
Disease type (eg, MM, chronic lymphocytic leukemia, non-Hodgkin’s lymphoma) will be 
described for all treated patients. 
MM characteristics at diagnosis 
The following MM characteristics at initial diagnosis will be described for patients with MM: time 
from initial diagnosis to first isatuximab administration (in years), International Staging System 
(ISS) stage, and MM subtype (as collected in the eCRF). 
MM characteristics at study entry 
The following MM characteristics at study entry will be displayed:  ISS stage, MM subtype 
(Table 2), % of plasma cells in bone marrow at baseline (<20%, [20-40%), [40-60%), and 60%), 
patients with plasmacytomas, patients with bone lesions, ȕ2-microglobulin level in mg/L 
(quantitative results and by category:  <3.5 mg/L, [3.5-5.5 mg/L) and 5.5 mg/L), albumin in g/L 
(quantitative results and by category:  <35 g/L and 35 g/L). 
Table 2 - ISS staging definition 
Stage 
Definition 
Stage I 
ȕ2-microglobulin <3.5 mg/L and albumin  35 g/L 
Stage II 
[ȕ2-microglobulin <3.5 mg/L and albumin <35 g/L] or [ȕ2-microglobulin 3.5 - <5.5 mg/L] 
Stage III 
ȕ2-microglobulin 5.5 mg/L 
ISS = International Staging System 
(electronic 1.0)


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Table 3 - Derivation of MM subtype at study entry 
Dose level 
Subtype 
Criteria 
10 mg/kg Q2W 
Serum M-Protein 
Serum M-protein >0 g/dL and 1 post baseline assessment 
 
Urine M-Protein 
Serum M-protein = 0 g/dL or missing 
and 
urine M-protein 200 mg/24 hours and 1 post baseline assessment 
 
Kappa light chain (LC) 
Serum M-protein = 0 g/dL or missing 
and 
urine M-protein <200 mg/24 hours or missing 
and 
kappa LC >lambda LC and kappa LC 10 mg/dL and 
1 post baseline assessment 
 
Lambda LC 
Serum M-protein = 0 g/dL or missing 
and 
urine M-protein <200 mg/24 hours or missing 
and 
lambda LC >kappa LC and lambda LC 10 mg/dL and 
1 post baseline assessment 
>10 mg/kg Q2W (including 
expansion cohort) 
Serum M-Protein 
Serum M-protein 0.5 g/dL and 1 post baseline assessment 
 
Urine M-Protein 
Serum M-protein <0.5g/dL or missing 
and 
urine M-protein 200 mg/24 hours and 1 post baseline assessment 
 
Kappa LC 
Serum M-protein<0.5g/dL or missing 
and 
urine M-protein <200 mg/24 hours  or missing 
and 
kappa LC >lambda LC and kappa LC 10 mg/dL and 
1 post baseline assessment 
 
Lambda LC 
Serum M-protein <0.5 g/dL or missing 
and 
urine M-protein <200 mg/24 hours or missing 
and 
lambda LC >kappa LC and lambda LC 10mg/dL and 
1 post baseline assessment 
LC = light chain; MM = multiple myeloma; Q2W = every 2 weeks 
Molecular subtype (for patients with MM only) 
Molecular subtype included cytogenetics analysis (17p deletion, t (4, 14), t (14; 16) and 1q gains 
(CKS1B)) as per local laboratory. 
(electronic 1.0)


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Prior anticancer therapies (for patients with MM only) 
x 
Prior anticancer treatments:  number of prior lines (as a quantitative variable), main 
anticancer treatments (ie, alkylating agent, immunomodulatory drug [IMiD], proteasome 
inhibitors [PI] agent, PI or IMiD agent, PI and IMiD agent, bortezomib, carfilzomib, 
lenalidomide, pomalidomide, thalidomide, elotuzumab, bendamustine, bortezomib or 
lenalidomide, bortezomib and lenalidomide, carfilzomib or pomalidomide, carfilzomib and 
pomalidomide), time from completion of last line of treatment to first isatuximab 
administration (months), best response to last line, duration of last line of therapy 
x 
Prior transplant:  number (%) of patients with transplant, type of transplant, number of 
transplant by patient 
x 
Prior surgery:  number (%) of patients with any prior surgery related to cancer, type of 
surgery, and time from last surgery to first SAR650984 administration (months) 
x 
Prior radiotherapy:  number (%) of patients with any prior radiotherapy related to cancer, 
intent, and time from last radiotherapy to first study treatment infusion (months) 
Any technical details related to computation, dates, and imputation for missing dates, are 
described in Section 2.5. 
2.1.2 Prior or concomitant medications (other than anticancer therapies) 
All medications taken within 7 days prior to registration into the study, at any time during the 
treatment period, and up to 30 days after the last isatuximab administration were to have been 
reported in the eCRF. 
The following variables were collected in the medication eCRF page:  drug/medication (brand or 
generic name), reason (eg, curative, prophylaxis), start date and end date (if available)/ongoing 
(otherwise). 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
version in effect at Sanofi at the time of database lock. 
x 
Prior medications are those the patient used prior (<) to first isatuximab administration.  
Prior medications can be those discontinued before first administration or those ongoing 
during the treatment phase. 
Concomitant medications are any treatments received by the patient concomitantly to isatuximab, 
from first dose to the date of last administration +30 days.  A given medication can be classified 
both as a prior medication and as a concomitant medication.  Any anti-cancer treatment 
administered after the date of the last isatuximab administration will not be considered as a 
concomitant medication and will be regarded as a post anticancer treatment (see Section 2.1.10). 
x 
Post-treatment medications (excluding post anticancer treatments) are those the patient 
took from 31 days after last isatuximab administration up to the end of the study. 
(electronic 1.0)


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Premedications 
As defined in Section 8.2.1 of the amended study protocol (version 10, 22 August 2014), patients 
were to routinely receive premedications prior to isatuximab infusion to reduce the risk and 
severity of hypersensitivity reactions. Premedications were defined in the protocol as 
noninvestigational medicinal product(s). The recommended premedication agents were: 
diphenhydramine 25-50 mg IV (or equivalent), methylprednisolone 100 mg IV (or equivalent), 
ranitidine 50 mg IV (or equivalent), and acetaminophen 650-1000 mg po 15-30 minutes (but no 
longer than 60 minutes) prior to isatuximab infusion. Premedications were reported in the eCRF 
as part of the concomitant medications. Analysis of premedications will focus on corticosteroids 
and diphenhydramine given (start and stop dates) on the days of isatuximab administrations for 
prophylaxis reason. 
Any technical details related to computation, dates, and imputation for missing dates, are 
described in Section 2.5. 
2.1.3 Efficacy endpoints 
All efficacy endpoints were defined as secondary objectives. In addition, the assessment of the 
anti-cancer activity of isatuximab will focus on patients with MM. 
For patients with MM, disease assessments were performed every other cycle using the European 
Society for Blood and Marrow Transplantation (EBMT) criteria (1). 
The following efficacy endpoints will be derived for the Phase 1 part of the study: 
x 
Best overall response (BOR):  BOR is defined as the best sequential response, using the 
investigator’s assessment of response, from the start of treatment through the entire study 
excluding any time point following the start of other treatment for MM. The ordering of 
evaluations from best to worse is:  complete response (CR), partial response (PR), stable 
disease (SD), progressive disease (PD), not evaluable (NE). Sequential response will be 
determined as defined in Table 4. The following rules will also be applied: 
- 
BOR will be ‘NE’ for patients who completed only 1 cycle with investigator 
assessment of response at cycle 1 or end of treatment of SD or better. 
- 
BOR will be ‘PD’ for patients without response assessment who completed 1 or 
2 cycles of treatment and who discontinued treatment or died within 30 days due to 
PD. 
- 
The criteria of confirmation of PD will not be applied since some patients discontinued 
isatuximab before confirmation of PD. 
(electronic 1.0)


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Table 4 - Sequential response determination 
Overall response at cycle n 
Overall response at cycle n+2a 
Sequential response 
CR 
CR 
CR 
CR 
PR 
PRb 
PR 
PR/CR 
PR 
PR/CR 
NE/No further evaluation/SD/PD 
MRc 
MR 
Any 
MR 
Any 
MR 
MR 
NE/SD/PD 
PR/CR 
MRc 
SD 
No further evaluation/NE/PD 
SD 
NE/PD/SD 
SD 
SD 
NE 
SD 
SD 
PD 
NE/No further evaluation/PD 
PD 
NE 
PD 
PD 
NE 
NE/No further evaluation 
NE 
a Disease assessment were planned to be performed every other cycles. Disease assessment performed after start of new anticancer 
treatment (>) will be excluded from the derivation of the BOR. 
b Sequence provided for programming purpose 
c Unconfirmed PR or CR will be considered MR. 
BOR = best overall response; CR = complete response; MR = minor response; NE = not evaluable; PD = progressive disease; PR = partial 
response; SD = stable disease. 
x 
Overall response rate (ORR):  ORR is defined as the proportion of patients achieving a CR 
or PR as BOR. 
x 
Clinical benefit rate (CBR):  CBR is defined as the proportion of patients achieving a 
minor response (MR) or better as BOR. 
x 
Duration of response (DOR):  DOR is defined as the time from first response to the first 
documented tumor progression or death. If progression or death is not observed, the date of 
the last valid disease assessment performed before initiation of a new anticancer treatment 
will be used. DOR is determined only for patients who have achieved a response of PR 
and will not be calculated for patients who did not achieve a response. 
x 
Time to response (TTR):  TTR is defined as the time from first dose to first response 
(PR or better). 
x 
Follow-up duration (FUD):  Time from first dose to last disease assessment before start of 
other therapy for MM). 
x 
Best percent change in paraprotein:  Best percent change in paraprotein will be calculated 
for the MM subtype parameter defined at baseline (Section 2.1.1) excluding any time point 
following the start of other therapy for MM. 
A secondary analysis of BOR, ORR, TTR, and DOR will be performed using the best time point 
response (ie, without confirmation of response). 
(electronic 1.0)


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2.1.4 Safety endpoints 
The safety analysis will be based on the reported AEs and other safety information, such as 
clinical laboratory data, vital signs, and ECG (Section 1.4). 
Observation period 
The observation period will be divided into 3 periods:  pre-treatment, on-treatment, and 
post-treatment. 
x 
The pre-treatment period is defined as the time from when the patients give informed 
consent and the start of isatuximab. 
x 
The on-treatment period is defined as the time from first dose of isatuximab up to 
30 days after the last dose of isatuximab. 
x 
The post-treatment period is defined as the time from 31 days after the last dose of 
isatuximab to the study closure. 
2.1.4.1 Adverse events variables 
Adverse events occurring from informed consent signature until at least 30 days after the last 
isatuximab administration were to be collected in the eCRF. The severity of AEs was assessed 
according to NCI-CTCAE version 4.03. 
All AEs (including serious AEs [SAEs]) will be coded to a lower-level term (LLT), preferred 
term (PT), high-level term (HLT), high-level group term (HLGT), and associated primary system 
organ class (SOC) using the MedDRA version in effect at Sanofi at the time of database lock. 
The following AEs will be described: 
x 
Pre-treatment AEs:  defined as any AE reported during the pre-treatment period. 
x 
Treatment-emergent AEs (TEAEs):  defined as any AE that developed, worsened 
(according to the Investigator’s opinion), or became serious during the on-treatment 
period. 
x 
Post-treatment AEs:  defined as any AE reported during the post-treatment period. 
The following AEs were considered adverse events of special interest (AESIs): 
x 
Acute infusion associated reactions (IARs) 
x 
DLTs 
x 
Symptomatic overdose 
x 
Pregnancy occurring in a female patient or in a female partner of a male patient 
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Statistical Analysis Plan  
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Analysis of adverse events 
Analysis of AEs will include IARs, respiratory toxicities AEs, and hematological AEs. 
Infusion associated reactions 
Infusion associated reactions, commonly observed with monoclonal antibodies, generally include 
AEs with onset within 24 hours from the start of the isatuximab infusion (See Section 6.5 of the 
TED10893 protocol for guidelines for IARs management). As described above, IARs are 
considered to be AESI. 
Two analyses of IARs will be performed. The first one will be based on the investigator’s 
reporting of IARs (ie, as AESIs). This analysis will be called “IAR-AESI.”  For each IAR-AESI, 
the sites were instructed to report a generic term (infusion-related reaction) and each individual 
symptom. 
The second analysis of IAR (called IAR-AE) will include TEAEs occurring within 24 hours from 
the start of each isatuximab infusion.  In order to exclude AEs related to the premedications or 
related to the patient’s condition, only AEs that are considered to be related to isatuximab by the 
investigator will be included in the analysis. 
Respiratory adverse events 
Analysis of respiratory AEs will focus particularly on the following MedDRA HLGTs:  ‘Bronchial 
disorders (excl neoplasms)’, ‘Respiratory disorders NEC’ (excluding ‘Upper respiratory tract signs 
and symptoms’ HLT), and ‘Respiratory tract infections’. 
Hematological adverse events 
Hematological AEs (Hem-AEs) will include isatuximab drug-related hematological TEAEs of 
grade 3. 
2.1.4.2 Deaths 
The deaths observation periods were based on the observation periods defined in Section 2.1.4. 
x 
Death on-treatment:  deaths during the on-treatment period. 
x 
Death post-treatment:  deaths during the post-treatment period. 
2.1.4.3 Laboratory safety variables 
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis.  Clinical laboratory values after conversion will be analyzed into standard international 
units used in all listings and tables. 
(electronic 1.0)


Statistical Analysis Plan  
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Blood samples for clinical laboratories were taken as defined in the study flow charts and as 
clinically indicated.  The laboratory parameters will be classified as follows: 
x 
Hematology 
- 
Red blood cells and platelets and coagulation:  hemoglobin, hematocrit, mean 
corpuscular volume, red blood cell count, platelet count, prothrombin time (expressed 
as international normalized ratio), activated partial thromboplastin time, erythrocyte 
sedimentation rate 
- 
White blood cells:  white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils 
x 
Clinical chemistry 
- 
Metabolism:  glucose, total protein, albumin, peptide C 
- 
Electrolytes:  sodium, potassium, chloride, calcium, phosphorus, bicarbonate/carbon 
dioxide, magnesium 
- 
Renal function:  creatinine, creatinine clearance in mL per minute (qualitative 
variable: <30, [30-50[, [50-80], >80), blood urea nitrogen, uric acid 
- 
Liver function:  alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, lactate dehydrogenase, total bilirubin, conjugated bilirubin (direct) 
- 
Pregnancy test:  Serum ȕ-human chorionic gonadotropin (female patients) 
x 
Cytokines 
- 
TNF-Į, IL-6, IL-1B, IFN-Ȗ 
x 
High-sensitivity C-reactive protein (Hs-CRP) 
x 
Urinalysis 
- 
Urinalysis - quantitative analyses:  blood, protein, glucose, pH, ketones, bilirubin, 
leucocytes, nitrates, specific gravity 
Technical formulas are described in Section 2.5.1. 
2.1.4.4 Vital signs variables 
Vital signs include:  heart rate, systolic and diastolic blood pressure, respiratory rate, temperature, 
and weight. 
2.1.4.5 Electrocardiogram variables 
Twelve-lead ECG and Holter monitoring to detect atrio-ventricular conduction abnormalities, 
other potential ventricular arrhythmias, and QTc were performed during the study and reviewed by 
a central cardiologist. 
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ECGs provided the following measurements:  HR, PR interval, QRS axis, QRS interval, 
QT interval, QT using Bazett’s correction, QT using Fridericia’s correction, rhythm analysis, 
RR interval, ST segment, T wave, and Q wave. 
2.1.4.6 Other safety endpoints 
Other safety endpoints include: 
x 
ECOG PS 
x 
PSA, pituitary hormone levels (GH, FSH/LH, ACTH, TSH) 
x 
Chest X-ray, 
x 
Pulmonary function tests:  
- 
FEV1:  The CTCAE version 4.03 criteria will be used for the grading of  the severity 
abnormalities:  99%-70% (Grade 1); 60%-69% (Grade 2); 50%-59% (Grade 3); and 
49% (Grade 4) 
- 
DLCO:  Since the lower limit of normal was not collected, the following criteria will 
be used:  <40% (severe), 41%-60% (moderate); 60%-75% (mild); 76%-125% and 
>125% (mild increase). 
x 
Tumor lysis syndrome (TLS) 
- 
TLS will be derived using the criteria defined in Table 5. 
Table 5 - Tumor lysis syndrome definition 
Type 
Criteria 
Laboratory TLS (LTLS) 
2 simultaneous abnormalities within 3 days prior to and up to 
7 days after isatuximab administration: 
x 
Uric acid >8 mg/dL (>475.8 μmol/L) 
x 
Potassium >6.0 mmol/L 
x 
Phosphorus >4.5 mg/dL (>1.5 mmol/L) 
x 
Corrected calcium <7.0 mg/dL(<1.75 mmol/L) 
x 
Ionized calcium <1.12 mg/dL (<0.3mmol/L)a 
Clinical TLS (CTLS) 
LTLS in addition to one of the following complications: 
x 
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/hr for 6 hours 
x 
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 
x 
Dysrhythmias probably or definitely caused by 
hyperkaliemia 
a The corrected calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter +0.8x(4-albumin in grams per 
deciliter) 
(electronic 1.0)


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2.1.5 Pharmacokinetic variables 
Isatuximab plasma concentrations after single and repeated dose administrations will be analyzed 
using a nonlinear mixed-effects modeling approach with MONOLIX® software version 4.3 
(Lixoft).  A basic population PK model will be developed and the following PK individual 
parameters will be calculated: 
x 
Cumulative AUC over a 1-, 2- or 4-week interval (AUC1W, AUC2W, AUC4W) 
x 
Ctrough (pre-dose concentration) at 1, 2 or 4 weeks (Ctrough1W, Ctrough2W, 
Ctrough4W) 
x 
Clearance (CL) for linear non-specific elimination pathway 
In addition, isatuximab concentrations will be analyzed with the PKDMS software (Pharsight) 
using non-compartmental methods for all cohorts. The following PK parameters will be calculated 
following the first administration, and the second administration for patients from the accelerated 
dose escalation phase of the trial: 
x 
Concentration observed at the end of an IV infusion (Ceoi) 
x 
Maximum observed concentration (Cmax) 
x 
Time to reach Cmax (tmax) 
x 
Concentrations just before drug infusion (Ctrough) 
x 
AUClast 
x 
Tlast 
x 
Clast 
x 
AUC over the dosing interval (AUC1week or AUC2week) 
x 
Cmax, tmax, and AUC0-7day will also be calculated at cycle 3 for weekly dose regimen 
Ctrough are defined as sample collected before dosing, and in a time window of 12 to 16 days 
after the previous start of infusion for the Q2W administration, or in a time window of 6 to 8 days 
after the previous start of infusion for the QW administration. 
The time window define for concentration at end of infusion (Ceoi) is defined as below: 
x 
±5 minutes around the real time of end of infusion for accelerated dose escalation scheme 
(cohorts 1 to 5) (dose 0.0001 mg/kg to 0.1 mg/kg) 
x 
±15 minutes around the real time of end of infusion for basic dose escalation scheme 
(cohorts 6 to 13, EC1 and EC2 [HR]) (dose 0.3 mg/kg to 20 mg/kg). 
2.1.6 Immune response 
Human ADA to isatuximab were assessed throughout the Phase 1 part of the study. Blood samples 
were collected for ADA detection according to the flowcharts (see protocol). 
(electronic 1.0)


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2.1.7 Pharmacodynamic endpoints 
For the Phase 1 part of the study, CD38 RO and RD were assessed from bone marrow aspirates at 
the time points detailed in the protocol. 
2.1.8 Quality-of-life endpoints 
Not applicable. 
2.1.9 Health economic endpoints 
Not applicable. 
2.1.10 Further therapy after discontinuation of investigational medicinal product 
administration during the study 
Further therapies for MM after discontinuation of isatuximab were not collected in the eCRF for 
all patients and were entered in the medication eCRF page for some patients with “new” as a 
reason for why the drug was given. 
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patients who signed the screening informed consent. A listing 
of screening failure patients (ie, screened patients who were not treated with isatuximab) and 
reason for screening failure (when available) will be provided. 
The number and percentage (when applicable) of patients in each of the following analyses 
population will be provided: 
x 
All treated/safety population 
x 
DLT-evaluable population (escalation phase) 
x 
All-treated MM population 
x 
PK population 
x 
RD evaluable population 
x 
RO evaluable population 
For all above categories (except for the all treated [AT] population) percentages will be calculated 
using the number of patients in the AT population. For the AT population, no percentages will be 
calculated. 
(electronic 1.0)


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For patient study status, the number and percentage of patients in each of the following categories 
will be provided using the all treated/safety population: 
x 
Patients off treatment and reasons for treatment discontinuation 
x 
Patients on treatment at time of the analysis cutoff date 
All critical or major deviations potentially impacting efficacy analyses, randomization, and 
drug-dispensing irregularities, and other major or critical deviations will be summarized in a table 
giving numbers and percentages of patients with deviations. Protocol deviations will also be 
listed. 
2.2.1 Randomization and drug dispensing irregularities 
Not applicable, as this is a non-randomized study. 
2.3 
ANALYSIS POPULATIONS 
2.3.1 All treated/safety population 
The AT/safety population will include all patients who have given their informed consent and who 
have received at least 1 dose (even incomplete) of isatuximab. 
This population is the primary population for the analyses of efficacy and safety parameters. All 
analyses using this population will be based on the intended dose planned to be given at 
Cycle 1 - Day 1. 
2.3.2 Evaluable for DLT population 
The evaluable for DLT population is the subset of patients from the AT population who were 
treated during the dose escalation phase of the study with a DLT assessment at the end of Cycle 2. 
This population includes patients followed up to the end of the evaluation period or patients 
having experienced a DLT validated by the study committee, whichever was first. If there are 
missing or incomplete data that influenced the evaluation of DLT, the patient will not be evaluable 
for a DLT, except if a DLT is documented during Cycle 1 or 2. Patients excluded from this 
population were replaced. 
2.3.3 All-treated MM population 
The all-treated MM population will include patients with MM from the AT/safety population. 
2.3.4 Pharmacokinetic population 
The PK analysis will be performed on patients from the AT/safety population with a PK 
parameter. 
(electronic 1.0)


Statistical Analysis Plan  
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2.3.5 Pharmacodynamic population 
The RD evaluable population will include patients from the AT/safety population who have 
evaluable RD at baseline. 
The RO evaluable population will include patients from the AT/safety population who have 
evaluable RO during treatment. 
2.4 
STATISTICAL METHODS 
In summary tables, DLs will be grouped and presented as follows: 
x 
1 mg/kg Q2W, 
x 
3 mg/kg Q2W, 
x 
5 mg/kg Q2W, 
x 
10 mg/kg Q2W-DE+EC1, 
x 
10 mg/kg Q2W-HR (EC2), 
x 
10 mg/kg QW, 
x 
20 mg/kg Q2W, 
x 
20 mg/kg QW, 
x 
All patients. 
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum, and maximum.  Categorical and ordinal data will be 
summarized using the number and percentage of patients. 
Important data listings will be provided, for example, patient disposition, DLTs, AEs leading to 
discontinuation, SAEs, deaths, and specific TEAEs. Listings will be sorted by actual dose level 
and patient number. Repeated values of these key variables will be blanked out in the listings. 
2.4.1 Demographics and baseline characteristics 
Parameters described in Section 2.1.1 will be summarized using descriptive statistics. 
Past medical or surgical history will be summarized by SOC and PT (both sorted by alphabetical 
order). A listing of patients with respiratory toxicities (eg, chronic obstructive pulmonary disease 
[COPD]/asthma, dyspnea, tabagism) will be provided. 
Medical history and disease characteristics at diagnosis will be analyzed for the AT population 
only. Demographic characteristics will be analyzed for both the AT and the all-treated MM 
populations. MM characteristics at diagnosis, MM characteristics at study entry, molecular 
subtype, and prior anticancer therapies will be described for the all-treated MM population. 
(electronic 1.0)


Statistical Analysis Plan  
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2.4.2 Prior or concomitant medications (other than anticancer therapies) 
Prior and concomitant medications will be presented for the AT population. 
Medications will be summarized according to the WHO-DD dictionary, considering the first digit 
of the anatomical therapeutic chemical (ATC) class (anatomical category) and the first 3 digits of 
the ATC class (therapeutic category).  All ATC codes corresponding to a medication will be 
summarized, and patients will be counted once in each ATC category (anatomical or therapeutic) 
linked to the medication. Therefore, patients may be counted several times for the same 
medication. 
The table for prior and concomitant medications will be sorted by decreasing frequency of ATC 
followed by all other therapeutic classes based on the overall incidence across all DLs (ie, the all 
patients column).  In case of equal frequency regarding ATCs, alphabetical order will be used. 
Premedications 
Number (%) of patients with premedications (corticosteroids, diphenhydramine and any 
premedications) as defined in Section 2.1.2 will be provided. 
2.4.3 Extent of investigational medicinal product exposure 
The extent of isatuximab exposure will be assessed and summarized by DL and overall within the 
AT/Safety population. 
The dose information will be assessed by the following variables: 
x 
Number of cycles started 
x 
Duration of isatuximab exposure (or time on-treatment) (in weeks):  defined as (Day 1 date 
of last cycle – first dose date + theoretical duration of the cycle)/7. For the Phase 1 part of 
the study, the theoretical duration of a cycle is 14 days. 
x 
Actual dose (mg/kg):  for a given cycle and day of administration, the actual dose in mg/kg 
corresponds to the actual dose in mg administered at this time point divided by the actual 
body weight as measured at Day 1 of the cycle 
x 
Cumulative dose (mg/kg):  the cumulative dose is the sum of all actual doses of 
isatuximab, expressed in mg/kg, given from first to last administration 
x 
Actual dose intensity (ADI) in mg/kg/week: defined as the cumulative dose (in mg/kg) 
divided the duration of isatuximab exposure (in weeks) 
x 
Relative dose intensity (RDI) in %:  
 
k)
(mg/kg/wee
Intensity 
 
Dose
 
Planned
 
k)
(mg/kg/wee
 
ADI
100 u
 
x 
Planned dose intensities corresponds to the actual dose (mg/kg) received at Cycle 1-Day 1, 
regardless of dose/schedule changes (as defined in Section 6.4 of the protocol), divided by 
the theoretical cycle duration expressed in weeks (ie, 2 weeks). 
(electronic 1.0)


Statistical Analysis Plan  
19-Nov-2015 
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Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 26 
Total number of cycles started, number of cycles started by patients as a quantitative variable and 
by category (ie, number [%] of patients receiving at least 1 cycle, at least 2 cycles…), duration of 
isatuximab exposure, cumulative dose, RDI, and RDI by category (<80%, 80-105%, >105%) will 
be summarized by descriptive statistics. 
The following variables will be computed to describe dose delays/modifications: 
x 
Dose reduction:  Although not allowed in the study protocol, potential dose reductions will 
be screened and reported in the clinical study report. An isatuximab administration will be 
considered to be administered at a reduced dose if the actual dose administered is at least 
20% below the planned dose at Cycle 1 – Day 1. 
x 
Cycle delay:  A cycle will be deemed as delayed if the start date of the current cycle – 14 – 
start date of the previous cycle is >2 days. 
x 
Dose interruption:  A dose will be considered to be interrupted if the isatuximab 
administration is temporarily stopped during an infusion and then restarted (typically in 
case of Grade 2 IARs. Analysis of dose interruption will be performed using the dose 
interruption section of the eCRF. 
Dose delays/modification will be analyzed at the patient, cycle, and total number of isatuximab 
administration levels as follows: 
x 
Patient level 
- 
Number of patients treated (used for % calculation for this level) 
- 
Number (%) of patients with a least 1 dose delay 
- 
Number (%) of patients with a maximum delay between 3 and 7 days 
- 
Number (%) of patients with a maximum delay >7 days 
- 
Number (%) patients with a least 1 dose interruption 
x 
Cycle level 
- 
Number of cycles administered (used for % calculation for this level) 
- 
Number (%) of cycles delayed 
- 
Number (%) of cycles with delay between 4 and 7 days 
- 
Number (%) of cycles with >7 days 
x 
Total number of isatuximab administration level 
- 
Total number of isatuximab administration (used for % calculation for this level) 
- 
Number (%) of isatuximab administrations interrupted 
(electronic 1.0)


Statistical Analysis Plan  
19-Nov-2015 
SAR650984-TED10893 (Phase 1) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 27 
2.4.4 Analyses of efficacy endpoints 
Efficacy endpoints will be analyzed for the all-treated MM population. 
BOR, ORR, CBR, DOR, TTR, and FUD will be summarized with descriptive statistics. Best 
change in paraprotein will be displayed in a waterfall plot. In the waterfall plot, patients with BOR 
of PR will have negative percentage change. The patients will be ordered from highest positive 
change to smallest negative change.  A swimmer plot of time on treatment will also be provided. 
The patients will be ordered by the duration of exposure. Patients with the longest duration will be 
presented at the top of the plot. 
Listing of response data, including the following variables, will be provided: number of prior lines 
(including the main prior treatments given), duration of exposure (weeks), date of first dose, 
reason for discontinuation, MM type at baseline, best percent change in paraprotein, best overall 
response, date of first response, date of first disease progression/last assessment time to first 
response (weeks), DOR (weeks). 
2.4.5 Analyses of safety data 
The summary of safety results will be presented by grouped DLs and overall (see Section 2.4). 
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.1. Unless 
otherwise specified, the baseline value is defined as the last available value before or on the date 
of isatuximab administration. 
2.4.5.1 Analyses of adverse events 
Generalities 
The primary focus of AE reporting will be on TEAEs.  Pre-treatment and post-treatment AEs will 
be described separately. 
If an AE date of onset (occurrence, worsening, or becoming serious) is incomplete, an imputation 
algorithm will be used to classify the AE as pre-treatment, treatment-emergent, or post-treatment.  
The algorithm for imputing the date of onset will be conservative and will classify an AE as 
treatment emergent unless there is definitive information to determine it is pre-treatment or 
post-treatment.  Details on classification of AEs with missing or partial onset dates are provided in 
Section 2.5.3. 
For patients with multiple occurrences of the same AE within the observation period 
(pre-treatment, treatment-emergent, and post-treatment), the maximum severity grade will be 
used. 
(electronic 1.0)


Statistical Analysis Plan  
19-Nov-2015 
SAR650984-TED10893 (Phase 1) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 28 
Analysis of all treatment-emergent adverse events 
The following TEAE summaries will be generated for the safety population. 
x 
Overview of TEAEs, summarizing the number (%) of patients with any 
- 
TEAE (any grade) 
- 
TEAE of  Grade 3 
- 
Drug-related TEAE (any grade) 
- 
Drug-related TEAE of  Grade 3 
- 
Serious TEAE 
- 
TEAE with a fatal outcome 
- 
TEAE leading to treatment discontinuation 
- 
DLT 
- 
AESI (any grade) 
- 
AESI of  Grade 3 
The description of summary tables that will be provided for the analysis of TEAEs, drug-related 
TEAEs, serious TEAEs, drug-related serious TEAEs, IAR-AESI, IAR-AE, as well as TEAEs 
leading to dose modification is given in Table 6. 
Sorting within tables should ensure the same presentation for the set of all AEs within the 
observation period (pre-treatment, treatment-emergent, and post-treatment).  For that purpose, the 
table of all TEAEs presented by SOC and PT sorted by the internationally agreed SOC order and 
decreasing frequency of PTs within SOCs will define the presentation order for all other tables 
unless otherwise specified.  Sorting will be based on the incidence of AEs in the AT population 
(ie, all patients). 
 
