Clinical trial NCT03194867
Conditions: Plasma Cell Myeloma
Keywords: Anti-CD38 monoclonal antibody
Sponsor: Sanofi
Start date: 2018-02-21; Completion date: 2023-04-05
Enrollment: 109 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objectives:

* To evaluate the safety and tolerability of the combination of isatuximab (also known as SAR650984) and cemiplimab (also known as REGN2810) in patients with relapse/refractory multiple myeloma.
* To compare the overall response of the combination of isatuximab and cemiplimab versus isatuximab alone in patients with RRMM based on International Myeloma Working Group (IMWG) criteria.

Secondary Objectives:

* To evaluate the efficacy as assessed by clinical benefit rate (CBR), duration of response (DOR), time to response (TTR), progression free survival (PFS), and overall survival (OS).
* To assess the pharmacokinetics (PK) of isatuximab and cemiplimab when given in combination.
* To assess the immunogenicity of isatuximab and cemiplimab when given in combination.

Detailed description:
The duration of the study for a patient will include a period for screening of up to 21 days and 3-month post treatment follow up. The cycle duration is 28 days. Patients will continue treatment until disease progression, unacceptable adverse events, consent withdrawal, or any other reason.

Arms: arm 1: Isatuximab on Days 1, 8, 15, and 22, then Days 1 and 15 in 28-day cycles up to disease progression.

Cemiplimab on Days 1 and 15 in 28-day cycle up to disease progression. arm 2: Isatuximab on Days 1, 8, 15, and 22, then Days 1 and 15 in 28-day cycles up to disease progression.

Cemiplimab on Day 1 in 28-day cycle up to disease progression. arm 3: Isatuximab on Days 1, 8, 15 and 22, then Day 1 and 15 in 28-day cycles up to disease progression.
Interventions: intervention 1: Isatuximab SAR650984 intervention 2: Cemiplimab REGN2810
Intervention descriptions: intervention 1: Pharmaceutical form: solution for infusion

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

Route of administration: intravenous

Protocol documents:
Prot_000.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-002378 VERSION N°4.0 (04-FEB-2016) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL NO. 06 
COMPOUND: isatuximab/SAR650984 
A Phase 1/2 study to evaluate safety, pharmacokinetics and efficacy of 
isatuximab in combination with cemiplimab in patients with relapsed/refractory 
multiple myeloma 
STUDY NUMBER: TCD14906 
VERSION DATE / STATUS: 21-Mar-2022 / Approved 
Version Number: 
1 
EudraCT: 
IND Number(s): 
NCT:
WHO universal trial number: 
2017-001431-39 
133347 
NCT03194867
Not applicable 
Date: 
21-Mar-2022
Total number of pages: 
149 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
Document 
Country/Countries impacted 
by amendment 
Date, version 
Amended Protocol 06 
All 
21-Mar-2022, Version 1 (electronic 6.0) 
Amended Protocol 05 
All 
14-Aug-2020, Version 1 (electronic 5.0) 
Amended Protocol 04 
All 
11-Jun-2019, Version 1 (electronic 4.0) 
Amended Protocol 03 
All 
06-Aug-2018, Version 1 (electronic 3.0) 
Protocol Amendment 03 
All 
06-Aug-2018, Version 1 (electronic 1.0) 
Amended Protocol 02 
All 
17-Nov-2017, Version 1 (electronic 2.0) 
Protocol Amendment 02 
All 
17-Nov-2017, Version 1 (electronic 1.0) 
Amended Protocol 01 
All 
30-May-2017, Version 1 (electronic 1.0) 
Protocol Amendment 01 
All 
30-May-2017, Version 1 (electronic 1.0) 
Clinical Trial Protocol 
All 
12-Apr-2017, Version 1 (electronic 2.0) 
Amended protocol 06 (21 March 2022) 
This amended protocol (amendment 06) is considered to be non-substantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The study medication cemiplimab 250 mg, concentrated solution 50 mg/mL in 10 mL vials with 
5.0 mL withdrawable is no longer being produced by the manufacturer Regeneron. It is being 
replaced by cemiplimab 350 mg, concentrated 50 mg/mL in 10 mL vials with 7 mL withdrawable. 
However, the concentration remained the same (50 mg/mL); only the withdrawable amount is 
changed to 5.0 mL or 7.0 mL. The patient will continue to receive 5 mL (250 mg). 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical trial summary; Study 
Treatment(s) – Formulation – 
Cemiplimab;  
8.1.2.1 Pharmaceutical form 
The withdrawable amount of 
cemiplimab was changed to 5.0 mL 
or 7.0 mL. The 7.0 mL withdrawable 
was added.  
Cemiplimab 250 mg, concentrated solution 
50 mg/mL in 10 mL vials with 5.0 mL 
withdrawable is no longer produced by 
Regeneron and will be replaced by 
cemiplimab 350 mg, concentrated solution 
50 mg/mL in 10 mL vials with 7.0 mL 
withdrawable. However, the concentration 
remains same at 50 mg/mL; and the 
participant will continue to receive 5.0 mL. 
 
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NAMES AND ADDRESSES OF  
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
 
 
Company: 
Address: 
 
 
 
Tel: 
Fax: 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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CLINICAL TRIAL SUMMARY  
COMPOUND: isatuximab/ 
SAR650984 
STUDY No.: TCD14906 
TITLE 
A Phase 1/2 study to evaluate safety, pharmacokinetics and efficacy of isatuximab 
in combination with cemiplimab in patients with relapsed/refractory multiple 
myeloma  
INVESTIGATOR/TRIAL 
LOCATION 
Multiple sites & country 
PHASE OF DEVELOPMENT 
Phase 1/2 
STUDY OBJECTIVE(S)  
 
Primary objective(s): 
• 
To determine the safety and tolerability of the combination of isatuximab 
and cemiplimab.  
• 
To compare the overall response rate (ORR, defined as complete 
response [CR]+very good partial response [VGPR]+partial response 
[PR]) of the combination of Isatuximab and cemiplimab versus 
isatuximab alone in patients with RRMM based on International Myeloma 
Working Group (IMWG) criteria (Phase 2 only). 
Secondary objective(s): 
• 
To determine the following efficacy measurements (Phase 2 only): 
- 
Clinical benefit rate (CBR, CR + VGPR + PR + Minimal response 
[MR]),  
- 
Duration of response (DOR), 
- 
Time to response (TTR), 
- 
Progression free survival (PFS), 
- 
Overall survival (OS). 
• 
To determine pharmacokinetic profile of isatuximab and cemiplimab 
when given in combination. 
• 
To assess the immunogenicity of isatuximab and cemiplimab when given 
in combination. 
Exploratory Objectives: 
• 
To explore the minimal residual disease (MRD) in patients achieving a 
CR. 
• 
To assess the relationship between immune phenotypes, immune 
regulatory marker expression, adaptive immune response and 
parameters of clinical response. 
• 
To explore central/effector memory T cell proliferation. 
STUDY DESIGN 
This is Phase 1/2 study to evaluate the safety, tolerability, efficacy and 
pharmacokinetics (PK) of isatuximab in combination with cemiplimab in RRMM. 
The study will be conducted in 2 parts: 
• 
The Phase 1 (lead in) part is to confirm the feasibility of the 
isatuximab/cemiplimab combination.  
• 
The Phase 2 part will further evaluate the safety, efficacy and PK of the 
combination versus isatuximab monotherapy. Patients will be 
randomized in 1:1:1 in 3-arms or 1:1 in 2-arms study using an IRT. 
Isatuximab and cemiplimab are defined in this protocol as “study treatments”. 
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Phase 1 part: 
Given the promising early signs of anti-cancer activity and the acceptable safety 
profile of each of the two antibodies (no maximum tolerated dose [MTD] has been 
reached with either one as monotherapy), the starting dose will be 10 mg/kg once 
weekly (QW) for 4 weeks followed by once every 2 weeks (Q2W) for isatuximab 
and 250 mg Q2W for cemiplimab. Dose de-escalation will be performed if 
necessary as defined in the table below:  
Dose level (DL) 
Isatuximab 
Cemiplimab 
 
Dose level 1 (DL1) 
10 mg/kg  
QWx4 >Q2W 
250 mg 
Q2W 
 
Dose level -1 (DL-1) 
10 mg/kg  
QWx4 >Q2W 
250 mg 
Q4W 
 
Dose level -2 (DL-2) 
10 mg/kg  
Q2W 
250 mg 
Q4W 
Patients will continue treatment until disease progression, unacceptable adverse events, consent 
withdrawal, or any other reason. 
At dose level 1 (DL1), 3 patients will be enrolled for DLT evaluation (in Cycle 1):  
• 
If 0/3 patient has dose limiting toxicity (DLT), no more patients will be 
enrolled in Phase 1, and DL1 will be the recommended Phase 2 dose 
(RP2D). 
• 
If 1/3 patient has DLT at DL1, additional 3 patients will be enrolled at DL1 
for DLT assessment:  
- 
If a total of 1/6 patient treated at DL1 has DLT, DL1 will be the 
RP2D,  
- 
If a total of ≥2/6 patients have DLT at DL1, dose will be de-
escalated to dose level minus 1 (DL-1).  
• 
If ≥2/3 patients have DLT at DL1, dose will be de-escalated to dose level 
minus 1 (DL-1).  
At DL-1, the same DLT observation rule will be applied for selecting a RP2D and 
for dose de-escalation.  
At DL-2, the same DLT observation rule will be applied for selecting a RP2D, and if 
≥2/6 patients have DLT, study committee will analyze all the data collected up to 
this point and determine whether the study is to be terminated without proceeding 
to Phase II or if alternative doses and schedules could be further examined in 
Phase I, or changes in the study design could be made, based on the perceived 
benefit/risk to patients and on the PK results. 
The DLT observation period is 1 cycle (28 days). However, all adverse events (AE) 
during treatment unless due to disease progression or an obviously unrelated 
cause will be taken into consideration by the Study Committee for the 
determination of the MTD and RP2D. 
Enrollment of patients within and between cohorts is to be staggered by at least 
3 days. 
The NCI CTCAE version 4.03 will be used to assess the severity of AEs, causal 
relationship is to be determined by the investigator. The DLTs will be confirmed by 
the Study Committee. 
Hematologic DLT is defined as any of the followings unless due to disease 
progression or an obviously unrelated cause: 
• 
Grade 4 neutropenia lasting more than 7 consecutive days.  
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• 
Grade 3 to 4 neutropenia complicated by fever (temperature ≥38.5°C on 
more than one occasion) or microbiologically or radiographically 
documented infection. 
• 
Grade 3 to 4 thrombocytopenia associated with clinically significant 
bleeding requiring clinical intervention. Note: Platelet transfusions in the 
absence of bleeding will not be considered a DLT because 
thrombocytopenia is an anticipated complication of multiple myeloma 
(MM), particularly in a heavily pretreated patient population, and patients 
can enter the study with pre-existing thrombocytopenia. 
Non-hematologic DLT is defined as any of the followings unless due to disease 
progression or an obviously unrelated cause: 
• 
Grade 4 non-hematologic AE. 
• 
Grade ≥2 uveitis. 
• 
Grade 3 non-hematological AE lasting >3 days despite optimal 
supportive care. except: 
- 
Grade 3 fatigue, 
- 
Allergic reaction/hypersensitivity attributed to isatuximab or 
cemiplimab, 
- 
Grade 3 or 4 lab abnormality that is not clinically significant per 
investigator and study committee. 
• 
Delay in initiation of Cycle 2 more than14 days due to treatment related 
laboratory abnormalities/AE. 
In addition, any other AE that the investigator / Study Committee deem to be dose 
limiting, regardless of its grade, may also be considered as DLT. 
Phase 2 part: 
Phase 2 will have 3 arms (if the MTD or RP2D is at DL1 or DL-1) or 2 arms (if the 
MTD or RP2D is at DL-2) to assess the treatment response and safety of the 
combination therapy compared with isatuximab alone. After confirmation of 
eligibility criteria, patients will be randomly assigned using an interactive response 
technology (IRT), in a 1:1:1 ratio or 1:1 ratio in 1 of the 3- or 2-arm study, 
respectively, with 35 patients in each arms.  
If RP2D is DL1: 
• 
Arm 1 (control): isatuximab 10 mg/kg QWx4 followed by Q2W.  
• 
Arm 2 (DL1): isatuximab 10 mg/kg QWx4 followed by Q2W + cemiplimab 
250 mg Q2W. 
• 
Arm 3 (DL-1): isatuximab 10 mg/kg QWx4 followed by Q2W + 
cemiplimab 250 mg Q4W. 
If RP2D is DL-1:  
• 
Arm 1 (control): isatuximab 10 mg/kg QWx4 followed by Q2W.  
• 
Arm 2 (DL-1): isatuximab 10 mg/kg QWx4 followed by Q2W + 
cemiplimab 250 mg Q4W. 
• 
Arm 3 (DL-2): isatuximab 10 mg/kg Q2W + cemiplimab 250 mg Q4W. 
If RP2D is DL-2:  
• 
Arm 1 (control): isatuximab 10 mg/kg QWx4 followed by Q2W.  
• 
Arm 2 (DL-2): isatuximab 10 mg/kg Q2W + cemiplimab 250 mg Q4W. 
Anti-CD38 refractory cohort: 
Patients who received anti-CD38 mAb within 6 months before study entry and had 
disease progression while on treatment or within 60 days after the last treatment 
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will be enrolled in a separate cohort. A decision will be made to start the cohort 
after the planned Phase 2 interim analysis suggested a treatment benefit of the 
combination therapy including pass the futility check. The dose and schedule will 
be determined based on the efficacy and safety findings in the interim analysis.  
STUDY POPULATION  
 
Main selection criteria: 
Inclusion criteria: 
I 01. 
Age ≥18. 
I 02. 
Patients must have a known diagnosis of multiple myeloma with evidence 
of measurable disease, as defined below: 
- 
Serum M-protein ≥1 g/dL (≥0.5 g/dL in case of IgA disease),  
AND/OR 
- 
Urine M-protein ≥200 mg/24 hours, 
OR 
- 
In the absence of measurable M-protein, serum immunoglobulin 
free light chain ≥10 mg/dL, and abnormal serum immunoglobulin 
kappa lambda free light chain ratio (<0.26 or >1.65). 
I 03. 
Patients must have received prior treatment with an immunomodulatory 
drug (IMiD) (for ≥2 cycles or ≥2 months of treatment) and a proteasome 
inhibitor (PI) (for ≥2 cycles or ≥2 months of treatment). 
I 04. 
Patients must have received at least 3 prior lines of therapy (Note: 
Induction therapy and stem cell transplant ± maintenance will be 
considered as one line).  
I 05. 
Patients must have achieved MR or better with any anti-myeloma therapy 
(ie, primary refractory disease is not eligible). 
I 06. 
Patients understand and have signed the Written Informed Consent form 
and are willing and able to comply with the requirements of the study. 
I 07. 
Anti-CD38 refractory cohort only: Patients who received anti-CD38 mAb 
within 6 months before study entry and had disease progression while on 
treatment or within 60 days after the last treatment. 
Exclusion criteria: 
E 01. 
Has any concurrent hematologic malignancy other than multiple 
myeloma, including: 
- 
Active primary amyloid light-chain (AL) amyloidosis, 
- 
Concomitant plasma cell leukemia. 
E 02. 
 Has prior exposure to: 
- 
Isatuximab or participated clinical studies with isatuximab, 
- 
Any agent (approved or investigational) that blocks the PD-1/PD-L1 
pathway. 
E 03. 
Diagnosed or treated for another malignancy within 3 years prior to the 
study treatment with the exception of resected/ablated basal or 
squamous cell carcinoma of the skin, or carcinoma in situ of the cervix, or 
other local tumors considered cured by local treatment, or low risk 
prostate cancer after curative therapy. 
E 04. 
Evidence of other immune related disease /conditions, including: 
- 
Ongoing or recent (within 2 years) evidence of significant 
autoimmune disease that required systemic immunosuppressive 
treatment (ie, with use of disease modifying agents, corticosteroids 
or immunosuppressive drugs). Replacement therapy (eg, thyroxine, 
insulin, or physiologic corticosteroid replacement therapy for adrenal 
or pituitary insufficiency, etc) is not considered a form of systemic 
treatment, 
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- 
History of moderate immune-mediated acute drug reactions 
(eg, colitis, hepatitis, etc). 
E 05. 
History of non-infectious pneumonitis requiring steroids or current 
pneumonitis; history of the thoracic radiation.  
E 06. 
Has received a live-virus vaccination within 30 days of planned treatment 
start. Seasonal flu vaccines that do not contain live virus are permitted.  
E 07. 
Known to be HIV+, HBV+ or hepatitis A, B, or C active Infection, or active 
tuberculosis, or severe and active infection requiring systemic antibiotics, 
antivirals or antifungals within 2 weeks prior to first dose (except when 
used for chronic prophylaxis). 
E 08. 
Has allogenic haemopoietic stem cell (HSC) transplant. 
E 09. 
Has prior exposure to treatments, including: 
- 
Prior treatment with idelalisib (an PI3K inhibitor), 
- 
Any anti-myeloma drug treatment including dexamethasone within 
14 days before study entry (90 days if prior anti-CD38 treatment), 
- 
Patients who received anti-CD38 mAb within 6 months before study 
entry and had disease progression while on treatment or within 
60 days after the last treatment will be excluded except the anti-
CD38 refractory cohort, 
- 
Any major procedure within 14 days before the first study treatment: 
plasmapheresis, major surgery (kyphoplasty is not considered major 
procedure), radiotherapy (palliative radiotherapy may be given to 
control pain), 
- 
Any investigational drugs within 28 days or 5 half-lives from the 
first study treatment, whichever is longer. 
E 10. 
Congestive heart failure (New York Heart Association class III to IV), 
myocardial infarction within 6 months or with reduced ejection fraction, 
symptomatic coronary artery disease, major clinically significant 
electrocardiogram (ECG) and echocardiogram abnormalities, significant 
ventricular arrhythmias;  
E 11. 
Ongoing Grade ≥2 adverse events (excluding alopecia and those listed in 
eligibility criteria) from any prior anti-cancer therapy (NCI-CTC v4.03). 
E 12. 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 
>2. 
E 13. 
Inadequate hematological function including: 
- 
Platelets <50,000/mm3. Patient should be platelet transfusion 
independent for 2 weeks prior to screening lab values), 
- 
Absolute neutrophil count (ANC) ≤1000/mm3 (1 x 109/L). (use of 
colony-stimulating factors to achieve these counts is allowed), 
- 
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 guidance). 
E 14. 
Inadequate liver function including: 
- 
Total bilirubin >2 times of the upper limit of the normal range (ULN), 
- 
AST and/or ALT >3 x ULN. 
E 15. 
Inadequate renal function: estimated glomerular filtration rate (eGFR)  
<30 mL/min/1.73m2 (Modified Diet in Renal Disease [MDRD] Formula). 
E 16. 
Corrected serum calcium >14 mg/dl (>3.5 mmol/L). 
E 17. 
Pregnant or breastfeeding female patients. 
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E 18. 
Women of childbearing potential and male subjects with female partners 
of childbearing potential who are not willing to avoid pregnancy by using 
effective contraceptive (prior to initial dose, during the course of study 
and up to 6 months after the last study treatment. See Appendix J for 
guidance of the contraceptive and collection of pregnancy information.  
E 19. 
Known intolerance or hypersensitivity to any component of isatuximab 
and/or cemiplimab. 
E 20. 
Employees of the clinical study site or any other individuals directly 
involved in the conduct of the study, or immediate family members of 
such individuals. 
 
E 21. 
Patients who are accommodated in an institution because of regulatory or 
legal order, or prisoners or subjects who are legally institutionalized, or 
patients with any severe acute or chronic medical condition, including 
psychological disorder, which could impair the ability of the patient to 
participate in the study or interfere with interpretation of study results or 
patient unable to comply with the study procedures. 
Total expected number of 
patients: 
Approximately 108 to 138 patients 
Expected number of sites: 
Approximately 37 
STUDY TREATMENT(s) 
 
Investigational medicinal 
product(s)  
Isatuximab 
Cemiplimab 
Formulation: 
Isatuximab (also known as SAR650984): drug product concentrated solution for 
infusion in vials containing 20 mg/mL (500 mg/25 mL) isatuximab in 20 mM 
histidine, 10% (w/v) sucrose, 0.02% (w/v) polysorbate 80, pH 6.0. 
Cemiplimab (also known as REGN2810): drug product concentrated solution 
50 mg/mL in 10 mL vials with 5.0 mL or 7.0 mL withdrawable, containing 10 mM 
histidine, 5% (w/v) sucrose, 1.5% (w/v) L-proline, and 0.2% (w/v) polysorbate 80, 
pH 6.0. 
Route(s) of administration: 
Isatuximab: IV infusion 
Cemiplimab: IV infusion 
Dose regimen: 
Isatuximab:  
• 
For isatuximab alone as control, and at DL1 and DL-1: 10 mg/kg QW for 
4 weeks followed by Q2W (ie, on Days 1, 8, 15 and 22 in Cycle 1, and on 
Days 1 and 15 in Cycle 2 and beyond, of a 28-day cycle). 
• 
For DL-2: 10 mg/kg Q2W (ie, on Days 1 and 15 every cycle, of a 28-day 
cycle). 
Cemiplimab:  
• 
For DL1: 250 mg Q2W (ie, on Days 1 and 15 in all cycles of a 28-day 
cycle). 
• 
For DL-1 and DL-2: 250 mg Q4W (ie, on Day 1 all cycles of a 28-day 
cycle) 
When patients receive combination therapy, cemiplimab will be administered 
first followed by Isatuximab. 
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Non investigational medicinal 
product(s)  
 
All patients will receive following pre-medications to prevent or reduce infusion 
associated reactions, 30 to 60 minutes prior to the start of isatuximab infusion. 
Patients who do not experience an IAR during the first 4 administrations of 
isatuximab may have the need for subsequent pre-medication reconsidered at the 
investigator’s discretion in consultation with the sponsor. 
• 
Acetaminophen 650 to 1000 mg oral route (PO) (or equivalent). 
• 
Ranitidine 50 mg IV (or equivalent). 
• 
Diphenhydramine 25-50 mg IV (or equivalent). 
• 
Methylprednisolone 100 mg IV (or equivalent). 
Formulation: 
(Non-investigational products will be locally sourced and formulations may vary). 
Route(s) of administration: 
See above 
Dose Time: 
 
Dosing sequence: 
Pre-medications will be administered 30 to 60 minutes prior to isatuximab infusion. 
 
On Days 1 and 15 of each cycle, the administration sequence is: pre-medications 
followed by cemiplimab followed by isatuximab. 
On Days 8 and 22 of Cycle 1, the administration sequence is: pre-medications 
followed by isatuximab. 
ENDPOINT(S) 
Primary endpoint: 
Safety evaluation will be performed continuously throughout the study period and 
will include the following: 
• 
DLTs at Cycle 1 (Phase 1 part only). 
• 
Vital signs and physical exam. 
• 
Adverse event evaluation (throughout study) including immune related 
AEs. Severity grade will be determined according to the NCI CTCAE 
v4.03. 
• 
Laboratory tests in blood and urine. 
• 
Cytokines (TNF-α, IL-1-β, IL-6, IFN-γ), markers of complement (C3a, C4, 
CH50), LDH, serum tryptase. 
• 
Efficacy is the co-primary endpoint (Phase 2 part only) and will be 
assessed by ORR.  
• 
ORR: defined as the proportion of patients with CR (including stringent 
complete response [sCR]), VGPR, and PR as assessed by investigators 
using the IMWG response criteria. 
Secondary endpoint(s) (efficacy endpoints including CBR, DOR, TTR, PFS 
and OS apply to Phase 2 part only): 
• 
CBR: defined as the proportion of patients with CR (including sCR), 
VGPR, PR and minimal response (MR) as assessed by investigators 
using the IMWG response criteria. 
• 
DOR: defined as the time from the date of the first response (≥PR) that is 
subsequently confirmed to the date of first confirmed disease 
progression or death, whichever happens first. Disease progression will 
be determined according to IMWG criteria. Progression determined by 
M-protein or free light chain will be confirmed based on two consecutive 
assessments. In the absence of the confirmation of subsequent disease 
progression or death before the analysis cut-off date or the date of 
initiation of a further anticancer treatment, the DOR will be censored at 
the date of the last valid disease assessment not showing disease 
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progression performed prior to initiation of a further anticancer treatment 
and the analysis cut-off date, whichever is earlier. DOR will not be 
calculated for patients that do not achieve a PR or better. 
• 
TTR: defined as time from first study treatment administration (Cycle 1, 
Day 1) to first response (PR or better) that is subsequently confirmed. 
• 
PFS: defined as time from the first study treatment administration to the 
date of first documentation of disease progression that is subsequently 
confirmed or the date of death from any cause. Same censoring rules as 
DOR will be used.  
• 
OS: defined as the time from the first study treatment administration to 
death from any cause. Patients without death prior to the analysis cutoff 
date will be censored at the last date the patient was known to be alive or 
the cutoff date whichever comes first. 
 
• 
Immunogenicity of isatuximab and cemiplimab will be assessed before 
treatment, during treatment and at follow-up visits. 
• 
PK evaluation: for both isatuximab and cemiplimab, blood samples will 
be collected at selected time points in all patients treated in order to 
assess the PK profile of isatuximab and cemiplimab. Cemiplimab will be 
measured in serum and isatuximab in plasma. PK parameters for 
both compounds will be calculated using non-compartmental analysis. 
Exploratory endpoints: 
• 
MRD assessment in bone marrow in CR patients, as clinically indicated. 
• 
Immunophenotype (such as NK, T, MDSC cells, Treg/CD8 effector ratio) 
in blood and bone marrow, as well as immune regulatory marker  
(eg, PD1, PD-L1) expression on immune cell subsets will be analyzed 
and correlated with clinical response. 
• 
Whenever possible, genomic and protein expression of selected markers 
(including PD-L1) in malignant plasma and immune cells will be 
determined by IHC and RNA-specific assays in baseline bone marrow 
biopsy, optional C3 and EOT biopsy samples and correlated with clinical 
response. 
• 
The change in proliferative activity of effector / memory T cell subsets in 
response to treatment will be assessed by Ki67 flow cytometry assay in 
blood and any available bone marrow samples. 
• 
The T cell receptor sequence clonality in blood and bone marrow at 
baseline and any available on-treatment samples will be determined by 
TCR-beta sequencing assay and correlated with clinical response. 
• 
Humoral and cellular immune responses to myeloma-related tumor 
antigens will be analyzed in blood and correlated with clinical response. 
• 
Explore exposure-response relationships for efficacy, safety, and 
biomarkers for the combination. 
ASSESSMENT SCHEDULE 
Please see Section 1.1 Study Flowchart and Section 1.2 PK/PD. 
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STATISTICAL 
CONSIDERATIONS 
 
Sample size determination: 
In Phase 1, the actual sample size is expected to vary depending on DLTs 
observed and number of dose levels explored. The study will follow a standard 3+3 
design and 3 to 18 patients might be enrolled. 
In Phase 2, assuming ORR = 20% in control arm (isa alone arm) and ORR = 50% 
in combination arms, using Fisher’s exact test to compare the ORR in control vs 
combination arms, given the 1-sided type I error of 5% for each combination arm), 
35 patients per arm is required to achieve 79% power for each combination arm). 
Therefore a maximum number of 105 patients is required in Phase 2 randomization 
part.  
A separate anti-CD38 refractory cohort with 15 patients might be enrolled if a 
treatment benefit is suggested for the combination therapy at the interim analysis 
including pass the futility check. Assuming ORR =20% or more in the combination 
therapy, a size of 15 patients is required to test against a null hypothesis of 
ORR ≤1% (ie, no activity in the Isa alone arm) with a one-sided α of 0.05 and 
82% power.  
Including both Phase 1 and Phase 2 patient, a total of 108 to 138 patients are 
required. 
Main Analysis populations: 
Phase 1 and Phase 2 patients will be analyzed separately. For Phase 1, the 
all-treated (or safety) population will include all screened patients who received at 
least 1 dose (even incomplete) of study treatments. For Phase 2, the all treated (or 
safety) population will include all randomized patients who received at least 1 dose 
(even incomplete) of study treatments. This population is the primary population for 
the analyses of exposure and safety parameters.  
For Phase 2 patients only, the intent to treat ( ITT, or randomized) population 
include all patients with a signed informed consent form who have been allocated a 
randomization number by the IRT, regardless of whether the patient was treated or 
not. This population is the primary population for the analyses of efficacy 
parameters. 
The PK population will include patients from the treated/safety population with at 
least one drug concentration after study drug administration (whatever the cycle 
and even if dosing is incomplete). 
The anti-drug antibody (ADA, immunogenicity) population will include all patients 
from the all-treated/safety population with at least 1 available ADA result after the 
study drug administration. 
Primary endpoints: 
A listing of patients with DLTs will be provided for Phase 1 patients.  
For Phase 1 and Phase 2 patients separately, number (%) of patients experiencing 
treatment- emergent AEs (TEAE) by primary system organ class and preferred 
term will be summarized by CTCAE grade (all grades and Grade ≥3) for the all-
treated population. Same table will be prepared for drug related TEAEs, infusion 
associated reactions, TEAEs leading to treatment discontinuation, serious TEAEs 
and TEAEs with fatal outcome. For patients with multiple occurrences of the same 
AE within the TEAE period, the worst grade will be used. In addition, adverse 
events occurring or worsening during the ‘extended safety follow-up period’ 
(defined as the time period from 31days after the last dose of study treatments to 
90 days after the last dose of study treatments) will also be summarized. 
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 and Grade ≥3) using the worst grade during the on-
treatment period will be provided for the safety population. 
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For Phase 2 patients only, ORR will be summarized with descriptive statistics. 
Confidence interval will be computed using Clopper-Pearson method. The Fisher’s 
exact test will be performed to compare the ORR in control arm vs each of the 
combination arm, using a 1-sided significance level of 0.10 with Hochberg 
adjustment (at time of primary analysis of ORR; ie, cutoff date 6 months after 
last patient in). 
Analysis of secondary endpoints: 
For Phase 2 patients only, the analysis of CBR will be similar to that described for 
ORR. The DOR, PFS and OS will be analyzed using Kaplan-Meier methods. 
Pharmacokinetics:  
Descriptive statistics on concentrations and PK parameters will be provided for 
both isatuximab and cemiplimab. 
Analysis cutoff: 
Cutoff date for primary analysis of ORR will be 6 months after last patient 
first treatment. 
The final analysis cutoff date for OS analysis and updated analysis of ORR and 
other secondary endpoints will be approximately 12 months after last patient 
first treatment. 
 
Interim analysis: 
For Phase 2, an interim analysis of response rate (including confirmed and 
unconfirmed responses) will be conducted when the first 15 randomized patients in 
each arm have completed 2 cycles of treatment or permanently discontinue the 
treatment. A combination arm will be stopped early for futility when the conditional 
power is less than 30%. 
In addition, formal safety review by DMC are planned approximately every 
3 months to review data relating patient safety and quality of trial conduct. 
DURATION OF STUDY PERIOD 
(per patient) 
The duration of the study for a patient will include a period for screening of up to 
21 days. The cycle duration is 28 days. Patients will continue treatment until 
disease progression, unacceptable adverse events, consent withdrawal, or any 
other reason. 
After treatment discontinuation, patients will return to the study site 30 days 
(+5 days) after the last dose of study treatments for end-of-treatment assessments. 
The post-treatment follow-up period includes an extended safety follow-up period 
of 90 days after the last dose of study treatment, and further follow-up beyond 
90 days after last treatment until death or final study cut-off date, whichever occurs 
first. 
The further follow up schedule beyond 90 days after last treatment is according to 
the disease progression status:  
Patients who discontinue study treatment due to disease progression: follow-up 
visit will be done every 3 months from the date of last study treatment 
administration until death or final study cut-off date.  
Patients who discontinue the study treatment without disease progression: will be 
followed every month for disease assessment until confirmation of disease 
progression or start treatment with another anti-cancer therapy whichever comes 
first. After disease progression patient will be followed every 3 months as 
described just above until death or final study cut-off date. 
 