(electronic 1.0)


Statistical Analysis Plan  
19-Nov-2015 
SAR650984-TED10893 (Phase 1) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 29 
Table 6 - Adverse event summary tables to be provided for the analysis of TEAEs 
MedDRA coding 
variables 
Sorting (all patients column) 
Layout 
Events 
PT 
x PT:  Decreasing order of frequency  
x DLs:  n of patients with any event / n of patients 
with event of Grade 3 
x All patients:  n (%) of patients with any event and 
n (%) of patients with event of Grade 3 
TEAEs occurring in 10% of the patients (all patients) 
Drug-related TEAEs occurring in 10% of the patients 
(all patients) 
Serious TEAEs 
SOC, HLGT, HLT, and PT 
x SOC: internationally agreed order 
x HLGT, HLT, PT:  alphabetical order 
x DLs:  n of patients with any event / n of patients 
with event of Grade 3 
x All patients:  n (%) of patients with any event and 
n (%) of patients with event of Grade 3 
All TEAEs 
Drug-related TEAEs 
Respiratory TEAEs 
SOC, HLGT, HLT, and PT 
x SOC: internationally agreed order 
x HLGT, HLT, PT:  alphabetical order 
x DLs:  n (%) of patients with any event 
x All patients:  n (%) of patients with any event 
All TEAEs 
Drug-related TEAEs 
Serious TEAEs 
Drug-related serious TEAEs 
Respiratory TEAEs 
SOC, HLGT, HLT, and PT 
x SOC: internationally agreed order 
x HLGT, HLT, PT:  alphabetical order 
x DLs:  n (%) of patients with event of Grade 3 
x All patients:  n (%) of patients with event of 
Grade 3 
All TEAEs 
Drug-related TEAEs 
Respiratory TEAEs 
SOC and PT 
x SOC: internationally agreed order 
PT:  Decreasing order of frequency 
defined in the previous page. 
x DLs:  n of patients with any event / n of patients 
with event of Grade 3 
x All patients:  n (%) of patients with any event and 
n (%) of patients with event of Grade 3 
All TEAEs 
TEAEs leading to dose modification 
IAR-AESI 
IAR-AE 
Serious TEAEs 
Drug-related serious TEAEs 
Pre-treatment and post-treatment AEs 
(electronic 1.0)


Statistical Analysis Plan  
19-Nov-2015 
SAR650984-TED10893 (Phase 1) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 30 
MedDRA coding 
variables 
Sorting (all patients column) 
Layout 
Events 
SOC and PT 
x SOC:  internationally agreed order 
PT:  Decreasing order of frequency 
defined in the previous page. 
x DLs:  n (%) of patients with any event 
x All patients:  n (%) of patients with any event 
All TEAEs 
TEAEs leading to dose modification 
IAR-AESI 
IAR-AE 
SOC and PT 
x SOC:  internationally agreed order 
PT:  Decreasing order of frequency 
defined in the previous page. 
x DLs:  n (%) of patients with event of Grade 3 
x All patients:  n (%) of patients with event of 
Grade 3 
All TEAEs 
TEAEs leading to dose modification 
IAR-AESI 
IAR-AE 
AE = adverse event; AESI = adverse event of special interest; DL = dose level; HLGT = high-level group term; HLT = high-level term; IAR = infusion associated reaction; MedDRA = Medical 
Dictionary for Regulatory Activities; N = number of patients; n (%) = number and percentage of patients; PT = preferred term; SOC = system organ class; TEAE = treatment-emergent adverse 
event 
(electronic 1.0)


Statistical Analysis Plan  
19-Nov-2015 
SAR650984-TED10893 (Phase 1) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 31 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
TEAEs leading to treatment discontinuation will be listed. Given the small number of patients 
who discontinued treatment due to an AE, no summary table will be provided. 
2.4.5.2 Deaths 
Number (%) of patients who died by study period (on-treatment, post-treatment) and cause of 
deaths will be described. A listing of patients who died while participating in the study including 
cause of death, death date, days from last dose to death, preferred term, and causal relationship to 
isatuximab will be provided. 
2.4.5.3 Analyses of laboratory variables 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all laboratory tests (laboratory values, changes from baseline and % change from 
baseline) will be calculated for each. 
Each laboratory test result will be graded by CTCAE criteria (version 4.03), when applicable.  The 
number of patients with abnormal laboratory tests at baseline will be presented by grade.  The 
frequency of patients in each grade of laboratory tests during the on-treatment period will be 
summarized.  For patients with multiple occurrences of the same laboratory variable during the 
on-treatment period, the maximum grade (worst) per patient will be used. 
The number (%) by creatinine clearance category at baseline, on-treatment as well as shift table 
will also be provided. 
Shift tables showing the number of patients in each grade at baseline by worst grade during the 
on-treatment period will be provided for tests of interest. 
2.4.5.4 Analyses of vital sign variables 
The summary statistics (including number, mean, median, standard deviation, minimum, and 
maximum) of all vital signs variables (values changes from baseline and % change from baseline) 
will be calculated for each visit. 
The incidence of potentially clinically significant abnormality (PCSA) at any time during the 
on-treatment period will be summarized irrespective of the baseline level and according to the 
following baseline status categories: 
x 
Normal/missing 
x 
Abnormal according to PCSA criterion or criteria. 
The PCSA values are defined as abnormal values considered medically important by the Sponsor 
according to predefined criteria/thresholds based on literature review and defined by the Sponsor 
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Statistical Analysis Plan  
19-Nov-2015 
SAR650984-TED10893 (Phase 1) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 32 
for clinical laboratory tests, vital signs, and ECG. PCSA criteria will determine which patients had 
at least 1 PCSA during the on-treatment period, taking into account all evaluations performed 
during the on-treatment period, including nonscheduled or repeated evaluations. 
2.4.5.5 Analyses of electrocardiogram variables 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all ECG variables (central laboratory values and changes from baseline) will be 
calculated for each visit or study assessment (baseline, each postbaseline time point, last 
on-treatment and/or worst on-treatment value and/or other specific assessment). 
The incidence of PCSAs at any time during the on-treatment period will be summarized by 
treatment group irrespective of the baseline level and/or according to the following baseline status 
categories: 
x 
Normal/missing 
x 
Abnormal according to PCSA criterion or criteria 
ECG parameters extracted from continuous ECG recording (Holter) will be used to support the 
ECG-PD analyses. 
2.4.5.6 Analyses of other safety endpoints 
ECOG PS will be summarized by visit.  A shift table of baseline ECOG PS versus ECOG PS at 
the end of treatment will be provided. 
Number (%) of patients with LTLS and CTLS present prior to first dose and during the 
on-treatment period will be provided. Number (%) of patients with TLS reported as TEAE will 
also be reported. 
Number (%) of patients with respiratory abnormalities (DLCO and FEV1) using the worst grade 
during the on-treatment period will be provided. Respiratory TEAEs will also be analyzed as 
regards to medical history data (eg, COPD, cough, dyspnea, Tabagism). 
2.4.6 Analyses of pharmacokinetic, immune response and pharmacodynamic variables 
2.4.6.1 Pharmacokinetic variables 
The PK analysis using modeling approach will be performed on PK population’ patients treated at 
doses1 mg/kg. The PK analysis using non-compartmental analysis will be performed on the PK 
population. 
All pharmacokinetic parameters (excluding concentration at end of infusion (Ceoi) will be 
summarized using descriptive statistics (arithmetic and geometric mean, median, SD, standard 
error of the mean (SEM), coefficient of variation (CV), minimum, maximum, and number of 
available observations). In a first table, patients treated at 10 mg/kg Q2W in the dose escalation 
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Statistical Analysis Plan  
19-Nov-2015 
SAR650984-TED10893 (Phase 1) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 33 
phase of the study and in the EC1 will be presented separately. In a second table, patients treated 
at 10 mg/kg Q2W (ie, dose escalation, EC1 and EC2) will be pooled together. 
Individual data listings will also be provided. 
Dose proportionality will be evaluated with graphical methods (exposure parameters versus dose) 
and using the log transformed power model for AUC0-14day and AUClast from the non-
compartmental analysis after first administration in the biweekly regimen for patients from the 
basic dose escalation phase of the study: 
Log(parameter) = Log(a) + b*Log(dose). 
2.4.6.2 Immune response 
ADAs will be analyzed at the patient and at the number of ADA sample levels as follows: 
x 
Patient level 
- 
Number of patients treated (used for % calculation for this level) 
- 
Number (%) of patients with a least 1 positive ADA 
x 
Number of ADA sample levels 
- 
Number of ADA samples collected (used for % calculation for this level) 
- 
Number (%) of sample with positive ADA. 
Data listing of each ADA sample results for patients with positive ADA will be provided. Impact 
on PK, safety, and efficacy will be further explored by graphical method or descriptively. 
2.4.6.3 Pharmacodynamic variables 
CD38 RD and RO will be summarized with descriptive statistics. 
In addition, CD38 RD and RO will be summarized by clinical response 
(responders/non-responders). A graph showing ORR/non-responder rate (in y-axis) by CD38 RD 
level (ranging from 0 to 500 000 by increment of 1 000 in x-axis) will be provided. 
2.4.6.4 Pharmacokinetic/pharmacodynamic analysis 
A pharmacokinetic (PK)/pharmacodynamic (PD) analysis including patients with MM treated at 
doses 1 mg/kg with PK exposure parameters and covariates will be included in the PK/PD 
models. 
The efficacy endpoint considered in the PK/PD analysis will be ORR. 
The PK exposure parameters considered will be AUC and Ctrough at end of Week 2 and Week 4. 
(electronic 1.0)


Statistical Analysis Plan  
19-Nov-2015 
SAR650984-TED10893 (Phase 1) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 34 
The relationship between RO and dose as well as RO and isatuximab concentrations at 4 weeks 
(Ctrough) will be explored. A graph of CD38 RO versus isatuximab concentration at 4 weeks will 
be provided. 
The relationships between response rate and PK exposure parameters will be explored at 5% 
significance level. 
The relationships between PK exposure parameters, response to treatment and potential covariates 
will be explored using scatter plots.  A nonparametric local weighted smoothing plot will be used 
to explore the relationship between response rate and PK exposure parameters.  PK/PD 
relationship between ORR and PK exposure parameters will be analyzed using a logistic 
regression model.  The following covariates will be considered: 
x 
Demographics (age, body weight, race, height), 
x 
Liver function at baseline (total bilirubin, alanine aminotransferase (ALT) (or serum 
glutamate-pyruvate transferase (SGPT)), aspartate aminotransferase (AST) (or serum 
glutamate-oxaloacetate transferase (SGOT)), 
x 
Renal function at baseline  (creatinine clearance), 
x 
Total protein, albumin, serum alkaline phosphatases, 
x 
beta 2 microglobulin, 
x 
Paraprotein at baseline (serum M-protein, M-protein urine, lambda FLC, kappa 
FLC depending of the nature of the disease), 
x 
CD38 RD, 
x 
% of  cancer cells expressing CD38, 
x 
% of  bone  marrow plasma cells , 
x 
Number of prior lines of treatment, 
x 
Plasmacytoma at baseline, 
x 
Time of diagnosis, 
x 
Immunogenicity  (ADA [Yes/No]), 
x 
Nature of the disease  (M-protein or FLC), 
x 
ISS at study entry. 
Stepwise variable selection will be used to identify covariates to be included in the final model.  
Hosmer and Lemeshow goodness-of-fit test will be used to check for lack of fit. 
2.4.7 Analyses of quality of life/health economics variables 
Not applicable. 
(electronic 1.0)


Statistical Analysis Plan  
19-Nov-2015 
SAR650984-TED10893 (Phase 1) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 35 
2.4.8 Further therapy after discontinuation of investigational medicinal product 
administration during the study 
Further therapies for MM will be listed and not summary table will be provided since they were 
not collected in the eCRF for all patients. 
2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
Not applicable. 
2.5.2 Data handling conventions for secondary efficacy variables 
Not applicable. 
2.5.3 Missing data 
The analyses and summaries of continuous and categorical variables will be based on observed 
data only. Percentages will be calculated using as denominator the number of patients with a 
nonmissing observation in the considered population. When relevant, the number of patients with 
missing data will be presented. 
When incomplete or missing dates are found attempts will be made to retrieve the complete date, 
especially for dates within the month prior to first dose. However if some dates remain 
incomplete, the following rules will be applied: 
Handling of disease characteristics missing/partial dates 
x 
If the day is missing, it will be estimated by 1 
x 
If the month is missing, it will be estimated by 1 (only for medical history variables) 
x 
If the year is missing, no estimation will be performed. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date is 
missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and posttreatment medication. 
(electronic 1.0)


Statistical Analysis Plan  
19-Nov-2015 
SAR650984-TED10893 (Phase 1) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 36 
Handling of adverse events with missing or partial date/time of onset 
Missing or partial AE onset dates will be imputed so that if the partial AE onset date information 
does not indicate that the AE started prior to treatment or after the on-treatment period, the AE 
will be classified as treatment-emergent.  No imputation of AE end dates will be performed.  
These data imputations are for categorization purpose only and will not be used in listings.  No 
imputation is planned for date of AE resolution. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product 
If the assessment of the relationship to isatuximab is missing, then the relationship to isatuximab 
has to be assumed and the AE considered as such in the frequency tables of possibly related AEs, 
but no imputation should be done at the data level. 
Handling of parameters expressed as inequality or approximation 
For some parameters (such as laboratory parameters), if the value is expressed as an inequality or 
an approximation, the numeric portion of the entry may be used in calculations. 
2.5.4 Windows for time points 
Laboratory data 
An episode occurred during a cycle if the date of sampling is after (>) the first day of the cycle, but 
prior or equal () to the first day of the next cycle. 
2.5.5 Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and ECG will be used for 
computation of baseline and worst values and/or grades. 
2.5.6 Pooling of centers for statistical analyses 
Data from all sites will be pooled together for analyses. 
2.5.7 Statistical technical issues 
Not applicable. 
(electronic 1.0)


Statistical Analysis Plan  
19-Nov-2015 
SAR650984-TED10893 (Phase 1) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 37 
3 
INTERIM ANALYSIS 
Not applicable. 
(electronic 1.0)


Statistical Analysis Plan  
19-Nov-2015 
SAR650984-TED10893 (Phase 1) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 38 
4 
DATABASE LOCK 
The database will be locked when clinical review of the database will be completed, and all 
critical queries will be resolved. 
(electronic 1.0)


Statistical Analysis Plan  
19-Nov-2015 
SAR650984-TED10893 (Phase 1) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 39 
5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS® version 9.0 or higher. 
(electronic 1.0)


Statistical Analysis Plan  
19-Nov-2015 
SAR650984-TED10893 (Phase 1) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
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6 
REFERENCES 
1. Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, et al. Criteria for 
evaluating disease response and progression in patients with multiple myeloma treated by 
high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the 
EBMT. European Group for Blood and Marrow Transplant. Br J Haematol. 1998; 
102(5):1115-23. 
(electronic 1.0)


Statistical Analysis Plan  
19-Nov-2015 
SAR650984-TED10893 (Phase 1) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 41 
7 
LIST OF APPENDICES 
None. 
(electronic 1.0)




 
 
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-002643 VERSION 6.0 (06-JUL-2016) 
Page 1 
 
STATISTICAL ANALYSIS PLAN 
A Phase 1/2 Dose Escalation Safety, Pharmacokinetic and Efficacy Study of 
Multiple Intravenous Administrations of a Humanized Monoclonal Antibody 
(SAR650984) Against CD38 In Patients with Selected CD38 Hematological 
Malignancies 
SAR650984-TED10893 (Phase 2 Stage 1) 
STATISTICIAN: 
  
BIOSTATISTICS PROJECT LEADER: 
 
DATE OF ISSUE: 15-Feb-2017 
 
 
Total number of pages: 
59 
(electronic 1.0)


Statistical Analysis Plan  
15-Feb-2017 
SAR650984-TED10893 (Phase 2 Stage 1) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ...................................................................................................................1 
TABLE OF CONTENTS..................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................................................................5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................7 
1.1 
STUDY DESIGN AND RANDOMIZATION ......................................................................................7 
1.2 
OBJECTIVES...................................................................................................................................7 
1.2.1 
Primary objectives............................................................................................................................7 
1.2.2 
Secondary objectives.......................................................................................................................8 
1.2.3 
Exploratory objectives......................................................................................................................8 
1.3 
DETERMINATION OF SAMPLE SIZE.............................................................................................8 
1.4 
STUDY PLAN...................................................................................................................................9 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL................................10 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN .....................10 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ....................................................................11 
2.1 
ANALYSIS ENDPOINTS ...............................................................................................................11 
2.1.1 
Demographic and baseline characteristics ....................................................................................11 
2.1.2 
Prior or concomitant medications (other than anticancer therapies) .............................................14 
2.1.3 
Efficacy endpoints..........................................................................................................................15 
2.1.3.1 
Primary efficacy endpoint...............................................................................................................16 
2.1.3.2 
Secondary efficacy endpoints........................................................................................................18 
2.1.4 
Safety endpoints ............................................................................................................................20 
2.1.4.1 
Adverse events variables...............................................................................................................20 
2.1.4.2 
Deaths............................................................................................................................................22 
2.1.4.3 
Laboratory safety variables............................................................................................................22 
2.1.4.4 
Vital signs variables .......................................................................................................................22 
2.1.4.5 
Electrocardiogram variables ..........................................................................................................23 
2.1.4.6 
Other safety endpoints...................................................................................................................23 
2.1.5 
Pharmacokinetic variables .............................................................................................................24 
2.1.6 
Immunogenicity..............................................................................................................................24 
2.1.7 
Biomarker endpoints ......................................................................................................................25 
(electronic 1.0)


Statistical Analysis Plan  
15-Feb-2017 
SAR650984-TED10893 (Phase 2 Stage 1) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 3 
2.1.7.1 
Receptor occupancy/density..........................................................................................................25 
2.1.7.2 
Immune Genetic Determinants ......................................................................................................25 
2.1.7.3 
Immune phenotyping......................................................................................................................26 
2.1.7.4 
CD38 mRNA ..................................................................................................................................26 
2.1.7.5 
Soluble CD38.................................................................................................................................27 
2.1.8 
Health related quality-of-life (HRQL) endpoints .............................................................................27 
2.1.9 
Health economic endpoints............................................................................................................28 
2.1.10 
Further therapy after discontinuation of investigational medicinal product administration 
during the study..............................................................................................................................28 
2.2 
DISPOSITION OF PATIENTS .......................................................................................................28 
2.2.1 
Randomization and drug dispensing irregularities.........................................................................30 
2.3 
ANALYSIS POPULATIONS...........................................................................................................30 
2.3.1 
All treated (AT)/safety population...................................................................................................30 
2.3.2 
Randomized population .................................................................................................................30 
2.3.3 
Patient reported outcomes population ...........................................................................................30 
2.3.4 
Pharmacokinetic population...........................................................................................................30 
2.4 
STATISTICAL METHODS .............................................................................................................31 
2.4.1 
Demographics and baseline characteristics ..................................................................................31 
2.4.2 
Prior or concomitant medications (other than anticancer therapies) .............................................31 
2.4.3 
Extent of investigational medicinal product exposure and compliance .........................................32 
2.4.3.1 
Extent of investigational medicinal product exposure....................................................................32 
2.4.4 
Analyses of efficacy endpoints.......................................................................................................34 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ........................................................................................34 
2.4.4.2 
Analyses of secondary efficacy endpoints.....................................................................................35 
2.4.4.3 
Multiplicity issues ...........................................................................................................................35 
2.4.5 
Analyses of safety data..................................................................................................................35 
2.4.5.1 
Analyses of adverse events ...........................................................................................................36 
2.4.5.2 
Deaths............................................................................................................................................40 
2.4.5.3 
Analyses of laboratory variables....................................................................................................40 
2.4.5.4 
Analyses of vital sign variables ......................................................................................................40 
2.4.5.5 
Analyses of electrocardiogram variables .......................................................................................41 
2.4.5.6 
Analyses of other safety endpoints................................................................................................41 
2.4.6 
Analyses of pharmacokinetic and pharmacodynamic variables ....................................................41 
2.4.6.1 
PK variables ...................................................................................................................................41 
2.4.6.2 
PK/PD analysis ..............................................................................................................................41 
2.4.7 
Immune response ..........................................................................................................................42 
2.4.8 
Analyses of Biomarker variables....................................................................................................42 
2.4.8.1 
Receptor occupancy and receptor density ....................................................................................42 
2.4.8.2 
Immune Genetic variables .............................................................................................................42 
2.4.9 
Analyses of quality of life variables................................................................................................43 
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2.4.10 
Further therapy after discontinuation of investigational medicinal product administration 
during the study..............................................................................................................................46 
2.5 
DATA HANDLING CONVENTIONS ..............................................................................................46 
2.5.1 
General conventions ......................................................................................................................46 
2.5.2 
Data handling conventions for secondary efficacy variables.........................................................46 
2.5.3 
Missing data...................................................................................................................................46 
2.5.4 
Windows for time points.................................................................................................................48 
2.5.5 
Unscheduled visits .........................................................................................................................48 
2.5.6 
Pooling of centers for statistical analyses......................................................................................48 
2.5.7 
Statistical technical issues .............................................................................................................48 
3 
INTERIM ANALYSIS .....................................................................................................................49 
4 
DATABASE LOCK........................................................................................................................50 
5 
SOFTWARE DOCUMENTATION .................................................................................................51 
6 
REFERENCES...............................................................................................................................52 
7 
LIST OF APPENDICES.................................................................................................................53 
APPENDIX A 
ORGANIZATION FOR RESEARCH AND TREATMENT OF CANCER (EORTC)  
EQ-5D ............................................................................................................................................54 
APPENDIX B 
STATISTICAL CODE TO DERIVE THE EQ-5D HSUI SCORE ..........................................55 
APPENDIX C GENERIC RANGES FOR HEMATOLOGICAL AND BIOCHEMISTRY..............................58 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ANC: 
absolute neutrophil count 
AT: 
all treated 
BOR: 
best overall response 
CBR: 
clinical benefit rate 
CL: 
clearance 
CR: 
complete response 
CTCAE: 
common terminology criteria for adverse events 
DLT: 
dose limiting toxicity 
DOR: 
duration of response 
ECOG: 
eastern cooperative oncology group 
eCRF: 
electronic case report form 
EORTC: 
European organization for research and treatment of cancer 
EQ: 
euroqol 
FCGR: 
fc gamma receptor 
FDR: 
false discovery rate 
FIH: 
first in human 
FISH: 
fluorescence in situ hybridization 
FLC: 
free light chain 
GVHD: 
graft vs. host disease 
HLA: 
human leukocyte antigen 
HLGT: 
high-level group term 
HLT: 
high-level term 
HRQL: 
health related quality-of-life 
HSUI: 
health state utility index 
IAC: 
independent adjudication committee 
IAR: 
infusion associated reaction 
IFN-Ȗ: 
interferon-gamma 
IL: 
interleukin 
IMiD: 
immunomodulatory drug 
IMWG: 
international myeloma working group 
IVRS: 
interactive voice response system 
IWRS: 
interactive web response system 
KIR: 
killer-cell immunoglobulin-like receptor 
KPS: 
karnofsky performance status 
LLT: 
lower level term 
MedDRA: 
medical dictionary of regulatory activities 
MY: 
myeloma-specific module 20 
NCI: 
national cancer institue 
ORR: 
overall response rate 
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OS: 
overall survival 
PCSA: 
potentially clinically significant abnormalities 
PFS: 
progression free survival 
PI: 
proteasome inhibitor 
PK: 
pharmacokinetic, pharmacokinetics 
PR: 
partial response 
PRO: 
patient reported outcomes 
PS: 
performance status 
PT: 
preferred term 
Q2W: 
every 2 weeks 
Q4W: 
every 4 weeks 
QLQ: 
quality of life questionnaire 
QW: 
every week 
RD: 
receptor density 
RO: 
receptor occupancy 
RRMM: 
relapsed refractory multiple myeloma 
RS: 
raw score 
SAP: 
statistical analysis plan 
sCR: 
strigent complete response 
SD: 
standard deviation 
SI: 
serum immunoglobulin 
SMQ: 
standard MedDRA query 
SOC: 
system organ class 
TLS: 
tumor lysis syndrome 
TNF-Į: 
tumor necrosis factor alpha 
VAS: 
visual analogue scale 
VGPR: 
very good partial response 
 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN 
TED10893 is the first in human (FIH) study of isatuximab (SAR650984) and was originally 
designed as a dose escalation study to evaluate the safety and pharmacokinetics (PK) of 
isatuximab. The protocol was subsequently amended to include a Phase 2 part for the treatment of 
patients with relapsed refractory multiple myeloma (RRMM). This statistical analysis plan (SAP) 
describes the statistical methods to be used for the analyses of data collected during the Phase 2 
Stage 1 part of the study. This SAP should be read in conjunction with the amended study 
protocol (Version 11, 22 April 2016) and electronic case report form (eCRF). 
1.1 
STUDY DESIGN AND RANDOMIZATION 
The Phase 2 Stage 1 part evaluated the activity and safety of isatuximab given as a single agent at 
different dose levels/schedules, in patients with multiple myeloma who had previously received 
an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI) and have relapsed or 
relapsed/refractory disease. In the Phase 2 part, a cycle is 28 days. The Phase 2 Stage 1 study was 
conducted in 2 stages:  
x Stage 1a was to designed to evaluate the activity and safety of isatuximab at 3 doses: 
- 
Arm 1: 3 mg/kg every 2 weeks (Q2W) (Day 1 and 15 of each 28-day cycle) 
- 
Arm 2: 10 mg/kg Q2W (Day 1 and 15 of each 28-day cycle) 
- 
Arm 3: 10 mg/kg Q2W for 2 cycles (Day 1 and 15 of each 28-day cycle), then 
10 mg/kg (every 4 weeks (Q4W) (Day 1 of each 28-day cycle). 
Patients in Stage 1a were randomly assigned to one of 3 treatment arms (Arm 1, 2 or 3), in a 1:1:1 
ratio using an Interactive Voice Response System/Interactive Web Response System 
(IVRS/IWRS). Randomization was to be stratified according to the patients prior multiple 
myeloma therapy; Stratum 1: prior treatment with pomalidomide and/or carfilzomib. Stratum 2: 
no prior treatment with pomalidomide and/or carfilzomib. 
x Stage 1b commenced after Cohort 13 (ie, 20 mg/kg every week (QW)) in the Phase 1 part 
had completed the dose limiting toxicity (DLT)-observation period and enrollment in 
Stage 1a was completed, whichever was last. The following dose/schedule was evaluated: 
- 
Arm 4: 20 mg/kg every week (QW) for 1 cycle (Day 1, 8, 15 and 22 of Cycle 1) then 
20 mg/kg Q2W (Day 1 and 15 of each 28-day cycle) 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of the Phase 2 Stage 1 part of the study was to evaluate the activity of 
single-agent isatuximab, as assessed by the overall response rate (ORR), at different 
doses/schedules in patients with RRMM. 
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ORR is defined as the proportion of patients with stringent complete response (sCR), complete 
response (CR), very good partial response (VGPR) or partial response (PR) using the International 
Myeloma Working Group (IMWG) uniform response criteria. 
1.2.2 Secondary objectives 
The secondary objectives of the Phase 2 Stage 1 part of the study were to evaluate: 
x 
Safety 
x 
Efficacy as measured by:  
- 
Duration of response (DOR) 
- 
Clinical benefit rate (CBR) 
- 
Progression free survival (PFS) 
- 
Overall survival (OS) 
- 
Patient-reported changes in health-related quality of life, symptoms of multiple 
myeloma and generic health status 
- 
Pharmacokinetic profile of SAR650984 
- 
Immunogenicity of SAR650984 
- 
Investigate the relationship between CD38 receptor density and CD38 receptor 
1.2.3 Exploratory objectives 
x 
To assess minimal residual disease (MRD) in patients achieving a CR and correlate with 
clinical outcome 
x 
To investigate the relationship between tumor cell CD38 mRNA, multiple myeloma 
molecular subtype (as defined by marker expression, cytogenetics, and/or genomics) and 
parameters of clinical response 
x 
To investigate the relationship of soluble CD38 and parameters of PK and clinical 
response 
x 
To investigate the relationship between immune genetic determinants, immune phenotype 
and parameters of clinical response 
1.3 
DETERMINATION OF SAMPLE SIZE 
Although Stage 1b was added in protocol amendment 10 and enrollment started after the 
completion of accrual in Stage 1a, the sample size for Stage 1 was calculated considering Stage 1a 
and 1b as a whole, with 4 doses/schedules. 
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Stage 1 of the Phase 2 portion of the study was based on a selection design (1). Such a design is 
used to maximize the probability of selecting the best of the four isatuximab doses tested during 
Stage 1, using ORR as the endpoint. No statistically significant difference between the four 
treatment arms is required to select a recommended dose for Stage 2. 
A total of 96 patients (24 patients by arm) will provide at least 80% probability to select the better 
isatuximab dose assuming an ORR of 10% in the 3 mg/kg arm and assuming the difference in 
ORR between the best dose and the 3 mg/kg arm is at least 15%. 
1.4 
STUDY PLAN 
Safety evaluations were performed continuously throughout the study and included the following:  
x 
Adverse events (AEs) evaluation. Severity grade were determined according to the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03. 
x 
Laboratory tests in blood and urine 
x 
Physical examinations and vital signs 
x 
Karnofsky performance status (KPS) 
x 
Cytokines (tumor necrosis factor alpha [TNF-Į], interleukin [IL]-1-ȕ, IL-6, interferon-
gamma [IFN-Ȗ]), markers of complement (C3, C4, CH50), serum tryptase 
x 
Chest X-ray and ECG (baseline only) 
Disease response evaluation for patients was performed at screening and Day 1 of every cycle, 
starting at Cycle 2 unless otherwise stated, and included: 
x 
M-protein quantification (serum and/or 24-hour urine), serum free light chain levels 
x 
Serum ȕ2-microglobulin 
x 
Corrected serum calcium 
x 
Bone marrow biopsy/aspiration to be performed to confirm a CR/sCR, at the end of 
treatment (EOT) visit and as clinically indicated. 
x 
Radiologic imaging of plasmacytoma (every 2 cycles if present at baseline) 
x 
Bone skeletal survey (to be performed when clinically indicated or to confirm there was no 
progression at time of response) 
The following additional evaluations were also performed: 
x 
Receptor density (RD) on bone marrow samples 
x 
Receptor occupancy (RO) on bone marrow samples 
x 
Level of soluble CD38 
x 
Level of human anti-drug antibodies (ADA) 
x 
Immune phenotyping and molecular analysis on blood and bone marrow 
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Pharmacokinetic (PK) samples were collected in all patients receiving isatuximab as depicted in 
the PK study flowcharts included in the protocol. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
No modifications to the statistical section of the protocol were made in this SAP. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
Not applicable. 
 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The baseline value is defined as the last available value on or before the date first isatuximab 
administration, except for patient reported outcomes (PRO) endpoints, where the baseline value is 
the available value at Cycle 1 Day 1. 
All baseline safety and efficacy parameters (apart from those listed below) will be presented, 
along with the on-treatment summary statistics in the safety and efficacy sections (Section 2.4.5 
and Section 2.4.4). 
Demographic characteristics 
Demographic variables include gender (Male, Female), race (Caucasian/white, Black, 
Asian/Oriental and other), ethnicity (Hispanic, Non-Hispanic), age in years (quantitative and 
qualitative variable : <65, [65 - 75[and 75 years), weight (kg) and Karnofsky performance status 
(Eastern Cooperative Oncology Group (ECOG) performance status (PS). The correspondence 
between KPS (collected in the eCRF) and ECOG PS is presented in Table 1. 
Table 1 – Performance status scales: Karnofsky & ECOG scores 
Karnofsky Status 
Karnofsky 
Grade 
ECOG 
Grade 
ECOG Status 
Normal, no complaints 
100 
0 
Fully active, able to carry on all pre-disease 
performance without restriction 
Able to carry on normal activities. Minor 
signs or symptoms of disease 
90 
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 
Normal activity with effort 
80 
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 
Care for self. Unable to carry on normal 
activity or to do active work 
70 
2 
Ambulatory and capable of all selfcare but unable 
to carry out any work activities. Up and about 
more than 50% of waking hours 
Requires occasional assistance, but able 
to care for most of his needs 
60 
2 
Ambulatory and capable of all selfcare but unable 
to carry out any work activities. Up and about 
more than 50% of waking hours 
Requires considerable assistance and 
frequent medical care 
50 
3 
Capable of only limited selfcare, confined to bed 
or chair more that 50% of waking hours 
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Karnofsky Status 
Karnofsky 
Grade 
ECOG 
Grade 
ECOG Status 
Disabled. Requires special care and 
assistance 
40 
3 
Capable of only limited selfcare, confined to bed 
or chair more that 50% of waking hours 
Severely disabled. Hospitalization 
indicated 
though death nonimminent 
30 
4 
Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair 
Very sick. Hospitalization necessary. 
Active supportive treatment necessary 
20 
4 
Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair 
Moribund 
10 
4 
Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair 
Dead 
0 
5 
Dead 
Source: 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 Dec;5(6):649-55. 
Medical or surgical history 
Medical or surgical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) in effect at Sanofi at the time of database lock. 
Disease characteristics at initial diagnosis 
The following MM characteristics at initial diagnosis will be summarized: time from initial 
diagnosis to first isatuximab administration (in years) and by category (<5 years and  5 years), 
International Staging System (ISS) stage, and subtype (as collected in the eCRF). 
Disease characteristics at study entry 
The following MM characteristics at study entry will be summarized: ISS stage (Table 2), 
measurable paraprotein at baseline (Table 3), % of plasma cells in bone marrow at baseline 
(quantitatively and by category: 0, (0 - 5%), [5-20%), [20-50%), and 50%), patients with 
plasmacytomas, patients with bone lesions, ȕ2-microglobulin level in mg/L (quantitatively and by 
category: <3.5 mg/L, [3.5-5.5 mg/L) and 5.5 mg/L), albumin in g/L (quantitatively and by 
category: <35 g/L and 35 g/L). 
Table 2 - ISS staging definition 
Stage   
Definition 
Stage I          ȕ2-microglobulin <3.5 mg/L and albumin  35 g/L 
Stage II         [ȕ2-microglobulin <3.5 mg/L and albumin <35 g/L] or [ȕ2-microglobulin 3.5 - <5.5 mg/L] 
Stage III 
ȕ2-microglobulin 5.5 mg/L 
ISS=International Staging System 
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Table 3 – Derivation of measurable paraprotein at study entry 
Measurable paraprotein 
Criteria 
Serum M-Protein 
Serum M-protein  0.5 g/dL 
 
Urine M-Protein 
Serum M-protein <0.5 g/dL or missing 
and 
urine M-protein 200 mg/24hours  
 
Kappa LC 
Serum M-protein <0.5 g/dL or missing 
and 
urine M-protein <200 mg/24 hours or missing 
and 
kappa LC>lambda LC and kappa LC  10mg/dL  
 
Lambda LC 
Serum M-protein <0.5 g/dL or missing 
and 
urine M-protein <200 mg/24 hours or missing 
and 
lambda LC>kappa LC and lambda LC 10 mg/dL  
Cytogenetic abnormalities (Molecular subtype) 
Molecular subtypes were determined on cytogenetic analysis from central or local (if central 
assessment was not available) fluorescence in situ hybridization (FISH)/karyotyping reports or 
central FISH assessment. A patient is considered as high risk if bearing del17p and/or t(4;14). 
Prior anticancer therapies 
x 
Prior anticancer treatments: Prior anticancer treatment were collected by line in the eCRF, 
and the following variables will be derived; number of prior lines (quantitatively and by 
category: 1, 2, …7 and  8 ), main anticancer treatments (ie, alkylating agent, IMiD, PI 
agent, PI or IMiD agent, PI and IMiD agent, bortezomib, carfilzomib, lenalidomide, 
pomalidomide, thalidomide, elotuzumab, bendamustine, bortezomib or lenalidomide, 
bortezomib and lenalidomide, carfilzomib or ixazomib, pomalidomide, carfilzomib and 
pomalidomide), time from completion of last line of treatment to first isatuximab 
administration (months), best response to last line, duration of last line of therapy. 
In addition, the refractory status to each anticancer treatment will be derived. A patient is 
considered to be refractory if any of the following conditions are met: 
- 
Progression date and anticancer treatment end date are complete and progression date 
is within () 60 days of anticancer treatment end date. (progression date – anticancer 
treatment end date  60 days). If only the day is missing for either date or both dates, 
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and the progression date and anticancer treatment end date corresponds to two 
consecutive months within the same year, then, the patient will be considered 
refractory, otherwise they will be considered not refractory. 
- 
Best overall response is SD or PD. 
- 
Reason for treatment discontinuation is “disease progression”. 
x 
Prior transplant: patients with transplant, type of transplant, number of transplant by 
patient, time from last transplant to first isatuximab administration (months) 
x 
Prior surgery: patients with any prior surgery related to cancer, type of surgery, location of 
surgery and time from last surgery to first isatuximab administration (months) 
x 
Prior radiotherapy: number (%) of patients with any prior radiotherapy related to cancer, 
intent, and time from last radiotherapy to first isatuximab administration (months) 
Any technical details related to computation, dates, and imputation for missing dates, are 
described in Section 2.5. 
Vital signs  
Vital signs at baseline are weight in kilograms. 
Renal status  
Creatinine clearance in mL per minute (qualitative variable : <30, [30-50[, [50-80], >80) 
calculated from serum creatinine concentration measured at baseline. 
Any technical details related to computation, dates, and imputation for missing dates are described 
in Section 2.5. 
2.1.2 Prior or concomitant medications (other than anticancer therapies) 
All medications taken by the patient within 7 days prior to enrollment into the study, at any time 
during the treatment period and up to 30 days after the last isatuximab administration were to have 
been reported in the eCRF. 
The following information was collected in the medication eCRF page: drug/medication (brand or 
generic name), reason (eg, curative, prophylaxis), start date and end date (if available)/ongoing 
(otherwise). 
All medications will be coded using the World Health Organization-drug Dictionary (WHO-DD) 
version in effect at Sanofi at the time of database lock. 
x 
Prior medications are those the patient used prior (<) to first isatuximab administration. 
Prior medications can be those discontinued before first administration or those ongoing 
during the treatment phase. 
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x 
Concomitant medications are any treatments received by the patient concomitantly to 
isatuximab, from first dose to the date of last administration +30 days. A given medication 
can be classified both as a prior medication and as a concomitant medication. Any anti-
cancer treatment administered after the date of the last isatuximab administration will not 
be considered as a concomitant medication and will be regarded as further anti-myeloma 
therapy (see Section 2.4.10). The analysis of concomitant medications will include 
premedication (see below). 
x Post-treatment medications (excluding post anticancer treatments) are those the patient 
took from 31 days after last isatuximab administration up to the end of the study. 
Premedications 
As defined in Section 8.2.2 of the amended study protocol (version 11, 22 April 2016), patients 
were to routinely receive premedications prior to isatuximab infusion to reduce the risk and 
severity of hypersensitivity reactions commonly associated with monoclonal antibodies. 
Premedications were defined in the protocol as noninvestigational medicinal product(s). The 
recommended premedication agents were: diphenhydramine 25-50 mg IV (or equivalent), 
methylprednisolone 100 mg IV (or equivalent), ranitidine 50 mg IV (or equivalent), and 
acetaminophen 650-1000 mg po 15-30 minutes (but no longer than 60 minutes) prior to 
isatuximab infusion. Premedications were reported on a specific eCRF page. 
Any technical details related to computation, dates, and imputation for missing dates, are 
described in Section 2.5. 
2.1.3 Efficacy endpoints 
Response assessments were to be performed on a monthly basis using the International Myeloma 
Working Group (IMWG) criteria and included: 
x 
M-protein quantification (serum and 24-hr urine) 
x 
Serum free light chain levels 
x 
Corrected serum calcium 
In case of plasmacytoma at baseline, radiological evaluations were to be performed every 2 
cycles. 
In case of bone lesions at baseline, bone lesion evaluations were to be performed when clinically 
indicated or to confirm a response or progression. Bone marrow biopsy/aspiration were to be 
performed to confirm a sCR, CR, at the EOT visit and as clinically indicated. 
An independent adjudication committee (IAC), blinded to treatment arm, independently assessed 
clinical response using the IMWG response criteria. 
Biological responses (PR) and progression were to be confirmed on 2 consecutive biological 
(serum and/or urine M protein) disease assessments. No confirmation was required for 
radiological assessment. 
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2.1.3.1 Primary efficacy endpoint 
The primary efficacy endpoint is ORR, defined as the proportion of patients with sCR, CR, VGPR 
or PR as best overall response (BOR) as assessed by the IAC. The BOR will be derived using 
disease assessments performed from the start of treatment through the entire study excluding any 
assessments performed after the cutoff date or following the start of further therapies for MM.  
The first disease assessment performed during further therapy will be used to confirm PD if 
performed within 3 months of last isatuximab administration (see Figure 1). The ordering of 
evaluations from best to worse is: sCR, CR, VGPR, PR, MR, stable disease (SD), progressive 
disease (PD), not evaluable (NE). BOR for patients without response assessment by the IAC will 
be ‘Not evaluable’. 
Figure 1 – Determination of BOR when disease assessments are performed after new anti-myeloma 
therapies are started or performed after the cutoff date 
 
 
Subgroup analyses of BOR using IAC assessment will be performed for the variables listed in 
Table 4. 
Table 4 – List of variables for subgroup analyses 
Variable 
Description  
Age 
<70 years versus 70 years 
Number of previous lines of therapy 
3 vs > 3 
Gender 
Male vs female 
Region of the world 
USA versus Other countries 
ECOG PS 
0-1 vs 2 
ISS staging at study entry 
I vs II vs III 
Previous transplant 
Yes vs No 
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Variable 
Description  
Measurable paraprotein at baseline 
Serum M-Protein; Urine M-Protein, Light chain 
High risk cytogenetic 
Yes vs No 
Baseline creatinine clearance 
<60 ml/min vs 60 ml/min 
Refractory to lenalidomide and bortezomib 
Yes vs No 
Refractory to IMid 
Yes vs No 
Refractory to PI 
Yes vs No 
Refractory to IMiD and PI 
Yes vs No 
Refractory to pomalidomide and carfilzomib 
Yes vs No 
Quadruple refractory (refractory to lenalidomide and 
bortezomid and pomalidomide and carfilzomib) 
Yes vs No 
 
A sensitivity analysis of ORR will be performed using investigator’s assessment of response. For 
this analysis, BOR will be the best sequential response as determined by the criteria defined in 
Table 5. In addition, the following rules will be applied: 
x 
BOR will be NE for patients who received 1 (Stage 1a) or 2 (Stage 1b) isatuximab 
administrations with investigator assessment of response of SD or better at Cycle 1 or end 
of treatment.  
x 
BOR will be PD for patients without response assessment who received 1 cycle of 
treatment and who died due to PD or had symptomatic deterioration within 30 days of last 
isatuximab administration.  
x 
The criteria of confirmation of PD will not be applied since some patients discontinued 
isatuximab before confirmation of PD.  
Table 5 - Sequential response determination 
Overall response at cycle n 
Overall response at cycle n+1a 
Sequential response 
sCR 
sCR 
sCR 
sCR/CR 
CR 
CR 
sCR/CR 
VGPR 
VGPRb 
sCR/CR 
PR 
PR 
VGPR 
sCR/CR/VGPR 
VGPRb 
VGPR 
PR 
PR 
PR 
sCR/CR/VGPR/CR/PR 
PR 
sCR/CR/VGPR/MR 
NE/No further evaluation/SD/PD 
MRc 
MR 
Any 
MR 
Any 
MR 
MR 
NE/SD/PD 
sCR/CR/VGPR/PR 
MRc 
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Overall response at cycle n 
Overall response at cycle n+1a 
Sequential response 
NE/PD/SD 
SD 
SD 
SD 
No further evaluation/NE/PD 
SD 
NE 
SD 
SD 
PD 
No further evaluation/NE/PD 
PD 
NE 
PD 
PD 
NE 
No further evaluation 
NE 
a Disease assessment were planned to be performed every cycle. Disease assessment performed after the start of new anticancer 
treatment will be excluded from the derivation of BOR. 
b Sequence provided for programming purpose. 
c Unconfirmed PR or CR will be considered MR. 
BOR=best overall response; sCR=stringent complete response; CR=complete response; MR=minor response; NE=not 
evaluable; PD=progressive disease; PR=partial response; SD=stable disease. 
2.1.3.2 Secondary efficacy endpoints 
Secondary efficacy endpoints are defined below. 
x 
Duration of Response (DOR): DOR is defined as the time from the date of the first IAC 
determined response ( PR) that is subsequently confirmed, to the date of first IAC 
determined PD or death, whichever happens earlier (if reported before the analysis cutoff 
date or the date of initiation of a new anticancer treatment). If progression or death are not 
observed before the analysis cut-off date or the date of initiation of new anticancer 
treatment, DOR 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 
anticancer treatment or the analysis cut-off date. DOR is determined only for patients who 
have achieved a confirmed response of PR.  
x 
CBR: defined as the proportion of patients with sCR, CR, VGPR, PR or MR as BOR 
according to IMWG criteria, as determined by the IAC. 
x PFS (in months): defined as the time interval from the date of first isatuximab 
administration to the date of the first IAC-confirmed disease progression or the date of 
death due to any cause, whichever comes first. For patients who did not experience 
IAC-confirmed disease progression or death before the analysis cut-off date of or the date 
of initiation of new anticancer treatment, PFS will be censored at the date of the last valid 
disease assessment not showing disease progression performed prior to initiation of a 
further anticancer treatment or the analysis cut-off date, whichever comes first. As defined 
in Section 2.1.3.1, the first disease assessment performed during further therapy will be 
used to confirm PD if performed within 3 months of last isatuximab administration. Date 
of PFS event/censoring relative to date of further anti-myeloma therapies and cutoff date 
are illustrated in Figure 2. Subgroup analysis for variables defined in Table 4 will be 
performed. 
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Sensitivity analyses of DOR, CBR and PFS will be performed using the investigator’s assessment 
of response. For these analyses, the criteria of confirmation of PD will not be applied (see  
Section 2.1.3.1). 
Figure 2 - Date of PFS event/censoring relative to the date of further anti-myeloma therapies and 
the cutoff date 
 
 
 
x 
OS (in months): defined as the time interval from the date of first isatuximab 
administration to death from any cause. In the absence of the confirmation of death before 
the cut-off date, OS will be censored at the cut-off date or at the last date the patient is 
known to be alive. 
Other efficacy endpoints include: 
x 
Best percent change in paraprotein: Best percent change in paraprotein will be calculated 
for the measurable paraprotein parameter defined at baseline (Section 2.1.1) excluding 
anytime point following the start of other anticancer therapy. 
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x Duration of follow-up (DFU) (in months): DFU is defined as the time from first dose to 
last disease assessment before start of other therapy or cut-off date, whichever comes first.  
x Time to first response (TTR) (in months) is defined as the time from first dose to first 
response (PR or better) that is subsequently confirmed 
2.1.4 Safety endpoints 
The safety analysis will be based on the reported AEs and other safety information, such as 
clinical laboratory data, vital signs, and ECG (Section 1.4). 
Observation period 
The observation period will be divided into 3 periods: pre-treatment, on-treatment, and post-
treatment. 
x 
The pre-treatment period is defined as the time from when the patient gave informed 
consent and the start of isatuximab administration. 
x 
The on-treatment period is defined as the time from the first dose of isatuximab up to 
30 days after the last dose of isatuximab. 
x 
The post-treatment period is defined as 31 days after the last dose of isatuximab to the 
study closure. 
2.1.4.1 Adverse events variables 
Adverse events occurring from signature of informed consent form up to 30 days after the last 
isatuximab administration were to be recorded in the eCRF.  
All isatuximab related AEs and SAEs ongoing at time of study treatment discontinuation were to 
be followed during the follow-up period until resolution or stabilization. 
All AEs (including serious AEs [SAEs]) will be coded to a lower-level term (LLT), preferred term 
(PT), high-level term (HLT), high-level group term (HLGT), and associated primary system organ 
class (SOC) using the version of MedDRA in effect at Sanofi at the time of database lock. 
The severity of AEs was assessed according to NCI-CTCAE version 4.03.  
The following AEs will be described: 
x 
Pre-treatment AEs: defined as any AE reported during the pre-treatment period. 
x 
Treatment-emergent AEs (TEAEs): defined as any AE that developed, worsened 
(according to the Investigator’s opinion), or became serious during the on-treatment 
period. 
x 
Post-treatment AEs: defined as any AE reported during the post-treatment period. 
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The following AEs are considered adverse events of special interest (AESIs): 
x 
Acute infusion associated reactions (IARs) 
x 
Symptomatic overdose 
x 
Pregnancy occurring in a female patient or in a female partner of a male patient 
Analysis of adverse events 
Analysis of AEs will include IARs, respiratory TEAEs, and specific hematological analyses. 
Infusion associated reactions 
Infusion associated reactions, commonly observed with monoclonal antibodies, generally include 
AEs with onset date within 24 hours from the start of each isatuximab infusion (See Section 6.5 of 
the TED10893 protocol for guidelines for IARs management). As described above, IARs are 
considered to be AESI. 
Two analyses of IARs will be performed. The first one will be based on the investigator’s 
reporting of IARs (ie, as AESIs). For each IAR-AESI, the sites were instructed to report a generic 
term (infusion-related reaction) and each individual symptom. 
The second analysis of IAR will include TEAEs occurring within 24 hours from the start of each 
isatuximab infusion.  
Respiratory TEAEs 
Analysis of respiratory TEAEs will focus particularly on the following groupings:  
x 
Lower respiratory events, selected using HLGT ‘Bronchial disorders (excluding 
neoplasms)’,  HLGT ‘Lower respiratory tract disorders (excluding obstruction and 
infection)’ excluding HLT ‘Lower respiratory tract radiation disorders’  and HLGT 
‘Respiratory disorders NEC’ (excluding ‘Upper respiratory tract signs and symptoms’ 
HLT), 
x 
Respiratory infections, selected using HLGT ‘Respiratory tract infections’, HLT ‘Lower 
respiratory tract and lung infections’ and HLT ‘Upper respiratory tract infection’  
Hematological adverse events 
Neutropenia (from laboratory abnormalities) will be displayed along with neutropenic infections 
and febrile neutropenia. 
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2.1.4.2 Deaths 
The deaths observation period are per the observation periods defined in Section 2.1.4. 
x 
Death on-treatment:  deaths occurring during the on treatment period  
x 
Death post-treatment:  deaths occurring during the post-treatment period  
2.1.4.3 Laboratory safety variables  
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis.  Clinical laboratory values will be converted into standard international units and these 
international units will be used in all listings and tables. 
Blood samples for clinical laboratories parameters were taken as defined in the study flow charts 
and as clinically indicated. The laboratory parameters will be classified as follows: 
x 
Hematology  
- 
Red blood cells and platelets and coagulation:  hemoglobin, hematocrit, mean 
corpuscular volume, red blood cell count, platelet count, prothrombin time (expressed 
as international normalized ratio), partial thromboplastin time 
- 
White blood cells:  white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils 
x 
Clinical chemistry  
- 
Metabolism: glucose, total protein, albumin, 
- 
Electrolytes:  sodium, potassium, chloride, calcium, phosphorus, bicarbonate/carbon 
dioxide, magnesium, 
- 
Renal function:  creatinine, creatinine clearance, blood urea nitrogen, uric acid, 
- 
Liver parameters:  alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, lactate dehydrogenase, bilirubin (total and direct). 
x 
Urinalysis 
- 
Urinalysis - qualitative analyses: blood, protein, glucose, ketones, bilirubin , 
leucocyte, nitrates,  
- 
Urinalysis - quantitative analyses: pH. 
Technical formulas are described in Section 2.5.1. 
2.1.4.4 Vital signs variables 
Vital signs include:  heart rate, systolic and diastolic blood pressure, respiratory rate, temperature, 
and weight. 
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2.1.4.5 Electrocardiogram variables  
Twelve-lead ECG was performed at screening and as clinically indicated. 
2.1.4.6 Other safety endpoints 
Other safety endpoints include: 
x 
Cytokines  
- 
TNF-Į, IL-6, IL-1B, IFN-Ȗ 
x 
IAR laboratory test 
- 
Markers of complement (C3a, C4, CH50) 
- 
Serum tryptase 
x 
Chest X-ray at baseline and as clinically indicated. 
x 
Tumor lysis syndrome (TLS) 
- 
Criteria for laboratory and clinical parameters which could be indicative of TLS are 
given in Table 6. 
Table 6 – Criteria for laboratory and clinical parameters which could be indicative of TLS 
Type 
Criteria 
Laboratory TLS (LTLS) 
2 simultaneous abnormalities within 3 days prior to and up to 7 days 
after isatuximab administration: 
x 
Uric acid >8 mg/dL (>475.8 μmol/L) 
x 
Potassium >6.0 mmol/L 
x 
Phosphorus >4.5 mg/dL (>1.5 mmol/L) 
x 
Corrected calcium <7.0 mg/dL(<1.75 mmol/L)a 
x 
Ionized calcium <1.12 mg/dL (<0.3mmol/L) a 
Clinical TLS (CTLS) 
LTLS in addition to one of the following complications: 
x 
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/hr for 6 hours 
x 
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 
 
x 
Dysrhythmias probably or definitely caused by hyperkalemia 
a The corrected calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter + 0.8 x (4 - albumin in grams per 
deciliter) 
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2.1.5 Pharmacokinetic variables 
Isatuximab plasma concentrations after single and repeated dose administrations will be analyzed 
using a nonlinear mixed-effects modelling approach using MONOLIX software version 2016 
R1(Lixoft).  A population PK model without covariates will be developed and the following PK 
individual parameters will be calculated: 
x 
Cumulative AUC over a 1, 2 or 4 week interval (AUC1W, AUC2W, AUC4W) 
x 
Ctrough (pre-dose concentration) at 1, 2, 4, 6 weeks and every 2 weeks up to Week 24 
(CT1W, CT2W, CT4W, CT6W, CT8W, CT10W, CT12W, CT14W, CT16W, CT18W, 
CT20W, CT24W) 
x 
Cmax at Cycle 1 Day 1, Cycle  2 Day 1 and Cycle 4 Day 1  
x 
Clearance (CL) for linear non-specific elimination pathway 
x 
Accumulation ratios (Cmax CnDn/ Cmax C1D1 and Ctrough nW/Ctrough1W) 
2.1.6 Immunogenicity 
Human ADA to isatuximab was assessed during the study as defined in the protocol. 
Observation period 
The observation period will be divided into 2 periods: ADA pre-treatment and ADA on-study 
observation. 
x 
ADA pre-treatment period: The ADA pre-treatment period is defined as the time from 
signed informed consent to the first isatuximab administration.  
x 
ADA on-study observation period: the ADA on-study observation period is defined as the 
time from first isatuximab administration until the end of the study.  
Patients with at least one ADA result during the ADA on-study observation period will be 
considered evaluable for ADA. 
ADA attributes: 
x 
Pre-existing ADA is defined as ADA that was present in samples drawn during the ADA 
pretreatment period.  
x 
Treatment boosted ADA is defined as preexisting ADA with an increase in titer value 
between pre-treatment and post-treatment samples of at least two titer steps during the 
ADA on-study observation period. With a 2-fold serial dilution, this means that the post-
treatment sample titer value is at least () 4 fold of pretreatment titer value.  
x 
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.  
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x 
Transient ADA response is defined by: 
- 
Treatment induced ADA detected only at one sampling time point during the ADA 
on-study observation period (excluding the last sampling time point), OR 
- 
Treatment induced ADA detected at two or more sampling time points during ADA 
on-study observation period, where the first and last ADA-positive samples 
(irrespective of any negative samples in between) are separated by a period less than 
16 weeks, and the patient’s last sampling time point is ADA negative. 
x 
A persistent ADA response is defined by: 
- 
Treatment induced ADA detected at two or more sampling time points during the 
ADA on-study observation period, where the first and last ADA-positive on study 
samples are separated by at least 16 weeks (irrespective of any negative samples in 
between), OR 
- 
Treatment induced ADA detected in the last two sampling time points (both are 
positive), irrespective of the time period in between.  
x Indeterminate ADA is defined by treatment induced ADA detected only at the last 
sampling time point with all previous samples being negative or the last two samples are 
ADA-positive and separated by a period of less than 16 weeks. 
ADA response endpoints: 
x An ADA positive patient is defined as a patient with at least one treatment-induced or 
treatment-boosted ADA positive sample at any time during the on-study observation 
period 
x ADA incidence is defined as the number of ADA positive patients among evaluable 
patients divided by the number of evaluable patients.  
x ADA prevalence is defined as the sum of the number of patients with preexisting ADA 
and the number of patients with treatment induced ADAs, divided by the number of 
evaluable patients. 
2.1.7 Biomarker endpoints 
2.1.7.1 Receptor occupancy/density 
CD38 receptor occupancy (RO) and receptor density (RD) were assessed from bone marrow 
aspirates at the time points detailed in the protocol. 
2.1.7.2 Immune Genetic Determinants 
Germline genetic data of Fc gamma receptor (FCGR), human leukocyte antigen (HLA) and killer-
cell immunoglobulin-like receptor (KIR) genes have been analyzed on blood samples collected on 
Day 1 of Cycle 1: 
x 
FCGR polymorphisms (FCGR2A and FCGR3A): For each gene, the results will be of the 
form AA, Aa or aa with A and a-alleles, the major and minor allele, respectively. 
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x 
HLA genotypes: HLA-A, HLA-B and HLA-C have been typed for each gene. The results 
will be epitope genotypes (see Table 7) and allele genotypes. 
Table 7 - Epitopes of HLA Class I recognized by KIR 
  
  
Amino-acid at positiona 
  
HLA class I 
Epitope  
77 
80 
81 
82 
83 
  
HLA-B 
Bw6 
Ser 
Asn 
Leu 
Arg 
Gly 
  
  
Bw4 
Asn 
Thr 
Ala 
Leu 
Arg 
  
  
Bw4 
Asn 
Ile 
Ala 
Leu 
Arg 
  
  
Bw4 
Asp 
Thr 
Leu 
Leu 
Arg 
  
  
Bw4 
Ser 
Thr 
Leu 
Leu 
Arg 
  
  
Bw4 
Ser 
Thr 
Ala 
Leu 
Arg 
  
 
 
 
 
 
 
 
 