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1 
FLOW CHARTS  
1.1 STUDY FLOWCHART  
Evaluationa 
Screening/ 
Baseline 
Cycle 1b 
Subsequent 
Cyclesb 
End of 
Treatment 
(EOT)  
Post treatment 
Follow-up Periodjj 
D-21 to D1 
D1 
D8 
D15 
D22 
D1 
D15 
30 days after 
last IMP 
admin  
At 60 days 
after last IMP 
admin 
At 90 days 
after last 
IMP admin 
Beyond 
90 days after 
last IMP 
admin  
Informed Consent / Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Demography, Medical/Surgical and Disease Historyc 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examinationd 
X(within 7 days prior to 
first dose) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight / Height(at baseline only)e  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vital Signsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Performance Status (ECOG) 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
12-Lead ECGg  
X 
 
 
 
 
 
 
 
 
 
 
Chest X-rayh 
X 
 
 
 
 
 
 
 
 
 
 
Laboratory Assessments: 
Pregnancy Testi  
X (within 7 days prior to 
first dose) 
 
 
 
 
X 
 
X 
X 
X 
X 
Hepatitis B virus (HBV) serology 
 
Xkk 
 
 
 
 
Blood Chemistryj 
X 
Xl 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematologyk 
X 
Xl 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulationm 
X 
As clinically indicated 
 
 
 
 
Urinalysisn 
X 
Xl 
 
X 
 
X 
X 
X 
X 
X 
 
Isatuximab/cemiplimab IAR Labso 
 
Prior C1D1 then if IAR ≥G2  
 
 
 
 
Markers of potential TLSp 
 
As clinically indicated 
 
 
 
 
Serum β2-microglobulinq 
X 
 
 
 
 
X 
 
X 
 
 
 
Immunoglobulins: IgG, IgA, IgD, IgE, IgMq 
X 
 
 
 
 
X 
 
X 
X 
X 
 
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Evaluationa 
Screening/ 
Baseline 
Cycle 1b 
Subsequent 
Cyclesb 
End of 
Treatment 
(EOT)  
Post treatment 
Follow-up Periodjj 
D-21 to D1 
D1 
D8 
D15 
D22 
D1 
D15 
30 days after 
last IMP 
admin  
At 60 days 
after last IMP 
admin 
At 90 days 
after last 
IMP admin 
Beyond 
90 days after 
last IMP 
admin  
Blood typing interference test r 
X 
 
 
 
 
C2 only 
 
 
 
 
 
PKs 
See PK/PD Flow-Chart 
ADAt 
See PK/PD Flow-Chart 
Adaptive immune response (including TCR repertoire) 
(blood and bone marrow aspirate)u 
X 
 
 
 
 
C3 (blood 
only) and 
in case of 
CR 
 
 
 
 
 
Adaptive immune response (humoral and cellular 
response) (Blood)v 
 
X 
 
 
 
C2, 
C4,C7,C10 
 
X 
 
 
 
Immunophenotyping (Blood and bone marrow aspirate)w 
X 
 
 
 
 
 C3  
 
X (Blood only) 
 
 
 
FISH (bone marrow aspirate)x 
X 
 
 
 
 
 
 
 
 
 
 
PD1-PDL1 expression (Bone marrow biopsy y 
X 
 
 
 
 
C3 
 
X 
 
 
 
MRD assessment (bone marrow aspirate) 
X 
In case of CR 
 
 
 
 
Disease Assessmentz 
 
 
 
 
 
 
 
 
 
 
 
- 
Serum M-Proteinaa 
X 
Xl 
 
 
 
X 
 
X 
Xdd 
 
- 
sFLCbb 
X 
Xl 
 
 
 
X 
 
X 
Xdd 
 
- 
Urine M-Protein (24-hr urine)cc 
X 
Xl 
 
 
 
X 
 
X 
Xdd 
 
- 
Bone Marrow for disease 
assessmentee 
X 
to confirm CR and as clinically indicated 
X (if clinically 
indicated) 
X (if clinically indicated)dd  
 
- 
Bone disease assessment 
(Skeletal survey or low-dose 
whole body CT)ff 
X  
 
 
 
 
X (if 
clinically 
indicated) 
 
X (if clinically 
indicated) 
X (if clinically indicated)dd 
 
- 
Plasmacytoma assessment 
(PET/CT/MRI)gg 
X  
 
 
 
 
X (if 
clinically 
indicated) 
 
X (if clinically 
indicated) 
X (if clinically indicated)dd 
 
Isatuximab Administrationhh 
 
X 
X 
X 
X 
X 
X 
 
 
 
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Evaluationa 
Screening/ 
Baseline 
Cycle 1b 
Subsequent 
Cyclesb 
End of 
Treatment 
(EOT)  
Post treatment 
Follow-up Periodjj 
D-21 to D1 
D1 
D8 
D15 
D22 
D1 
D15 
30 days after 
last IMP 
admin  
At 60 days 
after last IMP 
admin 
At 90 days 
after last 
IMP admin 
Beyond 
90 days after 
last IMP 
admin  
Cemiplimab Administration 
 
X 
 
X 
 
X 
X 
 
 
 
AE/SAE Assessmentii 
X 
Continuously throughout study period 
X (ongoing related AE, ongoing SAE, new related 
AE/SAEs) 
Prior/Concomitant Medication 
X (within 21 days prior to 
first dose) 
Continuously throughout study period 
X (related to AE/SAEs) 
- 
New anticancer therapy 
 
 
X 
X 
a Evaluation: Assessments to be performed prior to study treatment and prior to premedication administration unless otherwise indicated. Inform consent should be signed before any study specific procedures. In 
Phase 2 part, randomization to take place once the consented patient has completed all the necessary screening procedures and is deemed eligible for study entry by the Investigator or designee. All eligible 
patients must be randomized using Interactive Response Technology (IRT). Every effort should be made to start treatment within 3 working days of randomization. 
b Cycle: A cycle is 28 days. The treatment window is ±1 day for each of the weekly administrations ±2 day for each of the Q2W administrations and ±4 day for each of the Q4W administrations. A dose is deemed 
to have been delayed if the treatment is ≥2 days beyond the theoretical day of treatment for weekly dose, ≥3 days beyond the theoretical day of treatment for Q2W dose and ≥5 days beyond the theoretical day of 
treatment for Q4W dose. The reason for dose delay will be captured. Cycle 1 Day 1 refers to the day the patient receives the first study treatment administration. 
c Demography: Includes age, gender and race. Medical/Surgical History: Includes relevant history of previous/associated pathologies, other than multiple myeloma including respiratory function history, and 
smoking status. Disease History: Includes date of initial diagnosis, subtype, stage and previous anti-MM therapy (type, duration, reason for discontinuation and response to). 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. If not previously performed, blood type, phenotype or genotype and 
screen should be done prior to first study treatment administration. The transfusion service should be made aware that the patient is receiving an anti-CD38 treatment (isatuximab). During the study treatment 
period the transfusion service should follow the recommendations issued in the AABB bulletin in case a blood red cells transfusion is needed. The web link to the AABB bulletin will be indicated on the study 
patient card (see Appendix I). Patients should keep together their study patient card with their blood type card throughout the duration of the study treatment. 
d Physical Examination: To be performed at screening (<7 days prior to first dose), 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 
cycle,at the EOT visit and post treatment follow up visits at 60 and 90 days after last treatment Consists of examination of major body systems, including neurological, digestive exam, respiratory (signs and 
symptoms, respiratory rate), hepatic and spleen span, lymph node examination. Only main diagnoses will be reported in the eCRF as AEs or medical history. Signs and symptoms related to multiple myeloma 
ongoing at baseline will be recorded in medical history and will be reported in AE page in case they worsen or become serious during study treatment. Laboratory abnormalities at baseline will be recorded in 
laboratory pages. 
e Weight / Height: Height is required at baseline only. Weight is required at Screening, prior to starting infusion and at the EOT visit. 
f 
Vital Signs: Blood pressure, heart rate, temperature, and respiration rate required at Screening, to be taken just before starting infusion, every hour during the infusion, and at the end of infusion on D1, D8, D15 
and D22 of Cycle 1; and to be taken just before starting infusion at D1 and D15 of each subsequent cycle and as clinically indicated, at the EOT visit, and at post treatment follow up visits at 60 and 90 days after 
last treatment. 
g 12-Lead ECG: To be performed at Screening and then as clinically indicated. 
h Chest X-ray: To be performed at Screening and then as clinically indicated.  
i 
Pregnancy Test: Women of child bearing potential must have a negative serum pregnancy test result within 7 days prior to first IMP administration. During the study, test to be done on Day1 of each cycle prior to 
the study treatment, at the end of treatment, and then every month for 5 months following the last dose of Isatuximab or 6 months following the last dose of cemiplimab, whichever comes last (urine pregnancy test 
can be performed at home after study treatment discontinuation).  
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j 
Blood Chemistry: To be done at Screening, then prior to pre-medication and IMP administration on D1, D8, D15 and D22 of Cycle 1 and on D1 and D15 of every subsequent cycle, at the EOT visit, 60 and 
90 days after last treatment 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, urea or blood urea nitrogen (BUN), serum creatinine, eGFR(MDRD formula), glucose (fasting), albumin 
and total protein. Thyroid stimulating hormone (TSH) will be assessed every second cycle, and free T4 if TSH is outside of the normal range. 
k Hematology: To be done at Screening, then prior to pre-medication and IMP administration on D1, D8, D15 and D22 of Cycle 1 and D1 and D15 of every subsequent cycle, at the EOT visit, 60 and 90 days after 
last treatment and as clinically indicated. Hematology includes: Hemoglobin, hematocrit, RBC, WBC with differential, 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. Blood group card to be obtained before study entry. 
l 
Blood chemistry, hematology, urinalysis and efficacy labs assessments are not required to be repeated prior to D1 Cycle 1 if the screening labs were performed within 3 days prior to first IMP administration. 
m 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). 
n Urinalysis: Quantitative urinalysis ( includes Na, K, Ca, Cl, RBC, protein, glucose, pH, ketones, bilirubin, leucocytes, nitrates and specific gravity) to be done at baseline, EOT, 60 and 90 days after last treatment 
and during the treatment period if hematuria is observed or clinically indicated – Dipstick (qualitative) will be performed on D1 and D15 of each new cycle. 
o 
Isatuximab/Cemiplimab IAR Labs: include cytokines (TNF- α, IL-1-β, , IL-6, and IFN-γ), markers of complement activation (C3a, C4, CH50) and serum tryptase, lactate dehydrogenase [LDH]. Baseline sample 
to be drawn prior to first isatuximab administration at Cycle 1. Then if an isatuximab infusion associated reaction (IAR) of ≥Grade 2 occurs, additional blood sampling during the AE is required for analysis.  
p 
Markers of potential TLS: to be done in case of suspicion of TLS (uric acid, BUN/creatinine, potassium, phosphate, calcium and corrected calcium).  
q 
Serum β2-microglobulin and Immunoglobulins (IgG, IgA, IgM, IgD and IgE): To be performed at Screening, D1 of each cycle starting from Cycle 2, and at the EOT visit. After EOT, during the follow up visits, 
Immunoglobulins to be performed only in patients discontinued study without disease progression and have not started new anti-cancer treatment (IgD or E only if the heavy chain component of the disease is 
known to be E or D). 
r 
Blood typing interference test: at screening: blood type (if not already done) and phenotype (according to the site protocol). Recommended phenotype include Rh system (C/c and E/e), Kell system (K/k); Duffy 
system (Fya/Fyb); kidd system (Jka/Jkb); MNS system (M/N, S/s), and Indirect Antiglobuline Test (IAT, indirect Coombs test). On Cycle 2 Day 1 and before each transfusion: Indirect Antiglobuline Test (IAT, 
indirect Coombs test or Antibody screen). Blood type card will be kept by the patient with the study card. Blood transfusions are to be recorded in the eCRF. The blood bank needs to be informed that the patient is 
receiving a treatment with an anti-CD38 and a potential interference with the Coombs test is possible. 
s 
Pharmacokinetics (PK): isatuximab and cemiplimab. See PK/PD flow chart. 
t 
ADA (Anti-Drug Antibodies): isatuximab and cemiplimab. See PK/PD flow chart. 
u Adaptive immune response (including TCR repertoire assessment) (Blood and bone marrow): To be performed at screening, and D1 of Cycle 3 prior to IP administration (blood only) and in case of 
CR. 
v Adaptive immune response (humoral and cellular response) (Blood) : To be performed prior to pre-medication and IMP administration on D1 of Cycle 1, Cycle 2, Cycle 4, Cycle 7 and Cycle 10 and in disease 
progression patients at EOT. Humoral response will be assessed in allsites. Cellular response will be assessed in patients at selected sites. 
w Immunophenotyping (Bone marrow aspirate and blood): To be performed at screening, D1 of Cycle 3 prior to IP administration and at the EOT visit (blood only).  
x FISH: Bone marrow aspirate: to be performed at screening. 
y PD1-PDL1 expression (Bone marrow biopsy): Access to archival bone marrow biopsy material will be requested at screening and if available, retrospective expression analysis will be performed by IHC. For any 
patients that have bone marrow biopsy available at baseline, there will be optional biopsies performed at pre-dose on Day 1 of Cycle 3 and at the EOT visit. 
z Disease Assessment: All lab tests include M-protein quantification (serum and 24-hour urine, immunoelectrophoresis, and immunofixation) and serum free light chain levels should be repeated on C1D1 if not 
performed within 3 days prior to first IMP administration, and all radiologic assessments to be performed within 21 days prior to first IMP administration. Response is assessed on the basis of clinical and laboratory 
findings on D1 of every cycle (starting C2, prior to IMP administration), whenever disease progression is suspected (eg, symptomatic deterioration) and at the EOT visit. The availability of the results must not 
prevent the initiation of the next cycle. 
aa Serum M-Protein: To be performed at Screening, D1 of every cycle prior to IMP administration (not required to be repeated at Cycle 1 if screening labs were performed within 3 days prior to first IMP 
administration), and at the EOT visit. Immunofixation to be performed at baseline and required after treatment due to disappearance of the M component in the electrophoresis. 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). 
bb sFLC: To be performed at Screening, D1 of every cycle prior to IMP administration (not required to be repeated at Cycle 1 if screening labs were performed within 3 days prior to first IMP administration), and at 
the EOT visit. 
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cc Urine M-Protein (24-hr urine): 24-hour urine collection for Bence Jones protein with urine electrophoresis at Screening, D1 of every cycle prior to IMP administration (not required to be repeated at Cycle 1 if 
screening labs were performed within 3 days prior to first IMP administration), and at the EOT visit. Urine immunofixation to be performed in this 24 hours urine at baseline and if required due to disappearance of 
the M component in the electrophoresis. If negative at baseline, to be repeated every 3 months and to confirm response or PD. 
dd Disease assessments during follow-up period are only required for patients 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 PET/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. 
ee Bone marrow (biopsy/aspiration) for disease assessment: To be performed at Screening, to confirm a sCR, CR and as clinically indicated. 
ff 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 study treatment), and during the trial as 
clinically indicated and to confirm response according to IMWG criteria.  
gg Plasmacytoma assessment (including extramedullary and bone plasmacytoma): PET/CT/MRI scan too be performed at screening in patients with known or suspected extramedullary disease, and during the 
trial as clinically indicated and to confirm response according to IMWG criteria. The same modality (PET-CT or MRI) should be used throughout the study for each individual patient. 
hh Cemiplimab/Isatuximab Administration: At the start of each treatment cycle, the patient’s weight will be determined.  
ii AE/SAE assessment: All AEs, including adverse 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 all ongoing related non-serious AEs, ongoing SAE and new related AE/SAEs are to be followed to resolution or stabilization. Severity will be graded according 
to NCI-CTC v4.03. 
jj Follow-up: The post-treatment follow-up period includes an extended safety follow-up period of 90 days after the last dose of study treatment, and further follow up beyond the 90 days after the last dose of study 
treatments until death or final study cut-off date, whichever occurs first.  
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 or final study cut-off date. 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 for disease assessment until confirmation of PD or start treatment with another anti-cancer therapy whichever comes first. 
After PD patient will be followed every 3 months as described just above. 
kk Includes HBsAg, anti-HBsAb, and anti-HBcAb (total and IgM) and HBV DNA in case of positive anti-HBsAg (see Section 6.5.7). Once at any time if HBV status unknown before treatment started and to be 
repeated if clinically indicated for patient still on treatment at the time of amended protocol 05. 
 
Abbreviations: ADA=anti-drug antibodies; AE=adverse event; ALT=alanine aminotransferase; ANC=absolute neutrophil count; ALP=alkaline phosphatase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; 
C=Cycle; CR=complete remission; CRF=case report form; D=Day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=end-of-treatment visit; FUP=follow-up visit; HBcAb=hepatitis B core 
antibody; HBsAb=hepatitis B surface antibody; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; IgM=immunoglobulin M; IMP=investigational medicinal product; INR=international normalized ratio; 
LDH=lactate dehydrogenase; MDRD=Modification of Diet in Renal Disease Study; PD=pharmacodynamic or progressive disease; PK=pharmacokinetic; PR=partial remission; PS=performance status; PT=prothrombin 
time; aPTT=activated partial thromboplastin time; SAE=serious adverse event; sFLC=serum free light chain, SGOT=serum glutamate-oxalate transferase; SGPT=serum glutamate-pyruvate transferase; WBC=white 
blood cell.  
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1.2 
PK/PD FLOWCHART FOR ISATUXIMAB QW/Q2W + CEMIPILIMAB Q2W  
1.2.1 Isatuximab QW/Q2W + cemipilimab Q2W (DL1) - Treatment phase: Cycle 1 (Rich sampling)  
 
a For cemiplimab ADA during treatment phase, samples to be collected every third Cycle from C5 (ie, on D1 of C5, C8, C11, C14, etc) till the last study treatment. In response to AEs of special interest, such as 
anaphylaxis or hypersensitivity, ADA samples closer to the event may be collected, based on the judgment of the Investigator and/or medical monitor. If isatuximab is stopped and cemiplimab treatment continues, 
cemiplimab ADA samples should be collected as planned per PK/PD flow-chart 
b Isatuximab PK and ADA samples to be collected each cycle till the last study treatment. However, collection can be stopped earlier upon notification from the Sponsor based on the updated knowledge of 
isatuximab PK and immunogenicity. After FUP 90(±7) days after last IMP administration, no further ADA will be sampled even if the status is positive or inconclusive. 
c Isatuximab predose sample (SOI) may be collected at the same time as the predose sample of cemiplimab (SOI) before cemiplimab infusion start. 
d Sample (ie, cemiplimab 336h drawn at C1D15 and isatuximab 168h drawn at C1D8) must be collected even if the infusion planned for cemiplimab at C1D15 and for isatuximab at C1D8 is not done or delayed. 
Abbreviations: AB=Antibody, ADA= Anti-drug antibody, C= Cycle, D= Day, EOI= End of infusion, EOT= End of Treatment (Post-treatment Safety), FUP= Follow-up period (Post-treatment safety), ID= Identifiant, 
IMP=investigational medicinal product, IV= Intravenous, P=Plasma, PK= Pharmacokinetic, RNT= relative nominal time, S= Serum, SOI= start of infusion,  
Procedure 
Treatment Phase 
C1 
D1 
D4 
D8 
D15 
D22 
Cemiplimab 
IV infusion 
X------------X 
 
 
 
 
X---------------X 
 
 
Sample RNT (h) 
SOI 
EOI 
EOI+4h 
 
72h 
168h 
336h  
(SOI C1D15) 
EOI 
 
 
Sample Time 
window  
[-24h,SOI] 
[-5 min,EOI] 
±30min 
 
±5h 
±24h 
[-24h,SOI] 
[-5 min,EOI] 
 
 
PK sample ID 
S00 
S01 
S02 
 
S03 
S04 
S05c, d 
S06 
 
 
ADA Sample IDa 
AB00 
 
 
 
 
 
 
 
 
Procedure 
C1 
D1 
D4 
D8 
D15 
D22 
 
IV infusion 
 
X-------------X 
 
 
X--- 
 
X------------X 
X--- 
Isatuximab 
Sample RNT (h) 
SOI 
 
EOI 
EOI+4h 
72h 
168h  
(SOI C1D8) 
SOI 
 
EOI 
SOI 
Sample Time 
window  
 
 
±10min 
±30min 
±5h 
[-24h,SOI] 
 
 
±10min 
[-24h,SOI] 
PK sample IDb 
P00c 
 
P01 
P02 
P03 
P04c, d 
P05c 
 
P06 
P07 
ADA Sample IDb 
AB00c 
 
 
 
 
 
 
 
 
 
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1.2.2 Isatuximab QW/Q2W + cemipilimab Q2W (DL1) - Treatment phase: Cycle 2 and beyond (Sparse sampling)  
 
Procedure 
Treatment Phase  
C2~C3 
C4 
C5 and 
beyondd 
D1 
D15 
D1 
D15 
D1 
Cemiplimab 
IV infusion 
X-------X 
 
X--------X 
X-------X 
 
 
X--------X 
X--- 
Sample RNT (h) 
SOI 
EOI 
 
SOI 
EOI 
SOI 
EOI 
 
 
SOI 
EOI 
SOI 
Sample Time 
window  
[-24h,SOI] 
[-5 min,EOI] 
 
[-24h,SOI] 
[-5 
min,EOI] [-24h,SOI] 
[-5 
min,EOI] 
 
 
[-24h,SOI] 
[-5 min,EOI] 
[-24h,SOI] 
PK sample ID 
S00 
S01 
 
S02 
S03 
S00 
S01 
 
 
S02 
S03 
S00 
ADA Sample IDa 
AB00 (C2) 
 
 
 
 
 
 
 
 
 
 
AB00a 
Procedure 
C2~C3 
C4 
C5 and 
beyondd 
D1 
D15 
D1 
D15 
D1 
Isatuximab 
IV infusion 
X-----X 
  
X--- 
  
X-----X 
X--- 
X--- 
Sample RNT (h) 
SOI 
 
EOI 
SOI 
 
SOI 
 
EOI 
EOI+1h 
SOI 
 
SOI 
Sample Time 
window  
 
±10min 
 
 
 
±10min ±10min 
PK sample IDb 
P00c 
 
P01 (C2) 
P02c 
 
P00c 
 
P01 
P02 
P03c 
 
P00c 
ADA Sample IDb 
AB00c 
 
  
 
 
AB00c 
 
 
 
 
 
AB00c 
a For cemiplimab ADA during treatment phase, samples to be collected every third Cycle from C5 (ie, on D1 of C5, C8, C11, C14, etc) till the last study treatment. In response to AEs of special interest, such as 
anaphylaxis or hypersensitivity, ADA samples closer to the event may be collected, based on the judgment of the Investigator and/or medical monitor. If isatuximab is stopped and cemiplimab treatment continues, 
cemiplimab ADA samples should be collected as planned per PK/PD flow-chart 
b Isatuximab PK and ADA samples to be collected each cycle till the last study treatment. However, collection can be stopped earlier based on the updated knowledge of isatuximab PK and immunogenicity. After 
FUP 90(±7) days after last IMP administration, no further ADA will be sampled even if the status is positive or inconclusive. 
c Isatuximab predose sample (SOI) may be collected at the same time as the predose sample of cemiplimab (SOI) before cemiplimab infusion start 
d Follow-up procedures after the extended safety period of 90 days after last study treatment dose will not be performed anymore for patients still under treatment at the time of amended protocol 05. 
 
Abbreviations: AB=Antibody, ADA= Anti-drug antibody, C= Cycle, D= Day, EOI= End of infusion, EOT= End of Treatment (Post-treatment Safety), FUP= Follow-up period (Post-treatment safety), ID= Identifiant, 
IMP=investigational medicinal product, IV= Intravenous, P=Plasma, PK= Pharmacokinetic, RNT= relative nominal time, S= Serum, SOI= start of infusion 
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1.2.3 Isatuximab QW/Q2W + cemipilimab Q2W (DL1) - End of treatment and follow-up periods  
 
Procedure 
EOT 
FUP 
Cemiplimab 
 Sample RNT (h) 
30 (±7) days after last IMP admin 
60 (±7) days after last IMP admin 
90 (±7) days after last IMP admin 
 PK sample ID 
SF00 
SF01 
 ADA Sample ID 
ABF00 
  
ABF01 
Procedure 
EOT 
FUP 
Isatuximab 
 Sample RNT (h) 
30 (±7) days after last IMP admin 
60 (±7) days after last IMP admin 
90 (±7) days after last IMP admin 
 PK sample ID 
PF00 
 
 
 ADA Sample ID 
ABF00 
 
ABF01 
NOTE: Follow-up procedures after the extended safety period of 90 days after last study treatment dose will not be performed anymore for patients still under treatment at the time of amended protocol 05. ADA and 
PK collection was interrupted at cut-off of primary analysis planned 6 months after LPI. 
Abbreviations: AB=Antibody, ADA= Anti-drug antibody, C= Cycle, D= Day, EOI= End of infusion, EOT= End of Treatment (Post-treatment Safety), FUP= Follow-up period (Post-treatment safety), ID= Identifiant, 
IMP=investigational medicinal product, IV= Intravenous, LPI=last patient in, P=Plasma, PK= Pharmacokinetic, RNT= relative nominal time, S= Serum, SOI= start of infusion 
 
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1.3 
PK/PD FLOWCHART FOR ISATUXIMAB QW/Q2W + CEMIPILIMAB Q4W  
1.3.1 Isatuximab QW/Q2W + cemipilimab Q4W (DL-1) - Treatment phase: Cycle 1 (Rich sampling) and Cycle 2  
 
Procedure 
Treatment Phase 
C1 
C2 
D1 
D4 
D8 
D15 
D22 
D1 
D15 
Cemiplimab 
IV infusion 
X------------X 
 
 
 
 
 
 
X-----X 
 
 
Sample RNT (h) 
SOI 
EOI 
EOI+4h 
 
72h 
168h 
336h 
 
 SOI 
(672h at 
C1D29) 
EOI 
 
336h 
Sample Time 
window  
[-24h,SOI] 
[-5 min,EOI] 
±30min 
 
±5h 
±24h 
 
 
[-24h,SOI] [-5 min,EOI] 
 
 
PK sample ID 
S00 
S01 
S02 
 
S03 
S04 
S05e 
 
S00d 
S01 
 
S02e 
ADA Sample IDa 
AB00 
 
 
 
 
 
 
 
AB00 
 
 
 
Procedure 
C1 
C2 
D1 
D4 
D8 
D15 
D22 
D1 
D15 
 
Isatuximab 
IV infusion 
 
X------------X 
 
 
X 
X------------X 
X 
 
X-----X 
X 
Sample RNT (h) 
SOI 
 
EOI 
EOI+4h 72h 
168h  
(SOI D8) 
SOI 
EOI 
SOI 
SOI 
 
EOI 
SOI 
Sample Time 
window  
 
- 
±10min 
±30min ±5h 
[-24h,SOI] 
[-24h,SOI] 
±10min 
[-24h,SOI] 
 
- 
±10min [-24h,SOI] 
PK sample IDb 
P00c 
 
P01 
P02 
P03 
P04d 
P05 
P06 
P07 
P00c 
 
P01 
P02 
ADA Sample IDb 
AB00c 
 
 
 
 
 
 
 
 
AB00c 
 
 
 
a For cemiplimab ADA during treatment phase, samples to be collected every third Cycle from C5 (ie, on D1 of C5, C8, C11, C14, etc) till the last study treatment. In response to AEs of special interest, such as 
anaphylaxis or hypersensitivity, ADA samples closer to the event may be collected, based on the judgment of the Investigator and/or medical monitor. If isatuximab is stopped and cemiplimab treatment continues, 
cemiplimab ADA samples should be collected as planned per PK/PD flow-chart 
b Isatuximab PK and ADA samples to be collected each cycle till the last study treatment. However, collection can be stopped earlier upon notification from the sponsor based on the updated knowledge of 
isatuximab PK and immunogenicity. After FUP 90(±7) days after last IMP administration, no further ADA will be sampled even if the status is positive or inconclusive. 
c Isatuximab predose sample (SOI) may be collected at the same time as the predose sample of cemiplimab (SOI) before cemiplimab infusion start. 
d Sample (ie, T672h at C1D29 corresponding to C2D1 for cemiplimab and C1D8 T168h for isatuximab) must be collected even if the infusion planned for cemiplimab at C2D1 and/or infusion planned for isatuximab 
at C1D8 is not done or delayed. 
e Cemiplimab predose sample on D15 may be collected on at the same time as the predose sample of isatuximab (SOI) before isatuximab infusion start  
Abbreviations: AB=Antibody, ADA= Anti-drug antibody, C= Cycle, D= Day, EOI= End of infusion, EOT= End of Treatment (Post-treatment Safety), FUP= Follow-up period (Post-treatment safety), ID= Identifiant, 
IMP=investigational medicinal product, IV= Intravenous, P=Plasma, PK= Pharmacokinetic, RNT= relative nominal time, S= Serum, SOI= start of infusion, 
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1.3.2 Isatuximab QW/Q2W + cemipilimab Q4W (DL-1) - Treatment phase: Cycle 3 and beyond (Sparse sampling)  
 
Procedure 
Treatment Phase  
C3 
C4 
C5 and beyonde 
D1 
D15 
D1 
D15 
D1 
Cemiplimab 
IV infusion 
X-------X 
 
X-------X 
 
 
 
X 
Sample RNT (h) 
SOI 
EOI 
336h 
SOI 
EOI 
 
 
336h 
SOI 
Sample Time window  
[-24h,SOI] 
[-5 min, EOI] 
 
[-24h,SOI] 
[-5 min, EOI] 
 
 
 
[-24h,SOI] 
PK sample ID 
S00 
S01 
S02c 
S00 
S01 
 
 
S02c, d 
S00 
ADA Sample IDa 
 
 
 
 
 
 
 
 
AB00a 
Procedure 
C3 
C4 
C5 and beyonde 
D1 
D15 
D1 
D15 
D1 
Isatuximab 
IV infusion 
 
X 
X 
 
X-----X 
X 
X 
Sample RNT (h) 
SOI 
 
SOI 
SOI 
 
EOI 
EOI+1h 
SOI 
SOI 
Sample Time window   
 
[-24h,SOI] 
 
 
±10min 
±10min 
[-24h,SOI] 
 
PK sample IDb 
P00c 
 
P02 
P00c 
 
P01  
P02 
P03d 
P00c 
ADA Sample IDb 
AB00c 
 
AB00c 
 
  
 
  
  
AB00c 
a For cemiplimab ADA during treatment phase, samples to be collected every third Cycle from C5 (ie, on D1 of C5, C8, C11, C14, etc) till the last study treatment. In response to AEs of special interest, such as 
anaphylaxis or hypersensitivity, ADA samples closer to the event may be collected, based on the judgment of the Investigator and/or medical monitor. If isatuximab is stopped and cemiplimab treatment continues, 
cemiplimab ADA samples should be collected as planned per PK/PD flow-chart 
b Isatuximab PK and ADA samples to be collected each cycle till the last study treatment. However, collection can be stopped earlier upon notification from the sponsor based on the updated knowledge of 
isatuximab PK and immunogenicity. After FUP 90(±7) days after last IMP administration, no further ADA will be sampled even if the status is positive or inconclusive. 
c Isatuximab predose sample (SOI) may be collected at the same time as the predose sample of cemiplimab (SOI) before cemiplimab infusion start. 
d Cemiplimab predose sample on C4D15 may be collected on at the same time as the predose sample of isatuximab (SOI) before isatuximab infusion start. 
e Follow-up procedures after the extended safety period of 90 days after last study treatment dose will not be performed anymore for patients still under treatment at the time of amended protocol 05. 
Abbreviations: AB=Antibody, ADA= Anti-drug antibody, C= Cycle, D= Day, EOI= End of infusion, EOT= End of Treatment (Post-treatment Safety), FUP= Follow-up period (Post-treatment safety), ID= Identifiant, 
IMP=investigational medicinal product, IV= Intravenous, P=Plasma, PK= Pharmacokinetic, RNT= relative nominal time, S= Serum, SOI= start of infusion 
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1.3.3 Isatuximab QW/Q2W + cemipilimab Q4W (DL-1) - End of treatment and follow-up periods  
 
Procedure 
EOT 
FUP 
Cemiplimab 
Sample RNT (h) 
30 (±7) days after last IMP admin 
60 (±7) days after last IMP admin 
90 (±7) days after last IMP admin 
PK sample ID 
SF00 
SF01 
 
ADA Sample ID 
ABF00 
  
ABF01 
Procedure 
EOT 
FUP 
Isatuximab 
Sample RNT (h) 
30 (±7) days after last IMP admin 
60 (±7) days after last IMP admin 
90 (±7) days after last IMP admin 
PK sample ID 
PF00 
 