HLA class I 
Epitope  
77 
80 
81 
82 
83 
Associated allotypes 
 
 
 
 
 
 
 
 
HLA-A 
Aw4 
Asn 
Ile 
Ala 
Leu 
Arg 
A*23; A*24 
  
Aw4 
Ser 
Ile 
Ala 
Leu 
Arg 
A*32 
  
A3 
Key residues not yet published 
A*03 
  
A11 
Key residues not yet published 
A*11 
 
 
 
 
 
 
 
 
HLA class I 
Epitope  
77 
80 
  
  
  
  
 
 
 
 
 
 
 
 
HLA-C 
C1 
Ser 
Asn 
  
  
  
  
  
C2 
Asn 
Lys 
  
  
  
  
a Numbering from the first codon of the mature protein 
 
x 
KIR genotypes: The presence or absence of 16 KIR genes was screened. A KIR gene will 
be defined as present if at least one assay gives positive results; otherwise it will be 
defined as negative. 
2.1.7.3 Immune phenotyping 
Immune phenotyping in bone marrow (baseline) and/or peripheral blood (D1 of Cycle 1, D1 of 
Cycle 3 and EOT) were assessed. The immune cell populations include B-cell, T-cell and NK-cell 
subsets were determined by multiparametric flow cytometry based on the expression of different 
cell surface markers.  
2.1.7.4 CD38 mRNA 
Myeloma cells (CD138+ cells) were immunopurified from baseline bone marrow aspirates and 
RNA was extracted. CD38 mRNA levels were determined by quantitative RT-PCR after 
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normalization to the expression of a control gene. Five different splicing isoforms (A, B, C, D and 
E) exist for CD38 mRNA. Expression of all isoforms (CD38_ALL) and combined A/B/D 
(CD38_ABD) were determined. 
2.1.7.5 Soluble CD38 
Soluble CD38 levels in peripheral blood plasma samples at C1D1 and C3D1 were assessed. 
2.1.8 Health related quality-of-life (HRQL) endpoints  
HRQL was assessed using the European Organization for Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire (QLQ)-C30 (cancer-specific module with 30 questions) 
and the EORTC QLQ-myeloma-specific module with 20 questions (MY20). Health status and 
health utility were assessed using the EuroQol (EQ)-5D-3L measure which has 5 dimensions and 
three levels per dimension. Data was captured electronically throughout the study. 
The EORTC QLQ-C30 is comprised of: 
x 
the five functional scales (physical functioning, role functioning, emotional functioning, 
cognitive functioning, and social functioning), with high scores representing a high level 
of functioning 
x 
the three symptom scales (fatigue, nausea and vomiting, and pain), with high scores 
representing a high level of symptomatology or problems 
x 
the GHS/ quality of life scale, with high scores representing better HRQL 
x 
and the six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and 
financial difficulties) scales, with high scores representing a high level of symptomatology 
or problems 
The EORTC MY20 is comprised of: 
x 
the 2 functional subscales (body image, future perspective), with high scores representing 
a high level of functioning 
x 
and the 2 symptoms scales (disease symptoms and side-effects of treatment), with high 
scores representing a high level of symptomatology or problems 
The EQ-5D-3L is comprised of 5 dimensions, mobility, self-care, usual activities, 
paint/discomfort and anxiety and the visual analogue scale (VAS) which assesses a patient’ 
current health status. The 5 dimensions are assessed on three levels; level 1 (no problems/no 
pain/not anxious, level 2 (some problems/moderate pain or anxiety) and level 3 (extreme 
problems).  
The VAS assesses a patient’s health status on a given day on a 20 cm vertical line labelled of 0 
(worst imaginable health state) to 100 (best imaginable health state). Higher scores on the VAS 
indicate a better health state.  
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In addition to the 5 dimensions and the VAS, there is the health state utility index (HSUI) score, 
which is derived by combining the response on each of the five dimensions into an overall score. 
The VAS score and HSUI score measure the patient’s overall health state. 
2.1.9 Health economic endpoints 
Not applicable. 
2.1.10 Further therapy after discontinuation of investigational medicinal product 
administration during the study 
Further therapies after discontinuation of isatuximab were collected on a specific eCRF page. The 
following information was collected: drug/medication (brand or generic name), reason (eg, 
curative, prophylaxis), start date and end date (if available)/ongoing (otherwise). 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
version in effect at Sanofi at the time of database lock. 
2.2 
DISPOSITION OF PATIENTS 
A summary of screened patients (those who signed the screening informed consent form), those 
screened failed (ie, screened patients with at least one inclusion/exclusion criteria not met/met 
who were not treated with isatuximab), and those eligible but not treated with isatuximab will be 
presented. In addition, a listing of screened failed patients and reason for screening failure (when 
available) will be provided. 
The number and percentage of patients in each of the analysis populations defined in Section 2.3 
will be provided. Percentages will be calculated using the number of patients in the AT/safety 
population. For the AT/safety population, no percentages will be calculated. A listing showing 
which of the analysis populations a patient belongs to, will also be presented. 
In addition, the number and percentage of patients in each of the following categories will be 
provided using the AT/safety population: 
x 
Patients in each country and center  
x 
Patients off treatment and reasons for treatment discontinuation 
x 
Patients on treatment at time of the analysis  
Listing of the reasons for treatment discontinuation and patients still on treatment at time of the 
analysis will be provided. 
A summary of the key dates of the study including the following will be presented: 
x 
Date of first consent signed 
x 
Date of last consent signed 
x 
Date of first patient first dose 
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x 
Date of last patient first dose 
x 
Last cycle day 1 date 
x 
Date of last visit completed 
Major deviations potentially impacting efficacy/safety analyses include:  
x 
No known diagnosis of MM.  
x 
No evidence of  measurable disease ie, none of the following: 
- 
Serum M-protein <1.0 g/dL  
- 
Urine M-protein <200 mg/24 hours. 
- 
In absence of measurable m-protein: serum immunoglobulin (SI) free light chain 
(FLC) <10mg/dL and 0.26  SI serum kappa lambda FLC ratio  1.65  
x 
No prior treatment with or IMiD and PI (for 2 cycles of 2 months of treatment) 
x 
Did not receive at least three prior lines of therapy for MM and is not double refractory to 
IMiD and PI 
x 
Did not achieve an MR or better to at least one prior line of therapy 
x 
Did not receive an alkylating agent  
x 
Informed consent not signed. 
x 
Age <18 years. 
x 
Prior autologous stem cell transplant within 12 weeks of the first dose of study treatment 
x 
Prior allogenic transplant within 1 year with evidence of active graft vs. host disease 
(GVHD) 
x 
Patients with a Karnofsky performance status <60% 
x 
Total bilirubin 2 x ULN 
x 
AST or ALT 3 x ULN 
x 
Calculated or measured creatinine clearance <30 mL/minute 
x 
Absolute neutrophil count (ANC) 1000/mm3 
x 
Hemoglobin <7.0 g/dL  
x 
Platelet count 50 000/mm3  
x 
Received isatuximab dose different from planned dose on Day 1 of Cycle 1, defined as a 
50% increase/decrease of planned dose.  
x 
No premedication given for prevention of IAR during any infusion of Cycle 1 
x 
No pregnancy test and age <55, or pregnancy test is positive  
All major deviations will be summarized showing the number and percentage of patients with 
major deviations. Major protocol deviations will also be listed. 
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2.2.1 Randomization and drug dispensing irregularities 
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report.  If the number of irregularities is large enough to make a tabular summary useful, the 
irregularities will be categorized and summarized among randomized patients (number and 
percentages).  Nonrandomized and treated patients in Stage 1a (if any) will be described 
separately. 
Randomization and drug-dispensing irregularities to be prospectively identified include but are 
not limited to:  
x 
Isatuximab administration without IVRS transaction 
x 
Randomization by error 
x 
Patient randomized twice 
x 
Stratification error 
2.3 
ANALYSIS POPULATIONS 
2.3.1 All treated (AT)/safety population 
The AT/safety population will include all patients who gave their informed consent and who have 
received at least 1 dose (even incomplete) of isatuximab. 
This population is the primary population for the analyses of efficacy and safety parameters. All 
analyses using this population will be based on the actual dose given at Cycle 1 - Day 1, except 
for patients who were unable to complete the first isatuximab administration at Cycle 1 – 
Day 1due to grade 3 IAR. These patients will be analyzed in the treatment group corresponding 
to the planned dose at Cycle 1 – Day 1. 
2.3.2 Randomized population 
The randomized population includes all patients from Stage 1a who gave their informed consent 
and were assigned a randomization number. 
2.3.3 Patient reported outcomes population 
There will be no population flag for PRO. PRO endpoints will be analyzed using patients from the 
all treated population who have a baseline assessment and/or an on-treatment assessment, 
depending on the analysis being performed. 
2.3.4 Pharmacokinetic population 
The PK population is a subset of the AT/safety population and includes patients with a PK 
parameter. 
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There will be no population flag for biomarker. Biomarker endpoints will be analyzed using 
patients from the all treated population who have one assessment on the biomarker of interest.  
2.4 
STATISTICAL METHODS 
In the summary tables, treatment groups will be presented as follows: 
x 
3 mg/kg Q2W 
x 
10 mg/kg Q2W 
x 
10 mg/kg Q2W/Q4W 
x 
20 mg/kg QW/Q2W 
x 
All  
Continuous data will be summarized using the number of available data, mean, standard deviation 
(SD), median, minimum, and maximum. Categorical and ordinal data will be summarized using 
the number and percentage of patients. 
Important data listings will be provided, such as, patient disposition, AEs leading to 
discontinuation, SAEs, deaths, and specific TEAEs. Listings will be sorted by actual dose level 
and patient number. Repeated values of these key variables will be blanked out in the listings. 
2.4.1 Demographics and baseline characteristics 
Parameters described in Section 2.1.1 will be summarized using descriptive statistics. 
Past medical or surgical history will be summarized by primary SOC and PT (both sorted by 
alphabetical order). Past medial history occurring in 10% of patients will also be summarized by 
PT sorted by decreasing frequency. 
MM disease characteristics at diagnosis and at study entry, molecular subtype, and prior 
anticancer therapies will be described for the AT/safety population. 
2.4.2 Prior or concomitant medications (other than anticancer therapies) 
The prior and concomitant medications will be presented for the AT/safety population.  
Medications will be summarized by treatment group and overall according to the WHO-DD 
dictionary, considering the first digit of the anatomic category (ATC) class (anatomic category) 
and the first 3 digits of the ATC class (therapeutic category).  All ATC codes corresponding to a 
medication will be summarized, and patients will be counted once in each ATC category 
(anatomic or therapeutic) linked to the medication. Therefore, patients may be counted several 
times for the same medication.  
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The table for prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the overall incidence across treatment groups.  In case of equal 
frequency regarding ATCs, alphabetical order will be used. 
Premedications 
Number (%) of patients with premedications including diphenhydramine and steroids as defined 
in Section 2.1.2 will be provided. Number of infusions with premedications may be summarized 
when applicable. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of isatuximab exposure will be assessed and summarized by treatment group within the 
AT/safety population.  
2.4.3.1 Extent of investigational medicinal product exposure 
The dose information will be assessed by the following: 
x 
Number of cycles started 
x 
Total number of infusions 
x 
Duration of isatuximab exposure (or time on-treatment) (in weeks): defined as (date of last 
day of last cycle – date of first day of first cycle)/7. The date of last day of last cycle is 
defined as follows: 
- 
Minimum(date of last dose + 7 days, date of death) if last cycle is administered QW 
- 
Minimum(date of last dose + 14 days, date of death) if last cycle is administered Q2W 
- 
Minimum(date of last dose + 28 days, date of death) if last cycle is administered Q4W 
x 
Actual dose (mg/kg): for a given cycle and day of administration, the actual dose in mg/kg 
corresponds to the actual dose in mg administered at each time point divided by the actual 
body weight as measured at each time point (cycle and day) 
x 
Cumulative dose (mg/kg): the cumulative dose is the sum of all actual doses of 
isatuximab, expressed in mg/kg, given from first to last administration  
x 
Actual dose intensity (ADI) in mg/kg/week: defined as the cumulative dose (in mg/kg) 
divided by the duration of isatuximab exposure (in weeks) 
x 
Relative dose intensity (RDI) in %: 
k)
(mg/kg/wee
Intensity 
 
Dose
 
Planned
 
k)
(mg/kg/wee
 
ADI
100 u
 
x 
Planned dose intensities in mg/kg/week corresponds to the planned dose (mg/kg) at 
Cycle 1-Day 1, regardless of dose changes, multiplied by the theoretical total number of 
doses during the started cycles (count 2 for Q2W cycles, 1 for Q4W cycles and 4 for QW 
cycles), and divided by the theoretical cycle duration expressed in weeks (ie, 4 weeks per 
cycle started). 
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The total number of infusions, total number of cycles started, number of cycles started by patients 
as a quantitative variable and by category (ie, number [%] of patients receiving at least 1 cycle, at 
least 2 cycles, etc), duration of isatuximab exposure, cumulative dose, ADI and RDI will be 
summarized by descriptive statistics.  
The following variables will be derived to describe dose delays/modifications: 
x 
Cycle delay: A cycle will be deemed as delayed if the Day 1 start date of the current cycle 
– 28 – Day 1 start date of the previous cycle is >3 days. 
x 
Dose delay (within a cycle): A dose is deemed as delayed if the actual start date of the 
infusion – theoretical start date of an infusion is >1 day for weekly administration, is >2 
days for Q2W administration and is >4 days for Q4W administration. Infusion delay does 
not apply to the first infusion of each cycle, in which case it is considered as cycle delays. 
x 
Dose interruption: A dose will be considered to be interrupted if the isatuximab 
administration is temporarily stopped during an infusion and then restarted (typically in 
case of Grade 2 IARs). Analysis of dose interruption will be performed using the dose 
interruption section of the eCRF. 
x 
Dose omission: a dose is considered omitted if the dose is not administered for the 
scheduled visit and there are positive dose(s) afterwards. 
x 
Dose reduction: Although not allowed in the study protocol, potential dose reductions will 
be screened and reported in the clinical study report. The first administration will not be 
counted as a dose reduction. For the second and subsequent isatuximab administrations, 
dose reduction will be determined using the dose level intervals provided in Table 8, by 
comparing the current dose level to the previous dose level. If the current dose level is not 
within the same dose level interval as the previous dose level, then the current dose level is 
considered reduced. 
Table 8 – Dose reduction criteria 
Actual dose level 
Dose level interval 
Dose level 1 (3 mg/kg) 
>1.5 mg/kg and 6.5 mg/kg 
Dose level 2 (10 mg/kg) 
>6.5 mg/kg and 15 mg/kg 
Dose level 3 (20 mg/kg): 
>15 mg/kg and 25 mg/kg 
 
x 
Infusions not completed: patients who received less than 90% of the planned dose at an 
infusion 
Cycle delayed will be analyzed at the patient and cycle levels, as follows (the number of patients 
who received 2 cycles will be used for % calculation): 
x 
Number (%) of patients with a least 1 cycle delayed 
- 
Number (%) of patients with a cycle delayed between 4 and 7 days (using maximum 
delay) 
- 
Number (%) of patients with a cycle delayed >7 days (using maximum delay) 
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x Number (%) of cycles delayed 
- 
Number (%) of cycles delayed between 4 and 7 days 
- 
Number (%) of cycles delayed >7 days 
Dose delayed/modification will be analyzed at the patient, cycle and the total number of 
isatuximab administration levels as follows: 
x Patient level 
- 
Number (%) of patients with at least 1 dose delayed (using number of patients with 2 
infusions as denominator for % calculation) 
For the following variables, number of patients treated will be used for % calculation: 
- 
Number (%) of patients with at least one dose omission 
- 
Number (%) of patients with at least one dose reduction 
- 
Number (%) of patients with a least 1 infusion interrupted 
- 
Number (%) of patients with at least 2 infusions interrupted 
x Total number of isatuximab administration level 
- 
Total number of isatuximab infusions (used for % calculation for this section) 
- 
Number (%) of isatuximab infusions interrupted   
- 
Number (%) of isatuximab infusions interrupted more than once   
- 
Number of infusion interrupted at (with % calculated using the total number of 
infusions interrupted): 1st infusion, 2nd infusion, subsequent infusions 
- 
Time from infusion start to first interruption in minutes (quantitative and qualitative: 
5–10, 11-30, 31–40, 41 –50, 51 –60, 61–90, 91–120, >120) 
- 
Number (%) of infusions not completed (patients who received less than 90% of the 
planned dose). 
Duration of infusion is defined as the time from the start (date/time) of infusion to the end 
(date/time) of infusion. It will be summarized for first and subsequent infusions. 
2.4.4 Analyses of efficacy endpoints 
All primary, secondary and exploratory analyses will be performed using the AT/safety 
population.  
2.4.4.1 Analysis of primary efficacy endpoint(s) 
ORR, BOR and CBR as assessed by IAC will be summarized with descriptive statistics. A 95% 
two-sided confidence interval will be computed for both ORR and CBR using Clopper-Pearson 
method. The same analysis will be performed using investigator assessments of response. 
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ORR as assessed by IAC will also be summarized descriptively for subgroups variable defined in  
Table 4. 
2.4.4.2 Analyses of secondary efficacy endpoints 
The following analyses will be performed using both IAC and investigator assessments of 
response. 
x 
CBR: see above. 
x 
DOR: Kaplan-Meier estimates of the 25th, 50th and 75th percentiles including the 95% 
confidence interval as well as Kaplan-Meier curves will be provided for DOR for patients 
who achieve a response  PR. 
x 
PFS: PFS will be analyzed using the Kaplan-Meier method. The Kaplan-Meier estimates 
of the 25th, 50th and 75th percentiles and the 95% confidence interval of the median will 
also be computed. The Kaplan-Meier curves will be plotted. 
OS will be analyzed using the same method as PFS.  
DFU and TTR will be summarized with descriptive statistics. 
A listing of response (as assessed by IAC) data will be provided for the all treated population and 
for patients who are ADA positive at baseline or during the on-study period,  and will include the 
following variables,: high risk status, number of prior lines of anti-myeloma treatment, selected 
prior treatments given (alkylating agent, bortezomib, carfilzomib, lenalidomide, pomalidomide, 
thalidomide), duration of exposure (weeks), reason for treatment discontinuation, measurable 
paraprotein at baseline, best percent change in paraprotein, best overall response, date of first 
response PR, date of first disease progression/last disease assessment, indication of progressive 
disease, time to first response and DOR. 
A listing of best percent change in % plasma cell in bone marrow biopsy will be provide and will 
include the following variables: measurable paraprotein at baseline, best percent change in 
paraprotein, BOR, baseline plasma cells count, post baseline plasma cells count and best percent 
change in plasma cells count. 
A swimmer plot of time on a treatment and a waterfall plot of best percent change in paraprotein 
will be provided. 
A listing of patients MRD negative will be provided (if any).  
2.4.4.3 Multiplicity issues 
Not applicable. 
2.4.5 Analyses of safety data 
The analysis of safety data will be presented by treatment group and overall (see Section 2.4). 
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General common rules 
All safety analyses will be performed on the AT/safety population as defined in Section 2.3.1. 
Unless otherwise specified, the baseline value is defined as the last available value before or on 
the date of first isatuximab administration. 
2.4.5.1 Analyses of adverse events 
Generalities 
The primary focus of adverse event reporting will be on treatment-emergent adverse events.  
Pre-treatment and post-treatment AEs will be described separately.  
If an AE date of onset (occurrence, worsening, or becoming serious) is incomplete, an imputation 
algorithm will be used to classify the AE as pretreatment, treatment-emergent, or post-treatment.  
The algorithm for imputing date of onset will be conservative and will classify an AE as treatment 
emergent unless there is definitive information to determine it is pretreatment or post-treatment.  
Details on classification of adverse events with missing or partial onset dates are provided in 
Section 2.5.3.  
For patients with multiple occurrences of the same AE within the observation period (pre-
treatment, treatment emergent and post-treatment), the maximum severity grade will be used. 
Analysis of adverse events 
An overview of TEAEs including the number (%) of patients with the following events will be 
provided: 
x 
TEAE 
x 
TEAE of Grade 3 
x 
Drug-related TEAE 
x 
Drug-related TEAE of Grade 3 
x 
Serious TEAE 
x 
Serious drug-related TEAE 
x 
TEAE with a fatal outcome 
- 
TEAE leading to treatment discontinuation 
- 
AESI 
- 
AESI of Grade 3 
- 
IAR (excluding symptoms) 
- 
IAR of Grade 3 (excluding symptoms) 
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Analysis of adverse events will be performed according to following:  
x TEAEs (regardless relationship to study treatment), 
x Drug related TEAEs,  
x Analysis of TEAEs 
- 
IAR 
- 
Respiratory TEAEs  
- 
Hematological adverse events 
x Deaths, serious adverse events, adverse events leading to withdrawal, and other significant 
adverse events (ie, TEAE leading to dose modification, other AESI, pre- and post-
treatment AE) 
The description of the main summary tables that will be provided for the analysis of TEAEs, 
drug-related TEAEs, serious TEAEs, drug-related serious TEAEs, IAR-AESI, IAR-AE, as well as 
TEAEs leading to dose discontinuation or modification is given in Table 9. 
Sorting within tables will ensure the same presentation for the set of all AEs within the 
observation period (pre-treatment, treatment-emergent, and post-treatment). For that purpose, the 
table of all TEAEs presented by SOC and PT sorted by the internationally agreed SOC order and 
decreasing frequency of PTs within SOCs will define the presentation order for all other tables 
unless otherwise specified. Sorting will be based on the incidence of AEs in the AT/safety 
population (ie, all patients). 
Additional analyses will include: 
x 
IAR-INV (generic term):  
- 
Analysis by patient: worst grade, number of episodes by patient, patients with IAR at 
the first and subsequent infusion and number (%) of patients with at least two IARs at 
the same infusion.  
- 
Analysis by infusion: worst grade by infusion (a patient can have several IAR episodes 
at the same infusion). 
x 
Analysis by episode: proportion of IARs occurring at each infusion, IAR duration and day 
of onset. 
x 
Listing of IAR-INV. 
x 
Respiratory TEAEs: Respiratory TEAEs may also be analyzed as regards to medical 
history data (eg, chronic obstructive pulmonary disease, cough, dyspnea, tabagism). 
x 
Hematological adverse event: 
- 
Number (%) of patients with neutropenia (from laboratory abnormalities) neutropenic 
infections and febrile neutropenia by grade. 
x 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation. 
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- 
Given the small number of patients who discontinued treatment due to a TEAE, no 
summary table will be provided. Instead, a listing will be provided.  
x 
Other AESI (not consistent with IAR) will be listed. 
x 
Deaths : see Section 2.4.5.2. 
 
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Table 9 – Description of summary tables to be provided for the analysis of TEAEs 
MedDRA coding variables 
Sorting (all patients column) 
Layout 
Events 
PT 
x PT: Decreasing order of 
frequency 
Treatment groups and All patients: n 
(%) of patients with any event and n (%) 
of patients with event of Grade 3 
x TEAEs occurring in 5% of the patients (all patients) 
x Drug-related TEAEs occurring in 5% of the patients 
(all patients) 
x Serious TEAEs in 5%a of the patients (all patients) 
SOC, HLGT, HLT, and PT 
x Primary SOC: internationally 
agreed order 
x HLGT, HLT, PT: alphabetical 
order 
Treatment groups and All patients: n 
(%) of patients with any event and n (%) 
of patients with event of Grade 3 
 
x All TEAEs 
x Drug-related TEAEs 
x Respiratory TEAEs 
x Serious TEAEs 
x Drug-related serious TEAEs 
SOC and PT 
x Primary SOC: internationally 
agreed order 
x PT: decreasing order of 
frequency defined be the all 
TEAEs table (see previous page) 
Treatment groups and All patients: n 
(%) of patients with any event and n (%) 
of patients with event of Grade 3 
 
x All TEAEs 
x Serious TEAEs 
x Drug-related serious TEAEs 
x TEAEs leading to treatment discontinuation 
x TEAEs leading to dose interruption 
x TEAEs leading to dose delay 
x TEAEs leading to dose reduction 
SOC and PT 
x Primary SOC: internationally 
agreed order 
x PT: decreasing order of 
frequency (all patients) 
Treatment groups and All patients: n 
(%) of patients with any event and n (%) 
of patients with event of Grade 3 
x IAR-AESI 
x IAR-AE 
x Pre-treatment and post-treatment AEs 
x IAR-AESI 
a The threshold presented is 5%, however, other threshold(s) could be used if deemed clinically relevant. 
AE=adverse event; AESI=adverse event of special interest; HLGT=high-level group term; HLT=high-level term; IAR=infusion associated reaction; MedDRA=Medical Dictionary for 
Regulatory Activities; n (%)=number and percentage of patients; PT=preferred term; SOC=system organ class; TEAE=treatment-emergent adverse event. 
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2.4.5.2 Deaths 
Number (%) of patients who died by study period (on-treatment and post-treatment) and within 
60 days from first dose, and cause of death will be summarized. A listing of patients who died 
while participating in the study including cause of death, death date, days from first and last dose, 
days from last dose to death, preferred term, and causal relationship to isatuximab will be 
provided. 
2.4.5.3 Analyses of laboratory variables  
Each laboratory test result will be graded by CTCAE criteria (version 4.03), when applicable. For 
hematological parameters and for some biochemistry parameters, sanofi sponsor generic normal 
ranges will be used for the grading of laboratory abnormalities (see list of parameters in  
Appendix C, Table 12 and Table 13). For other biochemistry parameters (eg, for hepatic 
parameters, grading will be derived using the central laboratory normal ranges). 
The number (%) of patients with abnormal laboratory tests at baseline and during the on-treatment 
period will be presented by all grades and each grade. For patients with multiple occurrences of 
the same laboratory variable during the on-treatment period, the maximum grade (worst) per 
patient will be used. At baseline, the last available value before or on the date of first isatuximab 
administration will be used. 
Shift tables showing the number of patients in each grade at baseline by worst grade during the 
on-treatment period will be provided for selected laboratory test. 
For creatinine clearance, the number (%) of patients by category (>80, 50 – 80, 30 – <50 and less 
than 30 mL/min) and by period (baseline and on-treatment) as well as a shift table will be 
provided.  
For urate, potentially clinically significant abnormalities (PCSA) values defined as abnormal 
values considered medically important by the Sponsor according to predefined criteria/thresholds 
based on literature review will be derived. PCSA criteria will determine which patients had at 
least 1 PCSA during the on-treatment period, taking into account all evaluations performed during 
the on-treatment period, including nonscheduled or repeated evaluations. The incidence of PCSA 
any time during the on-treatment period will be summarized by treatment group and overall, 
irrespective of the baseline level.  
Listings of patients with laboratory abnormalities of Grade 3 and Grade 4 during the on-treatment 
period will be provided. The baseline value will be included in the listing. 
2.4.5.4 Analyses of vital sign variables 
The incidence of PCSA any time during the on-treatment period will be summarized by treatment 
group irrespective of the baseline level and/or according to the following baseline status 
categories:  
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x Normal/missing 
x Abnormal according to PCSA criterion or criteria 
Temperature and respiratory rate will be summarized at baseline and end of treatment, by 
treatment group and all. 
A listing of patients with at least one PSCA will be provided. 
2.4.5.5 Analyses of electrocardiogram variables 
The number (%) of patients with normal/abnormal ECG result at baseline will be summarized by 
treatment group and all. A listing of ECG results will be provided. 
2.4.5.6 Analyses of other safety endpoints 
A shift table of baseline ECOG PS versus best and worst ECOG PS on treatment will be provided.  
The number (%) of patients with laboratory and clinical parameters which could be indicative of 
TLS prior to first dose and during the on-treatment period will be provided. Number (%) of 
patients with TLS reported under the TLS standard MedDRA query (SMQ) (ie, haemorrhagic 
tumor necrosis, TLS, tumor necrosis) will also be provided. 
A listing of chest x-ray results will be provided. 
Cytokine parameters will be descriptively summarized at baseline, peak value (largest on 
treatment value), change and relative change from baseline to peak value, relative change from 
baseline to peak value by category (<10%, 10-25%, 25 – 50%, >50%), time point occurrence of 
peak value, by treatment group and overall and by responders/non-responders. A responder is a 
patient with IAC assessed response PR. 
2.4.6 Analyses of pharmacokinetic and pharmacodynamic variables 
2.4.6.1 PK variables 
Pharmacokinetic parameters of isatuximab will be summarized by descriptive statistics (such as 
the number of observations available, arithmetic and geometric mean, median, standard deviation 
(SD), standard error of the mean (SEM) (optional), coefficient of variation (CV), minimum, and 
maximum) under the responsibility of Pharmacokinetic, Dynamic and Metabolism, Translational 
Medicine and Early Development Sanofi. Steady state (based on Ctrough) will be assessed as well 
as the extent of the accumulation (accumulation ratios for Cmax and Ctrough). 
2.4.6.2 PK/PD analysis 
A pooled analysis of data from the Phase 1 and Phase 2 Stage 1 studies will be performed and the 
results reported in a separate document. 
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Statistical Analysis Plan  
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2.4.7 Immune response 
Using the ADA evaluable population, the number (%) of patients will be provided for the 
following: 
x Preexisting ADA 
x ADA negative at baseline 
x On study ADA 
- 
Treatment-induced ADA 
- 
Persistent ADA 
- 
Transient ADA 
- 
Indeterminate ADA 
- 
Treatment boosted ADA 
- 
Last sample positive 
x 
ADA prevalence 
x 
ADA incidence 
In addition, a data listing of each ADA sample result will be provided. The impact on PK, safety 
and efficacy endpoints may be further explored by graphical methods or descriptively, depending 
on the ADA prevalence. 
2.4.8 Analyses of Biomarker variables 
2.4.8.1 Receptor occupancy and receptor density 
CD38 RD and RO will be summarized with descriptive statistics by treatment groups and overall. 
For RD, descriptive statistics will also be provided for responders/non-responders. 
A responder is a patient with IAC assessed response PR. 
The relationship between ORR and CD38 RD might be explored using loess plot and mosaic plot. 
Certain transformation of CD38 receptor density, such as log transformation might also be used if 
needed. 
2.4.8.2 Immune Genetic variables 
2.4.8.2.1 Descriptive analysis 
Each genetic biomarker will be summarized with descriptive statistics by treatment group and 
overall.  
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2.4.8.2.2 Univariate analysis 
Each genetic biomarker will be tested for a potential prognostic/predictive effect for ORR.  
A logistic regression will be conducted separately for each genetic biomarker with a treatment 
effect, a biomarker effect and a biomarker×treatment interaction. Since the number of patients in 
each treatment group is small, only the main effect of the biomarkers may be investigated 
ignoring the interaction with treatment. 
In this analysis, some dose/schedules may be pooled together or removed from the model.  
For biomarkers coded as genotype (0, 1, 2), different coding may be investigated: additive, 
dominant or recessive. 
Distribution of p-values will be presented and Benjamini-Hochberg multiple correction procedure 
will be used to control the false discovery rate (FDR). 
Additional analyses using PFS instead of ORR might also be performed. 
2.4.8.2.3 Multivariate analysis 
If some biomarkers are determined to be potentially prognostic/predictive in the previous step, 
multivariate analysis combining several biomarkers will be considered (eg, logistic regression, 
SVM, Random Forest). A proper cross-validation scheme including the univariate selection step, 
will be put in place to estimate the generalization error of the model. 
Sensitivity, specificity and accuracy will be calculated to assess the predictive properties of the 
multivariate biomarker.  
2.4.9 Analyses of quality of life variables 
For each questionnaire the compliance profile over time will be summarized as follows: 
x number and percentage of forms received versus expected 
x and number and percentage of forms evaluable versus expected 
A questionnaire is expected at a given cycle as defined in the study flow chart and based on the 
number of cycles started by the patient. 
A questionnaire is considered received at a given cycle if at least one item on the form is 
completed at that cycle. 
A questionnaire is evaluable at a given cycle if the overall item response rate at the given cycle is 
greater than 80%. 
For each EORTC QLQ-C30 and QLQ-MY20 scales a descriptive summary at each visit and 
change from baseline will be provided for each group: the five functional scales (physical 
functioning, role functioning, emotional functioning, cognitive functioning, and social 
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Statistical Analysis Plan  
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functioning), the three symptom scales (fatigue, nausea and vomiting, and pain), the GHS / quality 
of life scale, and the six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and 
financial difficulties) of the QLQ-C30 and the 2 functional subscales (body image, future 
perspective), and 2 symptoms scales (disease symptoms and side-effects of treatment) of the 
MY20. The primary scales of importance are pain, fatigue, and physical functioning, and for 
these, the proportion of patients who achieve clinically meaningful improvements will be 
reported. A clinically meaningful improvement will be defined as a change from baseline  -10 
for the symptoms of pain and fatigue scales and as a change from baseline 10 for the physical 
functioning scale. 
If deemed relevant, the proportion of patients who achieve clinically meaningful improvements on 
the other scales of the EORTC QLQ-C30 and QLQ-MY20 will be reported in a separate report. 
The responses of each EQ-5D item will be presented by visit and group. The tables will contain 
information on the frequency and proportion of the population reporting level 1 (no problems), 
level 2 (some problems) and level 3 (extreme problems) per item. Tables will also be presented 
cross-tabulating a visit with the baseline visit. Descriptive summary statistics (number, mean, 
standard deviation, median, range) will be provided for the HSUI and the VAS score at each visit. 
Change from baseline will be also described.  
Table 10 and Table 11 show the grouping of questions into scales for the EORTC-QLQ-C30 and 
the MY20 (2).  The EQ-5D can be found in Appendix A. 
Table 10 - EORTC-QLQ-C30 scales 
Scale 
       Subscale (abbreviation) 
 
No. of Items 
 
Item Number(s) 
Global health status/QoL (QL 2) 
2 
29 and 30 
Functional scales 
 
 
Physical functioning (PF) 
5 
1 to 5 
Role functioning (RF) 
2 
6 and 7 
Emotional functioning (EF) 
4 
21 to 24 
Cognitive functioning (CF 
2 
20 and 25 
Social functioning (SF) 
2 
26 and 27 
Symptom scales 
 
 
Fatigue (FA) 
3 
10, 12 and 18 
Nausea and vomiting (NV) 
2 
14 and 15 
Pain (P) 
2 
9 and 19 
Individual items 
 
 
Dyspnea (DY) 
1 
8 
Insomnia (SL) 
1 
11 
Appetite loss (AP) 
1 
13 
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Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
Page 45 
 
Constipation (CO) 
1 
16 
Diarrhea (DI) 
1 
17 
Financial difficulties (FI) 
1 
28 
Table 11 - EORTC-MY20 scales 
Scale  
    Subscale (abbreviation) 
 
No. Items 
 
Item Number(s) 
Functional scales 
 
 
Future perspective (MYFP) 
3 
48 to 50 
Body image (MYBI) 
1 
47 
Symptom scales 
 
 
Disease symptoms (MYDS) 
6 
31 to 36 
Side effects of treatment (MYSE) 
10 
37 to 46 
 
Computation of the Score for EORTC QLQ-C30 and QLQ-MY20 
x 
For all scales, the raw score (RS) is the mean of the component items:  
RS = (I1 + I2 +...+ I)/n. 
x 
For the Functional scales:  
Score = [1í ((RSí 1)/Range)]x100 
x 
For Symptom scales / single items scales and the Global health status/QoL scale:  
Score = [(RS í 1)/ range]x100 
Handling of missing items 
x 
Multi-item Scales 
Have at least half of the items from a given scale been answered?  
- 
If Yes, use all the items that were completed, and apply the standard equations given 
above for calculating the scale scores; ignore any items with missing values when 
making the calculations.  
- 
If No, set scale score to missing.  
x 
Single-item Scales: 
- 
Set to missing if no response. 
The SAS® statistical code to derive the HSUI score for the EQ-5D-3L is provided in Appendix B. 
(electronic 1.0)


Statistical Analysis Plan  
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2.4.10 Further therapy after discontinuation of investigational medicinal product 
administration during the study 
Further therapies will be descriptively summarized by treatment group and overall 
2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
Not applicable. 
2.5.2 Data handling conventions for secondary efficacy variables 
Not applicable. 
2.5.3 Missing data 
The analyses and summaries of continuous and categorical variables will be based on observed 
data only. Percentages will be calculated using as the denominator the number of patients with a 
non-missing observation in the considered population. When relevant, the number of patients with 
missing data will be presented. 
When incomplete or missing dates were found in the eCRF, attempts were made to retrieve the 
complete date, especially for dates within the month prior to first dose. However, if some dates 
remain incomplete, the following rules will be applied: 
Handling of disease characteristics missing/partial dates  
x 
If the day is missing, it will be imputed to be 1 
x 
If the month is missing, it will be imputed to be 1 (only for medical history variables) 
x 
If the year is missing, no imputation will be performed 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and post-treatment medication. 
For post anticancer treatments, if the anticancer treatment start date is missing, it will be imputed 
as follows: 
1. If the anticancer treatment start day is missing and the anticancer treatment start month 
and year are the same as the isatuximab end month and year, the anticancer treatment start 
day will be set equal to the date of last isatuximab administration + 1. 
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Statistical Analysis Plan  
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2. If the anticancer treatment start day is missing and the anticancer treatment start month is 
not missing and the anticancer treatment start year is after the isatuximab end year, the 
anticancer treatment start day will be set to 01. 
3. If the anticancer treatment start day is missing and the anticancer treatment start month is 
after the isatuximab end month and the anticancer treatment start year is the same as 
treatment end year, the anticancer treatment start day will be set to 01. 
4. If the anticancer treatment start day and month are missing and the anticancer treatment 
start year is the same as isatuximab end year, the anticancer treatment start date will be set 
equal to the date of last isatuximab administration + 1 
5. If the anticancer treatment start day and month are missing and the anticancer treatment 
start year is after the isatuximab end year, the anticancer treatment start day and month 
will each be set to 01 
6. If the anticancer treatment start day is missing and anticancer treatment start month is 
before the isatuximab end month and the anticancer treatment start year is the same as 
treatment end year, the anticancer treatment start day will be set to 01 
7. If the anticancer treatment start day, start month and start year is missing, the anticancer 
treatment start date will be set equal to the treatment end date + 1. 
Handling of adverse events with missing or partial date of onset 
Missing or partial AE onset dates will be imputed so that if the partial AE onset date or visit 
number information does not indicate that the AE started prior to treatment or after the treatment-
emergent adverse event period, the AE will be classified as treatment-emergent.  No imputation of 
AE end dates will be performed.  These data imputations are for categorization purpose only and 
will not be used in listings.  No imputation is planned for date of AE resolution. 
Handling of adverse events with missing grade 
Missing grades, if any, will be included in the “all grades” category. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to isatuximab is missing, then the relationship to isatuximab 
has to be assumed and the AE considered as such in the frequency tables of possibly related AEs, 
but no imputation will be done at the data level. 
Handling of death with missing or partial date of death 
If the date the patient was last known to be alive is not missing, the imputation for missing or 
partial death date will proceed as follows: 
1. If the death day is missing and the death month and year are the same as the last month 
and year the patient was last known to be alive, the death day will be set equal to the last 
day the patient was known to be alive + 1. 
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Statistical Analysis Plan  
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Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
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2. If the death day is missing and the death month is after the month the patient was last 
known to be alive and the death year is the same as the year the patient was last known to 
be alive, the death day will be set to 01. 
3. If the death day and month are missing and the death  year is the same as the year the 
patient was last known to be alive, the death date will be set equal to the date the patient 
was last known to be alive + 1. 
4. If the death day and month are missing and the death year is after the year the patient was 
last known to be alive, the death day and month will both be set to 01. 
If the date the patient was last known to be alive is partial or missing, no imputation for missing or 
partial death date will be performed. 
Handling of parameters expressed as inequality or approximation 
For some parameters (such as laboratory parameters), if the value is expressed as an inequality or 
an approximation, the numeric portion of the entry may be used in calculations. 
2.5.4 Windows for time points 
Laboratory data 
A protocol planned laboratory test is considered to have occurred during a cycle if the date of 
sampling is after (>) the first day of the cycle, but prior to or equal () to the first day of the next 
cycle. For unscheduled tests, a test is considered to have occurred during a cycle if the date of 
sampling is equal to or after () the first day of the cycle, but prior (<) to the first day of the next 
cycle.  
Sponsor specified reference ranges will be used to calculate laboratory toxicities (see  
Section 2.4.5.3).  
2.5.5 Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs and ECG will be used for 
computation of baseline and worst values and/or grades. 
2.5.6 Pooling of centers for statistical analyses 
Data from all sites will be pooled together for analyses. 
2.5.7 Statistical technical issues 
Not applicable. 
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Statistical Analysis Plan  
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SAR650984-TED10893 (Phase 2 Stage 1) - isatuximab 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
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3 
INTERIM ANALYSIS 
An interim analysis of the data from Stage 1 was performed when all patients had completed at 
least two disease assessments. This analysis was performed for the selection of the isatuximab 
dose/schedule to be used in Stage 2. Response rate along with safety, PK, PD, and overall efficacy 
were analyzed. Another analysis was performed when all patients had been followed for at least 
4 months to confirm the dose/schedule selection. 
 
(electronic 1.0)


Statistical Analysis Plan  
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SAR650984-TED10893 (Phase 2 Stage 1) - isatuximab 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 50 
 
4 
DATABASE LOCK 
The database will be locked when clinical review of the database has been completed and all 
critical queries have been resolved. 
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Statistical Analysis Plan  
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Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 51 
 
5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses, except for biomarker analysis, will be generated using 
SAS® version 9.2 or higher. Biomarker analyses will be performed using R software 
version 3.3.2 (2016-10-31). 
 
(electronic 1.0)


Statistical Analysis Plan  
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SAR650984-TED10893 (Phase 2 Stage 1) - isatuximab 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 52 
 
6 
REFERENCES 
1. Simon R, Wittes RE, Ellenberg SS. Randomized phase II clinical trials. Cancer Treat Rep. 
1985 Dec;69(12):1375-81. 
2. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al.  The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst. 1993 Mar;85(5):365-76. 
3. Badia X, Roset R, Herdman M, Kind P. A comparison of United Kingdom and Spanish 
general population time trade-off values for EQ-5D health states. Med Decis Making. 2001 
Jan;21(1):7-16. 
4. Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states: development and 
testing of the D1 valuation model. Med Care. 2005 Mar;43(3):203-20. 
5. MVH Group. The Measurement and Valuation of Health. Final report on the modelling of 
valuation tariffs. York: MVH Group, Centre for Health Economics, 1995. 
6. Dolan P. Modeling valuations for EuroQol health states. Med Care. 1997 Nov;35(11):1095-
108. 
7. Alexander Kratz, MD, PhD, MPH, Maryjane Ferraro, PhD, MPH, Patrick M. Sluss, PhD, and 
Kent B. Lewandrowski, MD. Laboratory reference values. 
 
(electronic 1.0)


Statistical Analysis Plan  
15-Feb-2017 
SAR650984-TED10893 (Phase 2 Stage 1) - isatuximab 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 53 
 
7 
LIST OF APPENDICES 
 
(electronic 1.0)




Statistical Analysis Plan  
15-Feb-2017 
SAR650984-TED10893 (Phase 2 Stage 1) - isatuximab 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 55 
 
Appendix B 
Statistical code to derive the EQ-5D HSUI score 
(electronic 1.0)


Statistical Analysis Plan  
15-Feb-2017 
SAR650984-TED10893 (Phase 2 Stage 1) - isatuximab 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 56 
 
(electronic 1.0)


Statistical Analysis Plan  
15-Feb-2017 
SAR650984-TED10893 (Phase 2 Stage 1) - isatuximab 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 57 
 
(electronic 1.0)


Statistical Analysis Plan  
15-Feb-2017 
SAR650984-TED10893 (Phase 2 Stage 1) - isatuximab 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 58 
 
Appendix C 
Generic ranges for hematological and biochemistry  
Table 12 – Generic ranges for hematological parameters 
Test 
Gender 
Unit 
Lower limit of normal 
Hemoglobin 
F 
g/L 
120 
Hemoglobin 
M 
g/L 
135 
Lymphocytes 
 
109/L 
1 
Neutrophils 
 
109/L 
1.8 
Platelets 
 
109/L 
150 
Leukocytes 
 
109/L 
4.5 
Eosinophils 
 
109/L 
0 
Basophils 
 
109/L 
0 
Monocytes 
 
109/L 
0.18 
Hematocrit 
M 
% 
0.41 
Hematocrit 
F 
% 
0.36 
Erythrocytes 
F 
1012/L 
4 
Erythrocytes 
M 
1012/L 
4.5 
Based on Kratz et al. (7) 
 
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Statistical Analysis Plan  
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SAR650984-TED10893 (Phase 2 Stage 1) - isatuximab 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 59 
 
The current list of generic ranges for biochemistry parameters (for adults) is provided in the table 
below: 
Table 13 – Generic ranges for biochemistry parameters 
Test 
Unit 
Lower – Upper limit of normal 
Albumin 
g/L 
35 - 55 
Blood Urea Nitrogen (BUN) 
mmol/L 
NA-17 
Calcium 
mmol/L 
2.2 - 2.6 
Chloride 
mmol/L 
80 - 115 
Glucose 
mmol/L 
3.9 - 7 
Bicarbonate (HCO3) 
mmol/L 
22 - 29 
Potassium 
mmol/L 
3.5 - 5 
Magnesium 
mmol/L 
0.8 - 1.2 
Sodium 
mmol/L 
129 - 160 
Phosphate 
mmol/L 
1 - 1.4 
Protein 
g/L 
55 - 80 
Urea 
mmol/L 
3.6 - 7.1 
 
(electronic 1.0)




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consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
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According to template: QSD-002643 VERSION 6.0 (06-JUL-2016)
Page 1
STATISTICAL ANALYSIS PLAN
A Phase 1/2 Dose Escalation Safety, Pharmacokinetic and Efficacy Study of 
Multiple Intravenous Administrations of a Humanized Monoclonal Antibody 
(SAR650984) Against CD38 In Patients with Selected CD38+ Hematological 
Malignancies
SAR650984-TED10893 (Phase 2 - Stage 2)
STATISTICIAN:
DATE OF ISSUE: 06-Aug-2019
Total number of pages:
64
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Statistical Analysis Plan
06-Aug-2019
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Version number: 1
Property of the Sanofi Group - strictly confidential
Page 2
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN ...................................................................................................................1 
TABLE OF CONTENTS..................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................................................................5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................7 
1.1 
STUDY DESIGN AND RANDOMIZATION ......................................................................................7 
1.2 
OBJECTIVES...................................................................................................................................8 
1.2.1 
Primary objectives............................................................................................................................8 
1.2.2 
Secondary objectives.......................................................................................................................8 
1.2.3 
Exploratory objectives......................................................................................................................8 
1.3 
DETERMINATION OF SAMPLE SIZE.............................................................................................8 
1.4 
STUDY PLAN...................................................................................................................................9 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL................................10 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN .....................10 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ....................................................................12 
2.1 
ANALYSIS ENDPOINTS ...............................................................................................................12 
2.1.1 
Demographic and baseline characteristics ....................................................................................12 
2.1.2 
Prior or concomitant medications (other than anticancer therapies) .............................................15 
2.1.3 
Efficacy endpoints..........................................................................................................................16 
2.1.3.1 
Primary efficacy endpoint...............................................................................................................16 
2.1.3.2 
Secondary efficacy endpoints ........................................................................................................19 
2.1.4 
Safety endpoints ............................................................................................................................23 
2.1.4.1 
Adverse events variables...............................................................................................................24 
2.1.4.2 
Deaths............................................................................................................................................26 
2.1.4.3 
Laboratory safety variables............................................................................................................26 
2.1.4.4 
Vital signs variables .......................................................................................................................27 
2.1.4.5 
Electrocardiogram variables ..........................................................................................................27 
2.1.4.6 
Other safety endpoints...................................................................................................................27 
2.1.5 
Pharmacokinetic variables .............................................................................................................28 
2.1.6 
Immunogenicity..............................................................................................................................28 
2.1.7 
Biomarker endpoints ......................................................................................................................29 
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2.1.7.1 
Immune Genetic Determinants ......................................................................................................29 
2.1.7.2 
Immune phenotyping......................................................................................................................30 
2.1.7.3 
CD38 mRNA ..................................................................................................................................30 
2.1.7.4 
Soluble CD38.................................................................................................................................30 
2.1.8 
Health related quality-of-life (HRQL) endpoints .............................................................................31 
2.1.9 
Health economic endpoints............................................................................................................31 
2.1.10 
Further therapy after discontinuation of investigational medicinal product administration 
during the study..............................................................................................................................31 
2.2 
DISPOSITION OF PATIENTS .......................................................................................................31 
2.2.1 
Randomization and drug dispensing irregularities.........................................................................33 
2.3 
ANALYSIS POPULATIONS...........................................................................................................34 
2.3.1 
Randomized population .................................................................................................................34 
2.3.2 
All treated (AT)/safety population...................................................................................................34 
2.3.3 
Pharmacokinetic population...........................................................................................................34 
2.3.4 
ADA evaluable population..............................................................................................................34 
2.3.5 
Biomarker population .....................................................................................................................34 
2.4 
STATISTICAL METHODS .............................................................................................................34 
2.4.1 
Demographics and baseline characteristics ..................................................................................35 
2.4.2 
Prior or concomitant medications (other than anticancer therapies) .............................................35 
2.4.3 
Extent of investigational medicinal product exposure and compliance .........................................36 
2.4.3.1 
Overall exposure............................................................................................................................36 
2.4.3.2 
Isatuximab exposure......................................................................................................................37 
2.4.3.3 
Dexamethasone exposure (ISAdex arm only) ...............................................................................39 
2.4.4 
Analyses of efficacy endpoints.......................................................................................................40 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ........................................................................................40 
2.4.4.2 
Analyses of secondary efficacy endpoints.....................................................................................41 
2.4.4.3 
Multiplicity issues ...........................................................................................................................43 
2.4.5 
Analyses of safety data..................................................................................................................43 
2.4.5.1 
Analyses of adverse events ...........................................................................................................43 
2.4.5.2 
Deaths............................................................................................................................................49 
2.4.5.3 
Analyses of laboratory variables....................................................................................................49 
2.4.5.4 
Analyses of vital sign variables ......................................................................................................50 
2.4.5.5 
Analyses of electrocardiogram variables .......................................................................................51 
2.4.5.6 
Analyses of other safety endpoints ................................................................................................51 
2.4.6 
Analyses of pharmacokinetic and pharmacodynamic variables ....................................................51 
2.4.6.1 
PK variables ...................................................................................................................................51 
2.4.7 
Immune response ..........................................................................................................................52 
2.4.8 
Analyses of Biomarker variables....................................................................................................52 
2.4.8.1 
Genetic variables ...........................................................................................................................52 
2.4.8.2 
Other variables...............................................................................................................................52 
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2.4.9 
Analyses of quality of life variables ................................................................................................54 
2.4.10 
Further therapy after discontinuation of investigational medicinal product administration
during the study..............................................................................................................................54 
2.5 
DATA HANDLING CONVENTIONS ..............................................................................................54 
2.5.1 
General conventions ......................................................................................................................54 
2.5.2 
Data handling conventions for secondary efficacy variables.........................................................54 
2.5.3 
Missing data...................................................................................................................................54 
2.5.4 
Windows for time points.................................................................................................................56 
2.5.5 
Unscheduled visits .........................................................................................................................57 
2.5.6 
Pooling of centers for statistical analyses......................................................................................57 
2.5.7 
Statistical technical issues .............................................................................................................57 
3 
INTERIM ANALYSIS .....................................................................................................................58 
4 
DATABASE LOCK........................................................................................................................59 
5 
SOFTWARE DOCUMENTATION .................................................................................................60 
6 
REFERENCES...............................................................................................................................61 
7 
LIST OF APPENDICES.................................................................................................................62 
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Page 5
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
AE:
adverse event
AESI:
adverse event of special interest
ANC:
absolute neutrophil count
AT:
all treated
BOR:
best overall response
C1P2F2:
cell line 1, process 2, formulation 2
CBR:
clinical benefit rate
CL:
clearance
CMQ:
customized MedDRA queriies
CR:
complete response
CTCAE:
common terminology criteria for adverse events
DOR:
duration of response
ECOG:
eastern cooperative oncology group
eCRF:
electronic case report form
FCGR:
fc gamma receptor
FDR:
false discovery rate
FIH:
first in human
FISH:
fluorescence in situ hybridization
FLC:
free light chain
GVHD:
graft vs. host disease
HLA:
human leukocyte antigen
HLGT:
high-level group term
HLT:
high-level term
HRQL:
health related quality-of-life
IAC:
independent adjudication committee
IAR:
infusion associated reaction
IFN-γ:
interferon-gamma
IL:
interleukin
IMiD:
immunomodulatory drug
IVRS:
interactive voice response system
IWRS:
interactive web response system
KIR:
killer-cell immunoglobulin-like receptor
KPS:
karnofsky performance status
LLT:
lower level term
MDRD:
Modification of Diet in Renal Disease
MedDRA:
medical dictionary of regulatory activities
MR:
minimal response
NCI:
national cancer institue
NE:
not evaluable
ORR:
overall response rate
OS:
overall survival
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PCSA:
potentially clinically significant abnormalities
PD:
progressive disease
PFS:
progression free survival
PI:
proteasome inhibitor
PK:
pharmacokinetic
PR:
partial response
PS:
performance status
PT:
preferred term
RRMM:
relapsed refractory multiple myeloma
SAP:
statistical analysis plan
SD:
standard deviation, stable disease
SI:
serum immunoglobulin
SOC:
system organ class
TLS:
tumor lysis syndrome
TNF-α:
tumor necrosis factor alpha
VGPR:
very good partial response
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Statistical Analysis Plan
06-Aug-2019
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Page 7
1
OVERVIEW AND INVESTIGATIONAL PLAN
TED10893 is the first in human (FIH) study of isatuximab (SAR650984) and was originally 
designed as a dose escalation study to evaluate the safety and pharmacokinetics (PK) of 
isatuximab. The protocol was subsequently amended to include a Phase 2 part for the treatment of 
patients with relapsed refractory multiple myeloma (RRMM) consisting in a dose/schedule
finding portion (Stage 1) and in a Stage 2 expansion to further evaluate the activity and safety of 
isatuximab alone or in combination with dexamethasone at a dose and schedule selected in Stage 
1. This statistical analysis plan (SAP) describes the statistical methods to be used for the analyses 
of data collected during the Phase 2 Stage 2 part of the study. This SAP should be read in 
conjunction with the amended study protocol (Version - 12, 12 July 2017) and electronic case 
report form (eCRF).
1.1
STUDY DESIGN AND RANDOMIZATION
The Phase 2 Stage 2 part of TED10893 will evaluate the activity and safety of isatuximab (cell 
line 1, process 2, formulation 2, C1P2F2) with or without dexamethasone (denoted by ISAdex and 
ISA arms, respectively) in patients with multiple myeloma who had previously received an 
immunomodulatory drug (IMiD) and a proteasome inhibitor (PI) and have relapsed or 
relapsed/refractory disease. In the Phase 2 part, a cycle is 28 days. The dose and schedule were 
selected from the interim analysis of Stage 1a and b: 20 mg/kg every week for 4 infusions 
followed by 20 mg/kg every 2 weeks. This dose was determined based on response rate along 
with safety, PK/PD and overall efficacy from Phase 1 and Phase 2 Stage 1. For Patients in the 
ISAdex arm, dexamethasone will be administered at the dose of 40 mg/day (20 mg/day for 
≥75 year old patients) on day 1, 8, 15, 22 of each cycle.
Patients will be randomly assigned to one of the 2 treatment arms in a 2:1 ratio (for ISA and 
ISAdex arms, respectively) using an Interactive Voice Response System/Interactive Web 
Response System (IVRS/IWRS). Enrollment will stop when the targeted number of patients is 
reached in both arms.
The data cutoff date for the protocol planned interim analysis of safety will be 15 Nov 2017. 
According to protocol, the data cutoff for the primary analysis of the overall response rate (ORR)
will be 4 months after the last enrolled patient receives first study treatment. However, for 
operational reasons and to provide mature data on time-to-event endpoints, only 1 analysis using 
cutoff date 12 months after the date of the first dose of the last patient will be reported in the 
clinical study report.
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1.2
OBJECTIVES
1.2.1
Primary objectives
The primary objective of the Phase 2 Stage 2 part of the study is to evaluate the activity of single-
agent isatuximab (ISA arm) and in combination with dexamethasone (ISAdex arm), as assessed 
by the overall response rate (ORR) in patients with RRMM.
1.2.2
Secondary objectives
The secondary objectives of the Phase 2 Stage 2 part of the study were to evaluate:
x
Safety.
x
Efficacy as measured by:
-
Duration of response (DOR).
-
Clinical benefit rate (CBR).
-
Progression free survival (PFS).
-
Overall survival (OS).
-
Very good partial response (VGPR) or better rate
x
Pharmacokinetic profile of isatuximab.
x
Immunogenicity of isatuximab.
1.2.3
Exploratory objectives
x
To assess minimal residual disease (MRD) in patients achieving a CR and correlate with 
clinical outcome.
x
To investigate the relationship between tumor cell CD38 mRNA, multiple myeloma molecular 
subtype (as defined by marker expression, cytogenetics, and/or genomics) and parameters of 
clinical response.
x
To investigate the relationship of soluble CD38 and parameters of PK and clinical response.
x
To investigate the relationship between immune genetic determinants, immune phenotype,
adaptive immune response and parameters of clinical response.
1.3
DETERMINATION OF SAMPLE SIZE
Isatuximab arm (ISA arm): 105 patients need to be randomized and treated in the ISA arm. Given 
an assumed true ORR of 28%, the null hypothesis ORR ≤15% will be rejected using an exact 
binominal test at a one-sided alpha of 0.025 with 90% power, if the observed ORR is greater than 
or equal to 22.9% (24 responders).
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Isatuximab+dexamethasone arm (ISAdex arm): 55 patients need to be randomized and treated in 
the ISAdex arm. Given an assumed true ORR of 33%, the null hypothesis ORR ≤ 15% will be 
rejected using an exact binominal test at a one-sided alpha of 0.025 with 85% power, if the 
observed ORR is greater than or equal to 27.3% (15 responders).
The sample size calculation was performed using nQuery Advisor 7.0 software.
1.4
STUDY PLAN
Safety evaluations will be performed continuously throughout the study and will include the 
following:
x
Adverse events (AEs) evaluation. Severity grade determined according to the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
x
Laboratory tests in blood and urine.
x
Physical examinations and vital signs.
x
ECOG performance status.
x
Cytokines (tumor necrosis factor alpha [TNF-α], interleukin [IL]-1-β, IL-6, interferon-gamma 
[IFN-γ]), markers of complement (C3, C4, CH50), serum tryptase, markers of potential tumor 
lysis syndrome (TLS) (uric acid, lactate dehydrogenase [LDH], BUN/creatinine, potassium, 
sodium and calcium) (removed following Amendment Version - 12, 12 July 2017).
x
Chest X-ray and ECG (baseline only).
Disease response evaluation will be performed at screening and Day 1 of every cycle, starting 
from Cycle 1 unless otherwise stated, and include:
x
M-protein quantification (serum and/or 24-hour urine), serum free light chain levels.
x
Serum β2-microglobulin (only at baseline).
x
Corrected serum calcium.
x
Bone marrow biopsy/aspiration to be performed to confirm a CR/sCR, at the end of treatment 
(EOT) visit and as clinically indicated.
x
Radiologic imaging of plasmacytoma (every 12 weeks if present at baseline).
x
Skeletal survey or low-dose whole-body CT scan (to be performed once a year and anytime 
during the study if clinically indicated).
The following additional evaluations will also be performed:
x
Level of soluble CD38 (removed following Amendment Version - 12, 12 July 2017).
x
Level of human anti-drug antibodies (ADA).
x
Immune phenotyping and molecular analysis on blood and bone marrow.
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x
Adaptive immune response (including TCR repertoire).
x
Optional pharmacogenetic sample.
Pharmacokinetic (PK) samples will be collected in all patients receiving isatuximab as depicted in
the PK study flowcharts included in the protocol.
1.5
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL
No modifications to the statistical section of the protocol were made in this SAP.
1.6
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN
SAP version 
number
Date 
approved
Rationale
Description of statistical changes
Amendment 
n°1
Safety analyses were added 
to better characterize the 
safety profile.
The following analyses have been 
added: 
-
Neutropenic 
complications
-
Thrombocytopenia and 
haemorrhages
-
Hemolytic disorders
-
Autoimmune disorders
-
Second primary 
malignancies
Additional endpoints were 
added to further characterize 
the efficacy of study 
treatments.
The following analyses have been 
added: 
-
VGPR or better rate 
-
Time to best response 
-
Additional evidence of 
clinical benefit.
-
Duration of follow-up
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SAP version 
number
Date 
approved
Rationale
Description of statistical changes
Subgroup analyses were 
added to further evaluate the 
efficacy in specific 
subgroups.
The following subgroups have been 
added: 
-
Age 
-
Regulatory region
-
Race 
-
MM type at diagnosis
-
At least four prior lines of 
therapy and refractory to
at least two PIs and 
refractory to at least two 
IMIDs
-
At least three prior lines 
of therapy including at 
least one PI and at least 
one IMID.
The following exploratory 
analyses were added to 
further evaluate difference 
between the 2 arms in 
efficacy
-
Comparison of ORR 
according to IRC between 
the 2 arms using the  
Fisher test
-
Hazard ratio PFS from 
Cox proportional hazard 
model and comparison of 
PFS between the 2 arms 
using the logrank test
The following analysis was 
added to further evaluate 
clinical benefit in term of 
further anti-cancer therapies
-
Time to next treatment
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2
STATISTICAL AND ANALYTICAL PROCEDURES
2.1
ANALYSIS ENDPOINTS
2.1.1
Demographic and baseline characteristics
The baseline value is defined as the last available value on or before the date of first study 
treatment (isatuximab or dexamethasone) administration. For efficacy laboratory parameters (eg, 
serum and urine M-protein), unscheduled assessment performed on the date of first study 
treatment administration (Cycle 1 Day 1) will be considered as baseline value; for other laboratory 
tests, unscheduled assessment performed on the date of first study treatment administration will be 
considered as post baseline. For patients randomized and not treated, the baseline value is defined 
as the last available value obtained up to the date and time of randomization.
All baseline safety and efficacy parameters (apart from those listed below) will be presented, 
along with the on-treatment summary statistics in the safety and efficacy sections (Section 2.4.5
and Section 2.4.4).
Demographic characteristics
Demographic variables include gender (Male, Female), race (White, Black or African American,
Asian, American Indian or Alaska Native, Not reported, Unknown), ethnicity (Hispanic or Latino,
Not-Hispanic or Latino, Not reported, Unknown), age in years (quantitative and qualitative 
variable : <65, [65 - 75[and ≥75 years), geographical region (Eastern Europe, Western Europe, 
North America, Other countries, see definition in Appendix B), regulatory region (Western 
countries, Other countries, see definition in Appendix B), weight (kg) and Eastern Cooperative 
Oncology Group (ECOG) performance status (PS).
Medical or surgical history
Medical or surgical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) in effect at Sanofi at the time of database lock.
Disease characteristics at initial diagnosis
The following MM characteristics at initial diagnosis will be summarized: time from initial 
diagnosis to first study treatment administration in years (quantitatively and by category : <5 years 
and ≥5 years), International Staging System (ISS) stage, and subtype (as collected in the eCRF).
Disease characteristics at study entry
The following MM characteristics at study entry will be summarized: ISS stage (Table 1),
measurable paraprotein at baseline (Table 2), % of plasma cells in bone marrow at baseline 
(quantitatively and by category: 0, ]0 - 5%[, [5-20%[, [20-50%[, and ≥50%), patients with 
plasmacytomas (as per investigator and IAC), patients with bone lesions (as per investigator and 
IAC), β2-microglobulin level in mg/L (quantitatively and by category: <3.5 mg/L, [3.5-5.5 mg/L[
and ≥5.5 mg/L), albumin in g/L (quantitatively and by category: <35 g/L and ≥35 g/L).
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Table 1 - ISS staging definition
Stage  
Definition
Stage I             β2-microglobulin <3.5 mg/L and albumin ≥ 35 g/L 
Stage II            [β2-microglobulin <3.5 mg/L and albumin <35 g/L] or [β2-microglobulin 3.5 - <5.5 mg/L] 
Stage III 
β2-microglobulin ≥5.5 mg/L 
ISS=International Staging System 
Table 2 – Derivation of measurable paraprotein at study entry
Measurable paraprotein
Criteria
Serum M-Protein 
Serum M-protein ≥ 1 g/dL (or 0.5 g/dL in case of IgA) 
 