 
ADA Sample ID 
ABF00 
 
ABF01 
NOTE: Follow-up procedures after the extended safety period of 90 days after last study treatment dose will not be performed anymore for patients still under treatment at the time of amended protocol 05. ADA and 
PK collection was interrupted before amended protocol 05. 
Abbreviations: AB=Antibody, ADA= Anti-drug antibody, C= Cycle, D= Day, EOI= End of infusion, EOT= End of Treatment (Post-treatment Safety), FUP= Follow-up period (Post-treatment safety), ID= Identifiant, 
IMP=investigational medicinal product, IV= Intravenous, P=Plasma, PK= Pharmacokinetic, RNT= relative nominal time, S= Serum, SOI= start of infusion 
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2 
 TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL NO. 06 ....................................................................................... 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
1 
FLOW CHARTS ............................................................................................................................. 14 
1.1 
STUDY FLOWCHART ................................................................................................................... 14 
1.2 
PK/PD FLOWCHART FOR ISATUXIMAB QW/Q2W + CEMIPILIMAB Q2W ................................ 19 
1.2.1 
Isatuximab QW/Q2W + cemipilimab Q2W (DL1) - Treatment phase: Cycle 1 (Rich 
sampling) ........................................................................................................................................ 19 
1.2.2 
Isatuximab QW/Q2W + cemipilimab Q2W (DL1) - Treatment phase: Cycle 2 and beyond 
(Sparse sampling) .......................................................................................................................... 20 
1.2.3 
Isatuximab QW/Q2W + cemipilimab Q2W (DL1) - End of treatment and follow-up periods ......... 21 
1.3 
PK/PD FLOWCHART FOR ISATUXIMAB QW/Q2W + CEMIPILIMAB Q4W ................................ 22 
1.3.1 
Isatuximab QW/Q2W + cemipilimab Q4W (DL-1) - Treatment phase: Cycle 1 (Rich 
sampling) and Cycle 2 ................................................................................................................... 22 
1.3.2 
Isatuximab QW/Q2W + cemipilimab Q4W (DL-1) - Treatment phase: Cycle 3 and beyond 
(Sparse sampling) .......................................................................................................................... 23 
1.3.3 
Isatuximab QW/Q2W + cemipilimab Q4W (DL-1) - End of treatment and follow-up periods ........ 24 
2 
TABLE OF CONTENTS ................................................................................................................ 25 
2.1 
LIST OF TABLES ........................................................................................................................... 32 
2.2 
LIST OF FIGURES ......................................................................................................................... 32 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 33 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 35 
4.1 
INTRODUCTION ............................................................................................................................ 35 
4.1.1 
CD38 .............................................................................................................................................. 35 
4.1.2 
PD-1 ............................................................................................................................................... 35 
4.1.3 
Multiple myeloma (MM) .................................................................................................................. 36 
4.2 
DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCT ............................................... 37 
4.2.1 
Isatuximab ...................................................................................................................................... 37 
4.2.2 
Cemiplimab .................................................................................................................................... 38 
4.2.2.1 
Clinical data .................................................................................................................................... 38 
4.3 
RATIONALE ................................................................................................................................... 39 
4.3.1 
Study rationale ............................................................................................................................... 39 
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4.3.1.1 
Pre-clinical data .............................................................................................................................. 39 
4.3.2 
Rationale for dose selection ........................................................................................................... 41 
4.3.2.1 
Isatuximab ...................................................................................................................................... 41 
4.3.2.2 
Cemiplimab .................................................................................................................................... 42 
4.3.3 
Study design rationale ................................................................................................................... 43 
5 
STUDY OBJECTIVES ................................................................................................................... 44 
5.1 
PRIMARY OBJECTIVE(S) ............................................................................................................. 44 
5.2 
SECONDARY OBJECTIVE(S) ...................................................................................................... 44 
5.3 
EXPLORATORY OBJECTIVE(S) .................................................................................................. 44 
6 
STUDY DESIGN ............................................................................................................................ 45 
6.1 
DESCRIPTION OF THE STUDY ................................................................................................... 45 
6.2 
PART 1 ........................................................................................................................................... 45 
6.2.1 
Starting dose and dose de-escalation design ................................................................................ 45 
6.2.2 
Maximum administered dose / maximum tolerated dose .............................................................. 46 
6.3 
PART 2 ........................................................................................................................................... 46 
6.3.1 
Anti-CD38 refractory cohort ........................................................................................................... 47 
6.4 
RETREATMENT OF PATIENTS ................................................................................................... 47 
6.5 
DOSE DELAYS/ MODIFICATIONS ............................................................................................... 47 
6.5.1 
General rules .................................................................................................................................. 47 
6.5.2 
Dose delay and dose omission ...................................................................................................... 48 
6.5.3 
Dose modifications ......................................................................................................................... 49 
6.5.4 
General guidelines for the management of immune-related adverse events ................................ 50 
6.5.5 
General guidelines for the management of IARs ........................................................................... 51 
6.5.6 
Guidelines for the management of potential tumor lysis syndrome (TLS) ..................................... 53 
6.5.7 
Guidance in case of hepatitis B reactivation occurring under study treatment .............................. 54 
6.6 
DURATION OF STUDY PARTICIPATION .................................................................................... 54 
6.6.1 
Duration of study participation for each patient ............................................................................. 54 
6.6.2 
Determination of end of clinical trial (all patients) .......................................................................... 55 
6.7 
STUDY COMMITTEES .................................................................................................................. 55 
7 
SELECTION OF PATIENTS .......................................................................................................... 56 
7.1 
NUMBER OF PATIENTS ............................................................................................................... 56 
7.2 
INCLUSION CRITERIA .................................................................................................................. 56 
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7.3 
EXCLUSION CRITERIA ................................................................................................................ 56 
8 
STUDY TREATMENTS ................................................................................................................. 59 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT ............................................................................... 59 
8.1.1 
Isatuximab ...................................................................................................................................... 59 
8.1.1.1 
Pharmaceutical form ...................................................................................................................... 59 
8.1.1.2 
Dose of drug per administration ..................................................................................................... 59 
8.1.1.3 
Preparation, reconstitution and administration .............................................................................. 59 
8.1.2 
Cemiplimab .................................................................................................................................... 60 
8.1.2.1 
Pharmaceutical form ...................................................................................................................... 60 
8.1.2.2 
Dose of drug per administration ..................................................................................................... 60 
8.1.2.3 
Preparation, reconstitution and administration .............................................................................. 60 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................................. 60 
8.2.1 
Acetaminophen or equivalent ........................................................................................................ 61 
8.2.2 
Ranitidine or equivalent ................................................................................................................. 61 
8.2.3 
Diphenhydramine or equivalent ..................................................................................................... 61 
8.2.4 
Methylprednisolone or equivalent .................................................................................................. 61 
8.3 
DOSING REGIMEN AND SEQUENCE ......................................................................................... 61 
8.3.1 
Dosing regimen .............................................................................................................................. 61 
8.3.2 
Doing sequence ............................................................................................................................. 62 
8.4 
RATE AND DURATION OF INFUSION ......................................................................................... 62 
8.5 
PACKAGING AND LABELING ...................................................................................................... 63 
8.5.1 
Isatuximab ...................................................................................................................................... 63 
8.5.2 
Cemiplimab .................................................................................................................................... 63 
8.6 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 63 
8.6.1 
Isatuximab ...................................................................................................................................... 63 
8.6.2 
Cemiplimab .................................................................................................................................... 63 
8.7 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP IN PHASE 2 ......................... 64 
8.8 
RESPONSIBILITIES ...................................................................................................................... 64 
8.8.1 
Treatment accountability and compliance...................................................................................... 64 
8.8.2 
Return and/or destruction of treatments ........................................................................................ 65 
8.9 
CONCOMITANT TREATMENT ..................................................................................................... 65 
8.9.1 
Prophylaxis for opportunistic infections.......................................................................................... 65 
8.9.2 
Prohibited concomitant treatments: ............................................................................................... 65 
8.9.3 
Contraceptive measures and pregnancy counseling ..................................................................... 66 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 67 
9.1 
SAFETY ......................................................................................................................................... 67 
9.1.1 
Dose-limiting toxicities (Phase 1 only) ........................................................................................... 67 
9.1.2 
Adverse events .............................................................................................................................. 68 
9.1.3 
Laboratory safety variables ............................................................................................................ 68 
9.1.4 
Clinical examinations ..................................................................................................................... 68 
9.1.5 
Immunogenicity .............................................................................................................................. 68 
9.2 
EFFICACY ..................................................................................................................................... 69 
9.2.1 
Primary endpoint (Phase 2 only) .................................................................................................... 69 
9.2.2 
Secondary endpoints (Phase 2 only) ............................................................................................. 70 
9.3 
PHARMACOKINETIC EVALUATION ............................................................................................ 71 
9.3.1 
Sampling time ................................................................................................................................ 71 
9.3.2 
Pharmacokinetic sample handling procedure ................................................................................ 71 
9.3.3 
Bioanalytical methods and bioanalytical sites ................................................................................ 71 
9.3.4 
Pharmacokinetic parameters ......................................................................................................... 72 
9.3.4.1 
Non-compartmental analysis ......................................................................................................... 72 
9.3.4.2 
Population approach ...................................................................................................................... 72 
9.4 
SPECIFIC ASSESSMENTS: ISATUXIMAB IAR LABS - CYTOKINES, MARKERS OF 
ACTIVATED COMPLEMENTS AND SERUM TRYPTASE ........................................................... 73 
9.5 
EXPLORATORY BIOMARKER ANALYSES ................................................................................. 73 
10 
PATIENT SAFETY ......................................................................................................................... 75 
10.1 
SAFETY ENDPOINTS ASSESSED IN THIS TRIAL ..................................................................... 75 
10.2 
SAFETY INSTRUCTIONS ............................................................................................................. 75 
10.3 
DEFINITIONS OF ADVERSE EVENT AND SERIOUS ADVERSE EVENT .................................. 75 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING .......................... 76 
10.4.1 
Adverse events .............................................................................................................................. 76 
10.4.2 
Timely handling of certain AEs ...................................................................................................... 76 
10.4.3 
Follow-up ........................................................................................................................................ 76 
10.4.4 
Treatment discontinuation due to nonserious adverse event ........................................................ 77 
10.5 
ADVERSE EVENT OF SPECIAL INTEREST ................................................................................ 77 
10.5.1 
Laboratory abnormalities ............................................................................................................... 78 
10.6 
OBLIGATIONS OF THE SPONSOR ............................................................................................. 78 
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11 
HANDLING OF PATIENT TEMPORARY AND PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION ...................................... 80 
11.1 
PERMANENT TREATMENT DISCONTINUATION WITH INVESTIGATIONAL MEDICINAL 
PRODUCT(S) ................................................................................................................................. 80 
11.1.1 
List of criteria for permanent treatment discontinuation ................................................................. 80 
11.1.2 
Handling of patients after permanent treatment discontinuation ................................................... 81 
11.2 
REPLACEMENT OF PATIENTS ................................................................................................... 81 
12 
STUDY PROCEDURES ................................................................................................................ 82 
12.1 
VISIT SCHEDULE .......................................................................................................................... 82 
12.2 
SCREENING/BASELINE EVALUATION ....................................................................................... 82 
12.3 
REGISTRATION/RANDOMIZATION ............................................................................................. 84 
12.4 
TREATMENT PERIOD .................................................................................................................. 84 
12.4.1 
Cycle 1 (Day 1, Day 8, Day 15 and Day 22 all ±1 day) ................................................................. 84 
12.4.2 
Subsequent cycles (Day 1 and 15 both ±2 days) .......................................................................... 86 
12.4.3 
End of treatment ............................................................................................................................. 88 
12.4.4 
Post treatment follow up ................................................................................................................ 90 
12.4.4.1 60 and 90 days after last treatment visit ........................................................................................ 90 
12.4.4.2 Further follow-up visits until 12 months after LPI ........................................................................... 91 
12.4.5 
Post OS final study cut-off date ..................................................................................................... 93 
13 
STATISTICAL CONSIDERATIONS .............................................................................................. 94 
13.1 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 94 
13.2 
PATIENT DESCRIPTION .............................................................................................................. 94 
13.2.1 
Disposition of patients .................................................................................................................... 94 
13.2.2 
Protocol deviations ......................................................................................................................... 94 
13.3 
ANALYSIS POPULATIONS ........................................................................................................... 95 
13.3.1 
All-treated/safety population .......................................................................................................... 95 
13.3.2 
ITT population ................................................................................................................................ 95 
13.3.3 
Patients evaluable for DLT assessment ........................................................................................ 95 
13.3.4 
Pharmacokinetic population ........................................................................................................... 95 
13.3.5 
ADA evaluable population .............................................................................................................. 96 
13.4 
STATISTICAL METHODS ............................................................................................................. 96 
13.4.1 
Demographics and baseline characteristics .................................................................................. 96 
13.4.2 
Extent of investigational medicinal product exposure .................................................................... 97 
13.4.3 
Prior/concomitant medication/therapy............................................................................................ 98 
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13.4.4 
Analyses of efficacy variables ........................................................................................................ 98 
13.4.4.1 Analysis of primary efficacy endpoint............................................................................................. 98 
13.4.4.2 Analysis of secondary efficacy endpoints ...................................................................................... 99 
13.4.5 
Analyses of safety data .................................................................................................................. 99 
13.4.5.1 Dose-limiting toxicities.................................................................................................................... 99 
13.4.5.2 Analyses of adverse events ........................................................................................................... 99 
13.4.5.3 Deaths .......................................................................................................................................... 101 
13.4.5.4 Clinical laboratory evaluations ..................................................................................................... 101 
13.4.5.5 Other safety evaluations .............................................................................................................. 101 
13.4.6 
Analyses of pharmacokinetic variables ........................................................................................ 103 
13.5 
INTERIM ANALYSIS .................................................................................................................... 103 
14 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................. 104 
14.1 
ETHICAL AND REGULATORY STANDARDS ............................................................................ 104 
14.2 
INFORMED CONSENT ............................................................................................................... 104 
14.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC) ................................................................................................. 104 
15 
STUDY MONITORING................................................................................................................. 106 
15.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) ..................................................................... 106 
15.2 
RESPONSIBILITIES OF SPONSOR ........................................................................................... 106 
15.3 
SOURCE DOCUMENT REQUIREMENTS .................................................................................. 106 
15.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUESTS ......... 107 
15.5 
USE OF COMPUTERIZED SYSTEMS ........................................................................................ 107 
16 
ADDITIONAL REQUIREMENTS ................................................................................................. 108 
16.1 
CURRICULUM VITAE.................................................................................................................. 108 
16.2 
RECORD RETENTION IN STUDY SITES(S) ............................................................................. 108 
16.3 
CONFIDENTIALITY ..................................................................................................................... 108 
16.4 
PROPERTY RIGHTS ................................................................................................................... 109 
16.5 
DATA PROTECTION ................................................................................................................... 109 
16.6 
INSURANCE COMPENSATION .................................................................................................. 109 
16.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ............................... 110 
16.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE .......................................................................................................................................... 110 
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16.8.1 
By the Sponsor ............................................................................................................................. 110 
16.8.2 
By the Investigator ....................................................................................................................... 111 
16.9 
CLINICAL TRIAL RESULTS ........................................................................................................ 111 
16.10 
PUBLICATIONS AND COMMUNICATIONS ............................................................................... 111 
17 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................ 112 
18 
BIBLIOGRAPHIC REFERENCES ............................................................................................... 113 
19 
APPENDICES .............................................................................................................................. 117 
APPENDIX A 
MODIFICATION OF DIET IN RENAL DISEASE (MDRD) EQUATION ............................. 118 
APPENDIX B 
ECOG PERFORMANCE STATUS SCALE ....................................................................... 119 
APPENDIX C 
NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA FOR 
ADVERSE EVENTS..................................................................................................................... 120 
APPENDIX D 
IMWG RESPONSE CRITERIA.......................................................................................... 121 
APPENDIX E 
GUIDELINES FOR THE DETERMINATION OF THE NUMBER OF PRIOR LINES 
OF THERAPY IN MULTIPLE MYELOMA .................................................................................... 124 
APPENDIX F 
DEFINITION OF RELAPSED AND REFRACTORY MYELOMA ....................................... 126 
APPENDIX G 
RECOMMENDED DOSE MODIFICATION OR DISCONTINUATION AND 
SUPPORTIVE CARE GUIDELINES FOR SPECIFIC CEMIPLIMAB DRUG RELATED 
ADVERSE EVENTS..................................................................................................................... 127 
APPENDIX H 
INFUSION ASSOCIATED REACTIONS OBSERVED WITH ISATUXIMAB ..................... 137 
APPENDIX I 
CD38 BLOOD TEST INTERFERENCE GUIDELINE AABB2016 ....................................... 138 
APPENDIX J 
CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION ............................................................................................................................ 142 
APPENDIX K 
PROTOCOL AMENDMENT HISTORY ............................................................................. 144 
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2.1 
LIST OF TABLES  
Table 1 - Treatment dose and schedule ........................................................................................................ 45 
Table 2 - Dose reduction guidance ............................................................................................................... 49 
Table 3 - Isatuximab and cemiplimab dose modification guidelines ............................................................. 49 
Table 4 - General guidelines for immune related adverse events ................................................................ 51 
Table 5 - IAR management ........................................................................................................................... 52 
Table 6 - Laboratory and clinical abnormalities possibly consistent with TLS .............................................. 53 
Table 7 - Bioanalytical methods for immune response assessment ............................................................. 69 
Table 8 - Bioanalytical methods for isatuximab and functional cemiplimab pharmacokinetic analysis ........ 72 
Table 9 - List of pharmacokinetic parameters and definitions ....................................................................... 72 
 
2.2 
LIST OF FIGURES  
Figure 1 - Percentage of lysis of PD-L1 negative/positive RPMI-8226.CD38 MM cells by PD-1 
negative/positive NK-92 human NK cells ...................................................................................................... 40 
Figure 2 - Percentage of lysis of RPMI-8226.CD38 MM cells by NK-92.PD-1 in the presence of anti-PD-1 
nivolumab (left) or anti-PD-L1 MPDL328A (right) antibodies ........................................................................ 40 
Figure 3 - Percentage of CD14+ or CD56+ PBMCs that express PD-L1 or PD-1, respectively, after 6 days 
in culture alone or in the presence of U266 MM cells ................................................................................... 41 
Figure 4 - Isatuximab anti-MM myeloma activity alone and in combination with anti-PD-1 or anti-PD-L1 
antibodies measured by flow cytometry ........................................................................................................ 41 
 
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3 
LIST OF ABBREVIATIONS  
 
ADCC: 
antibody-dependent cellular-mediated cytotoxicity 
AE: 
adverse event 
AESI: 
adverse event of special interest 
AL: 
amyloid light-chain 
ALT: 
alanine aminotransferase 
ANC: 
absolute neutrophil count 
AST: 
aspartate aminotransferase 
BMA: 
bone marrow aspirate 
CBR: 
clinical benefit rate 
CR: 
complete response 
DL: 
dose level 
DLT: 
dose limiting toxicity 
DOR: 
duration of response 
DRF: 
discrepancy resolution form 
ECOG: 
eastern cooperative oncology group 
eGFR: 
estimated glomerular filtration rate 
FISH: 
fluorescence in situ hybridization 
FLC: 
free light chain 
FSH: 
follicle stimulating hormone 
GCP: 
good clinical practice 
HBcAb: 
hepatitis B core antibody 
HBsAb: 
hepatitis B surface antibody 
HBsAg: 
hepatitis B surface antigen 
HBV: 
hepatitis B virus 
HRT: 
hormonal replacement therapy 
HSC: 
haemopoietic stem cell 
ICH: 
international conference on harmonisation 
IEC: 
institutional ethics committee 
IgM: 
immunoglobulin M 
IMiD: 
immunomodulatory drug 
IMWG: 
international myeloma working group 
INR: 
international normalized ratio 
IRB: 
institutional review board 
ITT: 
intent to treat 
IV: 
intravenous 
LDH: 
lactate dehydrogenase 
LPI: 
last patient in 
mAb: 
monoclonal antibody 
MDRD: 
modified diet in renal disease 
MM: 
multiple myeloma 
MR: 
minimal response 
MRD: 
minimal residual disease 
MTD: 
maximum tolerated dose 
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ORR: 
overall response rate 
OS: 
overall survival 
PD: 
progression of disease 
PFS: 
progression free survival 
PI: 
proteasome inhibitor 
PK: 
pharmacokinetics 
PR: 
partial response 
PS: 
performance status 
PT: 
prothrombin time 
Q2W: 
once every 2 weeks 
QW: 
once weekly 
RBC: 
red blood cell 
RP2D: 
recommended Phase 2 dose 
RRMM: 
relapse and refractory multiple myeloma 
SAE: 
serious adverse event 
sCR: 
stringent complete response 
SCT: 
stem cell transplant 
SPD: 
sum of the products of the maximal perpendicular diameters of measured lesions 
TEAE: 
treatment-emergent adverse event 
TTR: 
time to response 
ULN: 
upper limit of the normal range 
VGPR: 
very good partial response 
WBC: 
white blood cell 
 