Urine M-Protein 
Serum M-protein <1 g/dL (or <0.5 g/dL in case of IgA)  
and 
urine M-protein ≥200 mg/24hours  
 
Kappa LC 
Serum M-protein <1 g/dL (or <0.5 g/dL in case of IgA)  
and 
urine M-protein <200 mg/24 hours  
and 
kappa LC>lambda LC and kappa LC ≥ 10mg/dL  
and  
abnormal FLC ratio (<0.26 or >1.65) 
 
Lambda LC 
Serum M-protein <0.5 g/dL or missing 
and 
urine M-protein <200 mg/24 hours or missing 
and 
lambda LC>kappa LC and lambda LC ≥10 mg/dL  
and  
abnormal FLC ratio (<0.26 or >1.65) 
Cytogenetic abnormalities (Molecular subtype)
Molecular subtypes will be determined on cytogenetic analysis from central or local (if central 
assessment is not available) fluorescence in situ hybridization (FISH) or karyotyping reports. A 
patient is considered as high risk if bearing del17p and/or t(4;14) and/or t(14;16) abnormalities.
The cut-offs for positivity are as follows:
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x
t(4;14) single fusion >15%, Dual fusion >3%; 
x
t(14;16) single fusion >15%, dual fusion >3%;
x
del17p13 >10%,
x
≥ 3 copies of 1q and at least one copy missing for 1p.
Prior anticancer therapies
x
Prior anticancer treatments: Prior anticancer treatment will be collected by both line and 
regimen in the eCRF. The following variables will be derived: number of prior lines 
(quantitatively and by category: 1, 2, …7 and ≥ 8), number of prior regimen (quantitatively 
and by category: 1, 2, …7 and ≥ 8), main anticancer treatments (ie, alkylating agent, IMiD, PI 
agent, PI or IMiD agent, PI and IMiD agent, monoclonal antibodies, anthracyclines, vinca 
alkaloids, corticosteroids and histone deacetylase inhibitors), main anticancer treatments in 
last regimen before study entry, time from completion of last regimen of treatment to first 
study treatment administration (months), best response to last regimen, duration of last 
regimen of therapy.
In addition, the refractory status to main anticancer treatment (as listed above) and 
refractory status of the last prior anticancer treatment received before enrolment will be 
derived. A patient is considered to be refractory if any of the following conditions are met:
-
Progression date and anticancer treatment end date are complete and progression date 
is within (≤) 60 days of anticancer treatment end date (progression date – anticancer 
treatment end date ≤ 60 days). If only the day is missing for either date or both dates, 
and the progression date and anticancer treatment end date corresponds to two 
consecutive months within the same year, then, the patient will be considered 
refractory, otherwise they will be considered not refractory.
-
Best overall response is SD or PD.
-
Reason for treatment discontinuation is “disease progression”.
x
Prior transplant: patients with transplant, type of transplant, number of transplant by patient, 
time from last transplant to first study treatment administration (months).
x
Prior surgery: patients with any prior surgery related to cancer, type of surgery and time from 
last surgery to first study treatment administration (months).
x
Prior radiotherapy: number (%) of patients with any prior radiotherapy related to cancer, 
intent, and time from last radiotherapy to first study treatment administration (months).
Any technical details related to computation, dates, and imputation for missing dates, are 
described in Section 2.5.
Vital signs 
Vital signs include: heart rate, systolic and diastolic blood pressure, respiratory rate, temperature 
and weight.
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Renal status 
Renal function, ie, glomerular filtration rate (GFR) in mL/min/1.73 m2 (qualitative variable: [15-
30[, [30-60[, [60-90], >90) will be calculated from serum creatinine concentration measured at 
baseline using Modification of Diet in Renal Disease (MDRD) formula, whenever race will be 
allowed to be collected.:
American)
-
African
 
if 
(1.212
 x 
Female)
 
if 
(0.742
 x 
(Age)
 x 
 
(Scr)
 x 
175
 
GFR
-0.203
-1.154
 
with serum creatinine in mg/dL and age in year.
2.1.2
Prior or concomitant medications (other than anticancer therapies)
All medications taken by the patient within 21 days prior to randomization into the study, at any 
time during the treatment period until end of treatment will be reported in the eCRF.
The following information will be collected in the medication eCRF page: drug/medication (brand 
or generic name), reason (eg, curative, prophylaxis), dose and unit, route, start date and end date 
(if applicable)/ongoing (otherwise).
All medications will be coded using the World Health Organization-drug Dictionary (WHO-DD) 
version in effect at Sanofi at the time of database lock.
x
Prior medications are those the patient used prior (<) to first study treatment administration. 
Prior medications can be those discontinued before first administration or those ongoing 
during the treatment phase.
x
Concomitant medications are any treatments received by the patient concomitantly to study 
treatment, from first dose to the date of last administration +30 days. A given medication can 
be classified both as a prior medication and as a concomitant medication. Any anti-cancer 
treatment administered after the date of the last study treatment administration will not be 
considered as a concomitant medication and will be regarded as further anti-myeloma therapy
regardless of the date of initiation (see Section 2.4.10). The analysis of concomitant 
medications will include premedication (see below).
x
Post-treatment medications (excluding post anticancer treatments) are those the patient took 
from 31 days after last study treatment administration up to the death or cut-off date.
Premedications
As defined in Section 8.2.1 of the amended study protocol (version 12, 12 July 2017), patients 
were to routinely receive premedications prior to isatuximab infusion to reduce the risk and 
severity of hypersensitivity reactions commonly associated with monoclonal antibodies. 
Premedications are defined in the protocol as non-investigational medicinal product(s). 
Premedications are reported on a specific eCRF page.
Any technical details related to computation, dates, and imputation for missing dates, are 
described in Section 2.5.
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2.1.3
Efficacy endpoints
Response assessments will be performed on Day 1 of each cycle prior to study treatment 
administration and at the EOT visit using the updated International Myeloma Working Group 
(IMWG) response criteria (1) and include:
x
M-protein quantification and qualification (immunofixation) (serum and 24-hr urine).
x
Serum free light chain levels, free light chain ratio.
x
Plasma cell count in Bone marrow biopsy/aspiration (if clinically indicated).
x
Plasmacytoma assessment by PET-CT/MRI (if clinically indicated).
x
Bone disease assessment: Skeletal survey 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.
x
Corrected serum calcium.
In case of plasmacytoma at baseline, radiological evaluations will be performed at baseline and 
repeated every 12 weeks (± 1 week), and if clinically indicated. Will also be done in case of 
suspicion of progression or if clinically indicated in a patient with no previous positive image for 
extramedullary disease.
In case of bone lesions at baseline, bone lesion evaluations will be performed when clinically 
indicated or to assess progression. Bone marrow biopsy/aspiration will be performed to confirm a
sCR, CR, at the EOT visit and as clinically indicated.
An independent adjudication committee (IAC), blinded to treatment arm, will independently 
assess clinical response using the IMWG response criteria.
Biological responses (≥PR) and progression should be confirmed on 2 consecutive biological 
(serum and/or urine M protein) disease assessments. No confirmation is required for radiological 
assessment.
2.1.3.1
Primary efficacy endpoint
The primary efficacy endpoint is ORR, defined as the proportion of patients with sCR, CR, VGPR 
or PR as best overall response (BOR) as assessed by the IAC. The BOR will be derived using 
disease assessments performed from the start of treatment through the entire study excluding any 
assessments performed after disease progression confirmation, the cutoff date or following the 
start of further therapies for MM.  The first disease assessment performed during further therapy 
will be used to confirm PD if performed within 3 months of last study treatment administration 
(see Figure 1). The ordering of evaluations from best to worse is: sCR, CR, VGPR, PR, MR,
stable disease (SD), progressive disease (PD), not evaluable (NE). BOR for patients without 
response assessment by the IAC will be ‘Not evaluable’.
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Figure 1 – Determination of BOR when disease assessments are performed after new anti-myeloma 
therapies are started or performed after the cutoff date
Subgroup analyses of BOR using IAC assessment will be performed for the variables listed in 
Table 3.
Table 3 – List of variables for subgroup analyses
Variable
Description 
Age 
<65 years vs [65-75] years vs ≥70 years 
Number of previous lines of therapy 
≤3 vs > 3 
Gender 
Male vs female 
Race 
Caucasian vs Non caucasian vs other 
Region of the world (geographical)a 
Western Europe vs North America vs Other countries 
ECOG PS at baseline 
0-1 vs 2 
ISS staging at study entry 
I-II vs III 
High risk cytogenetic 
Yes vs No 
Baseline creatinine clearance (GRF) 
<60 ml/min/1.73m2 vs ≥60 ml/min/1.73m2 
Refractory to IMiD 
Yes vs No 
Refractory to PI 
Yes vs No 
Quadruple refractory (refractory to lenalidomide and 
bortezomid and pomalidomide and carfilzomib) 
Yes vs No 
At least four prior lines of therapy and refractory to at 
least two PIs and refractory to at least two IMIDs 
Yes vs No 
At least three prior lines of therapy including at least 
one PI and including at least one IMID 
Yes 
Subgroup analyses will be conducted when at least 10 patients will be included in a subgroup.  
a
If the number of patients in North America is too small, North America will be merged with Europe. 
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Table 4 – List of variables for exploratory subgroup analyses
Variable
Description 
Region of the world (regulatory) 
Western countries vs Other countries 
Previous transplant 
Yes vs No 
MM type at diagnosis 
IgG vs. non IgG 
Measurable paraprotein at baseline 
Serum M-Protein; Urine M-Protein, Light chain 
Refractory to lenalidomide and bortezomib 
Yes vs No 
Refractory to IMiD and PI 
Yes vs No 
Refractory to pomalidomide and carfilzomib 
Yes vs No 
Subgroup analyses will be conducted when at least 10 patients will be included in a subgroup.  
A sensitivity analysis of ORR will be performed using investigator’s assessment of response. For 
this analysis, BOR will be the best sequential response as determined by the criteria defined in 
Table 5. Same as IAC BOR analysis, the investigator BOR will be derived using disease 
assessments performed from the start of treatment through the entire study excluding any 
assessments performed after disease progression (sequential response per Table 5), the cutoff date 
or following the start of further therapies for MM.  In addition, the following rules will be applied:
x
BOR will be NE for patients who received at most 2 isatuximab administrations with 
investigator assessment of response of SD or better at Cycle 1 or end of treatment. 
x
BOR will be PD for patients without response assessment who received 1 cycle of treatment 
and died due to PD or had symptomatic deterioration within 30 days of last study treatment
administration. 
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Table 5 - Sequential response determination for investigator response assessment
Overall response at cycle n
Overall response at cycle n+1a
Sequential response
sCR 
sCR 
sCR 
CR 
sCR 
CR 
sCR 
CR 
CR 
CR 
CR 
CR 
sCR/CR 
VGPR 
VGPRb 
sCR/CR 
PR 
PR 
VGPR 
sCR/CR/VGPR 
VGPRb 
VGPR 
PR 
PR 
PR 
sCR/CR/VGPR/CR/PR 
PR 
sCR/CR/VGPR/PR 
NE/No further evaluation/SD/PD 
MRc 
MR 
Any 
MR 
Any 
MR 
MR 
NE/SD/PD 
sCR/CR/VGPR/PR 
MRc 
NE/PD/SD 
SD 
SD 
SD 
No further evaluation/NE/PD 
SD 
NE 
SD 
SD 
PD 
No further evaluation/NE 
unPDe 
PD 
PD 
PD 
NE 
PD 
unPDe 
NE 
No further evaluation 
NE 
No evaluationd 
 
PDd 
a
Disease assessment are planned to be performed every cycle. Disease assessment performed after the start of new anticancer 
treatment will be excluded from the derivation of BOR. 
b
Sequence provided for programming purpose. 
c
Unconfirmed PR or CR will be considered MR. 
d
Only for analysis based on investigator assessment, BOR will be PD for patients without response assessment who received 1 cycle 
of treatment and died due to PD or had symptomatic deterioration within 30 days of last study treatment administration 
e
Unconfirmed PD, unless PD is based on radiological assessment that does not need confirmation. 
BOR=best overall response; sCR=stringent complete response; CR=complete response; MR=minor response; NE=not evaluable; 
PD=progressive disease; PR=partial response; SD=stable disease; VGPR=very good partial response. 
2.1.3.2
Secondary efficacy endpoints
Secondary efficacy endpoints (based on IAC) are defined below.
x
Duration of Response (DOR): DOR is defined as the time from the date of the first IAC 
determined response (≥ PR) that is subsequently confirmed, to the date of first IAC confirmed PD 
or death (if reported before the analysis cutoff date or the date of initiation of a new anticancer 
treatment), whichever happens earlier. If progression and death are not observed before the 
analysis cut-off date or the date of initiation of new anticancer treatment, DOR 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 anticancer treatment or the analysis cut-off date. DOR is 
determined only for patients who have achieved a confirmed response of ≥PR.
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x
CBR: defined as the proportion of patients with sCR, CR, VGPR, PR or MR as BOR 
according to IMWG criteria, as determined by the IAC.
x
PFS (in months): defined as the time interval from the date of first study treatment
administration to the date of the first IAC-confirmed disease progression or the date of death 
due to any cause before the analysis cut-off, whichever occurs first. For patients who did not 
experience IAC-confirmed disease progression or death before the analysis cut-off date or the 
date of initiation of new anticancer treatment, PFS will be censored at the date of the last valid 
disease assessment not showing disease progression performed prior to initiation of a further 
anticancer treatment or the analysis cut-off date, whichever occurs first. As defined in 
Section 2.1.3.1, the first disease assessment performed during further therapy or death due to 
PD reported after further therapy will be used to confirm PD if performed within 3 months of 
last study treatment administration. Progression based on radiological assessment does not 
require confirmation. Date of PFS event/censoring relative to date of further anti-myeloma 
therapies and cutoff date are illustrated in Figure 2. In addition, patient without PFS event 
(death or disease progression) and without any valid post-baseline disease assessments will be 
censored at the day of first dose (Cycle 1 Day 1). Subgroup analysis for variables defined in 
Table 3 and Table 4 will be performed.
x
OS (in months): defined as the time interval from the date of first study treatment 
administration to death from any cause. In the absence of the confirmation of death before the 
cut-off date, OS will be censored at the cut-off date or at the last date the patient is known to 
be alive, whichever comes first.
x
VGPR or better rate is defined as the proportion of patients achieving a VGPR or better rate as 
BOR. 
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Figure 2 - Date of PFS event/censoring relative to the date of further anti-myeloma therapies and 
the cutoff date based on IAC assessment
Sensitivity analyses of DOR, CBR and PFS will be performed using the investigator’s assessment 
of response. For these analyses, the rules for the criteria of confirmation of PD will be the same as 
for IAC (see Section 2.1.3.1). The definitions are included below:
x
Duration of response (DOR) per investigator assessment: DOR is defined as the time from the 
first response (sCR, CR, VGPR, PR) that is subsequently confirmed to the first sequential 
disease progression, clinical / symptomatic deterioration, or death (if reported before the 
analysis cutoff date or the date of initiation of a new anticancer treatment), whichever occurs 
first. If progression and death are not observed before the analysis cut-off date or the date of 
initiation of new anticancer treatment, DOR 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 anticancer treatment or the analysis cut-off date. DOR is determined only for patients 
who have achieved a confirmed response of ≥PR per investigator assessment.
x
Progression free survival (PFS) (in months) per investigator assessment: PFS is defined as the 
time interval from the date of first study treatment administration to the date of first sequential 
assessment of PD confirmed, clinical symptomatic deterioration or the date of death due to 
any cause, whichever occurs first. For patients who did not experience disease progression or 
death before the analysis cut-off date or the date of initiation of new anticancer treatment, PFS 
will be censored at the date of the last valid disease assessment not showing disease 
progression performed prior to initiation of a further anticancer treatment or the analysis 
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cut-off date, whichever comes first. Date of PFS event/censoring relative to date of further 
anti-myeloma therapies and cutoff date are illustrated in Figure 3. In addition, patient without 
PFS event (death or disease progression) and without any valid post-baseline disease 
assessments will be censored at the day of first dose (Cycle 1 Day 1).
Other efficacy endpoints include:
x
Best percent change in paraprotein: Best percent change in paraprotein will be calculated for 
the measurable paraprotein parameter defined at baseline (Section 2.1.1) excluding anytime 
point following the start of other anticancer therapy.
x
Duration of follow-up (DFU) (in months): DFU is defined as the time interval from the date of 
randomization to the date of last contact with the patient. Patients who have died will be 
censored on their date of death. Median follow-up duration (months) will be estimated using 
the Kaplan-Meier method.
x
Time to first response (TTR) (in months) is defined as the time from first dose to first response 
(PR or better) that is subsequently confirmed. In the absence of response patients will be 
censored at the earliest of the date of the last valid disease assessment before disease 
progression or death, the date of the last valid disease assessment before initiation of a further 
anti-myeloma treatment (if any) or the analysis cut-off date, whichever comes first.
x
Time to best response (TTBR) is defined as the time from first dose to the date of first 
occurrence of IAC determined best overall response (PR or better) that is subsequently 
confirmed. In the absence of response, patients will be censored at the earliest of the date of 
the last valid disease assessment before disease progression or death, the date of the last valid 
disease assessment before initiation of a further anti-myeloma treatment (if any) or the 
analysis cut-off date, whichever occurs first.
x
Additional evidence of clinical benefit : Renal response and renal function deterioration
Renal function impairment rate defined as patients with a GFR <60 mL/min/1.73m2 at baseline or 
during the treatment, the progression to severe or end stage renal impairment (<30) rate and the 
progression from moderate renal impairment ([30; 60[mL/min/1.73m2) to severe or end stage 
renal impairment will be described by treatment arm.
Renal response (MR/CR) rate among patients with GFR <50 mL/min/1.73m2 at baseline by 
treatment arm will also be described.
A renal response:
x
A complete renal response is defined as an improvement in eGFR from 
<50 mL/min/1.73m2 at baseline to ≥ 60 mL/min/1.73m2 at least 1 assessment during the 
on-treatment period.
x
A partial response is defined as an improvement in eGFR from <15 mL/min/1.73m2 at 
baseline to at least 1 assessment in the range [30 to 60[ mL/min/1.73m2 during the 
on-treatment-period. 
x
A minor response is defined as an improvement in eGFR from <15 mL/min/1.73m2 at 
baseline to at least 1 assessment in the range [15 to 30[ mL/min/1.73m2 during the 
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on-treatment-period  or from [15 to 30[ mL/min/1.73m2 at baseline to at least 1 
assessment in the range [30 to 60[ mL/min/1.73m2 during the on-treatment-period. 
x
A durable renal response is defined as a response that lasted ≥ 60 days.
Figure 3 - Date of PFS event/censoring relative to the date of further anti-myeloma therapies 
and the cutoff date using investigator’s assessment
2.1.4
Safety endpoints
The safety analysis will be based on the reported AEs and other safety information, such as 
clinical laboratory data, vital signs, and ECG (Section 1.4).
Observation period
The observation period will be divided into 3 periods: pre-treatment, on-treatment, and post-
treatment.
x
The pre-treatment period is defined as the time from when the patient gave informed 
consent and the start of study treatment administration.
x
The on-treatment period is defined as the time from the first dose of study treatment up to 
30 days after the last dose of study treatment.
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x
The post-treatment period is defined as the time starting the day after the end of the on-
treatment period up to the end of the study (as defined in the protocol).
2.1.4.1
Adverse events variables
Adverse events occurring from signature of informed consent form up to at least 30 days after the 
last study treatment administration will be recorded in the eCRF. In addition, all study treatment 
related AEs and SAEs ongoing at time of study treatment discontinuation will be followed during 
the follow-up period until resolution or stabilization.
All AEs (including serious AEs [SAEs]) will be coded to a lower-level term (LLT), preferred term 
(PT), high-level term (HLT), high-level group term (HLGT), and associated primary system organ 
class (SOC) using the version of MedDRA in effect at Sanofi at the time of database lock.
The severity of AEs will be assessed according to NCI-CTCAE version 4.03. 
The following AEs will be described:
x
Pre-treatment AEs: defined as any AE reported during the pre-treatment period.
x
Treatment-emergent AEs (TEAEs): defined as any AE that developed, worsened (according 
to the Investigator’s opinion), or became serious during the on-treatment period.
x
Post-treatment AEs: defined as any AE reported during the post-treatment period.
In addition, deaths (Section 2.1.4.2), serious adverse events, adverse events leading to withdrawal, 
and other significant adverse events will be analyzed. Other significant events will include: 
Adverse events of special interest (AESIs):
x
Acute infusion associated reactions (IARs).
x
Symptomatic overdose.
x
Pregnancy occurring in a female patient or in a female partner of a male patient.
Infusion associated reactions
Infusion associated reactions typically occur within 24 hours from the start of each isatuximab 
infusion (See Section 6.5 of the TED10893 protocol for guidelines for IARs management). As 
described above, IARs are AESIs.
Two analyses of IARs will be performed. The first one will be based on the investigator’s 
reporting of IARs (ie, as AESIs). For each IAR-AESI, the sites were instructed to report a generic 
term (infusion-related reaction) and each individual symptom. For IAR analyses based on the 
generic term, a customized MedDRA query (CMQ) including the single preferred term of infusion 
related reaction will be used.
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Another analysis of IAR will include TEAEs (one table including related TEAEs, one table 
including all TEAEs regardless of relationship) occurring within 24 hours from the start of each 
isatuximab infusion (ie, TEAEs with onset on the same calendar day of the isatuximab infusion or 
on the following day).
Respiratory TEAEs
Analysis of respiratory TEAEs will focus particularly on the following groupings using 
customized MedDRA queries (CMQ):
x
Lower respiratory events, selected using CMQ ‘Lower respiratory events’.
x
Respiratory infections, selected using infections, selected using CMQ ‘Respiratory infections’.
In addition, late respiratory events (ie, occurring, worsening or becoming serious more than 
30 days after last dose) will be analyzed as part of the post-TEAEs analysis.
Neutropenia and neutropenic complications
Neutropenia, febrile neutropenia and neutropenic infections will be analyzed using the following
data source:
x
Neutropenia based on laboratory results.
x
Febrile neutropenia selected using CMQ ‘Febrile neutropenia’
x
Neutropenic infections: defined as NCI-CTCAE Grade≥2 infections from SOC ‘Infections and 
Infestations’ (selected using CMQ ‘GLB_SOC infections and infestation’) concomitant with 
NCI-CTCAE Grade 3-4 neutropenia from laboratory results. Infection and Grade 3-4
neutropenia will be considered as concomitant if one of the following condition is met:
-
neutrophils count value measured the day of the start of the AE infection,
-
the last neutrophils count value measured before the start date of the AE infection is
within 7 days before the start of the AE infection,
-
the first neutrophils count value measured after the start date of the AE infection is 
within 2 days after the start of the AE infection.
Thrombocytopenia and hemorrhages
x
Thrombocytopenia will be analyzed based on laboratory results
x
Hemorrhages will be selected using the TEAEs from the CMQ ‘Haemorrhage terms (excl 
laboratory terms)’.
x
Moreover, severe thrombocytopenia (ie, Grade 4) with concomitant hemorrhage will be 
displayed if relevant. The first hemorrhages event occurring within 8 days after any 
occurrence of the thrombocytopenia (Lab) will be used for this analysis.
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Hemolytic disorders
Hemolytic disorders will be selected using the TEAEs from the CMQ ‘Haemolytic disorders 
Broad’.
Hemolytic disorders that occurred within 8 days after the blood cell transfusion (red blood cells or
platelets) will be displayed.
Autoimmune disorders
Autoimmune disorders will be selected using the TEAE from the CMQ ‘GLB_HLGT 
Autoimmune disorders’.
Second primary malignancies
Second primary malignancies will be selected using CMQ ‘Second primary malignancies’ and 
will be sub-categorized as ‘haematological’, ‘non-hematological skin tumors’, ‘non-hematological 
non-skin tumors’ and ‘other tumors’.
2.1.4.2
Deaths
The deaths observation periods are per the observation periods defined in Section 2.1.4.
x
Death on-treatment:  deaths occurring during the on treatment period.
x
Death post-treatment:  deaths occurring during the post-treatment period.
x
Death within 60 days from first dose of study treatment.
2.1.4.3
Laboratory safety variables
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis.  Clinical laboratory values will be converted into standard international units and these 
international units will be used in all listings and tables.
Blood samples for clinical laboratories parameters will be taken as defined in the study flow 
charts and as clinically indicated. The laboratory parameters will be classified as follows:
x
Hematology 
-
Red blood cells, platelets, and coagulation:  hemoglobin, hematocrit, mean 
corpuscular volume, red blood cell count, platelet count, prothrombin time (expressed 
as international normalized ratio), partial thromboplastin time
-
White blood cells: white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils
-
Blood type: Indirect Coombs Test, Indirect Antiglobulin Test (Only listing will be 
provided)
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x
Clinical chemistry 
-
Metabolism: glucose, total protein, albumin,
-
Electrolytes:  sodium, potassium, chloride, calcium, phosphorus, bicarbonate/carbon 
dioxide, magnesium,
-
Renal function:  creatinine, creatinine clearance, blood urea nitrogen, uric acid,
-
Liver parameters:  alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, lactate dehydrogenase,bilirubin (total and direct).
x
Urinalysis
-
Urinalysis - qualitative analyses: blood, protein, glucose, ketones, bilirubin , 
leucocyte, nitrates, 
-
Urinalysis - quantitative analyses: pH.
The baseline value of a laboratory parameter is defined as the last available value from the local 
laboratory assessment on or before the date first study treatment (isatuximab or dexamethasone) 
administration. In addition, unscheduled assessment performed on the date of first study treatment 
administration will be considered as post baseline. Note that since Phase 2 Stage 2 was initiated 
with both central and local laboratory assessment, and a change was made in amendment 12 to 
only collect local laboratory assessment. Therefore in the primary analysis of laboratory 
parameters during the on-treatment period, only local results will be used. In the sensitivity 
analysis of laboratory parameters during the on-treatment period, both local and central results 
will be used.  Technical formulas are described in Section 2.5.1.
2.1.4.4
Vital signs variables
Vital signs include:  heart rate, systolic and diastolic blood pressure, respiratory rate, temperature, 
and weight.
2.1.4.5
Electrocardiogram variables
Twelve-lead ECG will be performed at screening and as clinically indicated.
2.1.4.6
Other safety endpoints
Other safety endpoints include:
x
Chest X-ray at baseline and as clinically indicated.
x
Tumor lysis syndrome (TLS) as reported in the eCRF AE forms.
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2.1.5
Pharmacokinetic variables
Isatuximab plasma concentrations will be summarized and the following PK individual 
parameters will be calculated:
x
Cumulative AUC over a 1, 2 or 4 week interval (AUC1W, AUC2W, AUC4W)
x
Ctrough (pre-dose concentration) at 1, 2, 4 weeks
x
Cmax at Cycle 1 Day 1, Cycle 2 Day 1 and Cycle 4 Day 1 
x
Clearance (CL) for linear non-specific elimination pathway
x
Accumulation ratios (AUCss/AUC1W). AUCss is AUC at steady state. 
2.1.6
Immunogenicity
Human ADA to isatuximab will be assessed during the study as defined in the protocol.
Observation period
The observation period will be divided into 2 periods: ADA pre-treatment and ADA on-study 
observation.
x
ADA pre-treatment period: The ADA pre-treatment period is defined as the time from signed 
informed consent to the first isatuximab administration. 
x
ADA on-study observation period: the ADA on-study observation period is defined as the 
time from the first isatuximab administration until the end of the study (Note that ADA was 
collected until Cycle 10 following Amendment Version 12, 12 July 2017).
Patients with at least one evaluable ADA result during the ADA pre-treatment period will be 
considered as evaluable at baseline. Patients with at least one ADA result during the ADA 
on-study observation period will be considered evaluable for ADA.
ADA attributes:
x
Pre-existing ADA is defined as ADA that was present in samples drawn during the ADA 
pretreatment period. 
x
Treatment boosted ADA is defined as preexisting ADA with an increase in titer value 
between pre-treatment and on-study samples of at least two titer steps during the ADA 
on-study observation period. With a 2-fold serial dilution, this means that the post-treatment 
sample titer value is at least (≥) 4 fold of pretreatment titer value. 
x
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. 
x
Transient ADA response is defined by:
-
Treatment induced ADA detected only at one sampling time point during the ADA 
on-study observation period (excluding the last sampling time point), OR
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-
Treatment induced ADA detected at two or more sampling time points during ADA 
on-study observation period, where the first and last ADA-positive samples 
(irrespective of any negative samples in between) are separated by a period less than 
16 weeks, and the patient’s last sampling time point is ADA negative.
x
A persistent ADA response is defined by:
-
Treatment induced ADA detected at two or more sampling time points during the 
ADA on-study observation period, where the first and last ADA-positive on study 
samples are separated by at least 16 weeks (irrespective of any negative samples in 
between).
x
Indeterminate ADA is defined by:
-
Treatment-induced ADA detected only the last sampling time point with all prior 
samples being negative, OR,
-
The last two samples are ADA-positive and separated by a period of less than 
16 weeks.
ADA response endpoints:
x
An ADA positive patient is defined as a patient with at least one treatment-induced or
treatment boosted ADA positive sample at any time during the ADA on-study observation 
period.
x
ADA incidence is defined as the number of ADA positive patients among evaluable patients 
divided by the number of patients in the ADA evaluable population.
x
ADA prevalence is defined as the sum of the number of patients with preexisting ADA
among evaluable patients and the number of patients with treatment induced ADAs, divided 
by the number of patients in the ADA evaluable population.
2.1.7
Biomarker endpoints
2.1.7.1
Immune Genetic Determinants
Germline genetic data of Fc gamma receptor (FCGR), human leukocyte antigen (HLA) and killer-
cell immunoglobulin-like receptor (KIR) genes will be analyzed on blood samples collected on 
Day 1 of Cycle 1:
x
FCGR polymorphisms (FCGR2A and FCGR3A): For each gene, the results will be of the 
form AA, Aa or aa with A and a-alleles, the major and minor allele, respectively.
x
HLA genotypes: HLA-A, HLA-B and HLA-C have been typed for each gene. The results will 
be epitope genotypes (Table 6) and allele genotypes.
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Table 6 - Epitopes of HLA Class I recognized by KIR
Amino-acid at positiona
HLA class I
Epitope 
77
80
81
82
83
HLA-B 
Bw6 
Ser 
Asn 
Leu 
Arg 
Gly 
  
  
Bw4 
Asn 
Thr 
Ala 
Leu 
Arg 
  
  
Bw4 
Asn 
Ile 
Ala 
Leu 
Arg 
  
  
Bw4 
Asp 
Thr 
Leu 
Leu 
Arg 
  
  
Bw4 
Ser 
Thr 
Leu 
Leu 
Arg 
  
  
Bw4 
Ser 
Thr 
Ala 
Leu 
Arg 
  
 
 
 
 
 
 
 
 
HLA class I 
Epitope  
77 
80 
81 
82 
83 
Associated allotypes 
 
 
 
 
 
 
 
 
HLA-A 
Aw4 
Asn 
Ile 
Ala 
Leu 
Arg 
A*23; A*24 
  
Aw4 
Ser 
Ile 
Ala 
Leu 
Arg 
A*32 
  
A3 
Key residues not yet published 
A*03 
  
A11 
Key residues not yet published 
A*11 
 
 
 
 
 
 
 
 
HLA class I 
Epitope  
77 
80 
  
  
  
  
 
 
 
 
 
 
 
 
HLA-C 
C1 
Ser 
Asn 
  
  
  
  
  
C2 
Asn 
Lys 
  
  
  
  
a
Numbering from the first codon of the mature protein 
x
KIR genotypes: The presence or absence of 16 KIR genes will be screened. A KIR gene will 
be defined as present if at least one assay gives positive results; otherwise it will be defined as 
negative.
2.1.7.2
Immune phenotyping
Immune phenotyping in bone marrow (baseline) and/or peripheral blood (D1 of Cycle 1, D1 of 
Cycle 3 and EOT) will be assessed. The immune cell populations including B-cell, T-cell and 
NK-cell subsets will be determined by multiparametric flow cytometry based on the expression of 
different cell surface markers. 
2.1.7.3
CD38 mRNA
Not applicable.
2.1.7.4
Soluble CD38
Soluble CD38 will be assessed at baseline, C3D1 and EOT.
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2.1.8
Health related quality-of-life (HRQL) endpoints
Not applicable following Protocol Amendment 12.
2.1.9
Health economic endpoints
Not applicable.
2.1.10 Further therapy after discontinuation of investigational medicinal product 
administration during the study
Further therapies after discontinuation of study treatment will be collected on a specific eCRF 
page. The following information will be collected: drug/medication (brand or generic name), start 
date and end date (if available)/ongoing (otherwise).
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
version in effect at Sanofi at the time of database lock.
Time to Next Treatment
TNT is defined as the time from the date of first study treatment administration to the start of 
further anti-myeloma treatment. Patients who do not receive any further anti-myeloma treatment 
before the cut-off date will be censored at the date of their last FU visit or the cut-off date, 
whichever comes first. Patients with no FU visit will be censored at their last study treatment 
administration or the cut-off date whichever comes first.
2.2
DISPOSITION OF PATIENTS
Patients in each of the following categories will be provided in a summary table:
x
Number of screened patients (those who signed the screening informed consent form)
-
Number of screened patients not randomized.
x
Number of randomized patients
-
Number and percentage of randomized but not treated patients.
-
Number and percentage of randomized and treated patients.
Percentages will be calculated using the number of randomized patients. In addition, a listing of 
screened failed patients and reason for screening failure (when available) will be provided.
The number and percentage of patients in analysis populations (defined in Section 2.3) will be 
provided in a summary table. 
The number and percentage of patients in each of the following categories will be provided using 
the AT/safety population:
x
Patients in each country and center.
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x
Patients off treatment and reasons for treatment discontinuation.
x
For ISAdex arm only: Patients premature discontinuation of treatment.
x
Patients on treatment at time of the analysis.
x
Status at last study contact.
Listing of the reasons for treatment discontinuation and patients still on treatment at time of the 
analysis will be provided.
A summary of the key dates of the study including the following will be presented:
x
Date of first consent signed (using all screened patients).
x
Date of last consent signed (using all screened patients).
x
Date of first randomization.
x
Date of last randomization.
x
Date of first patient first dose.
x
Date of last patient first dose.
x
Last cycle day 1 date.
x
Date of last visit completed.
Major deviations potentially impacting efficacy/safety analyses include: 
Protocol deviations at inclusion:
x
No known diagnosis of MM. 
x
No evidence of  measurable disease ie, none of the following:
-
Serum M-protein <1.0 g/dL (or <0.5 g/dL for IgA).
-
Urine M-protein <200 mg/24 hours.
-
Serum immunoglobulin (SI) free light chain (FLC) <10mg/dL or 0.26 ≤ SI serum
kappa lambda FLC ratio ≤ 1.65.
x
No prior treatment with IMiD and/or PI (for ≥2 cycles of ≥2 months of treatment).
x
Did not receive at least three prior lines of therapy for MM and is not double refractory to 
IMiD and PI.
x
Did not achieve an MR or better to at least one prior line of therapy.
x
Did not have evidence of disease progression on or after the most recent prior regimen
x
Informed consent not signed.
x
Age <18 years.
x
Prior autologous stem cell transplant within 12 weeks of the first dose of study treatment.
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x
Prior allogenic transplant within 1 year with evidence of active graft vs. host disease (GVHD).
x
Patients with a ECOG performance status score >2.
x
Total bilirubin ≥2.5 x ULN.
x
AST or ALT ≥5 x ULN.
x
Calculated or measured creatinine clearance <15 mL/minute/1.73 m2
x
Absolute neutrophil count (ANC) ≤900/mm3.
x
Hemoglobin ≤7.5 g/dL.
x
Platelet count ≤40 000/mm3.
Protocol deviations during treatment:
x
Treatment different from randomization.
x
No premedication given for prevention of IAR during any infusion of Cycle 1.
x
No pregnancy test and age <55, or pregnancy test is positive.
x
Received other anti-MM therapy during treatment.
All major deviations will be summarized showing the number and percentage of patients with 
major deviations. Major protocol deviations will also be listed. A separate table on the eligibility 
deviations with number of violators per criterion by order of frequency will be provided.
2.2.1
Randomization and drug dispensing irregularities
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report.  If the number of irregularities is large enough to make a tabular summary useful, the 
irregularities will be categorized and summarized among randomized patients (number and 
percentages).  Nonrandomized and treated patients in Stage 2 (if any) will be described separately.
Randomization and drug-dispensing irregularities to be prospectively identified include but are 
not limited to: 
x
Study treatment administration without IVRS/IWRS transaction.
x
Randomization by error.
x
Patient randomized twice.
x
Treatment from the wrong arm is given.
x
For ISAdex arm only: initial dexamethasone dose not dispensed per age class (should be 
20 mg for age ≥75; 40 mg otherwise).
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2.3
ANALYSIS POPULATIONS
2.3.1
Randomized population
The randomized population includes all patients from Stage 2 who gave their informed consent 
and were assigned a randomization number by the IVRS/IWRS.
2.3.2
All treated (AT)/safety population
The AT/safety population will include all randomized patients who gave their informed consent 
and who have received at least 1 dose (even incomplete) of isatuximab; patients who received 
dexamethasone in addition to isatuximab (excluding when given as part of premedication) will be 
included in the ISAdex arm. Non-randomized but treated patients will not be part of the safety 
population; however, their safety data will be presented separately.
This population is the primary population for the analyses of efficacy and safety parameters. All 
analyses using this population will be based on the actual treatment given at Cycle 1 - Day 1 (ISA 
or ISAdex).
2.3.3
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 isatuximab concentration available post-
baseline. 
2.3.4
ADA evaluable population
The ADA evaluable population will include all treated patients with at least one ADA assessment 
with a reportable result during the ADA on-study observation period.
2.3.5
Biomarker population
There will be no population flag for biomarker. Biomarker endpoints will be analyzed using 
patients from the all treated population who have one assessment on the biomarker of interest. 
2.4
STATISTICAL METHODS
In the summary tables, treatment groups will be presented as follows:
x
ISA
x
ISAdex
x
All
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Continuous data will be summarized using the number of available data, mean, standard deviation 
(SD), median, minimum, and maximum. Categorical and ordinal data will be summarized using 
the number and percentage of patients.
Important data listings will be provided, such as, patient disposition, AEs leading to 
discontinuation, SAEs, deaths, and specific TEAEs. Listings will be sorted by treatment arm and 
patient number. Repeated values of these key variables will be blanked out in the listings.
2.4.1
Demographics and baseline characteristics
Parameters described in Section 2.1.1 will be summarized using descriptive statistics on the all 
treated population. Analyses for the randomized population will be included in the appendices if 
the size of the randomized population is different (>10%) from the size of the randomized 
population for any treatment group.
Past medical or surgical history will be summarized by primary SOC and PT (both sorted by 
alphabetical order). Past medial history occurring in ≥10% of patients will also be summarized by 
PT sorted by decreasing frequency.
MM disease characteristics at diagnosis and at study entry, molecular subtype, and prior 
anticancer therapies will be described for the AT/safety population.
2.4.2
Prior or concomitant medications (other than anticancer therapies)
The prior and concomitant medications will be presented for the AT/safety population. 
Medications will be summarized by treatment group and overall according to the WHO-DD
dictionary, considering the first digit of the anatomic category (ATC) class (anatomic category) 
and the first 3 digits of the ATC class (therapeutic category).  All ATC codes corresponding to a 
medication will be summarized, and patients will be counted once in each ATC category 
(anatomic or therapeutic) linked to the medication. Therefore, patients may be counted several 
times for the same medication. 
The table for prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the overall incidence across treatment groups.  In case of equal 
frequency regarding ATCs, alphabetical order will be used.
The tables for concomitant and post treatment medications will be sorted by decreasing frequency 
of ATC followed by all other therapeutic classes based on the incidence in the all column. In case 
of equal frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will 
be used.
Premedications
Number (%) of patients with premedications including diphenhydramine, methylprednisolone, 
ranitidine, and paracetamol as defined in Section 2.1.2 will be provided. Number of infusions with 
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premedications and number of infusions without IR premedications may be summarized when 
applicable.
2.4.3
Extent of investigational medicinal product exposure and compliance
The extent of study treatment exposure will be assessed and summarized by treatment group 
within the AT/safety population. 
2.4.3.1
Overall exposure
The dose information will be assessed by the following variables:
x
Number of cycles started, defined by maximum of isatuximab/dexamethasone cycles started.
x
Duration of overall exposure (or time on-treatment) (in weeks) is defined as (last day of last 
cycle – first day of first cycle)/7. The first day of first cycle is defined by the earliest of 
isatuximab and dexamethasone administration date. The last day of last cycle is defined by the 
last date among the following:
-
date of last dose of isatuximab + 7 days if last cycle is QW cycle, or date of last dose 
of isatuximab + 14 days if last cycle is Q2W cycle.
-
date of last dexamethasone + 7 days for ISAdex arm.
Total number of cycles started, number of cycles started by patients as a quantitative variable and 
by category (ie, number (%) of patients receiving at least 1 cycle, at least 2 cycles etc), duration of 
overall exposure will be summarized by descriptive statistics. 
Cycle delay is defined as follows:
x
A cycle is deemed as delayed if the start date of the current cycle – 28 – start date of the 
previous cycle is >3 days. Cycle delay is not defined for the first cycle.
Cycle delayed will be analyzed at the patient and cycle levels, as follows (the number of patients 
who received ≥2 cycles will be used for % calculation):
x
Number of patients who could have a cycle delayed (patients who received ≥2 cycles, used for 
% calculation in this section)
Number (%) of patients with a least 1 cycle delayed
-
Number (%) of patients with a cycle delayed between 4 and 7 days (using maximum 
delay).
-
Number (%) of patients with a cycle delayed >7 days (using maximum delay).
x
Number of cycles that could be delayed (cycle ≥2, used for % calculation in this section)
Number (%) of cycles delayed
-
Number (%) of cycles delayed between 4 and 7 days.
-
Number (%) of cycles delayed >7 days.
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2.4.3.2
Isatuximab exposure
The dose information will be assessed by the following:
x
Total number of cycles started
x
Number of cycles started by patient
x
Duration of isatuximab exposure (or time on-treatment) (in weeks) is defined depending on 
the isatuximab administration schedule as follows:
-
If treatment is discontinued at a cycle with QW isatuximab administration: [date of last 
dose of isatuximab + 7 days – date of first dose of isatuximab]/7.
-
If treatment is discontinued at a cycle with Q2W isatuximab administration:  [date of 
last dose of isatuximab + 14 days – date of first dose of isatuximab]/7.
x
Actual dose (mg/kg): for a given cycle and day of administration, the actual dose in mg/kg 
corresponds to the actual dose in mg administered at each time point divided by the actual 
body weight as measured at each time point (cycle and day)
x
Cumulative dose (mg/kg): the cumulative dose is the sum of all actual doses of isatuximab, 
expressed in mg/kg, given from first to last administration 
x
Actual dose intensity (ADI) in mg/kg/week: defined as the cumulative dose (in mg/kg) divided 
by the duration of isatuximab exposure (in weeks)
x
Relative dose intensity (RDI) in %: 
Planned dose intensities in mg/kg/week corresponds to the planned dose (20 mg/kg) 
multiplied by the theoretical total number of doses during the started cycles (count 2 for 
Q2W cycles, 4 for QW cycles), and divided by the theoretical cycle duration expressed in 
weeks (ie, 4 weeks per cycle started).
The total number of cycles started, number of cycles started by patients as a quantitative variable 
and by category (ie, number [%] of patients receiving at least 1 cycle, at least 2 cycles, etc),
duration of isatuximab exposure, cumulative dose, ADI and RDI will be summarized by 
descriptive statistics. 
The following variables will be derived to describe dose delays/modifications:
x
Dose delay (within a cycle): A dose is deemed as delayed if the actual start date of the 
infusion – theoretical start date of an infusion is >1 day for weekly administration, is >2 days 
for Q2W administration. Dose delay does not apply to the first infusion of each cycle.
x
Dose interruption: A dose will be considered to be interrupted if the isatuximab administration 
is temporarily stopped during an infusion and then restarted (typically in case of Grade 2 
IARs). Analysis of dose interruption will be performed using the dose interruption section of
the drug administration page in the eCRF.
x
Dose omission: a dose is considered omitted if the dose is not administered for the scheduled 
visit and there are positive dose(s) afterwards.
k)
(mg/kg/wee
Intensity 
 
Dose
 
Planned
k)
(mg/kg/wee
 
ADI
100u
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x
Dose reduction: Although not allowed in the study protocol, potential dose reductions will be 
screened and reported in the clinical study report. The first administration will not be counted as a 
dose reduction. For the second and subsequent isatuximab administrations, dose reduction will be 
determined using the dose level intervals provided in Table 7, by comparing the current dose level 
to the previous dose level. If the current dose level is not within the same dose level interval as the 
previous dose level, then the current dose level is considered reduced.
Table 7 – Isatuximab dose reduction criteria
Actual dose level
Dose level interval
Dose level 1 (low dose) 
>0 mg/kg and ≤15 mg/kg 
Dose level 2 (20 mg/kg): 
>15 mg/kg  
x
Infusions not completed: patients who received less than 90% of the planned dose at an 
infusion
Dose delayed/modification will be analyzed at the patient, cycle and the total number of 
isatuximab administration levels as follows:
x
Patient level
-
Number (%) of patients with at least 1 dose delayed (using number of patients with 
≥2 infusions as denominator for % calculation).
For the following variables, number of patients treated will be used for % calculation:
-
Number (%) of patients with at least one dose omission.
-
Number (%) of patients with at least one dose reduction.
-
Number (%) of patients with a least 1 infusion interrupted.
-
Number (%) of patients with at least 2 infusions interrupted.
x
Infusion level
-
Total number of isatuximab infusions (used for % calculation for this section).
-
Number (%) of isatuximab infusions :
-
Total interrupted.
-
Re-started
-
Not re-started
-
Number (%) of isatuximab infusions interrupted more than once.
-
Number of infusion interrupted at (with % calculated using the total number of 
infusions interrupted): 1st infusion, 2nd infusion, subsequent infusions.
-
Time from infusion start to first interruption in minutes (quantitative and qualitative: 
5-10, 11-30, 31–40, 41 –50, 51 –60, 61–90, 91–120, >120).
-
Number (%) of infusions not completed (patients who received less than 90% of the 
planned dose).
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Duration of infusion is defined as the time from the start (date/time) of infusion to the end 
(date/time) of infusion. It will be summarized for first and subsequent infusions.
2.4.3.3
Dexamethasone exposure (ISAdex arm only)
The dose information will be assessed by the following:
x
Total number of cycles started
x
Number of cycles started by patient
x
Duration of dexamethasone exposure (or time on-treatment) (in weeks) is defined as [date of 
last dose of dexamethasone + 7 days – date of first dose of dexamethasone]/7.
x
Actual dose (mg): for a given cycle and day of administration, the actual dose in mg 
corresponds to the actual dose in mg administered at each time point. Note that the planned 
dose is 40 mg for patients <75 years old, and 20 mg for patients ≥75 years old. 
x
Cumulative dose (mg): the cumulative dose is the sum of all actual doses of dexamethasone,
expressed in mg, given from first to last administration 
x
Actual dose intensity (ADI) in mg/week: defined as the cumulative dose (in mg) divided by 
the duration of dexamethasone exposure (in weeks)
x
Relative dose intensity (RDI) in %: 
x
Planned dose intensities in mg/week correspond to the planned dose (mg) at Cycle 1-Day 1
(taking into account patient’s age), regardless of dose changes.
The total number of cycles started, number of cycles started by patients as a quantitative variable 
and by category (ie, number [%] of patients receiving at least 1 cycle, at least 2 cycles, etc), 
duration of dexamethasone exposure, cumulative dose, ADI and RDI will be summarized by 
descriptive statistics. 
The following variables will be derived to describe dose delays/modifications:
x
Dose delay (within a cycle): A dose is deemed as delayed if the actual start date of the dose –
theoretical start date of a dose is >1 day for weekly administration. Dose delay does not apply 
to the first dose of each cycle.
x
Dose omission: a dose is considered omitted if the dose is not administered for the scheduled 
visit and there are positive dose(s) afterwards.
x
Dose reduction: The first administration will not be counted as a dose reduction. For the 
second and subsequent dexamethasone administrations, dose reduction will be determined 
using the dose level intervals provided in Table 7, by comparing the current dose level to the 
previous dose level. If the current dose level is not within the same dose level interval as the 
previous dose level, then the current dose level is considered reduced.
(mg/week)
Intensity 
 
Dose
 
Planned
 
(mg/week)
 
ADI
100u
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Table 8 – Dexamethasone dose reduction criteria
Actual dose level
Dose level interval
if starting dose is 40mg1
Dose level interval
if starting dose is 20mg2
Dose level 1 (low dose) 
>0 mg and ≤8 mg 
>0 mg and ≤4 mg 
Dose level 2 (16mg1/8mg2) 
>8 mg and ≤20 mg 
>4 mg and ≤ 10 mg 
Dose level 3 (24mg1/12mg2) 
>20 mg and ≤32 mg 
>10 mg and ≤16 mg 
Dose level 4 (40mg1/20mg2): 
>32 mg  
>16 mg 
1 in patients <75 y.o 
2 in patients ≥75 y.o 
 