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4 
INTRODUCTION AND RATIONALE  
4.1 
INTRODUCTION  
4.1.1 CD38  
CD38 is a type II glycosylated 45 kilodalton (kDa) membrane protein that was identified as a 
lymphocyte marker (1). CD38 has a role in leukocyte homeostasis through modulation of 
hematopoietic cell survival and differentiation (2). CD38 functions as a receptor binding to CD31 
and is involved in cell adhesion and signal transduction. The function of CD38 in signal 
transduction appears to be versatile depending on the cell lineage, the differentiation stage, and, 
possibly, the association with different co-receptors (2). CD38 is also an ecto-enzyme catalyzing 
the synthesis and hydrolysis of cyclic adenosine-diphosphate-ribose (cADPR) from nicotinamide 
adenine dinucleotide (NAD+) to ADP-ribose (3). These reaction products are implicated in 
calcium mobilization and intracellular signaling. 
The expression of CD38 in healthy humans can be detected on NK cells, monocytes, dendritic cells, 
macrophages, granulocytes, activated T and B cells, and plasma cells. In contrast, expression has not 
been detected in hematopoietic stem cells, resting T and B cells, or tissue macrophages. Several 
hematological malignancies express CD38 including those of B-lymphocyte, T-lymphocyte and 
myeloid origin. Moreover, CD38 was identified as a negative prognostic marker in some 
hematological malignancies, such as CLL. The expression of CD38 is especially notable in 
multiple myeloma (MM) as >98% of patients are positive for this protein (4, 5). The strong and 
uniform expression of CD38 on malignant clonal MM cells contrasts with the restricted 
expression pattern on normal cells suggesting this antigen may be useful for specific targeting of 
tumor cells. 
4.1.2 PD-1  
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades (6). The PD-1 receptor-ligand interaction is a major 
pathway hijacked by tumors to suppress immune control (7). The normal function of PD-1, 
expressed on the cell surface of activated T cells under healthy conditions, is to down-modulate 
unwanted or excessive immune responses, including autoimmune reactions. PD-1 (encoded by the 
gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4, which has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or  
PD-L2). The structures of murine PD-1 alone (8) and in complex with its ligands were 
first resolved (9, 10) and more recently the NMR-based structure of the human PD-1 extracellular 
region and analyses of its interactions with its ligands were also reported (11). PD-1 and family 
members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of 
signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based 
switch motif (ITSM). Following T cell stimulation, PD-1 recruits the tyrosine phosphatases  
SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation 
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of effector molecules, such as CD3ζ, PKCθ and ZAP70, which are involved in the CD3 T cell 
signaling cascade (12). The mechanism by which PD-1 down-modulates T cell responses is 
similar to, but distinct from that of CTLA-4 (13). PD-1 was shown to be expressed on activated 
lymphocytes, including peripheral CD4+ and CD8+ T cells, B cells, T regs and Natural Killer 
cells (14). Expression has also been shown during thymic development on CD4-CD8- (double 
negative) T cells (15) as well as subsets of macrophages (16) and dendritic cells (17). The ligands 
for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell 
types (18). PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably 
on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments (18). 
Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in 
the extracellular region and short cytoplasmic regions with no known signaling motifs. Binding of 
either PD-1 ligand to PD-1 inhibits T cell activation triggered through the T cell receptor. PD-L2 
is thought to control immune T cell activation in lymphoid organs, whereas PD-L1 serves to 
dampen unwarranted T cell function in peripheral tissues. Although healthy organs express little 
(if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this T cell 
inhibitor (19, 20) which, via its interaction with the PD-1 receptor on tumor-specific T cells, plays 
a critical role in immune evasion by tumors (21). As a consequence, the PD-1/PD-L1 pathway is 
an attractive target for therapeutic intervention in cancer (22). 
Two anti-PD1 antibodies, nivolumab and pembrolizumab, are now approved in melanoma and 
lung cancer. The promise of anti-PD1 antibodies is starting to be explored also in hematologic 
malignancies such as Hodgkin disease (22, 23), and the rationale for the use of anti-PD1 
antibodies in MM is elucidated in the following Section 4.3.2.2. 
4.1.3 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 light chain [paraprotein, M-protein or 
M-component]). It is a disease predominantly associated with advancing age with more than 
80% of patients aged 60 years or older. Patients with MM can experience bone pain, bone 
fractures, fatigue, anaemia, infections, hypercalcaemia and renal dysfunction (24). The disease 
course for MM varies with the aggressiveness of the disease and related prognostic factors. 
Median survival is approximately 3 years; however, some patients can live longer than 10 years 
(25).  
Treatment options and survival are based on the patient’s age, fitness and disease status. Patients 
under the age of approximately 65, presenting with symptomatic active disease in good physical 
health will generally receive initial therapy with autologous stem cell transplantation (ASCT). To 
achieve cytoreduction of the disease before collecting stem cells, induction chemotherapy is 
administered. Induction treatment regimens include alkylating agents, dexamethasone alone, 
thalidomide plus dexamethasone, and vincristine, Adriamycin® (doxorubicin), and dexamethasone 
(VAD; or modifications to this regimen); however, the later 2 regimens are associated with higher 
toxicity (24). Newer treatments with Velcade® (bortezomib) alone, bortezomib combinations, and 
Revlimid® (lenalidomide) plus dexamethasone show some promise as induction therapy, and 
these agents demonstrate higher response rates and lower toxicity (24, 26). In addition to these 
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new treatments, daratumumab has been recently approved in US and Europe in single agent based 
on response rate of 29.2% (95%CI: 20.8-38.9) in late stage relapse and refractory multiple 
myeloma (RRMM) patients previously treated with IMiDs and PI, supporting the use of CD38 
antibody in MM (27).  
The current aim of MM therapy is to control the disease as effectively as possible, to maximize 
quality of life and to prolong survival. Treatments for relapsed and/or refractory disease are often 
referred to as salvage therapy. The initial chemotherapy regimen (eg, bortezomib plus 
dexamethasone or bortezomib thalidomide plus dexamethasone or lenalidomide plus 
dexamethasone, or bortezomib plus melphalan plus prednisone depending if the patient was 
eligible for stem cell transplantation or not) can be reinstituted for relapsed/refractory disease if 
the disease relapsed more than 6 months after the last therapy ended. Subsequent treatment 
decisions are based on whether the patient experiences an indolent or aggressive relapse. In 
general, MM patients will receive an average of 4 to 8 different regimens during their lifespan 
utilizing agents such as proteasome inhibitors (eg, bortezomib, ixazomib and carfilzomib) and 
immune modulatory agents (eg, lenalidomide), monoclonal antibodies (elotuzumab), histone 
deacetylase (HDAC) inhibitors (panobinostat) alone or in combination. However, once a patient 
becomes refractory to those agents, survival is limited and newer treatment options are needed to 
treat patients after they have failed stem cell transplant (SCT), chemotherapy, proteasome 
inhibitors, and immunomodulatory drugs (IMiDs®). Despite the dramatic improvement in patient 
outcomes with newer therapies, MM remains an incurable disease. Thus, the treatment of patients 
who have received at least 3 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 this antigen may be a useful target for the in vivo depletion of tumor cells while 
sparing normal cells (28). 
Studies have shown the expression of PD-L1 on MM cells, and T and NK cells within the MM 
microenviroment expression PD-1(29). 
4.2 
DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCT  
4.2.1 Isatuximab  
Isatuximab (SAR650984) is a monoclonal antibody (mAb) that binds selectively to a unique 
epitope on the human surface antigen CD38. Isatuximab kills tumor cells via multiple biological 
mechanisms; antibody-dependent cellular-mediated cytotoxicity (ADCC), antibody-dependent 
cellular-mediated phagocytosis (ADCP), complement-dependent cytotoxicity (CDC) and direct 
induction of apoptosis (pro-apoptosis) without crosslinking. Isatuximab treatment of CD38 
expressing cells also results in inhibition of CD38 enzymatic activity (30).  
Please refer to the isatuximab Investigator’s Brochure for more information on the current safety 
and efficacy of isatuximab. 
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4.2.2 Cemiplimab  
Cemiplimab (REGN2810) is a high affinity hinge-stabilized IgG4P human antibody to the PD-1 
receptor (PDCD1, CD279) that blocks PD-1/PD L1-mediated T cell inhibition. Cemiplimab 
displayed a robust, dose-dependent suppression of MC38.Ova tumors in the syngeneic mouse 
tumor model. The nonclinical activity of cemiplimab is similar to two in-house generated 
anti-PD-1 comparator antibodies with identical amino acid sequence to nivolumab and 
pembrolizumab (based on publically available sequence data).  
4.2.2.1 Clinical data  
As of 20 Jan 2017, 459 patients have been treated with cemiplimab either as monotherapy or in 
combination with radiotherapy and/or other cancer therapy in the three ongoing studies. The 
majority of patients (n=353) have been treated in Study 1423. Study 1423 is a first-in-human 
study in patients with advanced malignancies of repeat dosing of cemiplimab as monotherapy, as 
well as in combination with hypofractionated radiation therapy (hfRT) and/or cyclophosphamide 
(CTX), or in combination with hfRT, CTX, and Granulocyte Macrophage Colony-Stimulating 
Factor, or in combination with docetaxel or docetaxel plus carboplatin. As of 20 Jan 2017, in 
Study 1423, a total of 353 patients have been enrolled and treated with 4 different dose levels 
(n=27 at 1 mg/kg, n=300 at 3 mg/kg, n=6 at 10 mg/kg, and n=20 a flat dose of 200 mg). The study 
design includes 60 patients in dose escalation cohorts and the rest in a series of expansion cohorts. 
As of 20 Jan 2017, the majority of patients (300 of 353) have been treated with 3 mg/kg 
cemiplimab. All patients except 12 patients have been treated on a Q2W schedule. There have 
been no patients with hematologic malignancies treated in Study 1423.  
Cemiplimab has been generally well tolerated, and the reported AEs have been similar to what 
have been observed with other PD-1 inhibitors. In study 1423, the most common treatment-
emergent adverse events (TEAEs) occurring in 10% or more of patients were fatigue, nausea, 
decreased appetite, anemia, constipation, arthralgia, diarrhea, dyspnea, cough, pyrexia, vomiting, 
asthenia, and back pain. No protocol-defined dose limiting toxicities have been observed. 
Potential immune-related TEAEs (irTEAEs) have been observed in33.7% patients including 
Grade 3 or higher in 8.2% patients. Treatment-related irTEAE occurring in more than 1% of 
patients included arthralgia (8.2%), diarrhea (6.5%), pruiritus (4.5%), hypothyroidism (4.2%), 
rash maculo-papular (3.7%), AST increased (3.4%), rash (2.8%), ALT increased (2.5%), 
pneumonitis (2.3%), rash pruritic (1.7%), stomatitis (1.7%), hyperthyroidism (1.1%) 
5.1% patients experienced serious irTEAE. Events of Grade 3 or higher occurring in more than 
1 patient included: AST increase (n=3, 0.8%), pneumonitis (n=3, 0.8%), ALT increased 
(n=2, 0.6%) and diabetic ketoacidosis (n=2, 0.6%). Events occurring in 1 patients (0.3%) 
included: arthralgia, autoimmune hepatitis, colitis, hepatic failure, hyperbilirubinaemia, 
hyperthyroidism, paraneoplastic encephalomyelitis, transaminases increased. the events of 
paraneoplastic encephalomyelitis and hepatic failure were with fatal outcome. Five patients 
(1.4%) experienced a total of 8 cemiplimab-related infusion-related reactions (IRRs), all were 
non-serious and Grade 2 except 1 Grade 1 event. One patient treated at 10 mg/kg monotherapy in 
Study 1423 with soft tissue sarcoma died because of anti-HuD paraneoplastic encephalomyelitis; 
16 other patients died due to progression of disease. 
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330 patients were evaluable to tumor response, with 17.6% objective response and 57.6% disease 
control. As of 20 January 2017, no patients with multiple myeloma have been treated with 
cemiplimab. However, in study 1504, as of 15 Jun 2016, 12 patients with hematologic 
malignancies (6 with Hodgkin’s lymphoma and 6 with non-Hodgkin’s lymphoma) have been 
enrolled and treated Q2W with cemiplimab as monotherapy (1 mg/kg [n=6] and 3 mg/kg [n=6]). 
The safety profile appears similar to that seen with cemiplimab in study 1423. After the data cut 
off, one fatal case of toxic epidermal necrolysis was reported in a patient with follicular 
lymphoma who had a protracted course of skin rash and stomatitis (Grade 3 highest grade) 
one month after discontinuation of idelalisib (administered as a prior treatment) that resolved 
2 weeks prior to initiation of cemiplimab. No efficacy information is available for this study at the 
present time. 
Please refer to the cemiplimab Investigator’s Brochure for more information on the current safety 
and efficacy of cemiplimab. 
4.3 
RATIONALE  
4.3.1 Study rationale  
Multiple myeloma is a high unmet medical need and as a result, several agents are currently under 
clinical investigation in MM. Some of them (including isatuximab) have shown clinical activity as 
monotherapy, but the clinical avenue for development of most of them is to search for rationally 
based or pre-clinically oriented combinations of these novel agents with standard of care of MM, 
looking for potentiation. Monoclonal antibodies are one of the most promising groups of drugs in 
development in the treatment of MM with several of them demonstrating activity in this 
disease (28).  
Clinically, isatuximab single agent has shown clinical response in RRMM patients and the 
treatment effect is enhanced by combination with immuno-modulation (IMiDs).  
As a single agent, nivolumab (anti-PD-1) had minimal activity in RRMM, with a stable disease 
rate of 63% in a Phase I trial; PR or better were not seen, with the exception of one CR occurring 
after local radiation therapy (31). Recent report shown that combined PD-L1 and CD38 inhibition 
improves tumor response in animal model (32). 
Based on preclinical studies indicating that isatuximab induced ADCC can be enhanced through 
the inhibition of PD-1, the combination therapy of isatuximab and cemiplimab (an anti-PD1 
antibody currently in clinical development) may provide another option for the treatment of 
RRMM. 
4.3.1.1 Pre-clinical data  
PD-1 and its ligand PD-L1 are reported to be expressed in the multiple myeloma tumor micro-
environment; PD-L1 in the plasma cells (33, 34) and PD-1 in T and NK cells (35, 36). More 
recently, data showing that PD-L1 blockade enhances NK and T cell mediated lysis of MM cells 
has been published (37). 
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4.3.2 Rationale for dose selection  
4.3.2.1 Isatuximab  
Isatuximab as a single agent has shown an efficacy dose effect between 3 mg/kg and 10 mg/kg 
and above.  
Although no evident difference is seen for tolerability, the available data in combination with 
lenalidomide does not demonstrate major differences in efficacy between 10 and 20 mg/kg with 
comparable response rate in heavily pretreated patients. Pharmacokinetics/pharmacodynamics 
(PK/PD) analyses including trial simulations and simulations of serum M protein-profiles showed 
higher predicted ORR and reduction in M-protein at 8/12 weeks at doses ≥10 mg/kg. However, 
the benefit in terms of ORR increase or in term serum M-protein reduction appeared limited when 
increasing the dose from 10 to 20 mg/kg QW x 4, Q2W. Therefore, based on clinical efficacy, 
safety, PK simulations and PK/PD analyses, the dose selected for further isatuximab combination 
studies is 10 mg/kg QW x 4 administrations followed by 10 mg/kg Q2W.  
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Based on these data, the dose of isatuximab 10 mg/kg has been selected in combination therapies.  
4.3.2.2 Cemiplimab  
Similar to the experience observed with other anti-PD-1 antibodies, cemiplimab dosing has been 
escalated safely in the FIH study R2810-ONC-1423. As of 15 June 2016, a total of 222 patients 
have been enrolled in study R2810-ONC-1423, including 71 patients in monotherapy cohorts at 1, 
3, and 10 mg/kg Q2W and at 200 mg Q2W flat dose, and 151 patients in combination therapy 
cohorts (eg, combinations with chemotherapy and/or hypo-fractionated radiation therapy). As of 
15 June 2016, no DLTs have been observed across the treatment regimens studied. Preliminary 
efficacy was observed with cemiplimab in several tumor types at all doses tested. Evidence of 
rapid and durable responses with cemiplimab was also observed in study R2810-ONC-1423, at all 
doses tested with no clear dose-response relationship, similar to the observations with other  
anti-PD-1 antibodies (38, 39). 
While the PK of cemiplimab in animals is described as non-linear with target-mediated elimination, 
linear kinetics are observed in the clinic at the dose levels between 1 and 10 mg/kg Q2W. The 
observed linear PK in patients is consistent with saturation of the target-mediated clearance pathway 
and a flat dose-response is observed across the treatment regimens studied, suggesting saturation of 
PD-1 binding at these doses. The 3 mg/kg Q2W dose was initially administered for maintenance 
therapy in the FIH study and was subsequently used in several other studies of the program. Based 
on feedback from regulatory authorities, it was subsequently decided to switch from body weight 
adjusted dosing to fixed flat dosing across the cemiplimab program. 
The preference for a fixed flat dose over a body-weight-adjusted dose for anti-PD-1 monoclonal 
antibodies is supported by a wide safety margin (no maximum tolerated dose observed), a flat E-R 
relationship for safety and efficacy over the therapeutic dosing range, and similar variability in 
exposure (CV%) after flat and body-weight-adjusted doses (40).  
Simulations of cemiplimab exposure at steady state in 1,000 patients using population PK 
analyses have demonstrated that the variability in cemiplimab exposure was similar for body 
weight-adjusted doses as compared to fixed flat doses, 250 mg Q2W doses of cemiplimab 
produced results similar to those after the 3 mg/kg Q2W doses over a similar treatment period.  
In the FIH study with cemiplimab, both the 1 mg/kg Q2W and the 3mg/kg Q2W doses had 
yielded preliminary efficacy signals in a number of tumor types. Acceptable safety data have also 
been obtained following a 10 mg/kg Q2W regimen with no DLTs observed as of 15 June 2016; 
Translated into a fixed flat dose, a 3 mg/kg Q2W dose would correspond to a 250 mg Q2W dose 
of cemiplimab, which are acceptable as a starting dose when cemiplimab is given in combination 
with isatuximab. Therefore, to match the weekly and bi-weekly dosing schedule for isatuximab 
(10 mg/kg QWx4 followed by 10 mg/kg Q2W), a fixed flat 250 mg Q2W dosing regimen of 
cemiplimab is preferred for patient’s convenience. 
Since changing the exposure of check point inhibitors such as nivolumab in combination with 
ipilimumab altered the safety, tolerability and efficacy of these drugs in NCSLC (41), two fixed 
flat dosing regimens of cemiplimab in combination with isatuximab will be assessed in this study: 
250 mg Q2W (DL1) and 250 mg Q4W (DL-1 and DL-2). 
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4.3.3 Study design rationale  
This is the first study of isatuximab in combination with cemiplimab. To evaluate the safety 
and clinical activity in RRMM, the study is designed in 2 parts. 
The Phase 1 part is to confirm the feasibility of the isatuximab / cemiplimab combination and 
select a recommended dose for Phase 2. The maximum tolerated dose (MTD) defined as the 
highest dose intensity at which 0 out of 3 or no more than 1/6 patients have DLT. Given the 
promising early signs of the activity and the acceptable safety profile of each of the two 
antibodies, and that MTD has not been reached in either one as monotherapy with isatuximab 
20 mg/kg QW and cemiplimab 10 mg/kg, no typical dose escalation is planned. A cohort of 
3 patients will be treated at starting dose of 10 mg/kg QWx4 followed by Q2W for isatuximab and 
250 mg Q2W for cemiplimab,which have been shown to be clinically active with an acceptable 
safety profile both as monotherapy and in combinations with other standard therapies. If 
necessary, dose will be de-escalated with typical 3+3 design rule.  
The Phase 2 part is a proof of concept study to determine the efficacy of the combination of 
isatuximab and cemiplimab in RRMM patients using ORR as primary endpoint, and to further 
evaluate the safety of the combination therapy. The efficacy of single-agent isatuximab and other 
CD38 drugs is well established in patients with RRMM who have received at least three prior 
lines of therapy including a PI and an IMiD or whose disease is double refractory to PI and IMiD 
(42, 43). A control arm consisting of isatuximab given as a single agent will be used in Phase 2 to 
characterize the treatment benefit and risk profile when cemiplimab is combined with isatuximab, 
and will serve to detect the risk ascribable to cemiplimab when it is combined to isatuximab in 
RRMM. To ensure that the most effective and safe dose of cemiplimab will be used in this study, 
two different doses will be assessed if it is permitted based on the MTD finding from Phase 1. 
Patients will be randomized in the 3 study arms of Phase 2. 
Patients will be followed until progression of disease (PD) or death for a maximum of 2 year after 
last patient is treated. This will allow the study to have a proper evaluation of the combination in 
term of PFS and OS. 
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5 
STUDY OBJECTIVES  
5.1 
PRIMARY OBJECTIVE(S)  
• To determine the safety and tolerability of the combination of isatuximab and cemiplimab.  
• Phase 2 only: To compare the overall response rate (ORR, defined as CR+VGPR+PR) of 
the combination of isatuximab and cemiplimab versus isatuximab alone in patients with 
RRMM based on International Myeloma Working Group (IMWG) criteria (44). 
5.2 
SECONDARY OBJECTIVE(S)  
• To determine the following efficacy measurements (Phase 2 only): 
- 
Clinical benefit rate (CBR, CR + VGPR + PR + Minimal response [MR]),  
- 
Duration of response (DOR), 
- 
Time to response (TTR), 
- 
Progression free survival (PFS), 
- 
Overall survival (OS). 
• To determine the pharmacokinetic profile of isatuximab and cemiplimab when given in 
combination. 
• To assess the immunogenicity of isatuximab and cemiplimab when given in combination. 
5.3 
EXPLORATORY OBJECTIVE(S)  
• To explore the minimal residual disease (MRD) in patients achieving a CR.  
• To assess the relationship between immune phenotypes, immune regulatory marker 
expression, adaptive immune response and parameters of clinical response. 
• To explore central/effector memory T cell proliferation. 
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6 
STUDY DESIGN  
6.1 
DESCRIPTION OF THE STUDY  
This is a Phase 1/2 study to evaluate the safety, tolerability, efficacy and PK of isatuximab in 
combination with cemiplimab in RRMM. 
The study will be conducted in 2 parts: 
• The Phase 1 (lead in) part is to confirm the feasibility of the isatuximab / cemiplimab 
combination. 
• The Phase 2 part will further evaluate the safety, efficacy and PK of the combination 
versus isatuximab monotherapy. Patients will be randomized in 1:1:1 in 3-arms or 1:1 in 
2-arms study using an IRT. 
Isatuximab and cemiplimab are defined in this protocol as “study treatments”. 
6.2 
PART 1  
6.2.1 Starting dose and dose de-escalation design  
Given the promising early signs of anti-cancer activity and the acceptable safety profile of each of 
the two antibodies (no MTD has been reached with either one as monotherapy), the starting dose 
will be 10 mg/kg QW for 4 weeks followed by Q2W for isatuximab and 250 mg Q2W for 
cemiplimab.  
Dose de-escalation will be performed if necessary as defined in the Table 1 below: 
Table 1 - Treatment dose and schedule  
Dose level  
Isatuximab 
Cemiplimab 
Dose level 1 (DL1) 
10 mg/kg  
QWx4 >Q2W 
250 mg  
Q2W 
Dose level -1 (DL-1) 
10 mg/kg  
QWx4 >Q2W 
250 mg  
Q4W 
Dose level -2 (DL-2) 
10 mg/kg  
Q2W 
250 mg 
Q4W 
Patients will continue treatment until disease progression, unacceptable adverse events, consent withdrawal, or any other 
reason. 
At dose level 1 (DL1), 3 patients will be enrolled for DLT evaluation in Cycle 1:  
• If 0/3 patient has DLT, no more patients will be enrolled in Phase 1, and DL1 will be the 
recommended Phase 2 dose (RP2D). 
• If 1/3 patients has DLT, additional 3 patients will be enrolled at DL1 for DLT assessment:  
- 
If a total of 1/6 patient has DLT at DL1, the DL1 will be the RP2D,  
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- 
If a total of ≥2/6 patients have DLT at DL1, dose will be de-escalated to dose level 
minus 1 (DL-1). 
• If ≥2/3 patients have DLT, dose will be de-escalated to dose level minus 1 (DL-1).  
At DL-1, the same DLT observation rule will be applied for selecting a RP2D and for dose  
de-escalation.  
At DL-2, the same DLT observation rule will be applied for selecting a RP2D. If ≥2/6 patients 
have DLT, study committee will analyze all the data collected up to this point and determine 
whether the study is to be terminated without proceeding to Phase II or if alternative doses and 
schedules could be further examined in Phase I, or changes in the study design could be made 
based on the perceived benefit/risk to patients and on the PK results. 
In Case 2 DLTs are observed before completion of enrollment no additional patients will be 
enrolled. Enrollment of patients within and between cohorts are staggered by at least 3 days. 
For DLT definition, see Section 9.1.1. 
The DLT observation period is 1 cycle (28 days). However, all AEs during treatment, unless due 
to disease progression or an obviously unrelated cause, will be taken into consideration by the 
Study Committee for the determination of the MTD and RP2D. 
The NCI CTCAE version 4.03 Appendix C will be used to assess the severity of AE, causal 
relationship is to be determined by the investigator. The DLTs will be confirmed by the Study 
Committee. 
6.2.2 Maximum administered dose / maximum tolerated dose  
The MAD is defined as the highest dose intensity at which at least 2 out of 3 or 2 out of 6 patients 
experienced DLTs during the initial DLT observation period (Cycle 1). The MTD is defined as 
the highest dose intensity at which 0 out of 3 or no more than 1 out of 6 patients experienced 
DLT. 
6.3 
PART 2  
Phase 2 will have 3 arms (if the MTD or RP2D is at DL1 or DL-1) or 2 arms (if the MTD or 
RP2D is at DL-2) to assess the treatment response and safety of the combination therapy 
compared with isatuximab alone. After confirmation of eligibility criteria, patients will be 
randomly assigned using an interactive response technology (IRT), in a 1:1:1 ratio or 1:1 ratio in 
1 of the 3- or 2-arm, respectively, with 35 patients in each arms. 
If RP2D is DL1: 
• Arm 1 (control): isatuximab 10 mg/kg QWx4 followed by Q2W. 
• Arm 2 (DL1): isatuximab 10 mg/kg QWx4 followed by Q2W + cemiplimab 250 mg Q2W. 
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• Arm 3 (DL-1): isatuximab 10 mg/kg QWx4 followed by Q2W + cemiplimab 250 mg 
Q4W. 
If RP2D is DL-1:  
• Arm 1 (control): isatuximab 10 mg/kg QWx4 followed by Q2W. 
• Arm 2 (DL-1): isatuximab 10 mg/kg QWx4 followed by Q2W + cemiplimab 250 mg 
Q4W. 
• Arm 3 (DL-2): isatuximab 10 mg/kg Q2W + cemiplimab 250 mg Q4W. 
If RP2D is DL-2:  
• Arm 1 (control): isatuximab 10 mg/kg QWx4 followed by Q2W. 
• Arm 2 (DL-2): isatuximab 10 mg/kg Q2W + cemiplimab 250 mg Q4W. 
6.3.1 Anti-CD38 refractory cohort  
Patients who received anti-CD38 mAb within 6 months before study entry and had disease 
progression while on treatment or within 60 days after the last treatment will be enrolled in a 
separate cohort. A decision will be made to start the cohort after the planned Phase 2 interim 
analysis suggested a treatment benefit of the combination therapy including pass the futility 
check. The dose and schedule will be determined based on the efficacy and safety findings in the 
interim analysis 
6.4 
RETREATMENT OF PATIENTS  
Study treatment can continue until disease progression, unacceptable adverse reactions, or 
patient/investigator decision to continue.  
A cycle is 28 days, and deemed to have been delayed if the treatment is >3 days beyond the 
theoretical day of treatment. The reason for dose delay will be provided.  
In the event of toxicity, in order for patients to be retreated, see Section 6.5 and Appendix G for 
retreatment recommendations. 
6.5 
DOSE DELAYS/ MODIFICATIONS  
6.5.1 General rules  
Dose modifications are permitted according to the guidelines described in this section.  
Dose modifications different from those stated in the protocol should only be made in consultation 
with the Sponsor unless required for immediate patient safety. 
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Dose adjustment and/or cycle delay are permitted in case of toxicity. Dose adjustments will be 
made according the worst grade of toxicity observed within a cycle. If a patient experiences 
several toxicities and there are conflicting recommendations, the most conservative dose 
adjustment recommended should be followed. Once a dose has been decreased, intra-patient  
re-escalation back to the previous dose level is not permitted.  
Administration of the study treatment will be discontinued in the event of a TEAE that persists 
despite appropriate dose modifications or any other AE that, in the opinion of the Investigator, 
warrants discontinuation. 
If one of the 2 drugs (cemiplimab or isatuximab) is prematurely permanently discontinued, the 
other drug can be continued until disease progression, unacceptable adverse reaction, patient’s 
refusal of further treatment, or in the absence of a clear benefit from therapy. The end of treatment 
assessment in this case will be 30 day after the date of the last IMP administration. 
All changes to study treatment administration must be recorded in the eCRF.  
6.5.2 Dose delay and dose omission  
Within a cycle, the treatment window is ±1 day for each of the weekly administrations, ±2 days 
for each of the Q2W administrations and ±4 days for each of the Q4W administration. A dose is 
deemed to have been delayed if the treatment is ≥2 days beyond the theoretical day of treatment 
for weekly dose, ≥3 days beyond the theoretical day of treatment for Q2W dose and ≥5 days 
beyond the theoretical day of treatment for Q4W dose. The reason for dose delay will be captured. 
Patient will receive the next infusion after recovery of the toxicity as described in Section 6.5.3 
and Section 6.5.4. If infusion has been delayed by 2 days within a cycle, next study treatment 
should be administered at the planned time interval between 2 administrations (eg, Day 15 
Cycle 1 administration is actually administered on Day 17, the planned Day 22 should be 
administered on Day 24).  
Patients may have dose omission if toxicity occurs and does not recover according to following 
rules: 
• In Cycle 1 if toxicity occurs and does not recover on the day of planned infusion or within 
the following 3 days, infusion of isatuximab and/or cemiplimab may be omitted.  
• In Cycle 2 and beyond, if toxicity occurs and does not recover on the day of planned 
infusion or within the following 7 days, infusion of isatuximab and/or cemiplimab may be 
omitted for patient on Q2W dose schedule.  
In case of consecutive dose omissions for the recovery of toxicity, following rules should be 
followed for restart or discontinue the treatment:  
• Dose interruption (cycle delay) up to 14 days, it is per Investigator’s decision to restart the 
treatment of cemiplimab and isatuximab.  
• After dose interruption of >14 days, it is per Investigator’s decision to restart the treatment 
of cemiplimab and isatuximab, if a clear benefit from therapy is observed and after 
consultation with the sponsor. 
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• Treatment with isatuximab and cemiplimab must be definitely discontinued if the 
interruption is longer than 84 days. 
6.5.3 Dose modifications  
Dose reduction of cemiplimab is permitted for patients treated at the starting dose level and will 
consist in time interval increase between 2 planned infusions (Table 2).  
Table 2 - Dose reduction guidance  
 
Isatuximab* 
Cemiplimab 
Dose level 
Dose (mg/kg) 
Frequency 
Dose (mg) 
Frequency 
Starting dose  
10 
QW x4 >Q2W 
250 mg 
Q2W 
Dose reduction 
10 
QW x4 >Q2W 
250 mg  
Q4W 
* No dose reduction for isatuximab 
Guidelines for isatuximab and cemiplimab dose modifications and treatment discontinuation due 
to hematological and non-hematological adverse reactions in general are outlined in Table 3.  
See Section 6.5.4 and Appendix G for guidance for immune-related AEs (irAEs) correlated with 
cemiplimab, and Section 6.5.5 for infusion associated reactions (IARs) correlated with isatuximab 
and cemiplimab.  
The final decision will be per Investigator’s judgment for the best interest of the patient.  
Table 3 - Isatuximab and cemiplimab dose modification guidelines  
Toxicity 
NCI CTCAE 
V4.03 
Isatuximab dose 
management  
Cemiplimab Dose 
management  
Action and Guidelines  
Hematological toxicity  
Grade 1, 2, 3 
No change in dose 
Patient should be given supportive 
care and monitored closely. 
Grade 3 
thrombocytopenia 
lasting >7 days or 
associated with 
bleeding 
Delay the dose until bleeding is controlled and platelet 
>50 000/mm3. Restart treatment with same dose and schedule. 
Patient should be given supportive 
care and monitored closely. 
Permanent discontinuation should 
be considered if toxicity does not 
resolve within 84 days of last 
infusion. 
Grade 4 
Delay the dose until ANC>1000/mm3, Platelet >50 000/mm3. 
Restart with same dose and schedule. 
Grade 4 lymphopenia: no change in dose  
Febrile neutropenia 
and/or neutropenic 
infection 
Delay the dose until fever and infection recover and 
ANC>1000/mm3. Restart with same dose and schedule. 
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Toxicity 
NCI CTCAE 
V4.03 
Isatuximab dose 
management  
Cemiplimab Dose 
management  
Action and Guidelines  
Non-hematological toxicity (other than irAE and IAR)  
Grade 1 
 No Change in Dose 
No Change in Dose 
N/A 
Grade 2 
Delay the dose until 
improves to Grade ≤1 or 
baseline. 
Restart treatment at same 
dose and schedule 
Delay the dose until improves to  
Grade ≤1 or baseline.  
Restart at same dose and 
schedule 
It is up to the investigator’s 
judgment whether to restart the 
treatment of isatuximab and 
cemiplimab if the interruption is 
within 14 days. 
If the treatment interruption is 
longer than 14 days, before 
restarting the treatment, the 
investigator must discuss with 
sponsor; if it is determined that it is 
to the best interest of the patient, 
the treatment may be restarted. 
If the interruption is longer than 
84 days, the treatment must be 
definitely discontinued. 
Grade 3  
Delay the dose until 
improves to Grade ≤1 or 
baseline.  
Restart at same dose and 
interval 
Delay the dose until improves to  
Grade ≤1 or baseline.  
1st episode lasts <14 days: restart 
at same dose  
1st episode lasts >14 days or 
recurrence: restart with first 
reduction dose (Q4W 
administration if began at Q2W 
starting dose). If began at DL-1, 
consider discontinuation 
2nd episode lasts >14 days or 
multiple recurrences discontinue 
treatment. 
Grade 4 
Permanent discontinue treatment for treatment related AEs 
Immune-related AE (irAE): see Table 4 and Appendix G for dose modification and patient management guideline) 
Infusion Associated Reaction (IAR): see Table 5 for IAR management guideline 
6.5.4 General guidelines for the management of immune-related adverse events  
Investigators must be extremely vigilant and be ready to intervene early in the management of 
immune-related AE (irAEs) because the onset of symptoms of irAEs (eg, pneumonitis) may be 
subtle.  
• Detailed guidance for the management of specific irAEs (Colitis, Endocrine AE, 
Pneumonitis, Renal AE, Dermatologic AE, Hepatitis, Ophthalmologic AE [Uveitis]), plus 
Nausea and Vomiting is provided in Section 19, Appendix G. 
• General guidance is provided in Table 4. 
• If a patient experiences several irAEs which involve different recommendations, the most 
conservative recommendation should be followed.  
The recommendations provided in Table 4 and Appendix G should be seen as guidelines, and the 
treating physician should exercise clinical judgment based on the symptoms and condition of the 
individual patient. 
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Any patient currently receiving cemiplimab who was previously treated with a 
phosphatidylinositol 3-kinase (PI 3-K) inhibitor and who develops stomatitis or mucositis should 
temporarily suspend study treatment. If this or any other immune-related AE occurs among these 
patients, the sponsor should be informed as soon as possible to discuss further management of the 
patient. An irAE of any grade in a patient previously treated with a PI 3-K inhibitor should be 
reported as an adverse event of special interest (AESI). 
Table 4 - General guidelines for immune related adverse events  
Severity 
Withhold/Restart 
/Discontinue 
isatuximab 
Treatment 
Withhold/Restart/Discontinue 
cemiplimab Treatment 
Supportive Care 
Grade 1 
No action 
No action 
Provide symptomatic treatment. 
Grade 2 
No action 
May delay the dose until Grade ≤1 
Consider systemic corticosteroids 
(Prednisone 0.5 to 1 mg/kg/day or 
equivalent) in addition to appropriate 
symptomatic treatment. 
Grade 3  
Grade 4 
Delay the dose 
Restart treatment 
when Toxicity 
improves to Grade ≤1 
or baseline.  
Delay the dose  
Restart treatment Toxicity improves to 
Grade ≤1 or baseline 
Discontinue if unable to reduce 
corticosteroid dose to <10 mg per day 
prednisone equivalent within 
12 weeks of toxicity. 
For any Grade 3-4 immune-related 
adverse event, if symptoms worsen or 
do not improve on adequate 
corticosteroids (Prednisone 1 to 
2 mg/kg/day or equivalent) within 48 to 
72 hours), consider additional 
immunosuppressive agents (to be 
selected from agents such as: 
infliximab, cyclophosphamide, 
cyclosporine, and mycophenolate 
mofetil). Referral of the patient to a 
specialized unit for assessment and 
treatment should be considered. 
6.5.5 General guidelines for the management of IARs  
See Appendix H. 
Patients should routinely receive premedications prior to isatuximab infusion as detailed in 
Section 8.2 to reduce the risk and severity of IARs commonly observed with mAbs.  
Infusion associated reactions (which include NCI-CTCAE, version 4.03 terms 
"allergic/hypersensitivity reactions" and "cytokine release syndrome/acute infusion reaction") 
typically occurs within 24 hours from the start of the infusion. If an IAR is observed, patients 
must also be informed of the potential risk of recurrent allergic reactions at subsequent infusions. 
Summary of IAR management is provided in Table 5. 
Patients who experience Grade 2 IARs may resume cemiplimab/isatuximab infusion after 
temporary interruption, under close monitoring and with therapy as needed. Patients may receive 
additional medication per the judgment of the Investigator. Additional recommended medications 
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are: diphenhydramine 25 mg IV (or equivalent) and methylprednisolone 100 mg IV (or 
equivalent). 
Once a Grade 2 IAR has improved or resolved to Grade ≤1, the infusion may be restarted: 
• For cemiplimab, the infusion should be restarted at one half the original infusion rate. 
• For isatuximab, the infusion should be restarted at one half the original infusion rate, see 
Section 8.4 for infusion rate. 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 IAR must have cemiplimab and/or isatuximab 
permanently discontinued and appropriate therapy should be administered: 
If a Grade 3 or high IAR occurred during cemiplimab infusion, cemiplimab should be 
permanently discontinue. Patient can continue treatment with isatuximab. 
If a Grade 3 or high IAR occurred after the start of isatuximab infusion, patient should be 
permanently discontinue the treatment of both cemiplimab and isatuximab. 
Should an IAR of Grade ≥2 occur, additional blood sampling during the AE is required for analysis 
of cytokine levels (TNF-α, , IL-6, IL-1-β, and IFN-γ), markers of complement activation (C3a, C4, 
CH50), serum tryptase, and markers of potential TLS (uric acid, lactate dehydrogenase [LDH], 
BUN/creatinine, potassium, phosphate, corrected calcium or ionized calcium). The infusion reaction 
and the therapy administered must be documented in the CRF. 
Grade 2 or higher IARs must be reported as AESIs (see Section 10.5). 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. 
Table 5 - IAR management  
Infusion Related Reaction grading 
(NCI-CTCAE v4.03 criteria) 
Recommendation 
Mild 
Grade 1 
Infusion interruption or intervention not indicated 
Continuation of cemiplimab/ isatuximab infusion is per the judgment of the 
Investigator following close direct monitoring of the patient’s clinical status. 
Cemiplimab/Isatuximab infusion may be stopped at any time if deemed 
necessary. If stopped, IAR will be classified as Grade 2 as per NCI-CTCAE 
definition. 
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 cemiplimab/isatuximab infusion. Give additional medication(s) with IV 
diphenhydramine 25 mg IV (or equivalent) and/ or IV methylprednisolone 
100 mg (or equivalent) as needed. cemiplimab*/Isatuximab** may be 
resumed only after patient recovery, with close monitoring.  
Blood samples for safety labs must be collected at listed as below: 
Important: additional blood sampling during the AE is required for analysis of 
cytokine levels (TNF-α, , IL-6, IL-1-β, and IFN-γ), markers of complement 
activation (C3a, C4, CH50), serum tryptase, and markers of potential TLS 
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Infusion Related Reaction grading 
(NCI-CTCAE v4.03 criteria) 
Recommendation 
Severe or Life-threatening 
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 cemiplimab/isatuximab infusion. Give additional medication(s) with 
diphenhydramine 25 mg IV (or equivalent) and/ or IV methylprednisolone 
100 mg (or equivalent) and/or epinephrine as needed. 
If IAR occurred during cemiplimab infusion, permanently discontinue 
cemiplimab. Continue treatment with isatuximab. 
If IAR occurred after the start of isatuximab infusion, permanently discontinue 
both cemiplimab and isatuximab. 
Blood samples for safety labs must be collected at listed as below: 
Important: additional blood sampling during the AE is required for analysis of 
cytokine levels (TNF-α, , IL-6, IL-1-β, and IFN-γ), markers of complement 
activation (C3a, C4, CH50), serum tryptase, and markers of potential TLS 
* Cemiplimab: The prepared infusion bag should be kept no more than 8 hours at room temperature between +15°C to +25°C (59°F to 
77°F), or no more than 24 hours at 5°C (with an acceptable operating range of 2°C to 8°C refrigerator). 
** Istuximab: the resulting solution for infusion should be used within 16 hours at room temperature between +15°C to +25°C (59°F to 77°F) 
from the bag preparation to the end of IV infusion of the patient or a new infusion should be prepared with the remaining dose to be 
administered the same day. 
6.5.6 Guidelines for the management of potential tumor lysis syndrome (TLS)  
In case of TLS, study treatment should be held until all serum chemistries have resolved. To 
ensure normal hydration, correct laboratory abnormalities, fluid overload, electrolyte or acid-base 
deviation. Management must be done according to the local site guideline. Use of xanthine 
oxidase or urate oxidase is allowed. 
TLS complications including renal function should be monitored, and study treatment can be 
reinstituted at full doses after resolution. 
Possible clinical and laboratory abnormalities which can be associated with TLS are presented in 
Table 6 (45). 
Table 6 - Laboratory and clinical abnormalities possibly consistent with TLS  
Laboratory  
Clinical  
Uric acid >8 mg/dL (>475.8 µmol/L) 
Potassium >6.0 mmol/L 
Phosphorus >4.5 mg/dL (>1.5 mmol/L) 
Corrected calciuma <7.0 mg/dL(<1.75 mmol/L) or ionized 
calcium <1.12 mg/dL (<0.3 mmol/L) 
• 
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 
• 
Seizures, cardiac dysrhythmia, neuromuscular irritability 
(tetany, paresthesias, muscle twitching, carpopedal 
spasm, Trousseau’s sign, Chvostek’s sign, 
laryngospasm, bronchospasm), hypotension, or heart 
failure probably or definitely caused by hypocalcemia 
• 
Dysrhythmias probably or definitely caused by 
hyperkalemia 
a The corrected calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter + 0.8x (4-albumin in grams per 
deciliter) 
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6.5.7 Guidance in case of hepatitis B reactivation occurring under study treatment  
Patient still on treatment at the time of amended protocol 05 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. 
6.6 
DURATION OF STUDY PARTICIPATION  
6.6.1 Duration of study participation for each patient  
The duration of the study for a patient will include a period for screening of up to 21 days. The 
cycle duration is 28 days. Patients will continue treatment until disease progression, unacceptable 
adverse events, consent withdrawal, or any other reason. 
After study treatment discontinuation, patients will return to the study site 30 days (+5 days) after 
the last dose of study treatments for end-of-treatment assessments. The post-treatment follow-up 
period include an extended safety follow-up period of 90 days after the last dose of study 
treatment, and further follow up period beyond 90 days after the last dose of study treatments until 
death or final study cut-off date, whichever occurs first.  
The further follow up schedule beyond 90 days after last treatment is adjusted according to the 
disease progression:  
• 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 or final study cut-
off date.  
• Patients who discontinue the study treatment without PD: will be followed every month 
for disease assessment until confirmation of PD or start treatment with another anti-cancer 
therapy whichever comes first. After PD patient will be followed every 3 months as 
described just above until death or final study cut-off date. 
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6.6.2 Determination of end of clinical trial (all patients)  
The cutoff date for primary analysis of ORR and reporting of other study endpoints will be 
6 months after last patient first treatment. 
The final analysis cutoff date for OS analysis and updated analysis of ORR and other secondary 
endpoints will be approximately 12 months after last patient first treatment date. 
Interim analysis 
For Phase 2 part, a formal interim analysis of response rate (including confirmed and unconfirmed 
responses) will be performed when the first 15 randomized patients in each arm completed 
2 cycles of treatment or permanently discontinue treatment. The purpose of the analysis is to stop 
combination arm early for futility when conditional power is <30%. Details can be found in 
Section 13.5.  
In addition, formal safety review by DMC are planned approximately every 3 months to examine 
unblinded patient safety data and quality of trial conduct. 
6.7 
STUDY COMMITTEES  
An independent Data Monitoring Committee (DMC), consisting of 3 external independent 
members (2 physicians with MM expertise and 1 statistician), not associated with the conduct of 
the study or other study committees will meet regularly as specified in the DMC charter. 
The DMC role will be to monitor the safety of the patients enrolled in the study (ie, exposed to 
study treatment and/or to study procedures) and to provide the sponsor with appropriate 
recommendations in due time to ensure the safety of the patients. During this exercise, the DMC 
will also institute any measures that may be required for ensuring the integrity of the study results 
during the execution of its primary mission. 
The DMC will convene every 3 months for regular safety and efficacy review, or on ad hoc basis 
when required. In addition, the DMC will also review the results from the interim analysis 
(see Section 13.5). After each meeting, the DMC will advise the sponsor’s representatives on 
recommendations regarding the continued safety of treating ongoing and future study patients, as 
well as the course of action regarding the conduct of the trial.  
The Study Committee will be comprised of the Investigators and Sponsor representatives. The 
Study Committee will be review clinical data on a regular basis, with a review being performed at 
least at the end of each dose level cohort, and at the end of the Phase 1 of the study.  
The Study Committee will convene regularly during Phase 1, eg, every 2 weeks, or ad hoc when 
required. 
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7 
SELECTION OF PATIENTS  
7.1 
NUMBER OF PATIENTS  
Approximately 108 to 138 patients. 
7.2 
INCLUSION CRITERIA  
I 01. Age ≥18. 
I 02. Patients must have a known diagnosis of multiple myeloma with evidence of measurable 
disease, as defined below: 
- 
Serum M-protein ≥1 g/dL (≥0.5 g/dL in case of IgA disease),  
AND/OR 
- 
Urine M-protein ≥200 mg/24 hours, 
OR 
- 
In the absence of measurable M-protein, serum immunoglobulin free light chain 
≥10 mg/dL, and abnormal serum immunoglobulin kappa lambda free light chain ratio 
(<0.26 or >1.65). 
I 03. Patients must have received prior treatment with an IMiD (for ≥2 cycles or ≥2 months of 
treatment) and a proteasome inhibitor (for ≥2 cycles or ≥2 months of treatment). 
I 04. Patients must have received at least 3 prior lines of therapy (Note: Induction therapy and 
stem cell transplant ± maintenance will be considered as one line). 
I 05. Patients, must have achieved MR or better with anyanti-myeloma therapy (ie, primary 
refractory disease is not eligible). 
I 06. Patients understand and have signed the Written Informed Consent form and arewilling 
and able to comply with the requirements of the trial. 
I 07. Anti-CD38 refractory cohort only: Patients who received anti-CD38 mAb within 6 months 
before study entry and had disease progression while on treatment or within 60 days after 
the last treatment. 
7.3 
EXCLUSION CRITERIA  
Patients who have met all the above inclusion criteria listed in Section 7.2 will be screened for the 
following exclusion criteria:  
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E 01. Has any concurrent hematology malignancy other than multiple myeloma, including: 
- 
Active primary AL amyloidosis, 
- 
Concomitant plasma cell leukemia. 
E 02. Has prior exposure to: 
- 
Isatuximab or participated clinical studies with isatuximab, 
- 
Any agent (approved or investigational) that blocks the PD-1/PD-L1 pathway. 
E 03. Diagnosed or treated for another malignancy within 3 years prior to the study treatment 
with the exception of resected/ablated basal or squamous cell carcinoma of the skin, or 
carcinoma in situ of the cervix, or other local tumors considered cured by local treatment, 
or low risk prostate cancer after curative therapy;  
E 04. Evidence of other immune related disease /conditions, including: 
- 
Ongoing or recent (within 2 years) evidence of significant autoimmune disease that 
required systemic immunosuppressive treatment (ie, with use of disease modifying 
agents, corticosteroids or immunosuppressive drugs.). Replacement therapy 
(eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc) is not considered a form of systemic treatment, 
- 
History of moderate immune-mediated acute drug reactions (eg, colitis, hepatitis, etc). 
E 05. History of non-infectious pneumonitis requiring steroids or current pneumonitis; history of 
the thoracic radiation. 
E 06. Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal 
flu vaccines that do not contain live virus are permitted. 
E 07. Known to be HIV+, HBV+ or hepatitis A, B, or C active Infection, or active tuberculosis, 
or severe and active infection requiring systemic antibiotics, antivirals or antifungals 
within 2 weeks prior to first dose (except when used for chronic prophylaxis). 
E 08. Has allogenic HSC transplant. 
E 09. Has prior exposure to treatment, including: 
- 
Prior treatment with idelalisib (an PI3K inhibitor) 
- 
Any anti-myeloma drug treatment including dexamethasone within 14 days before 
study entry (90 days if prior anti-CD38 treatment), 
- 
Patients who received anti-CD38 mAb within 6 months before study entry and had 
disease progression while on treatment or within 60 days after the last treatment will 
be excluded except the anti-CD38 refractory cohort. 
- 
Any major procedure within 14 days before the initiation of the first study treatment: 
plasmapheresis, major surgery (kyphoplasty is not considered major procedure), 
radiotherapy (palliative radiotherapy may be given to control pain). 
- 
Any investigational drugs within 28 days or 5 half-lives from the 1st study treatment, 
whichever is longer. 
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E 10. Congestive heart failure (New York Heart Association class III to IV) myocardial 
infarction within 6 months or with reduced ejection fraction, symptomatic coronary artery 
disease, major clinically significant electrocardiogram (ECG) and echocardiogram 
abnormalities, significant ventricular arrhythmias. 
E 11. Ongoing adverse events Grade ≥2 (excluding alopecia and those listed in eligibility 
criteria) from any prior anti-cancer therapy (NCI-CTC v4.03). 
E 12. Eastern Cooperative Oncology Group (ECOG) performance status (PS) >2. See 
Appendix B for ECOG performance status scale. 
E 13. Inadequate hematological function including: 
- 
Platelets <50 000/mm3. Patient should be platelet transfusion independent for 2 weeks 
prior to screening lab values),  
- 
ANC ≤1000/mm3 (1 x 109/L). (use of colony-stimulating factors to achieve these 
counts is allowed), 
- 
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 
guidance). 
E 14. Inadequate liver findings including: 
- 
Total bilirubin >2 x ULN, 
- 
AST and/or ALT >3 x ULN. 
E 15. Inadequate renal function: Estimated glomerular filtration rate (eGFR)  
<30 mL/min/1.73m2 (MDRD Formula). See Appendix A for MDRD equation.  
E 16. Corrected serum calcium >14 mg/dL (>3.5 mmol/L). 
E 17. Pregnant or breastfeeding female patients.  
E 18. Women of childbearing potential and male subjects with female partners of childbearing 
potential who are not willing to avoid pregnancy by using effective contraceptive (prior to 
initial dose, during the course of study and up to 6 months after the last study treatment). 
See Appendix J for guidance of the contraceptive and collection of pregnancy information.  
E 19. Known intolerance or hypersensitivity to any component of isatuximab and/or cemiplimab. 
E 20. Patient is a dependent on the sponsor or investigator (in conjunction with Section 1.61 of 
the ICH-GCP Ordinance E6), employees of the clinical study site or any other individuals 
directly involved in the conduct of the study, or immediate family members of such 
individuals. 
E 21. Patients who are accommodated in an institution because of regulatory or legal order, or 
prisoners or subjects who are legally institutionalized, or patients with any severe acute or 
chronic medical condition, including psychological disorder, which could impair the 
ability of the patient to participate in the study or interfere with interpretation of study 
results or patient unable to comply with the study procedures.  
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8 
STUDY TREATMENTS  
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT  
8.1.1 Isatuximab  
8.1.1.1 Pharmaceutical form  
The drug product is presented as a concentrate for solution for infusion in vials containing 
20 mg/mL (500 mg/25 mL) isatuximab in 20 mM histidine, 10% (w/v) sucrose, 0.02% (w/v) 
polysorbate 80, pH 6.0 buffer. 
It is supplied as a sterile, nonpyrogenic, injectable, 20 mg/mL concentrate for solution for infusion 
essentially free of visible particulates and is packaged in 30 mL glass vials fitted with elastomeric 
closure. Each vial contains a nominal content of 500 mg of isatuximab. The fill volume has been 
established to ensure removal of 25 mL. 
For administration to patients, the appropriate volume of isatuximab will be diluted in an infusion 
bag of 0.9% sodium chloride solution or 5% dextrose solution. The final infusion volume 
corresponding to the dose of isatuximab will be administered for a period of time that will depend 
on dose administered and will be based on protein amount given per hour. 
8.1.1.2 Dose of drug per administration  
Starting dose of isatuximab is 10 mg/kg, see Section 6.2.1. 
8.1.1.3 Preparation, reconstitution and administration  
Isatuximab concentrate for solution for infusion will be diluted in an infusion bag with 
0.9% sodium chloride solution or 5% dextrose solution to achieve the appropriate drug 
concentration for infusion. 
Infusion via a central line is preferred if available. In case of patients with local intolerance after 
peripheral IV infusion, decision to use central line is left to investigator decision. The final 
infusion volume corresponding to the dose of isatuximab will be administered by IV infusion for 
the period of time that will depend on total dose administered. 
Prior to dosing, each patient's dose will be individually prepared by the study pharmacist and 
labeled with protocol number, patient number, and treatment description. The patient’s weight 
should be measured prior to each treatment to allow calculation of the isatuximab dose. 
For infusion, an IV tubing administration set with a 0.20-μm in-line filter will be used; if an 
in-line filter is unavailable, a 0.20-μm filter unit may be attached to the administration set before 
administration. Further details are provided in the Pharmacy Manual. 
Detail instructions for dilution of the isatuximab concentrate for solution for infusion is provided 
in a Pharmacy Manual. 
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8.1.2 Cemiplimab  
8.1.2.1 Pharmaceutical form  
Cemiplimab drug product concentrated solution 50 mg/mL in 10 mL vials with 5.0 mL or 7.0 mL 
withdrawable, containing 10 mM histidine, 5% (w/v) sucrose, 1.5% (w/v) L-proline, and 
0.2% (w/v) polysorbate 80, pH 6.0. 
8.1.2.2 Dose of drug per administration  
Starting dose of cemiplimab is 250 mg, see Section 6.2.1. 
8.1.2.3 Preparation, reconstitution and administration  
Cemiplimab 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. 
Infusion via a central line is preferred if available. In case of patients with local intolerance after 
peripheral IV infusion, decision to use central line is left to investigator decision. The final 
infusion volume corresponding to the dose of cemiplimab will be administered by IV infusion for 
the period of time that will depend on total dose administered. 
Prior to dosing, each patient's dose will be individually prepared by the study pharmacist and 
labeled with protocol number, patient number, and treatment description.  
For infusion, an IV tubing administration set with a 0.20-μm in-line filter will be used; if an 
in-line filter is unavailable, a 0.20-μm filter unit may be attached to the administration set before 
administration. Further details are provided in the Pharmacy Manual. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S)  
Patients should routinely receive premedication 30 to 60 minutes prior to the start of the 
isatuximab infusion to reduce the risk and severity of IARs commonly observed with 
monoclonal antibodies.  
Patients who do not experience an IAR during the first 4 administrations of SAR650984 may have 
the need for subsequent pre-medication reconsidered at the investigator’s discretion in 
consultation with the sponsor. 
The recommended premedication agents and are listed below:  
• Acetaminophen 650 mg to 1000 mg PO (or equivalent). 
• Ranitidine 50 mg IV (or equivalent: other approved H2 antagonists [eg, cimetidine], oral 
proton pump inhibitors [eg, omeprazole, esomeprazole]). 
• Diphenhydramine 25-50 mg IV (or equivalent: eg, cetirizine, promethazine, 
dexchlorpheniramine, according to local approval and availability. Intravenous route is 
preferred for at least the first 4 infusions). 
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• Methylprednisolone 100 mg IV (or equivalent). 
The order of pre-medications should be: 
• Acetaminophen, ranitidine, diphenhydramine, and then methylprednisolone when 
methylprednisolone is administered via IV route.  
• Methylprednisolone (PO), acetaminophen (PO), ranitidine (IV), diphenhydramine (IV) 
when methylprednisolone is given via PO route. 
8.2.1 Acetaminophen or equivalent  
Commercial supplies of acetaminophen or equivalent will be used for this study. Please refer to 
package insert for further details as regards to formulation, storage and handling purposes. 
8.2.2 Ranitidine or equivalent  
Ranitidine is presented as a solution for IV infusion. Commercial supplies of ranitidine or 
equivalent will be used for this study. Please refer to package insert for further details as regards 
to formulation, storage and handling purposes. 
8.2.3 Diphenhydramine or equivalent  
Diphenhydramine is presented as a solution for IV infusion. Commercial supplies of 
diphenhydramine or equivalent will be used for this study. Please refer to package insert for 
further details as regards to formulation, storage and handling purposes. 
8.2.4 Methylprednisolone or equivalent  
Commercial supplies of methylprednisolone or equivalent will be used for this study. Please refer 
to package insert for further details as regards to formulation, storage and handling purposes. 
8.3 
DOSING REGIMEN AND SEQUENCE  
8.3.1 Dosing regimen  
Isatuximab:  
• For isatuximab alone as control, and at DL1 and DL-1: 10 mg/kg QW for 4 weeks 
followed by Q2W (ie, on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 
and beyond, of a 28-day cycle). 
• For DL-2: 10 mg/kg Q2W (ie, on Days 1 and 15 every cycle, of a 28-day cycle). 
Cemiplimab:  
• For DL1: 250 mg Q2W (ie, on Days 1 and 15 in all cycles of a 28-day cycle). 
• For DL-1 and DL-2: 250 mg Q4W (ie, on Day 1 in all cycles of a 28-day cycle). 
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8.3.2 Doing sequence  
In Phase 1, all patients will receive isatuximab and cemiplimab. 
In Phase 2, patients will be randomized to receive isatuximab alone or Isatuximab and 
cemiplimab. 
Emergency equipment and medication for the treatment of IARs (eg, antihistamines, 
bronchodilators, IV saline, corticosteroids, acetaminophen, and/or epinephrine) must be available 
for immediate use.  
•  Dosing sequence for patients receive isatuximab and cemiplimab administration: 
- 
Pre-medications as described in Section 8.2,  
followed by 
- 
Cemiplimab infusion over 30 minutes, 
followed by 
- 
Isatuximab iv infusion over approximately 2-4 hours. 
• Dosing sequence for patient receive isatuximab administration only: 
- 
Pre-medications as described in Section 8.2, 
followed by 
- 
Isatuximab iv infusion over approximately 2-4 hours. 
8.4 
RATE AND DURATION OF INFUSION  
The duration of infusion for cemiplimab is 30 minutes.  
For isatuximab, the rate of infusion for isatuximab should be initiated at 175 mg/hour: 
• First infusion: initiate infusion at 175 mg/hour. In the absence of IARs 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 175 mg/hour. In the absence of IAR after 1 hour 
of infusion, increase rate by 100 mg/hour increments every 30 minutes, to a maximum of 
400 mg/hour. 
Guidelines for patients who develop IARs are provided in Section 6.5.5. 
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8.5 
PACKAGING AND LABELING  
8.5.1 Isatuximab  
Isatuximab is packaged in 30 mL glass vials fitted with elastomeric closure. More detail 
information is provided in the pharmacy manual. 
The content of the labeling is in accordance with the local regulatory specifications and 
requirements. 
8.5.2 Cemiplimab  
Cemiplimab is packaged in USP Type 1 clear glass, 10 mL vial with 20 mm gray chlorobutyl 
rubber stopper with FluroTec® coating and 20 mm red flip-off seal. 
The content of the labeling is in accordance with the local regulatory specifications and 
requirements. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE  
8.6.1 Isatuximab  
Investigators or other authorized persons (eg, Pharmacists) are responsible for storing isatuximab 
in a secure and safe place with restricted access in accordance with local regulations, labeling 
specifications, policies, and procedures.  
Control of isatuximab storage conditions, especially control of temperature (eg, refrigerated 
storage), and information on in-use stability and instructions for handling the Sanofi compound 
should be managed according to the rules provided by the Sponsor.  
Isatuximab is to be stored at +2°C to +8°C (36°F to 46°F). All vials must be kept in their box until 
use. No protection from light is required for storage in the infusion bags.  
Details of the storage conditions for the diluted solution are provided in the Pharmacy Manual.  
8.6.2 Cemiplimab  
Investigators or other authorized persons (eg, Pharmacists) are responsible for storing cemiplimab 
in a secure and safe place with restricted access in accordance with local regulations, labeling 
specifications, policies, and procedures. 
Control of cemiplimab storage conditions, especially control of temperature (eg, refrigerated 
storage), and information on in-use stability and instructions for handling the compound should be 
managed according to the rules provided by the Sponsor. 
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Cemiplimab is to be stored at +2°C to +8°C (36°F to 46°F). All vials must be kept in their box 
until use. 
Details of the storage conditions for the diluted solution are provided in the Pharmacy Manual. 
8.7 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP IN PHASE 2  
Phase 2 will have 3 arms (if the MTD or RP2D is at DL1 or DL-1) or 2 arms (if the MTD or 
RP2D is at DL-2) to assess the treatment response and safety of the combination therapy with 
isatuximab alone as control. Patients will be randomized in study arms. IRT will be used for 
randomization. 
Any efforts should be done to start treatment within 3 working days even if a maximum up to 
5 working days can be allowed. 
8.8 
RESPONSIBILITIES  
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
The IMP will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allows the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
8.8.1 Treatment accountability and compliance  
Administration of the IMP will be supervised by the Investigator or Subinvestigator. 
The person responsible for drug dispensing is required to maintain adequate records of the IMP. 
These records (eg, drug movement form) include the date the IMP is received from the Sponsor, 
dispensed for patient and destroyed or returned to the Sponsor. The packaging batch number 
(PR Nr) on the vial must be recorded on the drug accountability form. 
The person responsible for drug administration to the patient will record precisely the date and the 
time of the drug administration to the patient. 
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8.8.2 Return and/or destruction of treatments  
Partially-used and used study treatment will be destroyed at the study site according to the 
standard practices of the site after an accurate accountability has been performed and signed by 
the Investigator (or the Pharmacist). A detailed treatment log form of the destroyed study 
treatment will be established with the Investigator (or the Pharmacist) and countersigned by the 
Investigator and the Monitoring Team. 
The Investigator must not destroy the unused IMP unless Sanofi provides written authorization. 
8.9 
CONCOMITANT TREATMENT  
A concomitant medication is any treatment received by the patient concomitantly to any study 
treatment(s). 
All treatments being taken by the patient 21 days prior to the first study treatment, at any time 
during the study in addition to the IMP are regarded as concomitant treatments and the type, dose 
and route of administration must be documented on the appropriate pages of the 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 IMP, they may 
be given at the discretion of the investigator and recorded in the e-CRF. 
• 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 e-CRF. 
8.9.1 Prophylaxis for opportunistic infections  
A recent study suggests that infections are the leading therapy-related causes of death in MM 
patients. Based on the NCCN guideline Version 1.2018, MM patients are at an intermediate risk 
of infection, prophylaxis for opportunistic infections is appropriate in this study. Broad-spectrum 
antimicrobial agents should be used in high-risk patients, per investigator’s discretion. 
8.9.2 Prohibited concomitant treatments:  
• Concurrent treatment with any other anti-myeloma therapy not specified in the protocol, 
including immunotherapy, hormonal therapy, targeted therapy or biological therapies, or 
other investigational drug, or curative radiotherapy. However, palliative radiotherapy may 
be given to control pain. The irradiated area should be as small as possible and should 
never involve more than 20% of the bone marrow in any given 3-week period. In all such 
cases, the possibility of tumor progression should be ruled out by physical, biochemical 
and radiological assessments of the tumor. The irradiated area cannot be used as a 
parameter for response assessment. 
• Concomitant systemic corticosteroids are prohibited, except used in the premedication as 
defined in the study protocol Inhaled glucocorticosteroids whenever indicated is allowed. 
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• Live vaccines should be avoided. However, giving the increased risk of infection, routine 
vaccinations are recommended for the patients and their contacts. Prophylactic vaccination 
is recommended for influenza A and B virus, pneumococci and haemophilus influenza. 
• Prophylactic use of hematopoietic growth factors (eg, G-CSF, GM-CSF, erythropoietin) 
during the DLT observation period. Curative treatment is allowed. 
8.9.3 Contraceptive measures and pregnancy counseling  
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) prior to first study treatment, while on therapy and for 
5 months following the last dose of Isatuximab and 6 months following the last dose of 
cemiplimab.  
A woman is considered of childbearing potential (WOCBP), ie, fertile, following menarche and 
until becoming post- menopausal unless permanently sterile.  
The following highly effective methods of contraception are accepted: 
• Sexual abstinence, 
• Diaphragm and spermicide PLUS male condom, or,  
• Intrauterine device PLUS male condom, or,  
• Medical method (such as hormonal contraceptive) PLUS male condom. 
The choice of effective method is left to Investigator judgment, in accordance to local regulation. 
Sterilized or infertile subjects are exempt from the requirement to use of contraception. In order to 
be considered sterilized or infertile, subjects must have undergone surgical sterilization 
(vasectomy/bilateral tubectomy, hysterectomy, bilateral ovariectomy) or be a postmenopausal 
woman defined as 12 months or more with no menses prior to enrollment and 50 years of age. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT  
9.1 
SAFETY  
The first co-primary objective of this study is to determine the safety and tolerability of the 
combination of isatuximab and cemiplimab in patients with RRMM.  
The safety profile will be assessed from the findings of physical examination (preferably by the 
same physician in each center), laboratory tests and reports of AEs, etc, and will be based on 
incidence, severity (as graded by the NCI-CTCAE v. 4.03), and cumulative nature of TEAEs 
(defined as AEs that develop or worsen in grade or become serious during the TEAE period). 
9.1.1 Dose-limiting toxicities (Phase 1 only)  
Potential DLTs are defined as the occurrence of any of the following adverse reactions at 
first cycle:  
Hematological DLT is defined as any of the followings unless due to disease progression or 
an obviously unrelated cause: 
• Grade 4 neutropenia lasting more than 7 consecutive days. 
• Grade 3 to 4 neutropenia complicated by fever (temperature ≥38.5°C on more than 
one occasion) or microbiologically or radiographically documented infection. 
• Grade 3 to 4 thrombocytopenia associated with clinically significant bleeding that 
requiring clinical intervention.  
Note: Platelet transfusions in the absence of bleeding will not be considered a DLT 
because thrombocytopenia is an anticipated complication of MM, particularly in a heavily 
pretreated patient population, and patients can enter the study with pre-existing 
thrombocytopenia. 
Non-hematologic DLT is defined as any of the followings unless due to disease progression or 
an obviously unrelated cause: 
• Grade 4 non-hematologic AE. 
• Grade ≥2 uveitis. 
• Grade 3 non-hematological AE lasting >3 days despite optimal supportive care. except: 
- 
Grade 3 fatigue, 
- 
Allergic reaction/hypersensitivity attributed to isatuximab or cemiplimab, 
- 
Laboratory abnormality that worsens to Grade 3 or 4 but is not clinically significant 
per investigator and study committee. 
• Delay in initiation of the 2nd cycle >14 days due to treatment related laboratory 
abnormalities/ AE. 
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In addition, any other AE that the investigator / Study Committee deem to be dose limiting, 
regardless of its grade, may also be considered as DLT. 
At the end of Cycle 1, each patient must be assessed by the Investigator as to whether or not the 
patient experienced a DLT. This information must be recorded on the appropriate eCRFs, and 
an electronic DLT notification (either DLT or not) will be sent to the Sponsor, before a 
subsequent cycle may begin.  
Potential and IMP-related DLTs will be considered as adverse event of special interest (AESI). As 
such, the Investigators will be required to report them to the Sponsor within 24 hours of the 
Investigator becoming aware of each event. The Investigator will complete the specific DLT form 
in the eCRF. 
The reported potential DLTs will be reviewed by the Study Committee in order to determine their 
relationship to the IMP.  
9.1.2 Adverse events  
Adverse events will be collected from the signing of the study main informed consent up to 
30 days after the last IMP administration. During the follow-up period, ongoing SAEs regardless 
of relationship to IMP and ongoing or new study treatment related AEs will be followed until 
resolution or stabilization. Adverse events encountered before the start of study treatment will be 
summarized separately. 
Adverse events will be graded according to the NCI CTCAE v.4.03, and will be coded to a 
“Preferred Term” and associated primary “System Organ Class” using MedDRA (Medical 
Dictionary for Regulatory Activities).  
The study-specific and general safety criteria are developed in Section 10. 
9.1.3 Laboratory safety variables  
Please refer to “Study Procedures” Section 12. 
9.1.4 Clinical examinations  
Please refer to “Study Procedures” Section 12. 
9.1.5 Immunogenicity  
It is of utmost importance to collect all blood samples at the specified times and according to the 
specifications for collection, storage, and shipment as defined in a separate laboratory manual. 
Samples missed or lost, for any reason should be recorded. Actual dates and times of blood 
collection should be recorded in the eCRF. The dates and times of drug administration should also 
be precisely recorded. 
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The cemiplimab and isatuximab ADA sampling times for blood collection can be found in the PK 
Flow Chart (Section 1.2 and Section 1.3). 
• For cemiplimab during treatment phase, samples for immunogenicity assessment are to be 
collected every third Cycle from C5 (ie, on D1 of C5, C8, C11, C14, etc) till the last study 
treatment. In response to AEs of special interest, such as anaphylaxis or hypersensitivity, 
ADA samples closer to the event may be collected, based on the judgment of the 
Investigator and/or medical monitor. If isatuximab is stopped and cemiplimab treatment 
continues, cemiplimab ADA samples should be collected as planned per PK/PD flow-
chart. 
• For isatuximab, samples for immunogenicity assessment are to be collected during the 
course of the study. However, collection can be stopped earlier based on the updated 
knowledge of isatuximab immunogenicity (note that collection was indeed interrupted at 
cut-off date of primary efficacy analysis 6 months after LPI). At FU 90 (±7) days after last 
IMP administration if ADA is positive or inconclusive no further ADA will be sampled. 
The ADA results will be communicated to investigational sites on an ongoing basis. 
Bioanalytical methods used for immunogenicity assessment are summarized in Table 7. 
Table 7 - Bioanalytical methods for immune response assessment  
Analyte 
ANTI ISATUXIMAB ANTIBODY 
ANTI CEMIPLIMAB ANTIBODY 
Matrix 
Plasma 
Serum 
Analytical technique 
PandA method 
Non-quantitative bridging immunoassay 
Lower Limit of Quantification 
Not applicable 
Not applicable 
Site of bioanalysis 
Covance Harrogate (UK)) 
Regeneron Pharmaceuticals, Inc. 
(Tarrytown, NY) 
 
9.2 
EFFICACY  
9.2.1 Primary endpoint (Phase 2 only)  
The second co-primary endpoint of the study is to determine the efficacy of the combination as 
assessed by ORR. ORR is defined as the proportion of patients with CR (including sCR), VGPR 
and PR as assessed by investigators using the IMWG response criteria (44). 
The following disease assessment procedures will be performed at screening (for eligibility) and 
again at Cycle 1 Day 1 prior to study treatment administration (baseline for response assessment) 
and then Day 1 of every cycle during treatment up to progression: 
• M-protein quantification (serum and urine) (local laboratory). 
• FLC quantification (local laboratory). 
• Quantitative immunoglobulins (local laboratory). 
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• In addition, other examinations for disease assessment will be done as clinically indicated 
(eg, to confirm a response, suspected PD) as below (local laboratory): 
- 
Bone marrow aspiration,  
- 
Bone disease assessment, 
- 
Extramedullary disease (plasmacytoma) assessment (including bone plasmacytoma). 
Response/progression will be determined according to IMWG criteria (44) (Appendix D). 
Response/progression based on M-protein and FLC will be confirmed based on 2 consecutive 
assessments. 
Progressive disease is defined for patients with measurable disease with one of the following: 
• Increase of ≥25% in serum M-protein from nadir (the absolute increase must be ≥0.5 g/dL) 
in 2 consecutive assessments; serum M-protein increases ≥1 g/dL in 2 consecutive 
assessments are sufficient to define relapse if starting M-protein t is ≥5 g/dL and/or,  
• Increase of ≥25% in urine M-protein from nadir (the absolute increase must be 
≥200 mg/24 h) in 2 consecutive assessments and/or,  
• Only in subjects without measurable serum and urine M-protein levels: increase of ≥25% 
in the difference between involved and uninvolved FLC levels and absolute increase must 
be >10 mg/dL and/or, 
• Definite development of new bone lesions or soft tissue extramedullary disease, or 
increase ≥50% from nadir in the sum of perpendicular diameters of existing soft tissue 
extramedullary disease lesions if >1 lesion, or ≥50% increase in the longest diameter of a 
previous soft tissue extramedullary disease lesion >1 cm in short axis. 
Clinical deterioration will not be considered progression in the primary analysis of ORR. 
Measurable disease is defined by at least one of the following measurement:  
• Serum M-protein ≥1g/dL or ≥0.5 g/dL for patients with IgA MM.  
• Urine M-protein ≥200 mg/24h.  
• In the absence of measurable M-protein, serum immunoglobulin FLC level ≥10 mg/dL 
provided abnormal serum immunoglobulin kappa lambda FLC ratio (<0.26 or >1.65). 
9.2.2 Secondary endpoints (Phase 2 only)  
• CBR: defined as the proportion of patients with CR (including sCR), VGPR, PR and 
minimal response (MR) as assessed by investigators using the IMWG response criteria. 
• DOR: defined as the time from the date of the first response (≥PR) that is subsequently 
confirmed to the date of first confirmed disease progression or death, whichever happens 
first PD will be determined according to IMWG criteria (See Appendix D). In the absence 
of the confirmation of subsequent disease progression or death before the analysis cut-off 
date or the date of initiation of a further anticancer treatment, the DOR will be censored at 
the date of the last valid disease assessment not showing disease progression performed 
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prior to initiation of a further anticancer treatment and the analysis cut-off date, whichever 
is earlier. DOR will not be calculated for patients that do not achieve a PR or better. 
• TTR: defined as time from first study treatment administration (C1D1) to first response 
(PR or better) that is subsequently confirmed. 
• PFS: defined as time from the first study treatment administration to the date of 
first documentation of progressive disease (PD) that is subsequently confirmed or the date 
of death from any cause. Same censoring rules as DOR will be used.  
• OS: defined as the time from the first study treatment administration to death from any 
cause. Patients without death prior to the analysis cutoff date will be censored at the 
last date the patient was known to be alive or the cutoff date whichever comes first. 
9.3 
PHARMACOKINETIC EVALUATION  
9.3.1 Sampling time  
It is of utmost importance to collect all blood samples at the specified times and according to the 
specifications for collection, storage, and shipment as defined in a separate laboratory manual. 
Samples missed or lost, for any reason should be recorded. Actual dates and times of blood 
collection should be recorded in the eCRF. The dates and times of drug administration should also 
be precisely recorded. 
The cemiplimab and isatuximab PK sampling times for blood collection can be found in the PK 
Flow Chart (Section 1.2 and Section 1.3). 
For isatuximab, samples for PK assessment are to be collected during the course of the study. 
However, collection can be stopped earlier based on the updated knowledge of isatuximab PK 
(note that collection was indeed interrupted before Amendment 05). 
9.3.2 Pharmacokinetic sample handling procedure  
Special procedures for collection, storage, and shipment will be provided in a separate laboratory 
manual. 
9.3.3 Bioanalytical methods and bioanalytical sites  
Bioanalytical methods are summarized in Table 8. 
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Table 8 - Bioanalytical methods for isatuximab and functional cemiplimab pharmacokinetic 
analysis  
Analyte 
Isatuximab 
Cemiplimab 
Matrix 
Plasma 
Serum 
Analytical technique 
Immunoassay 
Immunoassay 
Lower limit of quantification 
0.500 µg/mL 
78.0 ng/mL 
Site of bioanalysis 
Covance Harrogate, UK 
Regeneron Pharmaceuticals, Inc. 
(Tarrytown, NY) 
9.3.4 Pharmacokinetic parameters  
9.3.4.1 Non-compartmental analysis  
The following PK parameters will be calculated with PKDMS software (Pharsight), using  
non-compartmental methods from plasma of isatuximab and serum of cemiplimab concentrations. 
The parameters will include, but may not be limited to the following: 
Table 9 - List of pharmacokinetic parameters and definitions  
Parameters 
Analyte 
Definition 
cemiplimab 
Isatuximab 
Ceoi 
• 
• 
Concentration observed at the end of intravenous (IV) infusion 
Cmax 
•
• 
Maximum concentration observed after the first infusion 
tmax 
•
• 
Time to reach Cmax 
Clast 
•,  
• 
Last concentration observed above the lower limit of quantification after the first 
administration 
tlast 
•
• 
Time of Clast 
Ctrough 
• 
• 
Concentration observed just before treatment administration during repeated dosing 
AUC0-14d or 
AUC0-28d 
• 
 
Area under the concentration versus time curve calculated using the trapezoidal method 
over the dosing interval (DL1=14 days and DL-1=28 days) after the first administration 
AUC0-7d 
 