 
Dose delayed/modification will be analyzed at the patient, cycle and the total number of 
dexamethasone administration levels as follows:
x
Patient level
-
Number (%) of patients with at least 1 dose delayed (using number of patients with 
≥2 dose as denominator for % calculation).
For the following variables, number of patients treated will be used for % calculation:
-
Number (%) of patients with at least one dose omission.
-
Number (%) of patients with at least one dose reduction.
2.4.4
Analyses of efficacy endpoints
All primary, secondary and exploratory analyses will be performed using the AT/safety 
population.
The following hypothesis will be tested:
x
ISA arm: the null hypothesis ORR ≤15% will be tested using an exact binomial test at a one-
sided alpha of 0.025. If there are 105 patients, then the null hypothesis will be rejected when
the observed ORR is greater than or equal to 22.9% (24 responders).
x
ISAdex arm: the null hypothesis ORR ≤ 15% will be tested using an exact binominal test at a 
one-sided alpha of 0.025. If there are 55 patients, then the null hypothesis will be rejected 
when the observed ORR is greater than or equal to 27.3% (15 responders).
2.4.4.1
Analysis of primary efficacy endpoint(s)
ORR, including BOR, CBR and at least VGPR rate as assessed by IAC will be summarized with 
descriptive statistics. A 95% two-sided confidence interval will be computed for ORR, CBR and 
VGPR or better rate using Clopper-Pearson method. The same analysis will be performed using 
investigator assessments of response. In addition, for exploratory purpose, ORR and VGPR or better 
rate according to IAC assessment between the 2 arms will be compared using the Fisher exact test. 
ORR as assessed by IAC will also be summarized descriptively for subgroups variable defined 
in Table 3.
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The relationship between Responder/Non responder (binary variable, BOR of PR or better) and 
parameters defined in Table 3 and 4 will be analyzed by fitting a logistic regression 
model. Model development will involve univariate analyses for each parameter and 
Responder/Non responderendpoint. Considering the most significant parameters of the univariate 
analyses, multivariate analyses with stepwise inclusion and deletion of covariates will be 
performed. The significance level for variable entry or removal at each step will be less than 0.15 
for entry and 0.10 for removal. 
2.4.4.2
Analyses of secondary efficacy endpoints
The following analyses will be performed using both IAC and investigator assessments of 
response.
x
CBR: see above.
x
DOR: Kaplan-Meier estimates of the 25th, 50th and 75th percentiles including the 95% 
confidence interval as well as Kaplan-Meier curves will be provided for DOR for patients who 
achieve a response ≥ PR.
x
PFS: 
PFS will be analyzed using the Kaplan-Meier method by treatment group:
-
Kaplan-Meier estimates of the 25th, 50th and 75th percentiles and their associated 95% 
confidence interval will be provided. The 95% confidence intervals will be constructed 
using a log-log transformation of the survival function and the methods of Brookmeyer 
and Crowley. 
-
Number of patients at risk as well as the probabilities of surviving without disease 
progression at least 2, 4, 6, 8, 10, 12, 14 and 16 months with 95% CIs will be estimated 
for each treatment group using the Kaplan-Meier method.
-
The Kaplan-Meier curves will be plotted. These plots will include the number of 
patients at risk at key time points by treatment group.
-
The log rank test from the comparison of PFS between the 2 arms will be provided for 
exploratory purpose.
In addition, the hazard ratio (HR) and its 95% confidence interval (CI) will be estimated using 
the Cox proportional hazards model. Underlying assumptions of the Cox Proportional hazards 
model will be assessed by graphical methods (ie, log-log graphical methods).
A multivariate Cox proportional hazards model will be used to identify prognostic factors among 
the demographic and baseline characteristics factors described in the table above using a stepwise 
selection procedure with a 15% significance level for removing effects. For significant prognostic 
factors identified in the multivariate model, the balance between treatment groups will be 
assessed. If major confounding is identified through screening for treatment group imbalances in a 
prognostic factor at baseline, the treatment effect for PFS will be re-estimated after adjusting for 
the prognostic factors in the multivariate Cox proportional hazards model.  Differences between 
the adjusted and unadjusted models will be discussed in the clinical study report.
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x
For patients with events, the type of event (confirmed disease progression or death) will be
summarized by treatment group using counts and percentages. The type of disease progression 
will also be presented (progression diagnosed on M-protein or radiological progression).
x
For patients who died without evidence of disease progression, the time from the last disease 
assessment to the death will be summarized by treatment group using number, mean, 
standard deviation, median and range.
x
The number (%) of censored patients, the reason and timing of their censoring (ie, censored 
at randomization, censored at the last valid disease assessment before the initiation of further 
anti-myeloma treatment, censored at last valid disease assessment before the cut-off date, 
censored at the cut-off date), and the time from the last disease assessment to the cut-off date 
will be summarized by treatment group. For each censoring reason, when applicable, 
distinction will be made between cases where no event was observed and cases where an 
event was observed after the censoring.
x
Follow-up duration (months) will be defined as the time interval from the date of
randomization to the date of last contact with the patient. Patients who have died will be
censored on their date of death. Median follow-up duration (months) will be estimated using 
the Kaplan-Meier method.
x
VGPR or better rate: same as CBR
OS will be analyzed using the same method as PFS.
DFU and TTR will be analyzed using Kaplan-Meier methods and summarized with descriptive 
statistics (among responders only for TTR).
A listing of response (as assessed by IAC) data will be provided for the all treated population and 
for patients who are ADA positive (Section 2.1.4.4), and will include the following variables: high 
risk status, number of prior lines of anti-myeloma treatment, selected prior treatments given 
(alkylating agent, bortezomib, carfilzomib, lenalidomide, pomalidomide, thalidomide), duration of 
exposure (weeks), reason for treatment discontinuation, measurable paraprotein at baseline, best 
percent change in paraprotein, best overall response, date of first response ≥PR, date of first 
disease progression/last disease assessment, indication of progressive disease, time to first 
response, time to best response and DOR.
A listing of best percent change in % plasma cell in bone marrow biopsy will be provide and will 
include the following variables: measurable paraprotein at baseline, best percent change in 
paraprotein, BOR, baseline plasma cells count, post baseline plasma cells count and best percent 
change in plasma cells count.
A swimmer plot of time on a treatment (ie, duration of exposure) will be provided. Best percent 
change in paraprotein will be displayed in a waterfall plot. In the waterfall plot, patients will be 
ordered from highest positive change to smallest negative change. Patients with BOR ≥PR will 
have a negative percentage change. Patients with a >100% increase in paraprotein will be shown 
as 100% increase.
A listing of patients with MRD data will be provided (if any).
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Additional evidence of clinical benefit : Renal response and renal function deterioration
Number and percentage of patients in each renal response and renal function deterioration will be 
provided by treatment arm. 
2.4.4.3
Multiplicity issues
Not applicable.
2.4.5
Analyses of safety data
The analysis of safety data will be presented by treatment group and overall (see Section 2.4).
All safety analyses will be performed on the AT/safety population as defined in Section 2.3.1.
Unless otherwise specified, the baseline value is defined as the last available value before or on 
the date of first isatuximab/dexamethasone administration. In addition, unscheduled assessment 
performed on the date of first study treatment administration will be considered as post baseline.
2.4.5.1
Analyses of adverse events
The primary focus of adverse event analysis will be on treatment-emergent adverse events.  
Pre-treatment and post-treatment AEs will be described separately.
If an AE date of onset (occurrence, worsening, or becoming serious) is incomplete, an imputation 
algorithm will be used to classify the AE as pretreatment, treatment-emergent, or post-treatment.  
The algorithm for imputing date of onset will be conservative and will classify an AE as treatment 
emergent unless there is definitive information to determine it is pretreatment or post-treatment.  
Details on classification of adverse events with missing or partial onset dates are provided in 
Section 2.5.3.
For patients with multiple occurrences of the same AE within the observation period (pre-
treatment, treatment emergent and post-treatment), the maximum severity grade will be used.
Overview of TEAEs
An overview of TEAEs including the number (%) of patients with the following events will be 
provided:
x
TEAE.
x
TEAE of Grade ≥3.
x
Drug-related TEAE (related to either isatuximab or dexamethasone).
x
Drug-related TEAE of Grade ≥3.
x
Serious TEAE.
x
Serious drug-related TEAE.
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x
TEAE with a fatal outcome.
x
TEAE leading to definitive study drug discontinuation, ie, discontinuation of isatuximab in 
ISA arm, and discontinuation of isatuximab and dexamethasone in ISAdex arm.
x
TEAE leading to premature dexamethasone discontinuation, ie, discontinuation of 
dexamethasone before isatuximab, only applicable to ISAdex arm.
x
TEAE leading to premature isatuximab discontinuation, ie, discontinuation of isatuximab 
before dexamethasone, only applicable to ISAdex arm.
x
AESI.
x
AESI of Grade ≥3.
x
IAR (excluding symptoms).
x
IAR of Grade ≥3 (excluding symptoms).
Analysis of adverse events
Analysis of adverse events will be performed according to following:
x
TEAEs (regardless relationship to study treatment),
x
Drug related TEAEs, 
x
Deaths, serious adverse events, adverse events leading to withdrawal, and other significant 
adverse events as defined below.
Additional analyses will include:
x
IAR-AESI (using the CMQ corresponding to the generic term of infusion related reaction 
reported by investigator as an AESI):
-
Analysis by patient: worst grade, number of episodes by patient (only 1 episode, 
≥1 episode, ≥2 episodes - an episode corresponds to a unique AE reference ID), first 
occurrence of IARs (first and subsequent isatuximab infusion), patients with IAR at 
the first and subsequent isatuximab infusion and number (%) of patients with at least 
two episodes of IARs at the same infusion. 
-
Analysis by infusion: worst grade by infusion (a patient can have several IAR episodes 
at the same infusion).
-
Analysis by episode: proportion of IARs occurring at each infusion (infusion 1, 2, 3, 4, 
5 and >5), IAR duration and day of onset.
x
Summary (as described in Table 9) and listing of IAR-AESI including symptoms as reported 
by investigator.
x
IAR-AE (ie, TEAE occurring within 24 hours of each isatuximab administration) (see Table 9).
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x
Respiratory TEAEs:
-
Lower respiratory TEAEs analyzed by IAR status (IAR or Non-IAR). They may also 
be analyzed with regards to medical history data (eg, chronic obstructive pulmonary 
disease, cough, dyspnea) and smoking history.
-
Respiratory infection TEAEs analyzed by IAR status (IAR or Non-IAR). They may 
also be analyzed with regards to medical history and smoking history.
In addition, late respiratory events (ie, occurring, worsening or becoming serious more 
than 30 days after last dose) will be analyzed as part of the post-TEAEs analysis.
x
Thrombocytopenia and hemorrhages
The number (%) of patients will be provided for:
-
On-treatment thrombocytopenia (Lab) identified through grading of laboratory data 
per the NCI-CTCAE 4.03, by grade
-
Hemorrhages as defined in Section 2.1.4.1 by grade
-
Hemorrhages following Grades 4 thrombocytopenia (Lab). The first hemorrhages 
event occurring within 8 days after any occurrence of the thrombocytopenia (Lab) will 
be used for this analysis.
x
Hemolytic disorders
Hemolytic disorders that occurred within 8 days after the blood cell transfusion will be 
analyzed using selection defined in Section 2.1.4.1 and will be presented by PT. A listing 
of patients with hemolytic disorders will be provided. This listing will include the PT, 
study day of diagnosis (from first dose of study treatment), interval to onset from the last 
study treatment before the diagnosis (last drug administered), duration of AE, the cycle of 
occurrence, severity, seriousness, outcome, action taken on study treatment, study day of 
the blood transfusion, and results and sampling date of indirect anti-globulin test.
x
Autoimmune disorders
A listing of patients with autoimmune disorders (selected using definition in Section 2.1.4.1)
will be provided. This listing will include the PT, study day of diagnosis (from first dose of 
study treatment), interval to onset from the last study treatment before the diagnosis (last drug 
administered in a combination treatment), duration of AE, the cycle of occurrence, severity, 
seriousness, action taken on study treatment, and outcome.
x
Neutropenia and neutropenic complications
Neutropenia (from laboratory abnormalities) will be displayed along with febrile 
neutropenia and neutropenic infections (see Section 2.1.4.1).
Duration of Grade 3/4 neutropenia episode, cumulative duration of Grade 4 neutropenia by 
patient and time to first Grade 3/4 neutropenia will be analyzed using laboratory data.
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The start date of a Grade 4 laboratory neutropenia episode is defined as the date of first 
Grade 3/4 assessment for that episode. The end date of a Grade 4 neutropenia episode is 
defined as the first date of neutropenia assessment afterwards of Grade 0/1/2 for that 
episode assuming there will be at least 3 days between the first Grade ӊ2 neutropenia and 
the next GradeӋ3 assessment (if any).
If the start date of a new episode is within 3 days of the previous episode, then the two 
episodes will be considered as one episode. The worst grade of an episode is the worst 
grade of all assessments included in that episode
Duration of a Grade 3/4 neutropenia episode (in days) is defined as end date of an episode ̽
start date of an episode +1. If a patient does not have an end date before the cutoff date in an 
episode then the duration of the episode will be censored at the last neutrophil assessment of 
Grade 3/4 or the cutoff date, whichever comes first.
Time to first Grade 3/4 neutropenia (in days) is defined as: date of the first on-treatment 
Grade 3/4 neutropenia assessment ̽ date of first treatment +1. If a patient does not have 
Grade 3/4 neutropenia, time to first Grade 3/4 neutropenia will be censored at the last 
assessment of neutropenia of Grade 0/1/2 or the cutoff date, whichever comes first. If a 
patient does not have any on-treatment assessment of neutropenia, then the patient will be 
censored at Day 1.
x
Second primary malignancies
A listing of patients who reported second primary malignancies during the study will be 
provided (as per the CMQ) and by categories (‘haematological’, ‘non-hematological skin 
tumors’, ‘non-hematological non-skin tumors’ and ‘other tumors’). This listing will 
include diagnosis, study day of diagnosis (from first dose), number of days from last study
treatment to diagnosis, prior exposure to anti-myeloma treatments, and whether or not 
patient received subsequent anti-cancer treatment.
x
Analysis of all treatment-emergent adverse event(s) leading to definitive treatment 
discontinuation. Analysis of all treatment-emergent adverse event(s) leading to premature 
dexamethasone discontinuation. Analysis of all treatment-emergent adverse event(s) leading 
to premature isatuximab discontinuation.
-
If the number of patients who discontinued treatment due to a TEAE is ≤ 5, no 
summary table will be provided. Instead, listing(s) will be provided. 
x
Summary of TEAEs leading to dose interruption of isatuximab, summary of TEAEs leading to 
dose reduction includes reduction of isatuximab or dexamethasone (ISAdex arm), summary of
TEAEs leading to dose delay includes delay of isatuximab or dexamethasone (ISAdex arm).
x
Pregnancy and overdose being part of AESI, will be listed besides IARs) will be listed.
x
Deaths: see Section 2.4.5.2.
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The description of the main summary tables that will be provided for the analysis of TEAEs, 
drug-related TEAEs, serious TEAEs, drug-related serious TEAEs, IAR-AESI, IAR-AE, as well as 
TEAEs leading to dose discontinuation or modification is given in Table 9.
Sorting within tables will ensure the same presentation for the set of all AEs within the 
observation period (pre-treatment, treatment-emergent, and post-treatment). For that purpose, the 
table of all TEAEs presented by SOC and PT sorted by the internationally agreed SOC order and 
decreasing frequency of PTs within SOCs will define the presentation order for all other tables 
unless otherwise specified. Sorting will be based on the incidence of AEs in the AT/safety 
population (ie, all patients).
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Table 9 – Description of summary tables to be provided for the analysis of TEAEs
MedDRA coding variables
Sorting (all patients column)
Layout
Events
PT 
x PT: Decreasing order of frequency 
Treatment groups and All patients: n (%) 
of patients with any event and n (%) of 
patients with event of Grade ≥3 
x TEAEs occurring in ≥5% of the patients (all patients) 
x Drug-related TEAEs occurring in ≥5% of the patients (all 
patients) 
x Serious TEAEs in ≥5%a of the patients (all patients) 
SOC, HLGT, HLT, and PT 
x Primary SOC: internationally agreed 
order 
x HLGT, HLT, PT: alphabetical order 
Treatment groups and All patients: n (%) 
of patients with any event and n (%) of 
patients with event of Grade ≥3 
x All TEAEs 
x Drug-related TEAEs 
x Serious TEAEs 
x Drug-related serious TEAEs  
x Lower Respiratory TEAEs by IAR status and medical history  
x Respiratory infection TEAEs by medical history 
SOC and PT 
x Primary SOC: internationally agreed 
order 
x PT: decreasing order of frequency 
defined be the all TEAEs table (see 
previous page) 
Treatment groups and All patients: n (%) 
of patients with any event and n (%) of 
patients with event of Grade ≥3 
x All TEAEs 
x TEAEs occurring in ≥5% of the patients (all patients) 
x Drug-related TEAEs 
x Drug related TEAEs occurring in ≥5% of the patients (all 
patients) 
x Serious TEAEs 
x Serious TEAEs in ≥5%a of the patients (all patients) 
x Drug related serious TEAEs 
x TEAEs leading to definitive treatment discontinuation 
x TEAEs leading to premature dexamethasone 
discontinuation 
x TEAEs leading to premature isatuximab discontinuation 
x TEAEs leading to dose interruption 
x TEAEs leading to dose delay 
x TEAEs leading to dose reduction 
SOC and PT 
x Primary SOC: internationally agreed 
order 
x PT: decreasing order of frequency 
(all patients) 
Treatment groups and All patients: n (%) 
of patients with any event and n (%) of 
patients with event of Grade ≥3 
x IAR-AESI 
x IAR-AE 
x Pre-treatment and post-treatment AEs 
a
The threshold presented is 5%, however, other threshold(s) could be used if deemed clinically relevant. 
AE=adverse event; AESI=adverse event of special interest; HLGT=high-level group term; HLT=high-level term; IAR=infusion associated reaction; MedDRA=Medical Dictionary for Regulatory 
Activities; n (%)=number and percentage of patients; PT=preferred term; SOC=system organ class; TEAE=treatment-emergent adverse event. 
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2.4.5.2
Deaths
Number (%) of patients who died by study period (on-treatment and post-treatment) and within 
60 days from first dose of study treatment, and cause of death (PD, AE with subdivision of drug-
related AE and non-drug related AE, other) will be summarized. A listing of patients who died 
while participating in the study including cause of death, death date, days from first and last dose 
to death, preferred term, and causal relationship to isatuximab/dexamethasone (when applicable) 
will be provided.
The following summaries of deaths will be generated:
x
Summary of AEs leading to death, by Primary SOC and PT 
-
In context of disease progression (death within 30 days from last study treatment 
administration and the cause of death is disease progression),
-
In context other than disease progression (death within 30 days from last study 
treatment administration and for whom cause of death is not disease progression or the 
death occurred more than 30 days from last study treatment administration and the 
cause of death is adverse event).
2.4.5.3
Analyses of laboratory variables
Each laboratory test result will be graded by CTCAE criteria (version 4.03), when applicable. For 
hematological parameters and for some biochemistry parameters, Sanofi sponsor generic normal 
ranges will be used for the grading of laboratory abnormalities (see list of parameters in 
Appendix A, Table 11 and Table 12). For other biochemistry parameters (eg, for hepatic 
parameters), grading will be derived using the local laboratory normal ranges.
The number (%) of patients with abnormal laboratory tests at baseline and during the on-treatment 
period will be presented by all grades and each grade. For patients with multiple occurrences of 
the same laboratory variable during the on-treatment period, the maximum grade (worst) per 
patient will be used. At baseline, the last available value before or on the date of first study 
treatment administration will be used (excluding repeated tests).
Shift tables showing the number of patients in each grade at baseline by worst grade during the 
on-treatment period will be provided for selected laboratory test.
For renal function using MDRD formula, the number (%) of patients by category ( [15-30[, [30-
60[, [60-90], >90 mL/min/1.73m2) and by period (baseline and on-treatment) as well as a shift 
table will be provided.
For urate, Chloride and BUN, potentially clinically significant abnormalities (PCSA) values 
defined as abnormal values considered medically important by the Sponsor according to 
predefined criteria/thresholds based on literature review (Table 10) will be derived. PCSA criteria 
will determine which patients had at least 1 PCSA during the on-treatment period, taking into 
account all evaluations performed during the on-treatment period, including nonscheduled or
repeated evaluations. The incidence of PCSA any time during the on-treatment period will be 
summarized by treatment group and overall, irrespective of the baseline level.
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Table 10 - Potentially clinically significant abnormalities criteria for laboratory tests
Parameter
PCSA
Comments
Clinical Chemistry 
eGFR 
(mL/min/1.73m2) 
(Estimate of GFR 
based on an MDRD 
equation) 
≥15 - <30 (severe decrease in GFR) 
≥30 - <60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
Use is optional. 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Blood Urea Nitrogen ≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Listings of patients with laboratory abnormalities of Grade 3 and Grade 4 during the on-treatment 
period will be provided. The baseline value will be included in the listing.
2.4.5.4
Analyses of vital sign variables
The incidence of PCSA (Table 11) any time during the on-treatment period will be summarized 
by treatment group irrespective of the baseline level and/or according to the following baseline 
status categories:
x
Normal/missing.
x
Abnormal according to PCSA criterion or criteria.
Table 11 - Potentially clinically significant abnormalities criteria for vital signs
Parameter
PCSA
Comments
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
Temperature and respiratory rate will be summarized at baseline and end of treatment, by 
treatment group and all.
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A listing of patients with at least one PCSA will be provided.
2.4.5.5
Analyses of electrocardiogram variables
The number (%) of patients with normal/abnormal ECG result at baseline will be summarized by 
treatment group and all. A listing of ECG results will be provided.
2.4.5.6
Analyses of other safety endpoints
A shift table of baseline ECOG PS versus best and worst ECOG PS on treatment will be provided. 
A listing of patients with TLS reported in eCRF AE forms (using a SMQ: Tumor lysis syndrome)
during the study will be provided. The clinical chemistry parameters regarding hyperkalemia, 
hyperphosphatemia, hypocalcemia, and hyperuricemia will be listed to corroborate any report of 
TLS identified with the above SMQ.
A listing of chest x-ray results will be provided.
2.4.6
Analyses of pharmacokinetic and pharmacodynamic variables
2.4.6.1
PK variables
Isatuximab plasma concentrations after single and repeated dose administrations will be analyzed 
using a nonlinear mixed-effects modelling approach using MONOLIX software version 2016 R1 
(or more recent version) (Lixoft).  Individual estimates of PK parameters will be obtained using 
parameter estimates from the basic population model developed in TED10893 Phase 1  and 
Phase2 stage 1 (POH0458 study) as priors (Empirical Bayes estimates) and individual 
concentrations. Exposure parameters (Cmax, Ctrough and cumulated AUC) will be derived using the 
individual parameters.
Pharmacokinetic parameters of isatuximab (listed in Section 2.1.5) will be summarized by 
descriptive statistics (such as the number of observations available, arithmetic and geometric 
mean, median, standard deviation (SD),  coefficient of variation (CV), minimum, and maximum) 
under the responsibility of Pharmacokinetic, Dynamic and Metabolism, Translational Medicine 
and Early Development Sanofi. Steady state (based on Ctrough) will be assessed as well as the 
extent of the accumulation.
Summary (number of patients, mean and CV%) of Ctroughobs of isatuximab by visit will be 
provided. A listing of Ctroughobs for individual patient will also be provided. Ctroughobs will be 
kept for the descriptive statistics if sampling occurs within 7 days ± 1 day after the previous start 
of infusion for sampling done during Cycle 1 and within 14 days ± 3 days after the previous start 
of infusion for sampling done for subsequent cycle up to cycle 10.
Cycles in patients with dose delay and/or dose reduction, and samples with missing date and/or 
time and/or date and time of the previous dose, will be removed from the analyses.
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2.4.7
Immune response
Using the ADA evaluable population, the number (%) of patients will be provided for the 
following:
x
Preexisting ADA.
x
ADA negative at baseline.
x
On study ADA
-
Treatment-induced ADA.
-
Persistent ADA.
-
Transient ADA.
-
Indeterminate ADA.
-
Treatment boosted ADA.
-
Last sample positive.
x
ADA prevalence.
x
ADA incidence.
In addition, a data listing of each ADA sample result will be provided. The impact on PK, safety 
and efficacy endpoints may be further explored by graphical methods or descriptively, depending 
on the ADA prevalence.
2.4.8
Analyses of Biomarker variables
2.4.8.1
Genetic variables
Summary of BOR will be provided for the following patients:
x
High risk cytogenetic markers (del17p and/or t(4;14) and/or t(14;16))
x
Chromosomal abnormalities(gain(1q) and del(1p32)).
x
FcGR3A types: F/F, F/V, V/V and missing.
x
FCGR2A genotypes
x
HLA and KIR genotypes including:
-
HLA-B BW4-80lle+ and KIR3DL1+ vs HLA-B BW4-80lle- or KIR3DL1-.
-
KIR3DS1- vs KIR3DS1+.
2.4.8.2
Other variables
Descriptive statistics of soluble CD38 for the all treated population as well as for responders/non-
responders will be calculated. In addition, graphs showing responder/non-responder rate by 
soluble CD38 levels will be provided. 
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Graphs showing ORR/non-responder rate by biomarker levels will be provided for the following 
parameters at baseline for soluble CD38
A listing of response data will be provided for patients with MRD
x
Immune cell level (B-cell, T-cell and NK-cell subsets respectively in blood and bone
marrow samples) will be described 
x
Measurable paraprotein will be described as define below: 
Table 12 - Derivation of measurable paraprotein type at baseline
Measurable paraprotein at 
baseline
Criteria 
Serum M-Protein 
Serum M-protein ≥0.5 g/dL and urine M-protein <200 mg/24 hours or negative or missing 
urine M-protein 
Urine M-Protein 
Serum M-protein <0.5 g/dL or negative serum M-protein and urine M-protein ≥200 mg/24 
hours 
Serum and urine M-protein 
Serum M-protein ≥0.5 g/dL and urine M-protein ≥200 mg/24 hours 
2.4.8.2.1 Descriptive analysis
Each biomarker will be summarized with descriptive statistics by treatment group and overall. 
2.4.8.2.2 Univariate analysis
When applicable, each biomarker will be tested for a potential prognostic/predictive effect for 
ORR. 
A logistic regression will be conducted separately for each genetic biomarker with a treatment 
effect, a biomarker effect and a biomarker×treatment interaction. Since the number of patients in 
each treatment group is small, only the main effect of the biomarkers may be investigated 
ignoring the interaction with treatment.
In this analysis, some dose/schedules may be pooled together or removed from the model. 
For biomarkers coded as genotype (0, 1, 2), different coding may be investigated: additive, 
dominant or recessive.
Distribution of p-values will be presented and Benjamini-Hochberg multiple correction procedure 
will be used to control the false discovery rate (FDR).
Additional analyses using PFS instead of ORR might also be performed.
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2.4.8.2.3 Multivariate analysis
If some biomarkers are determined to be potentially prognostic/predictive in the previous step, 
multivariate analysis combining several biomarkers will be considered (eg, logistic regression, 
SVM, Random Forest). A proper cross-validation scheme including the univariate selection step, 
will be put in place to estimate the generalization error of the model.
Sensitivity, specificity and accuracy will be calculated to assess the predictive properties of the 
multivariate biomarker. 
2.4.9
Analyses of quality of life variables
No analysis is planned for quality of life variables.
2.4.10 Further therapy after discontinuation of investigational medicinal product 
administration during the study
Further therapies will be descriptively summarized by treatment group and overall.
Time to next treatment
TNT will be analyzed using Kaplan-Meier methods. 
2.5
DATA HANDLING CONVENTIONS
2.5.1
General conventions
Not applicable. General conventions are provided in the relevant sections. 
2.5.2
Data handling conventions for secondary efficacy variables
Not applicable.
2.5.3
Missing data
The analyses and summaries of continuous and categorical variables will be based on observed 
data only. Percentages will be calculated using as the denominator the number of patients with a 
non-missing observation in the considered population. When relevant, the number of patients with 
missing data will be presented.
When incomplete or missing dates were found in the eCRF, attempts were made to retrieve the 
complete date, especially for dates within the month prior to first dose. However, if some dates 
remain incomplete, the following rules will be applied:
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Handling of disease characteristics missing/partial dates 
x
If the day is missing, it will be imputed to be 1.
x
If the month is missing, it will be imputed to be 1 (only for medical history variables).
x
If the year is missing, no imputation will be performed.
Handling of medication missing/partial dates
No imputation of medication start/end dates or times will be performed.  If a medication date is 
missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and post-treatment medication.
For post anticancer treatments, if the anticancer treatment start date is missing, it will be imputed 
as follows:
1. If the anticancer treatment start day is missing and the anticancer treatment start month 
and year are the same as the study treatment end month and year, the anticancer treatment 
start day will be set equal to the date of last study treatment administration + 1.
2. If the anticancer treatment start day is missing and the anticancer treatment start month is 
not missing and the anticancer treatment start year is after the study treatment end year, the 
anticancer treatment start day will be set to 01.
3. If the anticancer treatment start day is missing and the anticancer treatment start month is 
after the study treatment end month and the anticancer treatment start year is the same as 
treatment end year, the anticancer treatment start day will be set to 01.
4. If the anticancer treatment start day and month are missing and the anticancer treatment 
start year is the same as study treatment end year, the anticancer treatment start date will 
be set equal to the date of last study treatment administration + 1.
5. If the anticancer treatment start day and month are missing and the anticancer treatment 
start year is after the study treatment end year, the anticancer treatment start day and 
month will each be set to 01
6. If the anticancer treatment start day is missing and anticancer treatment start month is 
before the study treatment end month and the anticancer treatment start year is the same as 
treatment end year, the anticancer treatment start day will be set to 01.
7. If the anticancer treatment start day, start month and start year is missing, the anticancer 
treatment start date will be set equal to the treatment end date + 1.
Handling of adverse events with missing or partial date of onset
Missing or partial AE onset dates or seriousness dates will be imputed so that if the partial AE 
onset date or visit number information does not indicate that the AE started prior to treatment or 
after the on-treatment period, the AE will be classified as treatment-emergent.  These data 
imputations are for categorization purpose only and will not be used in listings.  No imputation of 
AE end dates will be performed.
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Handling of adverse events with missing grade
Missing grades, if any, will be included in the “all grades” category.
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product 
If the assessment of the relationship to study treatment is missing, then the relationship to 
isatuximab/dexamethasone has to be assumed and the AE considered as such in the frequency 
tables of possibly related AEs, but no imputation will be done at the data level.
Handling of death with missing or partial date of death
The imputation for missing or partial death date will proceed as follows:
1. If the death day is missing and the death month and year are the same as the last month 
and year the patient was last known to be alive, the death day will be set equal to the last 
day the patient was known to be alive + 1.
2. If the death day is missing and the death month is after the month the patient was last 
known to be alive and the death year is the same as the year the patient was last known to 
be alive, the death day will be set to 01.
3. If the death day and month are missing and the death  year is the same as the year the 
patient was last known to be alive, the death date will be set equal to the date the patient 
was last known to be alive + 1.
4. If the death day and month are missing and the death year is after the year the patient was 
last known to be alive, the death day and month will both be set to 01.
If the date the patient was last known to be alive is partial or missing, no imputation for missing or 
partial death date will be performed. The last date the patient was known to be alive is the last of: 
date of last dose, date of last visit performed (when the patient is known to be alive according to 
subject vital status), date of last laboratory assessment, date of last vital signs.
Handling of parameters expressed as inequality or approximation
For some parameters (such as laboratory parameters), if the value is expressed as an inequality or 
an approximation, the numeric portion of the entry may be used in calculations.
2.5.4
Windows for time points
Laboratory data
A protocol planned laboratory test is considered to have occurred during a cycle if the date of 
sampling is after (>) the first day of the cycle, but prior to or equal (≤) to the first day of the next 
cycle. For unscheduled tests, a test is considered to have occurred during a cycle if the date of 
sampling is equal to or after (≥) the first day of the cycle, but prior (<) to the first day of the next 
cycle.
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Sponsor specified reference ranges will be used to calculate laboratory toxicities 
(see Section 2.4.5.3).
2.5.5
Unscheduled visits
Unscheduled visit measurements of laboratory data, vital signs and ECG will be used for 
computation of baseline and worst values and/or grades.
2.5.6
Pooling of centers for statistical analyses
Data from all sites will be pooled together for analyses.
2.5.7
Statistical technical issues
Not applicable.
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3
INTERIM ANALYSIS
An interim analysis of the safety data from Phase 2 Stage 2 may be performed if the enrollment is 
not completed by December 2017. No formal statistical hypothesis will be tested in this analysis.
A cutoff date will be defined for this analysis, and all patients treated before the cutoff date -
28 days will be included in the analysis. The analyses will include the following 
parameters/analyses (defined in Section 2): demographics and baseline characteristics, prior or 
concomitant medication, safety endpoints (AE, deaths, laboratory variables, vital signs, ECG, and 
other safety endpoint), PK variables, immunogenicity.
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4
DATABASE LOCK
The database will be locked when clinical review of the database has been completed and all 
critical queries have been resolved.
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5
SOFTWARE DOCUMENTATION
All summaries and statistical analyses, except for biomarker analysis, will be generated using 
SASp version 9.2 or higher. Biomarker analyses will be performed using R software version 3.3.2
(2016-10-31).
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6
REFERENCES
1. Palumbo A1, 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 Feb 20;32(6):587-600.
2. Kratz A, Ferraro M, Sluss P, Lewandrowski K. Laboratory reference values.
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7
LIST OF APPENDICES
Appendix A:
Generic ranges for hematological and biochemistry
Appendix B:
Definition of regions
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Appendix A: Generic ranges for hematological and biochemistry
Table 13 – Generic ranges for hematological parameters
Test
Gender
Unit
Lower limit of normal
Hemoglobin 
F 
g/L 
120 
Hemoglobin 
M 
g/L 
135 
Lymphocytes 
109/L 
1 
Neutrophils 
109/L 
1.8 
Platelets 
109/L 
150 
Leukocytes 
 
109/L 
4.5 
Eosinophils 
109/L 
0 
Basophils 
109/L 
0 
Monocytes 
109/L 
0.18 
Hematocrit 
M 
% 
0.41 
Hematocrit 
F 
% 
0.36 
Erythrocytes 
F 
1012/L 
4 
Erythrocytes 
M 
1012/L 
4.5 
INR 
 
ratio 
0.8 
Based on Kratz et al. (2) 
The current list of generic ranges for biochemistry parameters (for adults) is provided in the table 
below:
Table 14 – Generic ranges for biochemistry parameters
Test
Unit
Lower – Upper limit of normal
Albumin 
g/L 
35 - 55 
Blood Urea Nitrogen (BUN) 
mmol/L 
3.6 – 7.1 
Calcium 
mmol/L 
2.2 - 2.6 
Corrected calcium 
mmol/L 
2.2 – 2.6 
Glucose 
mmol/L 
3.9 - 7 
Bicarbonate (HCO3) 
mmol/L 
22 - 29 
Carbon dioxide 
mmol/L 
21 - 30 
Potassium 
mmol/L 
3.5 - 5 
Magnesium 
mmol/L 
0.8 - 1.2 
Sodium 
mmol/L 
136 - 145 
Phosphate 
mmol/L 
1 - 1.4 
Protein 
g/L 
55 - 80 
Urea 
mmol/L 
3.6 - 7.1 
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Appendix B: Definition of regions 
1) Geographical regions
Western Europe
North America
Other countries
Belgium
United States
Ukraine
Finland
Mexico
Turkey
Greece
Russian 
Federation
Italy
Argentina
Spain
Brazil
United Kingdom
Chile
Israel
Peru
2) Regulatory regions 
Western countries
Other countries
Belgium
Ukraine
Finland
Mexico
Greece
Turkey
Italy
Russian Federation
Spain
Argentina
United Kingdom
Brazil
United States
Chile
Israel
Peru
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