• 
Area under the concentration versus time curve calculated using the trapezoidal method 
over the dosing interval (7 days ) after the first administration 
9.3.4.2 Population approach  
Populations PK approaches may be used for both compounds and PK estimates may be used to 
conduct exploratory exposure-response analyses for safety and efficacy and PK/PD analyses for 
relevant biomarkers. If done, the data generated will be reported in stand-alone report(s). 
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9.4 
SPECIFIC ASSESSMENTS: ISATUXIMAB IAR LABS - CYTOKINES, MARKERS OF 
ACTIVATED COMPLEMENTS AND SERUM TRYPTASE  
Baseline sample will be drawn for assessment of cytokines (IL-1β, IL-6, TNFα and IFNγ), 
markers of activated complement (C3a, C4 and CH50), lactate dehydrogenase [LDH] and serum 
tryptase, prior to first isatuximab administration at Cycle 1. Then if an isatuximab infusion 
associated reaction (IAR) ≥Grade 2 occurs, additional blood sampling during the AE is required 
for analysis.  
Samples not collected, missed or lost, for any reason should be documented. Actual dates and 
times of blood collection should be recorded in the eCRF. The dates and the times of study 
treatment administration should also be precisely recorded. 
Special procedures for collection, storage, and shipment as well as bioanalysis methods and 
bioanalysis location will be provided in a separate Laboratory Manual. 
9.5 
EXPLORATORY BIOMARKER ANALYSES  
Bone marrow and blood samples will be collected for the following biomarker analyses: 
• Correlation of multiple myeloma molecular subtype (as defined by marker expression, 
cytogenetics) with parameters of clinical response. Cytogenetics analysis (including, but 
may not limited to, 17p deletion, t[4, 14] and t[14, 16] ) will be performed. 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. 
• Correlation of immunophenotype in bone marrow and/or peripheral blood with parameters of 
clinical response. Blast cells and immune cell populations (including MDSC cell, T-cell, 
NK-cell subsets and Treg/CD8 effector ratio) will be characterized by multiparametric flow 
cytometry analysis 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 and blood will be collected at baseline and 
Day 1 of Cycle 3 and blood samples only will be collected at EOT. 
• Whenever possible, PD-L1 expression in malignant plasma and immune cells will be 
determined and correlated with clinical response. Access to archival bone marrow biopsy 
material will be requested at screening and if available, retrospective expression analysis 
will be performed by IHC assay. 
• Correlation of adaptive immune response (TCR repertoire profiling) with parameters of 
clinical response. Blood and bone marrow samples will be collected at screening, D1 of 
Cycle 3 (blood only) and at CR. 
• Correlation of adaptive immune response (humoral and cellular immune responses to 
myeloma-related tumor antigens) with parameters of clinical response. Blood will be collected 
prior to pre-medication and IMP administration on D1 of Cycle 1, Cycle 2, Cycle 4, Cycle 7 
and Cycle 10 and in disease progression patients at EOT. Humoral response will be assessed 
in all sites. Cellular response will be assessed in patients at selected sites. 
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•  MRD will be assessed by sequencing and/or flow cytometry in bone marrow samples 
from CR patients and correlated with parameters of clinical response. Method to measure 
MRD include multi-parametric flow cytometry (MFC) and more recently next generation 
sequencing to amplify and sequence immunoglobulin gene segments present in myeloma 
clone is a quantitative method for MRD detection. Bone marrow samples will be collected 
at CR. 
• Additional analysis, not specified in the protocol but related to the drug action and/or 
effect of isatuximab/cemiplimab, may be conducted on remaining samples pending 
evolving literature. 
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10 
PATIENT SAFETY  
10.1 
SAFETY ENDPOINTS ASSESSED IN THIS TRIAL  
Refer to Section 9.1 for definition of safety criteria, parameters to be analyzed and method of 
sample collection. 
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. Please refer to Section 9.1.2 Adverse Events 
monitoring 
All AEs will be managed and reported in compliance with all applicable regulations, and included 
in the final clinical study report. 
10.3 
DEFINITIONS OF ADVERSE EVENT AND SERIOUS ADVERSE EVENT  
An Adverse Event is any untoward medical occurrence in a patient or clinical investigation 
patient administered with a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
A Serious Adverse Event is any untoward medical occurrence that at any dose: 
• Results in death or, 
• Is life-threatening or, 
Note: The term "life-threatening" in the definition of "serious" refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization or, 
• Results in persistent or significant disability/incapacity or, 
• Is a congenital anomaly/birth defect, 
• Is a medically important event: 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the 
definition above. 
Note: Examples of such events (list is not exhaustive) are intensive treatment in an emergency 
room or at home (for allergic bronchospasm, blood dyscrasias, or convulsions) or asymptomatic 
ALT increase ≥10 ULN that does not result in hospitalization, or development of drug 
dependency or drug abuse. 
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10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING  
10.4.1 Adverse events  
All AEs regardless of seriousness or relationship to the IMP, spanning from the signature of the 
informed consent form (ie, occurring during the baseline period even in the absence of any 
administration of IMP), up to 30 days following the last administration of study treatment, are to 
be recorded on the corresponding page(s) included in the eCRF. 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. The 
Investigator should specify the date of onset, intensity, action taken with respect to IMP, 
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 IMP. 
Vital signs or ECG abnormalities are to be recorded as AEs only if they are symptomatic and/or 
requiring corrective treatment and/or leading to treatment discontinuation and/or modification of 
dosing and/or fulfilling a seriousness criterion and/or is defined as an AESI (see Section 10.3). 
Laboratory abnormalities are to be recorded as AEs only if they lead to treatment discontinuation 
and/or modification of dosing and/or fulfill a seriousness criterion and/or are defined as an AESI 
(DLT) (see Section 10.3). 
10.4.2 Timely handling of certain AEs  
In the case of a SAE, an AESI, a pregnancy report, or an overdose, the Investigator must 
immediately: 
• ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send e-notification to the monitoring team after 
approval of the Investigator within the e-CRF or after a standard delay. 
• There may be instances when copies of medical records for certain cases are requested by 
Sanofi. In such case, care should be taken to ensure that the patient's identity is protected 
and the patient's identifiers in the study are properly mentioned on any copy of a source 
document provided to the Company. For laboratory results, include the laboratory normal 
ranges 
• All further data updates should be recorded in the e-CRF as appropriate within 24 hours of 
knowledge. In addition, every effort should be made to further document each SAE that is 
fatal or life threatening within the week (7 days) following initial notification. 
• A back-up plan is used (using paper flow) when the e-CRF system does not work. 
10.4.3 Follow-up  
• 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. Ongoing 
related AEs at the end of study treatment will be followed until resolution or stabilization. 
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• In case of any SAE/AESI, 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 discontinued 
study treatment or has left the clinical trial and that additional investigations may be 
requested by the monitoring team; 
• In case of any AE or AESI brought to the attention of the Investigator at any time after the 
end of the study for the patient and considered by him/her to be caused by the IMP with a 
reasonable possibility, should be reported to the monitoring team. 
10.4.4 Treatment discontinuation due to nonserious adverse event  
In the case of a treatment discontinuation due to a nonserious AE: 
• ENTER (within 24 hours) the information related to treatment discontinuation due to a 
non-SAE in the appropriate screens of the e-CRF (AE with the box "action taken with 
IMP" ticked "permanently discontinued", together with the end of treatment form with 
reason that should be ticked "AE"); 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. 
10.5 
ADVERSE EVENT OF SPECIAL INTEREST  
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified or 
removed during a study by protocol amendment. 
The following conditions 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 event: 
• Grade ≥2 acute infusion associated reactions (IARs; Section 6.5.4 for manifestation/ 
symptoms typical of an IAR). An IAR occurs typically within 24 hours from the start of 
the infusion. 
• Grade ≥3 immune-related TEAEs. 
• Any grade of immune-related TEAEs in a patient previously treated with a PI 3-K 
inhibitor.  
• DLTs (as defined in Section 9.1.1) are considered as 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 event. The Investigator will attach the DLT-specific CRF page to 
the DLT/AESI form. 
• Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP/NIMP. 
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- 
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. It 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 IMP should be 
discontinued,  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined.  
• Symptomatic overdose (serious or nonserious) with IMP/NIMP (see Section 10.4.2): 
- 
An overdose (accidental or intentional) with the isatuximab or cemiplimab is defined 
as increase of at least 30% of the intended administered dose at each infusion 
expressed in unit per body weight) to be administered in the specified duration or if the 
dose is administered in less than half the recommended duration of administration,  
- 
An overdose (accidental or intentional) with the NIMP is defined as increase of at least 
30% of the intended administered dose at each administration expressed in unit per 
body weight), 
- 
In case of accidental or intentional overdose with the IMP/NIMP, even not fulfilling a 
seriousness criterion, is to be reported to the Sponsor immediately (within 24 hours) 
using the AE form together with the SAE complementary form to be entered in the 
eCRF.  
Of note, asymptomatic overdose has to be reported as a standard AE. 
10.5.1 Laboratory abnormalities  
Laboratory abnormalities should be monitored, documented, and managed according to the 
related flowchart (see Section 1.1). Laboratory values will be reported in the appropriate pages of 
e-CRF. 
Laboratory abnormalities should be reported as AE in case they lead to an action on study 
treatment, if they are serious, or AESIs (see Section 10.4.1). 
10.6 
OBLIGATIONS OF THE SPONSOR  
During the course of the study, the Sponsor will report in an expedited manner: 
• All SAEs that are unexpected and are at least reasonably related to the IMP (ie, suspected 
unexpected serious adverse reactions), to the regulatory authorities, Institutional Ethics 
Committees (IECs)/Institutional Review Boards (IRBs) as appropriate and to the 
Investigators.  
• All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
• The AESIs (eg, DLT) to those regulatory authorities who require such reporting.  
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Adverse events that are considered expected are specified in the reference safety information 
(current IB of each of the two IMPs).  
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
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11 
HANDLING OF PATIENT TEMPORARY AND PERMANENT 
TREATMENT DISCONTINUATION AND OF PATIENT STUDY 
DISCONTINUATION  
Pregnancy will lead to definitive treatment discontinuation in all cases. 
11.1 
PERMANENT TREATMENT DISCONTINUATION WITH INVESTIGATIONAL 
MEDICINAL PRODUCT(S)  
11.1.1 List of criteria for permanent treatment discontinuation  
Isatuximab or cemiplimab can be discontinued prematurely. Patients will remain on study 
treatment until the last IMP (isatuximab or cemiplimab) is discontinued. The reason for premature 
discontinuation will be captured in the appropriate eCRF page. 
Patients may withdraw from treatment with IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be done at the discretion of the Investigator. All efforts 
should be made to document the reason(s) for discontinuation and this should be documented in 
the e-CRF. 
Treatment with the IMP should be discontinued in any of the following cases: 
• At the patient’s request, at any time and irrespective of the reason (consent’s withdrawal), 
or at the request of their legally authorized representative. “Legally authorized 
representative” is considered to be an individual or judicial or other body authorized under 
applicable law to consent on behalf of a prospective patient to the patient’s participation in 
the procedure(s) involved in the research. Withdrawal of consent for treatment should be 
distinguished from withdrawal of consent for follow-up visits and from withdrawal of 
consent for non-patient contact follow-up, eg, medical records check. Patients requesting 
withdrawal should be informed that withdrawal of consent for follow-up may jeopardize 
the public health value of the study. Patients who withdraw should be explicitly asked 
about the contribution of possible AEs to their decision to withdraw consent, and any AE 
information elicited should be documented. Preferably the patient should withdraw 
consent in writing and, if the patient or the patient’s representative refuses or is physically 
unavailable, the site should document and sign the reason for the patient’s failure to 
withdraw consent in writing.  
• If, in the Investigator’s opinion, continuation of the study treatment would be detrimental 
to the patient’s wellbeing, such as: 
- 
Disease progression, 
- 
Unacceptable AE, 
- 
Poor compliance to the study protocol, 
- 
Any other reason such as intercurrent illness that prevents further administration of 
study treatment (will be specified). 
• Patient is lost to follow-up. 
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If patients are clinically stable, and possibly deriving clinical benefit from therapy with minimal 
toxicity, the patient will be maintained on treatment for the maximum period of time defined in 
Section 6.5.7. 
11.1.2 Handling of patients after permanent treatment discontinuation  
All permanent treatment discontinuation should be recorded by the Investigator in the appropriate 
screen of e-CRF when considered as confirmed. After study treatment is discontinued, patients 
should complete a follow-up visit 30 days after the last administration of the IMP as described in 
Section 12.4.3. 
Patients who have been withdrawn from the study treatment cannot be re-entered into the study. 
11.2 
REPLACEMENT OF PATIENTS  
During the dose Phase 1 part of the study, a patient may be considered not evaluable for DLT and 
may be replaced at the same dose level as described in Section 6.2.2. 
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12 
STUDY PROCEDURES  
12.1 
VISIT SCHEDULE  
During the course of the study, all patients entering the study must be evaluated according to the 
schedule outlined in the flow charts in Section 1.1, Section 1.2 and Section 1.3 and described 
below. The results of the evaluation will be recorded in the e-CRF pages until the patient is not 
followed anymore.  
12.2 
SCREENING/BASELINE EVALUATION  
The screening assessments are to be performed within 21 days prior to first study treatment, 
unless indicated otherwise. All of the inclusion criteria (and none of the exclusion criteria) must 
be met, and informed consent must be signed by the patient before any study-specific procedure is 
performed. 
The following procedures are to be performed/assessed: 
• Signed informed consent. 
• Demography (age, gender and race) and medical/surgical history (including smoking 
status). 
• Myeloma history and prior anti-myeloma treatment (including date of initial diagnosis of 
symptomatic multiple myeloma, stage and type of disease at diagnosis and study entry, 
heavy and light chain component, previous anti myeloma therapy – including drug name, 
transplant dates, intent, date of progression, best response and reason for discontinuation)  
• Physical examination to be performed at screening (less than 7 days prior to first study 
treatment) to include examination of main body systems including neurological, digestive 
exam, respiratory (signs and symptoms, respiratory rate), hepatic and spleen span, lymph 
node examination, weight and height (height at baseline only). 
• Vital signs including blood pressure, heart rate, respiration rate and body temperature. 
• Prior medication use within 21 days prior to the first study treatment administration. 
• 12-lead ECG. 
• ECOG PS. 
• All AEs/SAEs occurring after signed informed consent for all patients.  
• Chest X-ray. 
Local laboratory assessments 
• Serum pregnancy test to be performed within 7 days prior first study treatment 
administration for females of childbearing potential. 
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• Blood chemistry: to be done at screening : SGOT (AST), SGPT (ALT), bilirubin (total and 
direct), alkaline phosphatase, lactate dehydrogenase (LDH), sodium, potassium, chloride, 
bicarbonate/carbon dioxide, calcium, corrected serum calcium, magnesium, phosphate, 
uric acid, serum creatinine and eGFR (MDRD Formula), urea or BUN, fasting glucose, 
albumin and total protein. Thyroid stimulating hormone (TSH), and free T4. 
• Hematology: hemoglobin, hematocrit, RBC, WBC with differential (including ANC), and 
platelet count. 
• Coagulation: prothrombin time (PT) or international normalized ration (INR) and activated 
partial thromboplastin time (aPTT). 
• Quantitative urinalysis: red blood cells, leukocytes, protein, glucose, ketone, pH, bilirubin, 
Na, K, Ca, Cl, nitrates, specific gravity. 
• Serum β2-microglobulin. 
Disease assessment: 
• Laboratory disease assessment (local laboratory assessment): 
- 
Serum M-protein (immunoelectrophoresis and immunofixation), 
- 
Urine M-protein (immunoelectrophoresis and immunofixation), 
- 
Serum free light chains (sFLC, quantification and ratio involved/non-involved), 
- 
Immunoglobulins: IgG, IgA, IgM, IgD and IgE (IgD or E only if the heavy chain 
component of the disease is known to be E or D). 
Note: One additional serum sample will be collected for testing potential interference of 
isatuximab in M protein assessment. The sample will be collected at the same time as for 
serum M protein sample above (central laboratory). 
• Bone marrow aspirate (or biopsy as clinically indicated): 
- 
Bone marrow aspirate (BMA) for FISH including but may not be limited to t(4;14), 
t(14;16), del(17q) to determine risk status (central laboratory),  
- 
BMA for MRD assessment (central laboratory), 
- 
Bone marrow plasma cell infiltration (local laboratory). 
• Bone disease assessment: Skeletal survey or low-dose whole-body CT scan: including 
skull, all long bones, pelvis and chest (local assessment) 
•  Plasmacytoma assessment (PET-CT, CT scan or MRI) in patients with known or 
suspected have plasmacytoma (local assessment): 
Note: for bone lesion assessment or plasmacytoma, the same modality (skeletal survey or 
low-dose whole-body CT; PET-CT, CT or MRI) should be used throughout the study for 
each individual patient. 
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Other assessment 
• Bone marrow biopsy/aspirates and blood samples for exploratory biomarkers analysis 
(central laboratory): 
- 
Adaptive immune response (including TCR repertoire) (blood and BMA),  
- 
Immunophenotyping (blood and BMA), 
- 
PD1-PDL1 expression (archival bone marrow biopsy). 
• A blood sample for blood typing interference test (local laboratory). 
12.3 
REGISTRATION/RANDOMIZATION  
Registration will take place once the consented patient has completed all the necessary screening 
procedures and is deemed eligible for study entry by the investigator or designee.  
The results of the screening examinations will be recorded in each patient’s CRF. Source 
documentation to support the screening results must be maintained in the patient’s medical record. 
Re-screening is allowed once. 
12.4 
TREATMENT PERIOD  
12.4.1 Cycle 1 (Day 1, Day 8, Day 15 and Day 22 all ±1 day)  
The following procedures are to be performed/assessed on D1, D8, D15 and D22 prior to study 
treatment administration unless specified otherwise: 
• Physical examination: main diagnoses to be reported in the eCRF as AEs and newly 
occurring laboratory abnormalities to be recorded in laboratory pages.  
• Vital signs including blood pressure, heart rate and body temperature prior to start of each 
infusion, every hour during the infusion and at the end of infusion. 
• ECOG PS. 
• Body weight.  
• Study treatment administration. 
• All AEs/SAEs throughout the cycle.  
• Concomitant medications from registration and used throughout the cycle. 
Laboratory assessments (not required to be repeated at Cycle 1 Day 1 if performed within 3 days 
prior to first study treatment administration at screening and results were normal or not clinically 
significant. 
• Serum pregnancy test to be performed on Day1 of each cycle prior to study treatment 
administration for females of childbearing potential. 
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• 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. 
• Blood chemistry prior Day 1, Day 8, Day 15, and Day 22 administration: SGOT (AST), 
SGPT (ALT), bilirubin (total and direct), alkaline phosphatase, lactate dehydrogenase 
(LDH), sodium, potassium, chloride, bicarbonate/carbon dioxide, calcium, corrected 
serum calcium, magnesium, phosphate, uric acid, serum creatinine and eGFR (MDRD 
Formula), urea or BUN, fasting glucose albumin, total protein. 
• Hematology, to be done weekly prior Day 1, Day 8, Day 15, and Day 22 administration: 
hemoglobin, hematocrit, RBC, WBC with differential (including ANC), and platelet 
count. 
• Dipstick (qualitative) on D1 and D15. 
• IAR laboratory tests on D1 prior to first isatuximab administration: (TNF- α, IL-1-β, IL-6, 
and IFN-γ), markers of activated complement (C3a, C4 and CH50) and serum tryptase, 
lactate dehydrogenase [LDH]. If an isatuximab infusion associated reaction of 
Grade ≥2 occurs during the cycle, additional blood sampling during the AE is required for 
analysis of cytokine release (TNF-α, IL-1-β, , IL-6, and IFN-γ), markers of complement 
activation (C3a, C4, CH50), serum tryptase (central laboratory) and LDH.  
Blood sample collection for PK and ADA evaluation (see Section 1.2, Section 1.3) (central 
laboratory).  
Disease assessment on C1D1 (unless the disease assessment for the screening is done in the 
3 days prior first administration) (local laboratory):  
• Serum M-protein, 
• Urine M-protein, 
• sFLC. 
Note: One additional serum sample will be collected for testing potential interference of 
isatuximab in M protein assessment. The sample will be collected at the same time as for 
serum M protein sample above (central laboratory). 
Other assessment: 
• Blood samples for exploratory biomarkers analysis (central laboratory): 
- 
Adaptive immune response (humoral and cellular response): prior to pre-medication 
and IMP administration on Day 1. 
If clinically indicated only: 
• Coagulation at any time during the cycle. 
• Quantitative urinalysis: RBC, leukocytes, protein, glucose, ketone, pH, bilirubin, Na, K, 
Ca, Cl, nitrates, specific gravity. at any time during the cycle.  
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• Markers for TLS (uric acid, creatinine/BUN, potassium, phosphate, calcium and corrected 
calcium) at any time during the cycle.  
• Any other exams clinically indicated. 
• Disease assessment (BM, radiological, laboratory). The same method of assessment as at 
baseline is to be used throughout the study.  
12.4.2 Subsequent cycles (Day 1 and 15 both ±2 days)  
The following procedures are to be performed/assessed on D1 and 15 prior to study treatment 
administration unless specified otherwise, and as clinically indicated: 
• Physical examination: main diagnoses to be reported in the eCRF as AEs and newly 
occurring laboratory abnormalities to be recorded in laboratory pages.  
• Vital signs including blood pressure, heart rate, respiration rate and body temperature.  
• ECOG PS.  
• Weight. 
• Study treatment administration.  
• All AEs/SAEs throughout the cycles.  
• Concomitant medications used throughout the cycle. 
Laboratory assessments (safety assessment)  
• Serum pregnancy test to be performed on Day1 of each cycle prior to study treatment 
administration for females of childbearing potential 
• 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. 
• Blood chemistry: SGOT (AST), SGPT (ALT), bilirubin (total and direct), alkaline 
phosphatase, lactate dehydrogenase (LDH), sodium, potassium, chloride, 
bicarbonate/carbon dioxide, calcium, corrected serum calcium, magnesium, phosphate, 
uric acid, serum creatinine and eGFR (MDRD Formula), urea or BUN, fasting glucose, 
albumin and total protein. Thyroid stimulating hormone (TSH) and free T4 will be 
assessed every second cycle. 
• Hematology: hemoglobin, hematocrit, RBC, WBC with differential (including ANC), and 
platelet count. 
• Dipstick (qualitative). 
• Quantitative urinalysis if hematuria or clinically indicated only: red blood cells, 
leukocytes, protein, glucose, ketone, pH, bilirubin Na, K, Ca,, Cl, nitrates, specific gravity. 
• Serum 2 microglobulin prior to D1 of each cycle. 
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Disease assessment  
• Laboratory disease assessment: on Day 1 each cycle prior study treatment administration 
(reference value to assess response will be the value from the last lab taken before 
1st treatment administration) (local laboratory). 
- 
Serum M-protein: immunoelectrophoresis and if M protein undetectable, 
immunofixation will be performed, 
- 
Urine M-protein: immunoelectrophoresis and if M protein undetectable, 
immunofixation will be performed, 
- 
Serum free light chains (sFLC, quantification and ratio involved/non-involved), 
- 
Immunoglobulins: IgG, IgA, IgM, IgD and IgE (IgD or E only if the heavy chain 
component of the disease is known to be E or D.  
Note: One additional serum sample will be collected for testing potential interference of 
isatuximab in M-protein assessment. The sample will be collected at the same time as for 
serum M protein sample above (central laboratory). 
• Bone marrow aspirate (or biopsy as clinically indicated): 
- 
Bone marrow plasma cell infiltration to confirm CR, or if suspicion of disease 
progression in the absence of biochemical progression and as clinically indicated. 
(local laboratory) 
- 
BMA for MRD assessment in case of CR. In case of MRD positive, another bone 
marrow sample will be collected 3 months (3 cycles) later, in order to identify late 
negativity. A third sample may be collected after another 3 months, if the patient 
remains MRD positive and is still being treated. No more than 3 on-treatment bone 
marrow samples are to be obtained (central laboratory). 
• Bone disease assessments: skeletal survey or low-dose whole-body CT scan including 
skull, all long bones, pelvis and chest (Local assessment). 
- 
If clinically indicated. 
• Plasmacytoma assessment (PET-CT, CT scan or MRI) (local assessment): 
- 
If known extramedullary disease, 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. 
Note: for bone lesion assessment or plasmacytoma, the same modality (skeletal survey or low-
dose whole-body CT; PET-CT, CT or MRI) should be used throughout the study for each 
individual patient. 
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Other assessment: 
• If a isatuximab infusion associated reaction of Grade ≥2 occurs during the cycle, 
additional blood sampling during the AE is required for analysis of cytokine release 
(TNF-α, IL-1-β, IL-6, and IFN-γ), markers of complement activation (C3a, C4, CH50), 
serum tryptase (central laboratory) and LDH. 
• Blood sample collection for PK and ADA evaluation (see Section 1.2, Section 1.3) (central 
laboratory). 
• C2D1 only, a blood sample for blood typing interference test (local laboratory). 
• Bone marrow biopsy/aspirates and blood samples for exploratory biomarkers analysis 
(central laboratory): 
- 
Adaptive immune response (including TCR repertoire): at C3D1 (blood only) and in 
case of CR (blood and BMA), 
- 
Adaptive immune response (humoral and cellular response): prior to pre-medication 
and IMP administration at C2D1, C4D1, C7D1 and C10D1 (blood), 
- 
Immunophenotyping at C3D1 (blood and BMA), 
- 
PD1-PDL1 expression at C3D1 (optional bone marrow biopsy). 
If clinically indicated only: 
• Coagulation at any time during the cycle. 
• Quantitative urinalysis: RBC, leukocytes, protein, glucose, ketone, pH, bilirubin Na, K, 
Ca, Cl, nitrates, specific gravity at any time during the cycle.  
• Markers for TLS (uric acid, creatinine/BUN, potassium, phosphate, calcium and corrected 
calcium) at any time during the cycle. 
• Any other exams clinically indicated. 
12.4.3 End of treatment  
The EOT visit will occur 30 days after last study treatment administration or prior to start of 
further anti-myeloma therapy, whichever comes first.  
The following procedures are to be performed at the EOT visit: 
• Physical examination.  
• Vital signs. 
• Weight. 
• ECOG PS. 
• All AEs/SAEs occurring up to 30 days after last study treatment administration (will be 
collected in last treatment cycle). 
• Concomitant medications up to 30 days from last study treatment administration. 
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Local laboratory tests 
• Serum pregnancy test for females of childbearing potential.  
• Blood chemistry: SGOT (AST), SGPT (ALT), bilirubin (total and direct), alkaline 
phosphatase, lactate dehydrogenase (LDH), sodium, potassium, chloride, 
bicarbonate/carbon dioxide, calcium, corrected serum calcium, magnesium, phosphate, 
uric acid, serum creatinine and eGFR (MDRD Formula), urea or BUN, fasting glucose, 
albumin and total protein. 
• Hematology: hemoglobin, hematocrit, RBC, WBC with differential (including ANC), and 
platelet count. 
• Quantitative urinalysis: red blood cells, leukocytes, protein, glucose, ketone, pH, bilirubin, 
Na, K, Ca, Cl, nitrates, specific gravity. 
• Serum β2-microglobulin.  
Disease assessment 
• Laboratory disease assessment (local laboratory): 
- 
Serum M-protein: immunoelectrophoresis and if M-protein undetectable, 
immunofixation will be performed, 
- 
Urine M-protein: immunoelectrophoresis and if M-protein undetectable, 
immunofixation will be performed, 
- 
Serum FLC in case of CR (quantification and ratio involved/non-involved), 
- 
Immunoglobulins: IgG, IgA, IgM, IgD and IgE (IgD or E only if the heavy chain 
component of the disease is known to be E or D). 
Note: One additional serum sample will be collected for testing potential interference 
of isatuximab in M-protein assessment. The sample will be collected at the same time 
as for serum M-protein sample above (central laboratory). 
• Bone marrow aspirate (or biopsy as clinically indicated): bone marrow plasma cell 
infiltration to confirm CR, or if suspicion of disease progression in the absence of 
biochemical progression and as clinically indicated (local laboratory). 
• Bone disease assessments: skeletal survey or low-dose whole-body CT scan including 
skull, all long bones, pelvis and chest (Local assessment). 
- 
If clinically indicated. 
• Plasmacytoma assessment (PET-CT, CT scan or MRI) (local assessment): 
- 
If clinically indicated. 
Other assessment 
• Blood sample collection for PK and ADA evaluation (see Section 1.2, Section 1.3). 
• Bone marrow biopsy/aspirates and blood samples for exploratory biomarkers analysis: 
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- 
Adaptive immune response (humoral and cellular response) in disease progression 
patients (blood). 
- 
Immunophenotyping (blood only). 
- 
PD1-PDL1 expression (optional bone marrow biopsy). 
12.4.4 Post treatment follow up  
12.4.4.1 60 and 90 days after last treatment visit  
The following procedures are to be performed at the 60 and 90 days visit: 
• Physical examination.  
• Vital signs. 
• AE assessment: related AEs and all serious AEs (regardless of relationship to study 
treatment) ongoing at the time of study treatment discontinuation will be followed until 
resolution or stabilization. All (serious or non-serious) new AEs related to study treatment 
will be collected and followed until resolution or stabilization. 
• Further anti-myeloma therapy, including drug administered and best response. 
• Second primary malignancies. 
• Concomitant medications related to AE/SAE. 
Local laboratory tests 
• Serum pregnancy test for females of childbearing potential every month for 5 months 
following the last dose of isatuximab or 6 months following the last dose of cemiplimab, 
whichever comes last. 
• Blood chemistry: SGOT (AST), SGPT (ALT), bilirubin (total and direct), alkaline 
phosphatase, lactate dehydrogenase (LDH), sodium, potassium, chloride, 
bicarbonate/carbon dioxide, calcium, corrected serum calcium, magnesium, phosphate, 
uric acid, serum creatinine and eGFR (MDRD Formula), urea or BUN, fasting glucose, 
albumin and total protein. 
• Hematology: hemoglobin, hematocrit, RBC, WBC with differential (including ANC), and 
platelet count. 
• Quantitative urinalysis: red blood cells, leukocytes, protein, glucose, ketone, pH, bilirubin, 
Na, K, Ca, Cl, nitrates, specific gravity. 
Blood sample for PK and ADA evaluation (see Section 1.2, Section 1.3).  
Disease assessment (only for patients without confirmed disease progression and patients 
who have not yet started treatment with another anticancer therapy) 
• Laboratory disease assessment (local laboratory): 
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- 
Serum M-protein: immunoelectrophoresis,  
- 
Urine M-protein: immunoelectrophoresis,  
- 
Serum FLC in case of CR (quantification and ratio involved/non-involved), 
- 
Immunoglobulins: IgG, IgA, IgM, IgD and IgE (IgD or E only if the heavy chain 
component of the disease is known to be E or D), 
Note: One additional serum sample will be collected for testing potential interference 
of isatuximab in M-protein assessment for patient treated in IP arm. The sample will 
be collected at the same time as for serum M protein sample above (central 
laboratory). 
• Bone marrow plasma cell infiltration to confirm CR, or if suspicion of disease progression 
in the absence of biochemical progression and as clinically indicated (local laboratory). 
• Bone disease assessments if applicable: 
- 
Skeletal survey or low-dose whole-body CT if clinically indicated. 
• Extramedullary disease (plasmacytoma) assessment (including bone plasmacytoma) if 
applicable (PET-CT, CT scan or MRI): 
- 
If known extramedullary disease, and if clinically indicated, 
- 
To be done in case of suspicion of progression or if clinically indicated in a patient 
with no previous positive image for extramedullary disease. 
Note: for bone lesion assessment or extramedullary disease, the same modality 
(skeletal survey or low-dose whole-body CT; PET-CT, CT or MRI) should be used 
throughout the study for each individual patient. 
12.4.4.2 Further follow-up visits until 12 months after LPI  
For patients with confirmed disease progression (at EOT or during follow-up):  
The post-treatment follow-up period includes visits (or phone call) every 3 months (±7 days) after 
administration of the last study treatment. The following procedures are to be performed during 
the post-treatment follow up period: 
• AE assessment: related AEs and all serious AEs (regardless of relationship to study 
treatment) ongoing at the time of study treatment discontinuation will be followed during 
the follow-up period until resolution or stabilization. During the follow-up period, all 
(serious or non-serious) new AEs related to study treatment will be collected and followed 
until resolution or stabilization. 
• Pregnancy test for females of childbearing potential every month for 5 months following 
the last dose of isatuximab or 6 months following the last dose of cemiplimab, whichever 
comes last. 
• Further anti-myeloma therapy, include drug administered and best of responses. 
• Survival status (every 3 months). 
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For patients discontinued without disease progression and have not yet started treatment 
with another anticancer therapy:  
The post-treatment follow-up period includes visits every month after last study treatment 
administration. The following procedures are to be performed up to PD or start treatment with 
another anti-cancer therapy whichever comes first:  
• Disease assessment  
- 
Laboratory tests 
a) Serum M-protein: immunoelectrophoresis and if M protein undetectable, 
immunofixation will be performed, 
b) Urine M-protein: immunoelectrophoresis and if M protein undetectable, 
immunofixation will be performed, 
c) Serum free light chains in case of CR (sFLC, quantification and ratio involved/non-
involved), 
d) Immunoglobulins: IgG, IgA, IgM, IgD and IgE (IgD or E only if the heavy chain 
component of the disease is known to be E or D), 
Note: One additional serum sample will be collected for testing potential interference 
of isatuximab in M protein assessment for patient treated in IP arm. The sample will be 
collected at the same time as for serum M protein sample above (central laboratory). 
- 
Bone marrow aspirate (or biopsy as clinically indicated): bone marrow plasma cell 
infiltration to confirm CR, as clinically indicated (Local assessment). 
- 
Bone disease assessments: Skeletal survey or low-dose whole-body CT scan if 
clinically indicated. 
- 
Plasmacytoma assessment: 
a) If known extramedullary disease, if clinically indicated, 
b) To be done in case of suspicion of progression or if clinically indicated in a patient 
with no previous positive image for extramedullary disease. 
Note: for bone lesion assessment or extramedullary disease, the same modality (skeletal 
survey or low-dose whole-body CT; PET-CT, CT or MRI) should be used throughout the 
study for each individual patient. 
• AE assessment: related AEs and all serious AEs (regardless of relationship to study 
treatment) ongoing at the time of study treatment discontinuation will be followed during 
the follow-up period until resolution or stabilization. During the follow-up period, all 
(serious or non-serious) new AEs related to study treatment will be collected and followed 
until resolution or stabilization. 
• Pregnancy test for females of childbearing potential every month for 5 months following 
the last dose of isatuximab or 6 months following the last dose of cemiplimab, whichever 
comes last. 
• Further anti-myeloma therapy, include drug administered and best response. 
• Survival status (every 3 months). 
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12.4.5 Post OS final study cut-off date  
Patients still on study treatment after the final analysis cut-off date (12 month after last patient 
first treatment) can continue study treatment until at least 1 treatment discontinuation criterion as 
defined in Section 6.5.7 is met. The following information will be collected during the study 
treatment administration:  
• IP administration. 
• All SAEs regardless of relationship to study treatment and adverse events considered 
related to study treatment.  
• Pregnancy test for females of childbearing potential every month for 5 months following 
the last dose of isatuximab or 6 months following the last dose of cemiplimab, whichever 
comes last. 
• End of treatment reason.  
No follow-up information will be collected after these patients discontinue study treatment except 
all SAEs still ongoing at the end of study treatment and all adverse events considered as related to 
study treatment still ongoing or occurring after the end of study treatment, which will be followed 
until resolution/stabilization. 
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13 
STATISTICAL CONSIDERATIONS  
The statistical considerations presented in this section forms the basis for the Statistical Analysis 
Plan (SAP), which will provide accurate definitions and detailed specifications for the analyses to 
be performed on the data collected from this study. 
13.1 
DETERMINATION OF SAMPLE SIZE  
This study aims to determine the safety and efficacy of the combination of isatuximab and 
cemiplimab.  
In Phase 1 part, the objective is to determine the RP2D based on DLT occurrence. The actual 
sample size will depend on DLTs observed and number of dose levels actually explored. It is 
anticipated that 3 to 18 DLT-evaluable patients will be treated in the Phase 1 part of the study. 
In Phase 2 randomization part, the objective is to evaluate the efficacy and safety of the 
combination therapy. Assuming ORR = 20% in control arm (isa alone arm) and ORR = 50% in 
combination arms, using Fisher’s exact test to compare the ORR in control vs combination arms, 
given an overall 1-sided type I error of 5% for each combination arm, 35 patients per arm is 
required to achieve a power 79% power for each combination arm.  
A separate anti-CD38 refractory cohort with 15 patients might be enrolled if a treatment benefit is 
suggested for the combination therapy including pass the futility check at the interim analysis. 
Assuming ORR =20% or more in the combination therapy, a size of 15 patients is required to test 
against a null hypothesis of ORR ≤1% (ie, no activity in the Isa alone arm) with a one-sided α of 
0.05 and 82% power. 
Therefore, the total expected number of patients treated in the study (Phase 1 and 2) is 
108 to138 patients. 
13.2 
PATIENT DESCRIPTION  
13.2.1 Disposition of patients  
Screened patients are defined as any patients who signed the study informed consent.  
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 safety population. 
13.2.2 Protocol deviations  
Major protocol deviations which compromise the evaluation of the safety and efficacy will be 
derived adequately and determination of deviations will be finalized based on data review 
conducted prior to database lock. Decisions made on a patient’s status will be documented. 
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13.3 
ANALYSIS POPULATIONS  
13.3.1 All-treated/safety population  
For Phase 1, the all treated/safety population is defined as all screened patients who received at 
least one dose or a part of a dose of the study treatments, regardless of the amount of treatment 
administered. For Phase 2 randomization part, the all treated/safety population is defined as all 
randomized patients who received at least one dose or a part of a dose of the study treatments, 
regardless of the amount of treatment administered. Patients will be analyzed according to the 
treatment actually received. For Phase 2 anti-CD38 refractory cohort, the all treated/safety 
population is defined as patients who received as least one dose/a part of a dose of the study 
treatment, regardless of the amount of treatment administered.  
This population is the primary population for the analysis of all exposure and safety parameters 
(except for DLT evaluation). Phase 1 and Phase 2 patients will be analysed separately.  
13.3.2 ITT population  
For Phase 2 randomization part, the ITT population include all patients with a signed informed 
consent form who have been allocated a randomization number by the IRT, regardless of whether 
the patient was treated or not. Patient will be analyzed according to the treatment group allocated 
by IRT, regardless of treatment (if any) the patients actually received. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used for analysis.  
For Phase 2 anti-CD38 refractory cohort, the ITT population include all patients with a signed 
informed consent form and received at least one dose /a part of a dose of the study treatment.  
This population is the primary population for all efficacy analyses. 
13.3.3 Patients evaluable for DLT assessment  
For isatuximab/cemiplimab combination, the DLT evaluable population is defined as patients in 
the Phase 1 part receiving the planned doses of isatuximab and cemiplimab during Cycle 1, and 
who completed the DLT observation period of 28 days after the first IMP administration, unless 
they discontinue the study treatment(s) due to DLT. Dose-limiting toxicity will be validated by 
the Study Committee. Patients not evaluable for DLT will be replaced. 
13.3.4 Pharmacokinetic population  
The PK population will include patients from the treated/safety population with at least 
one non-missing drug concentration after the study drug administration (whatever the cycle and 
even if dosing is incomplete). 
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13.3.5 ADA evaluable population  
ADA population includes all patients from the treated/safety population with at least one ADA 
non-missing result after study drug administration. 
13.4 
STATISTICAL METHODS  
A list of study endpoints and their definitions are provided in Section 9. 
Unless otherwise specified, analyses will be descriptive and performed separately for Phase 1 and 
Phase 2 patients, based on the analysis population defined in Section 13.3. The baseline for a 
given parameter is defined as the last non-missing assessment for this parameter before 
first administration of study treatments. 
Continuous data will be summarized using number of available data, mean, SD, median, 
minimum and maximum for each dose level (if applicable). Summary tables will be presented by 
dose level(s) and overall (in case of more than 1 dose level), unless otherwise noted. 
13.4.1 Demographics and baseline characteristics  
Demographic and baseline characteristics (including age, gender, race, ethnicity, ECOG 
performance status), medical or surgical history, MM characteristics at diagnosis and at study 
entry will be summarized with descriptive statistics for the safety population in Phase 1 or ITT 
population in Phase 2.  
Prior anti-myeloma therapies 
The following parameters regarding prior anticancer will be summarized: 
• Prior anticancer treatment: number of prior lines (defined in Appendix E), number of prior 
regimen, main anticancer treatments (Alkylating agents, proteasome inhibitors, 
immunomodulators, monoclonal antibodies).  
• Refractory status to main anticancer treatments.  
• Description of last regimen given prior to study entry: 
- 
Time from completion of last regimen of treatment to first study treatment (months), 
- 
Main treatments,  
- 
Best response to last regimen, 
- 
Duration of last regimen of therapy, 
- 
Refractory status as defined above. 
• Prior transplant: number (%) of patients with transplant, type of transplant, time from 
last transplant to first study treatment (months). 
• Prior surgery: number (%) of patients with prior surgery, type of surgery and time from 
last surgery to first study treatment (months). 
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• Prior radiotherapy: number (%) of patients with prior radiotherapy, intent and time from 
last radiotherapy to first study treatment (months). 
13.4.2 Extent of investigational medicinal product exposure  
The following variables will be described to summarize the overall study treatment exposure 
(all study treatments together): 
• Overall number of cycles started.  
• Overall duration of exposure in weeks defined as [(Last day of last cycle – first day of 
first cycle)/7].  
The last day of last cycle is defined as the last date among the following: 
- 
Date of last dose of isatuximab + 7 days if last cycle is QW cycle or date of last dose 
of isatuximab + 14 days if last cycle is Q2W,  
- 
Date of last dose of cemiplimab + 14 days if last cycle is Q2W cycle or date of 
last dose of cemiplimab + 28 days if last cycle is Q4W cycle (if applicable).  
The first day of first cycle is defined as the date patient receive first isatuximab or/and 
cemiplimab. 
In addition, the following variables will be summarized with descriptive statistics for each IMP 
(ie, isatuximab and cemiplimab): 
• Number of cycles started with each drug. 
• Duration of exposure of each drug in weeks, defined as. 
- 
For isatuximab: [date of last dose of isatuximab + 7 days - first dose of isatuximab] 
/7 if last cycle is QW cycle or [date of last dose of isatuximab + 14 days - first dose of 
isatuximab]/7 if last cycle is Q2W cycle, 
- 
For cemiplimab: [date of last dose of cemiplimab + 14 days - first dose of 
isatuximab]/7 if last cycle is Q2W cycle or [date of last dose of isatuximab + 28 days - 
first dose of isatuximab]/7 if last cycle is Q4W cycle. 
• Number of infusions. 
• Cumulative dose (in mg/kg) for isatuximab/cemiplimab: The cumulative dose at is the sum 
of all doses administered from first to last dose. 
• Actual dose intensity (ADI): defined as the cumulative dose divided by the duration of 
exposure. 
• Relative dose intensity (RDI): defined as the ratio of the actual dose intensity to the 
planned dose intensity. The RDI is an indicator of the feasibility of the chosen schedule of 
administration. 
• Cycle delays: A cycle is deemed to have been delayed if the start date is >3 days beyond 
the scheduled Day 1. 
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• Isatuximab infusion delays within a cycle: a dose is deemed to have been delayed if the 
study treatment is ≥2 days beyond the theoretical day of treatment for weekly dose, and 
≥3 days beyond the theoretical day of treatment for Q2W schedule of administration. 
Infusion delay is not applicable to the 1st dose of each cycle. 
• Cemiplimab infusion delays within a cycle (only if RP2D is Q2W schedule): a dose is a 
dose is deemed to have been delayed if the study treatment is ≥3 days beyond the 
theoretical day of treatment. Infusion delay is not applicable to 1st dose of each cycle. 
• Infusion interruption (isatuximab and/or cemiplimab): administration of treatment was 
stopped during the infusion before it is completed regardless it is further restarted or not.  
• Dose omission: Partially administered cycle: Cycle with at least one isatuximab/ 
cemiplimab dose omitted. 
13.4.3 Prior/concomitant medication/therapy  
Prior and concomitant medications will be summarized on the safety population in Phase 1 or ITT 
population in Phase 2 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. 
13.4.4 Analyses of efficacy variables  
All efficacy analyses will be performed using the all ITT population in Phase 2 unless otherwise 
specified. 
13.4.4.1 Analysis of primary efficacy endpoint  
The ORR will be summarized by treatment arms/cohort with descriptive statistics. A 95%  
two-sided confidence interval(s) will be computed using Clopper-Pearson.  
For Phase 2 randomization part of the study, the Fisher’s exact test will be performed to compare 
the ORR in control arm vs each of the combination arm, using a 1-sided significance level of 
0.10 with Hochberg adjustment, (at time of primary analysis of ORR; ie, cutoff date 6 months 
after last patient first dose). If the maximum p-value (of two p-values) is less than 0.1, the null 
hypothesis for both combination arms will be rejected; else if minimal p-value is less than 0.05, 
the null hypothesis will be reject for this corresponding arm only. If only one combination arm is 
continued in addition to the control arm, then ORR will be tested using a 1-sided significant level 
of 0.05. 
Subgroup analyses of BOR will be performed including but not limited to the following variables 
listed: 
• Age: <70 years versus ≥70 years. 
• Number of previous lines of therapy: ≤3 vs >3. 
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• ISS staging at study entry: I vs II vs III. 
• High risk cytogenetic (such as del (17), t (4:14) or t (14:16) abnormality): Yes vs No. 
• Baseline creatinine clearance : <60 mL/min vs ≥60 mL/min. 
• Refractory to prior anticancer treatments (eg, IMiD, PI): Yes vs No.  
• PD-L1 level at baseline: ≥50% vs <50% 
For Phase 1 all treated population, a listing of response data will be provided. 
13.4.4.2 Analysis of secondary efficacy endpoints  
The following secondary endpoints will be analyzed by treatment arms / cohort (in case of more 
than 1 dose level): 
• CBR will be summarized with descriptive statistics. 
• Rate of patients ≥VGPR as BOR will be summarized with descriptive statistics. 
• DOR and TTR: Kaplan-Meier estimates such as median and Kaplan-Meier curves will be 
provided for DOR for patients who achieved a response (sCR, CR, VGPR and PR). 
• PFS and OS: the PFS and OS 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.  
Subgroup analyses for secondary endpoints may be performed if relevant. 
13.4.5 Analyses of safety data  
13.4.5.1 Dose-limiting toxicities  
The DLTs will be listed by patient on the patients evaluable for DLT population.  
13.4.5.2 Analyses of adverse events  
The observation period will be divided into 3 segments: screening, TEAE and post-treatment: 
• The screening period is defined as the time informed consent is signed until the first dose 
of study treatments administration. 
• The TEAE period is defined as the time from the first dose of study treatments up to 
30 days after last dose of study treatments. 
• The post-treatment period is defined as the time starting 31 days after the last dose of 
study treatments to study closure or death, whichever comes first. 
Pre-treatment AEs are defined as any AE during the screening period. 
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Treatment-emergent AEs are defined as AEs that develop, worsen (according to the Investigator 
opinion), or become serious during the TEAE period. 
Post-treatment AEs are defined as AEs that are reported during the post-treatment period. 
The grade will be taken into account in the summary. For patients with multiple occurrences of 
the same PT, the maximum grade will be used. 
The primary focus of AE reporting will be on TEAEs. Pre-treatment and post-treatment AEs will 
be described separately. 
13.4.5.2.1 Treatment-emergent adverse events  
An overall summary of TEAEs will be provided. The number and percentage of patients who 
experience any of the following will be provided: 
• TEAEs. 
• TEAEs of ≥ Grade 3. 
• Grade 5 TEAE (any TEAE with a fatal outcome during the treatment period). 
• Serious TEAEs. 
• Serious treatment-related TEAEs. 
• TEAE leading to permanent (full study treatment) discontinuation/premature (partial study 
treatment) discontinuation. 
• AESIs: IARs, pregnancy if any, and overdose if any will be presented separately. 
• IARs of Grade ≥3. 
• Potential immune-related TEAEs and immune-related reactions. 
• Treatment-related TEAEs. 
• Treatment-related TEAEs of ≥ Grade 3. 
The number and percentage of patients experiencing TEAEs by primary SOC and PT will be 
summarized by NCI CTCAE grade (all grades and ≥Grade 3). Similar tables will be prepared for 
treatment related TEAEs, AESIs, IARs, TEAEs leading to permanent/premature discontinuation , 
TEAEs leading to dose modification, serious TEAEs, TEAEs with fatal outcome and AEs/SAEs 
occurring during the extended safety follow-up period and the post-treatment dosing period.  
Sorting within tables should ensure the same presentation for the set of all AEs within the 
observation period (screening, TEAE and post-treatment). For that purpose, the table of all 
TEAEs will be presented by SOC and PT sorted by internationally agreed order unless otherwise 
specified. 
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13.4.5.3 Deaths  
The following death summaries will be generated: 
• Number (%) of patients who died by study period (TEAE and post-treatment) and reasons 
for death summarized on the safety population by treatment received. 
• TEAEs with fatal outcome (on the AE eCRF page as reported by the Investigator), and 
related TEAEs with fatal outcome summarized by primary SOC and PT. 
A listing of deaths will be provided. 
13.4.5.4 Clinical laboratory evaluations  
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. Complete blood count and serum 
chemistry results will be graded according to NCI-CTCAE version 4.03, when applicable. For 
patients with multiple occurrences of the same laboratory variable during the TEAE period, the 
maximum grade (worst) per patient will be used. The denominator used for percentage calculation 
is the number of patients with at least 1 evaluation of the laboratory test during the considered 
observation period. 
The number and proportion of patients with abnormal laboratory tests at baseline (ie, last 
assessment before the first dose of study treatments administration) will be presented for all 
grades together each grade separately. Similar tables showing abnormalities during the TEAE 
period will be provided. 
When the NCI-CTCAE V4.03 scale is not applicable, the number of patients with a laboratory 
abnormality out-of-normal laboratory range value will be displayed. 
13.4.5.5 Other safety evaluations  
Vital signs 
Potentially clinically significant abnormality (PCSA) values are defined as abnormal values 
considered medically important by the Sponsor according to predefined criteria/thresholds based 
on literature review. The incidence of PCSAs prior to study treatment administration at any cycle 
during the TEAE period (on-treatment PCSAs) will be summarized by treatment group whatever 
the baseline level and/or according to the following baseline categories: 
• Normal/missing. 
• Abnormal according to PCSA criterion or criteria. 
The incidence of PCSA during and after study treatment administration at any cycle during the 
TEAE period will also be summarized. 
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Others 
Cytokines (TNF-α, IL-1-β, , IL-6, IFN-γ), markers of complement (C3a, C4, CH50), serum 
tryptase will be summarized with descriptive statistics. A listing of patients with second primary 
malignancies will be summarized. 
Immunogenicity 
The observation period for ADAs will be divided into 2 periods:  
• The ADA pretreatment period will be defined as the time that informed consent is signed 
until the first study treatment administration. 
• 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:  
• Pre-existing ADA, defined as ADA that are present in samples drawn during the 
pretreatment period. 
• 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). 
• Treatment boosted ADA, defined as pre-existing ADA with a significant increase in the 
ADA titer during the study compared to the baseline titer.  
• 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. 
• ADA prevalence, defined as the sum of the number of patients with pre-existing ADA and 
the number of patients with treatment induced ADAs, divided by the number of evaluable 
patients. 
• ADA incidence, defined as the number of ADA positive patients divided by the number of 
evaluable patients. 
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.  
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.  
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13.4.6 Analyses of pharmacokinetic variables  
Individual concentrations and PK parameters of isatuximab and cemiplimab will be summarized 
by descriptive statistics (such as mean, geometric mean, median, standard deviation, standard 
error of the mean, coefficient of variation, minimum, and maximum) under the responsibility of 
Sanofi, Pharmacokinetic, Dynamic & Metabolism department. Individual and mean profiles will 
be presented graphically. 
13.5 
INTERIM ANALYSIS  
For the isatuximab/cemiplimab combination, preliminary interim analysis of safety and efficacy 
may be performed when the first 15 randomized patients in each arm of the Phase II part complete 
2 cycles of treatment or permanently discontinue treatment. Interim efficacy data will be analyzed 
for futility stopping of the arm(s). 
The analysis will include the first 15 randomized patients from each arm in the ITT population. 
Given the observed response rate from each combination arm, and assuming the numbers of 
response follow binomial distribution with response rate = 20% in control arm, and 50% in 
combination arm for the remaining 20 patients in each arm, the conditional power can be 
calculated based on 1-sided Fisher’s exact test at 0.05 significance level (for each arm separately) 
at the end of the trial. If the conditional power is <30% for a combination arm, the arm will be 
stopped early for futility.  
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14 
ETHICAL AND REGULATORY CONSIDERATIONS  
14.1 
ETHICAL AND REGULATORY STANDARDS  
This clinical trial will be conducted by the Sponsor, the Investigator, delegated Investigator staff 
and Subinvestigator(s), in accordance, with consensus ethics principles derived from international 
ethics guidelines, including the Declaration of Helsinki, and the International Conference on 
Harmonisation (ICH) guidelines for Good Clinical Practice (GCP), all applicable laws, rules, and 
regulations. 
Information regarding the clinical trial will be recorded in a free, publicly accessible, internet-
based registry, no later than 21 days after the first patient enrollment, in compliance with 
applicable regulatory requirements and with Sanofi public disclosure commitments.  
14.2 
INFORMED CONSENT  
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the study, 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, with the name of the patient filled in and personally dated by the patient or by the patient’s 
legally acceptable representative, and by the person who conducted the informed consent 
discussion. A copy of the signed and dated written informed consent form will be provided to the 
patient. 
The informed consent form used by the Investigator for obtaining the patient's informed consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics 
committee (IRB/IEC) for approval/favorable opinion. 
14.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)  
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the health authorities (competent regulatory authority) and the appropriate 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 IRB/IEC composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure with any 
addenda, Investigator’s CV, etc.) and the date of the review should be clearly stated on the written 
ethics committee (IRB/IEC) approval/favorable opinion. 
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The IMP will not be released at the study site and the Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the ethics committee (IRB/IEC) should be informed as soon as possible. 
They should also be informed of any event likely to affect the safety of patients or the continued 
conduct of the clinical trial, in particular any change in safety. All updates to the Investigator’s 
Brochure will be sent to the ethics committee (IRB/IEC) and to health authorities (competent 
regulatory authority), as required by local regulation. 
A progress report will be sent to the IRB/IEC at least annually and a summary of the clinical 
trial’s outcome at the end of the clinical trial. 
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15 
STUDY MONITORING  
15.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S)  
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the e-CRF, discrepancy resolution form [DRF], or other appropriate 
instrument) in an accurate manner according to the instructions provided and to ensure direct 
access to source documents by the Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The Subinvestigators 
will be supervised by and work under the responsibility of the Investigator. The Investigator will 
provide them with a copy of the clinical trial protocol and all necessary information. 
15.2 
RESPONSIBILITIES OF SPONSOR  
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the e-CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following aspects: 
patient informed consent, patient recruitment and follow-up, SAE documentation and reporting, 
AESI documentation and reporting, AE documentation, IMP allocation, patient compliance with the 
IMP regimen, IMP accountability, concomitant therapy use, and quality of data. 
15.3 
SOURCE DOCUMENT REQUIREMENTS  
According to the ICH GCP, the Monitoring team must check the CRF entries against the source 
documents, except for the preidentified source data directly recorded in the CRF. the informed 
consent form will include a statement by which the patient allowing 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 CRF (eg, patient's medical file, 
appointment books, original laboratory records). These personnel, bound by professional secrecy, 
must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality rules). 
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15.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUESTS  
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 the Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All e-CRFs 
should be completed in their entirety to ensure accurate interpretation of data.  
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification. 
Data are available within the system to the sponsor as soon as they are entered in the e-CRF.  
The computerized handling of the data by the Sponsor when available in the e-CRF 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  
Procedures shall be employed and controls designed to ensure the confidentiality of electronic 
records. Such procedures and controls shall include validation of systems to ensure accuracy and 
reliability, ability to generate accurate and complete copies of records, protection of records to 
enable retrieval, use of secure, computer-generated, time-stamped entries, use of operational 
system checks, use of device checks to determine validity of source data input, determination that 
person who develop, maintain, or use such systems have adequate education and training, the 
establishment and adherence of written policies to deter record falsification, the use of appropriate 
controls over systems documentation including the distribution of or use of documentation for 
system operation and maintenance, and revision and change control procedures which document 
time-sequenced development and modifications of systems documentation. 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
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16 
ADDITIONAL REQUIREMENTS  
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 signed, dated, and provided to the Sponsor 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 15 years after the 
completion or discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee. 
16.3 
CONFIDENTIALITY  
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the e-CRFs, the Investigator's Brochure, and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
IRB/IEC is expressly permitted, the IRB/IEC members having the same obligation of 
confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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16.4 
PROPERTY RIGHTS  
All information, documents, and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff/Subinvestigator not to 
mention any information regarding the Product in any application for a patent or for any other 
intellectual property rights. 
All the results, data, documents, and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market, or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
16.5 
DATA PROTECTION  
• The patient's personal data, which may be included in the Sponsor database, shall be 
treated in compliance with all applicable laws and regulations. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
• The Sponsor also collects specific data regarding the Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor's databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
16.6 
INSURANCE COMPENSATION  
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy as required by applicable law. An 
insurance certificate will be provided to the IECs/IRBs or regulatory authorities in countries 
requiring this document. 
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16.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES  
For the purpose of ensuring compliance with the clinical trial protocol, GCP, and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel are bound by professional secrecy, and 
as such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he/she will 
inform the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
16.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE  
16.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following: 
• The information on the IMP leads to doubt as to the benefit/risk ratio. 
• Patient enrollment is unsatisfactory. 
• The Investigator has received from the Sponsor all IMP, means and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon. 
• Noncompliance by the Investigator or Subinvestigator, or delegated staff with any 
provision of the clinical trial protocol, or breach of any applicable laws, regulations, or 
ICH GCP guidelines. 
• The total number of patients are included earlier than expected. 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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16.8.2 By the Investigator  
The Investigator may terminate his/her participation upon 30 days' prior written notice if the study 
site or the Investigator for any reason becomes unable to perform or complete the clinical trial. 
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
16.9 
CLINICAL TRIAL RESULTS  
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to Investigator. 
16.10 PUBLICATIONS AND COMMUNICATIONS  
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold his approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned within 12 months of the completion of this study at all sites, the Investigator shall have 
the right to publish or present independently the results of this study. The Investigator shall 
provide the Sponsor with a copy of any such presentation or publication for review and comment 
at least 30 days in advance of any presentation or submission for publication. In addition, if 
requested by the Sponsor, any presentation or submission for publication shall be delayed for a 
limited time, not to exceed 90 days, to allow for filing of a patent application or such other 
justified measures as the Sponsor deems appropriate to establish and preserve its proprietary 
rights.  
The Investigator shall not use the name(s) of the Sponsor and/or of its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the Collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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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 the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be recollected if 
necessary. 
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18 
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27. Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, BahlisAndrew Belch NJ, et al. Phase II 
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39. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. 
Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122-33. 
40. Freshwater T, Kondic A, Ahamadi M, Li CH, de Greef R, de Alwis D, et al. Evaluation of 
dosing startegy for pembrolizumab for oncology indications. J Immunother Cancer. 
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41. Hellman MD, Rizvi NA, Goldman JW, Gettinger SN, Borghaei H, Brahmer JR, et al. 
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42. Richter JR, Martin TG, Viji R, Cole CE, Atanackovic D, Zonder JA, et al. Updated data from 
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daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple 
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44. Kumar S, Paiva B, Anderson K, Durie B, Landgren O, Moreau P, et al. International Myeloma 
Working Group consensus criteria for response and minimal residual disease assessment in 
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APPENDICES  
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Appendix A 
Modification of diet in renal disease (MDRD) equation  
GFR (mL/min/1.73 m2) =  
175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if Female) x (1.212 if African-American) 
 
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Appendix B 
ECOG performance status scale  
 
Performance 
Status 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary 
nature, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 
50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
 
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Appendix C 
National Cancer Institute common terminology criteria for adverse 
events  
Refer to NCI CTCAE v. 4.03 (46) in the Study Reference Manual, or online at the following NCI 
website: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
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 D 
IMWG response criteria  
Disease response will be assessed using the updated International Myeloma Working Group 
Response Criteria (IMWG) (44). A confirmation assessment for disease response within 4 weeks 
is required in this protocol (either PR or better, or PD). 
Paraprotein value on Cycle 1 Day 1 will be taken as baseline value for response assessment. 
Adapted from updated International Myeloma Working Group Response Criteria 
IMWG MRD criteria (requires a complete response as defined below) 
Sustained MRD-negative 
MRD negativity in the marrow (NGF or NGS, or both) and by imaging as defined below, 
confirmed minimum of 1 year apart. Subsequent evaluations can be used to further specify the 
duration of negativity (eg, MRD-negative at 5 years) 
Flow MRD-negative 
Absence of phenotypically aberrant clonal plasma cells by NGF on bone marrow aspirates using 
the EuroFlow standard operation procedure for MRD detection in multiple myeloma (or validated 
equivalent method) with a minimum sensitivity of 1 in 10⁵ nucleated cells or higher 
Sequencing MRD-negative 
Absence of clonal plasma cells by NGS on bone marrow aspirate in which presence of a clone 
is defined as less than two identical sequencing reads obtained after DNA sequencing of bone 
marrow aspirates using the LymphoSIGHT platform (or validated equivalent method) with a 
minimum sensitivity of 1 in 10⁵ nucleated cells or higher  
Imaging-positive 
MRD-negative 
MRD negativity as defined by NGF or NGS plus disappearance of every area of increased tracer 
uptake found at baseline or a preceding PET/CT or decrease to less mediastinal blood pool 
SUV or decrease to less than that of surrounding normal tissue 
Standard IMWG response criteria 
Response 
IMWG criteria 
CR 
• 
Negative immunofixation on the serum and urine and 
• 
disappearance of any soft tissue plasmacytomas and 
• 
<5% plasma cells in bone marrow aspirates. 
• 
A normal FLC ratio of 0.26–1.65 is required. 
Two consecutive assessments are needed. No known evidence of progressive disease or 
new bone marrow lesions if radiographic studies were performed 
sCR 
CR as defined above plus: 
• 
normal FLC ratio (0.26 to 1.65) and 
• 
absence of clonal cells in bone marrow by immunohistochemistry (κ/λ ratio ≤4:1 or 
≥1:2 for κ and λ patients, respectively, after counting ≥100 plasma cells)  
Two consecutive assessments of laboratory parameters are needed. No known evidence 
of progressive disease or new bone marrow lesions if radiographic studies were 
performed 
VGPR 
• 
Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 
• 
≥90% reduction in serum M-protein plus urine M-protein level <100 mg/24 h. 
• 
FLC only: a ≥90% decrease in the difference between involved and uninvolved FLC 
levels. 
Two consecutive assessments are needed. No known evidence of progressive disease or 
new bone marrow lesions if radiographic studies were performed 
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PR 
• 
≥50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by 
≥90% or to <200 mg/24 h 
• 
If serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein 
criteria 
• 
If serum and urine M-protein are unmeasurable, and serum-free light assay is also 
unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, 
provided baseline bone marrow plasma-cell percentage was ≥30%. In addition to the 
above listed criteria, if present at baseline, a ≥50% reduction in the size (SPD) of soft 
tissue plasmacytomas is also required 
Two consecutive assessments are needed. No known evidence of progressive disease or 
new bone marrow lesions if radiographic studies were performed  
MR 
 
≥25% but ≤ 49% reduction in serum M-protein and reduction in 24h urine M-protein by 50-89%, 
which still exceed 200 mg/24H. 
In addition to the above listed criteria, if present at baseline, ≥50% reduction in size (SPD) of 
soft tissue plasmacytomas is also required 
No known evidence of progressive disease or new bone marrow lesions if radiographic 
studies were performed 
Stable Disease 
• 
Not meeting criteria for CR, VGPR, PR, MR or progressive disease 
Two consecutive assessments are needed. No known evidence of progressive disease or 
new bone marrow lesions if radiographic studies were performed 
Progressive disease 
Any one or more of the following criteria: 
Increase of ≥25% from lowest confirmed value in any one of the following criteria: 
• 
Serum M-protein (the absolute increase must be ≥0.5 g/dL) 
• 
Serum M-protein increase ≥1 g/dL if the lowest M component was ≥5 g/dL 
• 
Urine M-component (the absolute increase must be ≥200 mg/24 h)  
• 
In patients without measurable serum and urine M-protein levels, the difference 
between involved and uninvolved FLC levels (absolute increase must be >10 mg/dL) 
• 
In patients without measurable serum and urine M-protein levels and without 
measurable involved FLC levels, bone marrow plasma-cell percentage irrespective of 
baseline status (absolute increase must be ≥10%) 
• 
Appearance of new lesion(s), ≥50% increase from nadir in SPD of >1 lesion, or 
≥50% increase in the longest diameter of a previous lesion >1 cm in short axis; 
≥50% increase in circulating plasma cells (minimum of 200 cells per μL) if this is the 
only measure of disease  
Two consecutive assessments are needed. No known evidence of progressive disease or 
new bone marrow lesions if radiographic studies were performed 
Abbreviations: CR, complete response; FLC, free light chain; IMWG, International Myeloma Working Group; M, monoclonal;  
MRD, minimal residual disease; NGF, next-generation flow; NGS, next-generation sequencing; PD, progressive disease;  
PR, partial response; sCR, stringent complete response; SD, stable disease; SPD, sum of the products of the maximal perpendicular 
diameters of measured lesions; SUV, maximum standardized uptake value; VGPR, very good partial response. 
A plasmacytoma that has been radiated is not suitable for response assessment; however, it must 
be monitored to assess for progressive disease. 
For patients achieving very good partial response by other criteria, a soft tissue plasmacytoma 
must decrease by more than 90% in the sum of the maximal perpendicular diameter (SPD) 
compared with baseline. 
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Definite increase in the size of existing bone lesions or soft tissue plasmacytomas is defined as 
below: ≥50% increase in the size of at least one bidimensionally measurable lesion (in comparison 
with the measurements at Nadir) or appearance of a new lesion. Pathological fracture or collapse 
of bone are not necessarily evidence of disease progression.  
Reminder: definitions of Response and Progression are based on IMWG Uniform Reporting 
Criteria: 
• Any response (sCR, CR, VGPR, PR) or progression needs to be confirmed by 
two consecutive disease assessments according to the Study Flow Chart. A disease 
assessment at one time point not matched by the same disease assessment at the next time 
point will be considered unconfirmed (except for progression by imaging, bone marrow 
PC counts, where one time point is adequate for confirmed progression). 
• Urine M-protein is not needed to document partial response or minor response if baseline 
urine M-protein was not measurable; however, it is still required for complete response 
and very good partial response. 
• Serum FLC levels should only be used for response assessment when both the serum and 
urine M-component levels are deemed not measurable. 
• Documentation of response requires two consecutive readings of the applicable disease 
parameter (serum M-protein, urine M-protein), performed at any time (no minimum 
interval is required, it can be done the same day); however, to confirm response or 
progressive disease, two discrete samples are required; testing cannot be based upon the 
splitting of a single sample. 
• Patients will continue in the last confirmed response category until there is confirmation of 
progression or improvement to a higher response status; patients cannot move to a lower 
response category. 
• Percent decreases for response calculations are from baseline values (Cycle 1, Day 1). 
• Percent increases for progression calculations are from lowest response values or baseline 
values, whichever is the smaller number. The lowest value does not need to be confirmed. 
• The lowest value before suspected progression will be used for calculation of progression; 
if a serum and/or urine spike is considered too low to quantitate, this value can be assigned 
as zero as a baseline for documentation of subsequent progressive disease. Patients will be 
considered to have progressive disease if they meet the criteria for progression by a 
variable that was not considered measurable at baseline; however, for patients who had a 
measurable serum or urine M-spike at baseline, progression cannot be defined by increases 
in serum FLC alone. 
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Appendix E 
Guidelines for the determination of the number of prior lines of 
therapy in multiple myeloma  
Line of Therapy 
A line of therapy consists of ≥1 complete cycle of a single agent, a regimen consisting of a 
combination of several drugs, or a planned sequential therapy of various regimens (eg, 3-6 cycles 
of initial therapy with bortezomib-dexamethasone followed by stem cell transplantation 
consolidation, and lenalidomide maintenance is considered 1 line). 
New line of Therapy 
A treatment is considered a new line of therapy if any 1 of the following 3 conditions are met: 
1. Start of a new line of treatment after discontinuation of a previous line. If a 
treatment regimen is discontinued for any reason and a different regimen is started, it 
should be considered a new line of therapy. A regimen is considered to have been 
discontinued if all the drugs in that given regimen have been stopped. A regimen is not 
considered to have been discontinued if some of the drugs of the regimen, but not all, 
have been discontinued. 
The reasons for discontinuation, addition, substitution, or SCT do not influence how lines are 
counted. It is recognized that reasons for change may include end of planned therapy, toxicity, 
progression, lack of response, inadequate response. 
2. The unplanned addition or substitution of 1 or more drugs in an existing regimen. 
Unplanned addition of a new drug or switching to a different drug (or combination of 
drugs) due to any reason is considered a new line of therapy. 
3. Stem cell transplantation (SCT): In patients undergoing >1 SCT, except in the case 
of a planned tandem SCT with a predefined interval (such as 3 months), each SCT 
(autologous or allogeneic) should be considered a new line of therapy regardless of 
whether the conditioning regimen used is the same or different. It is recommend that 
data on type of SCT also be captured. 
Planned tandem SCT is considered 1 line. Planned induction and/or consolidation, 
maintenance with any SCT (frontline, relapse, autologous or allogeneic) is considered 
1 line. 
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Interruptions and dose modifications 
• If a regimen is interrupted or discontinued for any reason and the same drug or 
combination is restarted without any other intervening regimen, then it should be counted 
as a single line.  
• However, if a regimen is interrupted or discontinued for any reason, and then restarted at a 
later time point but 1 or more other regimens were administered in between, or the 
regimen is modified through the addition of 1 or more agents, then it should be counted as 
2 lines.  
• Modification of the dosing of the same regimen should not be considered a new line of 
therapy. 
(Based on Rajkumar, Richardson and San Miguel. Guidelines for the determination of the number 
of prior lines of therapy in multiple myeloma Blood 2015;126[7]:921-922.) 
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Appendix F 
Definition of relapsed and refractory myeloma  
Refractory Myeloma: 
Refractory myeloma is defined as disease that is non-responsive (failure to achieve minimal 
response or develops PD while on therapy) while on primary or salvage therapy, or progresses 
within 60 days of last therapy. There are 2 categories of refractory myeloma. 
• Relapsed and refractory myeloma: Relapsed and refractory myeloma is defined as disease 
that is non-responsive while on salvage therapy or progresses within 60 days of last 
therapy in patients who have achieved minimal response or better at some point previously 
to then progressing in their disease course. 
• Primary refractory myeloma: refractory myeloma is defined as disease that is non-
responsive in patients who have never achieved minimal response or better with any 
therapy. It includes patients who never achieve MR or better in whom there is no 
significant change in M protein and no evidence of clinical progression; as well as primary 
refractory, progressive disease where patients meet criteria for true progressive disease. 
Relapsed myeloma 
Relapsed myeloma is defined as previously treated myeloma which progresses and requires the 
initiation of salvage therapy but does not meet the criteria for either primary refractory myeloma 
or relapsed and refractory myeloma. 
(Adapted from Rajkumar VS, Harousseau J-L, et al. Consensus recommendations for the uniform 
reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. 
Blood. 2011;117(18):4691-95.) 
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Appendix G 
Recommended dose modification or discontinuation and 
supportive care guidelines for specific cemiplimab drug related 
adverse events  
Colitis Adverse Event Management 
Colitis 
events 
CTCAE v4.03  
Isatuximab 
Dose 
Management 
Cemiplimab 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 1 
Bowel 
obstruction 
Colitis 
Colitis 
microscopic 
No change in 
dose 
No change in 
dose 
• For diarrhea, treat symptomatically 
(loperamide, oral hydration, electrolyte 
substitution and ADA colitis diet). 
Endoscopy is recommended if symptoms 
persist.  
• Grade 1 diarrhea that persists for >I week 
should be treated with the addition of oral 
diphenoxylate hydrochloride and atropine 
sulfate four times daily and budesonide 
9 mg daily. 
All attempts should 
be made to rule out 
other causes such 
as metastatic 
disease, bacterial or 
parasitic infection, 
gastroenteritis or the 
first manifestation of 
an inflammatory 
bowel disease by 
examination for stool 
leukocytes, stool 
cultures, and a 
Clostridium difficile 
titer. 
Grade 2 
Enterocolitis 
hemorrhagic 
Gastrointestinal 
(GI) perforation 
Necrotizing 
colitis 
Diarrhea: all 
patients who 
experience 
diarrhea should 
be advised to 
drink liberal 
quantities of 
clear fluids. If 
sufficient oral 
intake is not 
feasible, fluid 
and 
electrolytes 
should be 
substituted via 
IV infusion. 
Delay or omit 
dose until 
≤Grade 1 
(See  
Section 6.5.2) 
Delay or omit 
dose until 
≤Grade 1 
(See 
Section 6.5.2) 
• GI consultation and endoscopy is 
recommended to confirm or rule out colitis 
for Grade 2 diarrhea that persists >1 week 
or Grade 1-2 diarrhea with rectal bleeding 
9additional guidelines for the treatment of 
persistent colitis are provided below). 
• Grade 2 diarrhea should be treated with 
addition of oral diphenoxylate hydrochloride 
and atropine sulfate four times daily and 
budesonide 9 mg daily. 
• Grade 2 diarrhea with diffuse ulceration 
and bleeding seen on endoscopy may 
require oral steroids with prolonged taper 
and represent an increased risk for the 
development of bowel perforation. 
• When symptoms improve to Grade 1 or 
less, steroid taper should be started and 
continued over no less than  
4 weeks. 
• In patients with Grade 2 enterocolitis, 
cemiplimab should be withheld and anti-
diarrheal treatment should be started. If 
symptoms are persistent for more than 
1 week, systemic corticosteroids should be 
initiated (eg, 0.5 mg/kg/day of prednisone 
or equivalent). When symptoms improve 
to Grade 1 or less, corticosteroid taper 
should be started and continued over at 
least 1 month.  
 
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Colitis 
events 
CTCAE v4.03  
Isatuximab 
Dose 
Management 
Cemiplimab 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 3 
Grade 4 
Grade 3: delay 
or omit dose 
until ≤Grade 1 
(See  
Section 6.5.2) 
 
Grade 4: 
discontinue 
treatment 
Delay or Omit 
dose until 
≤Grade 1 
(See 
Section 6.5.2) 
Discontinue if 
unable to reduce 
corticosteroid 
dose to 
<10 mg/day 
prednisone 
equivalent within 
12 weeks of 
toxicity. 
• Patients with Grade 3 enterocolitis, drug 
will be permanently discontinued and 
treatment with systemic corticosteroids 
should be initiated at a dose of 
1-2 mg/kg/day prednisone or equivalent. 
When symptoms improve to Grade 1 or 
less, corticosteroid taper should be started 
and continued over at least 1 month. 
• For Grade 3-4 diarrhea (or Grade 2 
diarrhea that persists after initial steroid 
treatment): 
- Rule out bowel perforation. Imaging with 
plain films or computed tomography 
(CT) can be useful. 
- Consider consultation with 
gastroenterologist and confirmation 
biopsy with endoscopy. 
- Treat with intravenous (IV) steroids 
(methylprednisolone 125 mg) followed 
by high dose oral steroids (prednisone 
1-2 mg/kg once per day or 
dexamethasone 4 mg every 4 hours). 
When symptoms improve to Grade 1 or 
less, corticosteroid taper should be 
started and continued over no less than 
4 weeks. Taper over 6-8 weeks in 
patients with diffuse and severe 
ulceration and/or bleeding. 
- If IV steroids followed by high-dose oral 
steroids does not reduce initial 
symptoms with 48-72 hours, consider 
treatment with infliximab at 5 mg/kg 
once every 2 weeks. Discontinue 
infliximab upon symptom relief and 
initiate a prolonged steroid taper over 
45-60 days. If symptoms worsen during 
steroid reduction, initiate a re-tapering of 
steroids starting at a higher dose of 80 
or 100 mg followed by a more prolonged 
taper and administer infliximab. 
CAUTION: Infliximab is contraindicated 
in patients with bowel perforation or 
sepsis. 
- If symptoms persist despite the above 
treatment a surgical consult should be 
obtained. 
All attempts should 
be made to rule out 
other causes such 
as metastatic 
disease, bacterial or 
parasitic infection, 
gastroenteritis or the 
first manifestation of 
an inflammatory 
bowel disease by 
examination for stool 
leukocytes, stool 
cultures, and a 
Clostridium difficile 
titer. 
 
If symptoms are 
persistent and/or 
severe, endoscopic 
evaluation should be 
considered. 
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Endocrine Adverse Event Management 
Endocrine 
events 
CTCAE 
v4.03  
IsatuximabDose 
Management 
Cemiplimab 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 1-2 
Hyperthyroidism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
No change in dose 
No change in 
cemiplimab dose 
• 
Monitor thyroid function or 
other hormonal level tests 
and serum chemistries more 
frequently (every 3-6 weeks) 
until returned to baseline 
values. 
• 
Replacement of thyroid 
hormone or thyroid 
suppression therapy as 
indicated. 
All attempts should be 
made to rule out other 
causes such as brain 
metastases, sepsis, 
and/or infection. An 
endocrinology 
consultation Is 
recommended. 
Grade 3-4 
Hyperthyroidism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Delay or omit dose 
until resolves to 
Grade ≤2 
(see Section 6.5.2) 
Delay or omit dose 
until on stable 
replacement dose 
as determined by 
resolution of 
symptoms and 
normalization of 
hormone levels. 
(see Section 6.5.2) 
• 
Consider endocrine 
consultation. 
• 
Rule out infection and 
sepsis with appropriate 
cultures and imaging. 
• 
Replacement of thyroid 
hormone or thyroid 
suppression therapy as 
indicated. 
Grade 1-4 
Adrenal 
insufficiency 
Hypophysitis 
Hypopituitarism 
Pan- 
hypopituitarism 
Grade 1, 2: no 
change in dose, 
Grade 3, 4: delay or 
omit dose until 
resolves to  
Grade ≤2 
(see Section 6.5.2) 
Delay or omit dose 
until on stable 
replacement dose. 
(see Section 6.5.2) 
• 
Thyroid hormone and/or 
steroid replacement therapy 
to manage adrenal 
insufficiency. 
• 
If Grade 1-2 hypophysitis is 
considered, pituitary gland 
imaging should be 
considered (magnetic 
resonance imaging [MRI] 
with gadolinium and 
selective cuts of the pituitary 
can show enlargement or 
heterogeneity and confirm 
the diagnosis). 
• 
Grade 3-4 hypophysitis with 
clinically significant adrenal 
insufficiency and 
hypotension, dehydration, 
and electrolyte 
abnormalities (such as 
hyponatremia and 
hyperkalemia) constitutes 
adrenal crisis. 
Hospitalization and IV 
methylprednisolone should 
be initiated. 
All attempts should be 
made to rule out other 
causes such as brain 
metastases, sepsis, 
and/or infection. An 
endocrinology 
consultation Is 
recommended 
 
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Pneumonitis Adverse Event Management 
Pneumonitis 
events 
CTCAE 
v4.03 Grade 
Isatuximab 
Dose 
Management 
cemiplimab 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 1 
Pneumonitis 
Interstitial lung 
disease 
Acute interstitial 
pneumonitis 
No change in 
Dose 
Consider delay or 
omit dose. (see 
Section 6.5.2). 
cemiplimab may 
be continued with 
close monitoring. 
• 
Radiological findings should be 
followed on serial imaging studies at 
least every 3 weeks. 
• 
Monitor for symptoms every 2-3 
days. 
• 
Consider pulmonary consultation 
and/or bronchoscopy if clinically 
indicated. 
All attempts should 
be made to rule out 
other causes such 
as metastatic 
disease, bacterial 
or viral infection. 
Grade 2 
Pneumonitis 
Interstitial lung 
disease 
Acute interstitial 
pneumonitis 
Delay or omit 
dose until 
resolves to 
Grade ≤1. 
(see 
Section 6.5.2) 
delay or omit dose 
until resolves to 
Grade ≤1. 
(see 
Section 6.5.2) 
To rule out other causes such as 
infection: 
• 
Consider pulmonary consultation 
with bronchoscopy and 
biopsy/bronchoalveolar lavage 
(BAL). 
• 
Consider pulmonary function tests 
• 
Follow radiological findings on serial 
imaging studies every 1-3 days 
If the patient is determined to have study 
drug-associated pneumonitis 
• 
Monitor symptoms daily, consider 
hospitalization 
• 
Treat with systemic corticosteroids at 
a dose of 1-2 mg/kg/day prednisone 
or equivalent. When symptoms 
improve to Grade 1 or less, steroid 
taper should be started and 
continued over no less than 4 weeks. 
• 
Treatment with cemiplimab may be 
resumed if the event improves to  
≤Grade 1 within 12 weeks and 
corticosteroids have been reduced to 
the equivalent of methylprednisolone 
10 mg by mouth daily or less. Repeat 
chest imaging monthly as clinically 
indicated. 
For Grade 2 pneumonitis that improves to 
≤Grade 1 within 12 weeks, the following 
rules should apply: 
• 
First episode of pneumonitis: may 
decrease the dose to 1 mg/kg in 
subsequent cycles. 
• 
Second episode of pneumonitis: 
Discontinue cemiplimab if upon 
rechallenge the patient develops a 
second episode of ≥Grade 2 
pneumonitis. 
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Pneumonitis 
events 
CTCAE 
v4.03 Grade 
Isatuximab 
Dose 
Management 
cemiplimab 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 3-4 
Pneumonitis 
Interstitial lung 
disease 
Acute interstitial 
pneumonitis 
Grade 3: delay or 
oimt dose until 
resolves to  
Grade ≤1. 
(see 
Section 6.5.2) 
Grade 4: 
discontinue 
treatment 
Discontinue 
cemiplimab 
• 
Consider pulmonary function tests 
with pulmonary consult. 
• 
Bronchoscopy with biopsy and/or 
BAL is recommended. 
• 
Treat with intravenous (IV) steroids 
(methylprednisolone 125 mg). When 
symptoms improve to Grade 1 or 
less, a high dose oral steroid 
(prednisone  
1-2 mg/kg once per day or 
dexamethasone 4 mg every 4 hours) 
taper should be started and 
continued over no less than 4 weeks.  
• 
Add prophylactic antibiotics for 
opportunistic infections. 
• 
If IV steroids followed by high-dose 
oral steroids does not reduce initial 
symptoms with 48-72 hours, 
consider treatment with infliximab at 
5 mg/kg once every 2 weeks. 
Discontinue infliximab upon symptom 
relief and initiate a prolonged steroid 
taper over 45-60 days. If symptoms 
worsen during steroid reduction, 
initiate a re-tapering of steroids 
starting at a higher dose of 80 or 
100 mg followed by a more 
prolonged taper and administer 
infliximab. 
All attempts should 
be made to rule out 
other causes such 
as metastatic 
disease, bacterial 
or viral infection. 
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Renal Adverse Event Management 
Renal events 
CTCAE v4.03 
Grade 
Isatuximab 
Dose 
Management 
Cemiplimab 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 1 
Nephritis 
Nephritis 
autoimmune 
No change in 
Dose 
Consider delay or 
omit dose if event 
does not improve 
with symptomatic 
treatment 
(see 
Section 6.5.2) 
• 
Provide symptomatic treatment. 
• 
Monitor creatinine weekly: when it 
returns to baseline, resume routine 
creatinine monitoring per protocol. 
All attempts should 
be made to rule out 
other causes such 
as obstructive 
uropathy, 
progression of 
disease, or injury to 
other 
chemotherapy 
agents. A renal 
consultation is 
recommended. 
Grade 2 
Renal failure 
Delay or omit 
dose until 
resolves to 
Grade ≤1 
(see 
Section 6.5.2) 
Consider delay or 
omit dose. 
(see 
Section 6.5.2) 
• 
Systemic corticosteroids at a dose 
of  
1-2 mg/kg/day of prednisone or 
equivalent may be indicated. 
When symptoms improve to Grade 
1 or less, corticosteroid taper 
should be started and continued 
for at least  
1 month. 
• 
Consider prophylactic antibiotics 
for opportunistic infections. 
• 
Consider renal biopsy. 
• 
If elevations persist >7 days or 
worse, treat as Grade 4. 
Grade 3-4 
Renal failure 
acute 
Grade 3: delay or 
omit dose until 
resolves to  
Grade ≤1. 
(see 
Section 6.5.2) 
Grade 3: 
discontinue 
treatment 
Discontinue 
cemiplimab 
• 
Renal consultation with 
consideration of ultrasound and/or 
biopsy as appropriate. 
• 
Monitor creatinine daily. 
• 
Treat with systemic corticosteroids 
at a dose of 1-2 mg/kg prednisone 
or equivalent once per day. 
• 
When symptoms improve to Grade 
1 or less, steroid taper should be 
started and continued over no less 
than 4 weeks. 
• 
Discontinue cemiplimab if unable 
to reduce corticosteroid dose for 
irAEs to ≤10 mg. 
• 
Cemiplimab treatment may be 
restated and the dose modified as 
specified in the protocol. 
 
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Dermatologic Adverse Event Management 
Skin 
events 
CTCAE 
v4.03  
Isatuximab 
Dosing 
managment 
Cemiplimab 
Dosing 
managemnt 
Action and Guidelines 
Diagnostic 
Considerations 
Grade  
1, 2 
No change in 
dose 
No change in dose 
Symptomatic treatment should be given 
such as topical glucocorticosteroids 
(eg, betamethasone 0.1% cream or 
hydrocortisone 1%) or urea-containing 
creams in combination with oral 
antipruitics (eg, diphenhrdeamine HCl 
or hydroxyzine HCl) 
Treament with oral steroids is at 
investigator discretion for Grade 2 
events. 
All attemps should be 
made to rule out other 
causes such as 
metastatic disease, 
infectious, or allergic 
dermatitis. 
Grade 3 
No change in 
dose 
 
Delay or omit dose 
until Grade ≤2. 
(see Section 6.5.2) 
Consider dermatology consultation and 
biopsy for confirmation of diagnosis. 
Treatment with oral steroids is 
recommended, starting with 1 mg/kg 
prednisone or equivalent once daily or 
dexamethasone 4 mg 4 times per day. 
When symptoms improve to Grade ≤1, 
steroids taper should be started and 
continue over no leass than 4 weeks. 
 
Grade 4 
Delay or omit 
dose until 
Grade ≤3 
(see 
Section 6.5.2) 
Discontinue treatment 
Dermatology consultation and 
consideration of biopsy and clinical 
dermatology photograph. Initiate with 
oral steroids with 1 mg/kg prednisone or 
equivalent. When symptoms improve to 
Grade ≤1, steroids taper should be 
started and continue over no leass than 
4 weeks.  
 
 
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Hepatitis Adverse Event Management 
Hepatitis 
CTCAE 
v4.03  
Isatuximab 
Dosing 
managment 
Cemiplimab 
Dosing 
managemnt 
Action and Guidelines 
Diagnostic 
Considerations 
Grade  
1, 2 
No change in 
dose 
Delay or omit dose if 
there is a treatment-
emergent concurrent 
elevation of ALT and 
bilirubine that 
corresponds to an 
upward shift of 2 or 
more grades in both 
parameters. 
(see Section 6.5.2) 
Monitor liver function tests more 
frequently until returned to baseline 
values 
All attemps should be 
made to rule out other 
causes such as 
metastatic disease, 
progressive liver 
disease, viral 
hepatitis, alternative 
drug toxicity, 
infectious caurses 
and/or myositis.  
Grade  
3, 4 
Delay or omit 
dose until 
Grade ≤2  
(see  
Section 6.5.2) 
Discontinue treatment 
if: ASTor ALT ≥5xULN 
Bilirubine ≥3xULN 
Consider appropriate consultation and 
liver biopsy to establish etiology of hepatic 
injury, if neccessary. 
Treat with high-dose IV 
glucocorticostroids for 24-48hours. When 
symptoms improves to Grade ≤1, a 
steroid taper with dexamethasone 4 mg 
every 4 hours or prednisone at 1-2 mg/kg 
shouldbe started and continued over no 
less tahn 4 weeks. 
If AST/ALT levels bot not decease 
48 hours after initiation of systemic 
steroids, oral mycophenolate mofdtil 
500 mg every 12 hours may be given. 
Inflixmab is not recommended due to its 
potential for hepatotoxicity. 
Several courses of steroids taper may be 
necessary as symtoms may worsen when 
the stroids dose is decreasesd. 
 
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Ophthalmology (Uveitis) Adverse Event Management 
Uveitis 
CTCAE 
v4.03  
Isatuximab 
Dosing 
managment 
Cemiplimab Dosing 
managemnt 
Action and 
Guidelines 
Diagnostic 
Considerations 
Grade 1 
No change in 
dose 
Discontinue treatment if 
symptoms persist despite 
treatment with topical 
immunosuppressive therapy 
Evaluation by an 
ophthalmologist is strongly 
recommended 
Treat with topical steroids 
such as 1% prednisolone 
acetate suspension and 
iridocyclitis 
All attemps should be made 
to rule out other causes 
such as metastatic disease, 
infection, or other oculas 
disease (eg, glaucoma or 
cataracts) 
Grade 2 
No change in 
dose 
Discontinue treatment if 
symptoms persist despite 
treatment with topical 
immunosuppressive therapy, and 
do not improve to Grade 1 within 
the retreatment period or requires 
systemic treatment 
Grade 
≥3 
Delay or omit 
dose until 
Grade ≤2 
(see 
Section 6.5.2) 
Discontinue treatment 
Treatment with systemic 
corticosteroids such as 
prednisolone at a dose of 
1-2 per day. When 
symtoms improve to 
Grade ≤1, steroid taper 
should be started and 
continued over no less than 
4 weeks. 
 
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Nausea and Vomiting Adverse Event Management 
Nauea and 
Vomiting  
CTCAE 
v4.03  
Isatuximab 
Dosing 
managment 
Cemiplimab Dosing 
managemnt 
Action and 
Guidelines 
Diagnostic 
Considerations 
Grade 1 
No change in dose 
No change in Dose 
Nausea and vomiting 
should be treated 
aggressively, and 
consideration should be 
given in subsequent 
cycles to the 
administration of 
prophylactic antiemetic 
therapy according to 
standard institution 
practice. Patients should 
be strongly encouraged 
to maintain liberal oral 
fluid intake. 
 
Grade 2 
Delay or omit dose 
until ≤Grade 1. 
(see Section 6.5.2) 
Restart treatment at 
same dose level. 
Delay or omit dose until 
≤Grade 1.  
(see Section 6.5.2) 
If patient treated with 
3 mg/kg, may consider 
decrease the dose to 
1 mg/kg if persisted Grade 2 
>14 days despite the anti-
emetic.  
 
Grade 3 
Delay or omit dose 
until ≤Grade 1. 
(see Section 6.5.2) 
 Restart at same 
dose level. 
Delay or omit until ≤Grade 1. 
(see Section 6.5.2)  
If patient treated with 
3 mg/kg, consider decrease 
the dose to 1 mg/kg if 
persisted  
Grade 2 >14 days for the 
1st occurrence despite the 
anti-emetic, or recurrence. 
 
Grade 4 
Discontinue treatment 
 
 
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Appendix H 
Infusion associated reactions observed with Isatuximab  
Types of infusion associated reactions 
• Anaphylactic reaction. 
• Cytokine release syndrome. 
• Drug hypersensitivity. 
Symptoms typically associated with infusion associated reactions 
 
• Abdominal pain 
• Apnea 
• Bronchospasm 
• Chest discomfort 
• Chest tightness  
• Chills 
• Cough 
• Dizziness 
• Dysgeusia 
• Dyspnea 
• Face edema 
• Feeling hot 
• Flushing 
• Headache 
• Head discomfort 
• Hoarseness  
• Hot flush 
• Hypertensive crisis 
• Hypotension 
• Hypoxia 
• Influenza like illness  
• Injection site pain 
• Lacrimation increased 
• Laryngospasm 
• Myalgia  
• Nasal congestion 
• Nausea 
• Pruritus 
• Pyrexia 
• Respiratory distress  
• Rhinitis  
• Rhinorrhea 
• Stridor  
• Tachycardia 
• Tongue edema 
• Throat irritation 
• Tracheal stenosis 
• Tremor 
• Urticaria 
• Vision blurred 
• Vomiting 
• Wheezing 
 
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Appendix I 
CD38 blood test interference guideline AABB2016  
 
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Appendix J 
Contraceptive guidance and collection of pregnancy information  
No reproductive toxicology studies have been conducted with isatuximab, so the most 
conservative contraceptive recommendation has to be followed.  
DEFINITIONS 
Nonreproductive potential 
1. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy. 
- 
Documented bilateral salpingectomy. 
- 
Documented bilateral oophorectomy. 
2. Postmenopausal: 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the highly effective contraception methods if they wish to continue their HRT during 
the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrolment. 
Reproductive potential 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
CONTRACEPTIVE GUIDANCE 
Male subjects 
• Male subjects with heterosexual partners of reproductive potential (WOCBP) are eligible 
to participate if they agree to use the following during the protocol defined timeline: 
- 
Refrain from donating sperm 
and 
- 
At least 1 of the following conditions applies: 
- 
Are and agree to remain abstinent from penile-vaginal intercourse on a long term and 
persistent basis, when this is their preferred and usual lifestyle 
or 
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- 
Agree to use a male condom plus an additional contraceptive method with a failure 
rate of 1% per year (see table for female subjects). 
• Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom for the time defined in the protocol. 
Female subjects: 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctlya 
• Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb 
- 
Oral. 
- 
Intravaginal. 
- 
Transdermal. 
• Progestogen-only hormone contraception associated with inhibition of ovulationb 
- 
Oral. 
- 
Injectable. 
Highly Effective Methods That Are User Independent 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulationb 
• IUD 
• IUS 
• Bilateral tubal occlusion 
• Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, an additional highly effective method(s) of contraception should be used. 
Spermatogenesis cycle is approximately 90 days.) 
• Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the subject.) 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for subjects participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy of the contraceptive 
method. In this case 2 highly effective methods of contraception should be used during the treatment period and for at least 5 months 
after the last dose of isatuximab or 6 months after cemiplimab, whichver comes lasts. 
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Appendix K 
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 other all other amendments are provided below: 
1. 
Amended clinical trial protocol 01 based on Amendment 01 (30-May-2017) 
Reason for amendment: 
• Change dose limiting toxicities (DLT) definition 
In section(s): tabulated clinical trial summary, Sections 6.2.1 and 9.1.1 of the protocol 
Rationale: Per FDA request 
• Added physical examinations, Hematology, biochemistry and urinalysis lab tests at 
visits 60 and 90 days after last dose of study treatment  
In section(s): tabulated clinical trial summary, Sections 1.2, 6.6.1 and 12.4.4.1 of the protocol 
Rationale: Per FDA request. 
2. 
Amended clinical trial protocol 02 based on Amendment 02 (17-Nov-2017) 
Reasons for amendment: 
• Revised Phase 1 and Phase 2 study design 
In section(s): tabulated clinical trial summary, sections 1.1, 1.2, 1.3, 4.3, 5.1, 5.2, 6.1, 6.2, 6.3, 6.5, 
6.7, 7.1, 7.2, 8.3, 8.7, 9.2.1, 13.1, 13.3, 13.4 of the protocol 
Rationale: recently FDA released statement regarding the risks associated with the use another 
anti-PD-1 (pembrolizumab) in combination with dexamethasone, and an immunomodulatory 
agent (lenalidomide or pomalidomide) for the treatment of patients with multiple myeloma. FDA 
confirmed that the imbalance in deaths observed in the pembrolizumab trials were due to toxicity 
and not disease progression. It is not clear if this safety risk is due to an interaction between the 
anti-PD-1 and the IMiD or anti-PD-1 in multiple myeloma. Therefore, the Phase 1 and Phase 2 
study design is revised to: 
• Changed dose de-escalation in Phase 1 to 3+3 design. 
• Added a control arm with isatuximab alone in Phase 2 for better assessment of benefit and 
risk profile when cemiplimab is combined with isatuximab.  
• In published data, for the combination of nivolumab and ipilimumab in NCSLC, changing 
the exposure of check point inhibitors altered the safety, tolerability and efficacy. To 
ensure that the most effective and safe dose of cemiplimab will be used in this study, 
two different doses will be assessed if it is permitted based on the MTD finding from 
Phase 1. Patients will be randomized in the 3 study arms of Phase 2. 
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• Changed patient population to include relapsed and /or refractory multiple myeloma 
(RRMM) patients received at least 3 prior lines of anti-cancer therapy.  
• Body weight based dose is changed to flat dose 
In section(s): tabulated clinical trial summary, Sections 6.1 and 8.3 of the protocol 
Rationale: Based on feedback from regulatory authorities, it was subsequently decided to switch 
from body weight adjusted dosing to fixed flat dosing across the cemiplimab program. 
• Added a DMC 
In section(s): tabulated clinical trial summary, sections 6.8 of the protocol 
Rationale: to have an independent committee monitory patient safety and to provide the sponsor 
with appropriate recommendations in due time to ensure the safety of the patients. 
• Add an exclusion criteria: Patients who have previously been treated with idelalisib 
(a PI3K inhibitor). 
In section(s): tabulated clinical trial summary, Sections 7.3 of the protocol. 
Rationale: In study R1979-ONC-1504, recent safety findings for 3 patients with indolent 
lymphoma previously treated with idelalisib, a phosphatidylinositol 3-kinase (PI 3 K) inhibitor. 
Following a single dose of cemiplimab monotherapy in each case, 2 patients experienced severe 
stomatitis and/or skin reactions. The third patient experienced myositis and myasthenia gravis 
after 2 doses of cemiplimab. 
• Add additional safety guidance language added for the management of patients 
developing stomatitis or mucositis. 
In section(s): Sections 6.5.4 of the protocol. 
Rationale: based on recent safety findings mentioned above. 
• An adverse event of special interest (AESI) has been added to the list of AESIs: an 
irAE of any grade in a patient previously treated with a PI 3-K inhibitor and 
additional safety guidance language added for the management of patients 
developing stomatitis or mucositis. 
In section(s): Sections 10.5 of the protocol. 
Rationale: based on recent safety findings mentioned above. 
• Clarify plasmacytoma assessment at screening: in patients with known or suspected 
extramedullary disease. 
In section(s): Sections 1.2 and 12.2 of the protocol. 
Rationale: further clarification. 
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• Change REGN2810 to cemiplimab. 
In section(s): entire document. 
Rationale: to be consistent with the usage of product name for both investigational products 
3. 
Amended clinical trial protocol 03 based on Amendment 03 (06-Aug-2018) 
Reasons for amendment: 
The main reasons of this amendment are to add a separate cohort in Phase 2 for patients with 
disease refractory to anti-CD38 Mab as the most recent treatment, to add assessment of humoral 
and cellular immune responses to myeloma-related tumor antigens in blood and their correlation 
with clinical response,  
Other modifications made in the document to either improve the clarity/consistency or correct 
errors. 
• Add a anti-CD38 refractory cohort in Phase 2 
In section(s): tabulated clinical trial summary, Sections 6.3 and 7.3 of the protocol. 
Rationale: Patients who received anti-CD38 mAb within 6 months before study entry and had 
disease progress while on treatment or within 60 days after the last treatment will be enrolled in a 
separate cohort. The enrollment will start only if a treatment benefit of the combination therapy is 
demonstrated in the interim analysis including pass the futility check. 
• Add assessment of humoral and cellular immune responses to myeloma-related 
tumor antigens in blood and their correlation with clinical response 
In section(s): tabulated clinical trial summary, Sections 1.1 and 9.5 of the protocol. 
Rationale: to further understand the mechanism of action of the combination therapy. 
• Update PK/PD flowcharts  
In section(s): Section 1.2 and Section 1.3 of the protocol. 
Rationale: to improve the clarity. 
• Added an appendix of contraceptive guidance and collection of pregnancy 
information and provided reference in exclusion criteria No. 18 
In section(s): Section 7.2 and appendix. 
Rationale: provide further clarification. 
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• Extended overall survival (OS) follow up period to 24 months after last patient 
first dose, best of response for post anticancer therapy will be collected during this 
study follow up period 
In section(s): CTS, Section 12.4 of the protocol. 
Rationale: to explore if the study treatment has benefit for OS and the effect of the study treatment 
to the response of next anti-cancer therapy. 
• Changed DMC review for every 4 months to every 3 months  
In section(s): Sections 6.7 and 6.8 of the protocol. 
Rationale: in response to ANSM’s request. 
• Updated cemiplimab clinical information  
In section(s): Section 4.2.2.1 of the protocol. 
Rationale: based on new information provided in IB ed.05 dated 12-May-2017.  
• Added an instruction for prophylaxis of opportunistic infections  
In section(s): Section 8.9 of the protocol. 
Rationale: in response to health authority’s request. 
• Added additional exclusion criterion  
In section(s): CTS and Section 7.3 of the protocol. 
Rationale: in response to health authority request. 
4. 
Amended protocol [04] (11 June 2019) 
This amended protocol (amendment 04) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it significantly impacts the safety or physical/mental integrity of 
participants. 
OVERALL RATIONALE FOR THE AMENDMENT 
Based on updated pharmacokinetic characterization of isatuximab, the plasma half-life has been 
re-estimated to 28 days. As duration of contraceptive measures is required to last for 5 half-lives, 
a revised duration of contraceptive measures and pregnancy testing of 5 months after the 
last isatuximab dose is required. 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 8.9,3 
Contraceptive measures 
and pregnancy 
counseling 
Amended to indicate that females of child 
bearing potential or male subjects with 
female partners of childbearing potential shall 
be required to use contraception for 5 
months following the last dose of isatuximab.  
Changed from 3 months due to re-estimation of 
isatuximab plasma half-life 
Study flowchart and 
Section 12.4.4.1 60 and 
90 days after last 
treatment visit 
Amended to indicate that monthly pregnancy 
tests will be required for 5 months following 
the last dose of Isatuximab or 6 months 
following the last dose of cemiplimab, 
whichever comes last. 
Due to re-estimation of isatuximab plasma half-
life 
5. 
Amended protocol 05 (14 August 2020) 
This amended protocol (amendment 05) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
Based on updated analysis of primary endpoint (overall response rate [ORR]) planned six months 
after last patient in (LPI) and other secondary endpoints (including overall survival [OS]) 
performed at the planned cutoff date 1 year after LPI, the addition to cemiplimab to SAR650984 
only resulted in marginal additive efficacy. No safety concerns were observed during periodic 
Data Monitoring Committee (DMC) review. No further efficacy data collection at longer follow-
up will be performed. Per DMC recommendation, the final OS analysis planned at 24 months 
after LPI will not be performed and the follow-up will stop after the extended safety period of 
90 days after last study treatment dose. Participants under treatment will continue to be treated as 
long as they benefit from it. 
A risk of hepatitis reactivation has been identified in the SAR650984 Investigator’s Brochure 
Edition 11 (30-Apr-2020). 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical trial summary; 1.1 Study 
flowchart; 1.2.2 ISATUXIMAB QW/Q2W 
+ CEMIPILIMAB Q2W (DL1) - 
Treatment phase: Cycle 2 and beyond 
(Sparse sampling); 1.2.3 ISATUXIMAB 
QW/Q2W + CEMIPILIMAB Q2W (DL1) 
- End of treatment and follow-up 
periods; 1.3.2 ISATUXIMAB QW/Q2W 
+ CEMIPILIMAB Q4W (DL-1) - 
Treatment phase: Cycle 3 and beyond 
(Sparse sampling); 1.3.3 ISATUXIMAB 
QW/Q2W + CEMIPILIMAB Q4W (DL-1) 
- End of treatment and follow-up 
periods; 6.6.1 Duration of study 
participation for each patient; 
6.6.2 Determination of end of clinical 
trial (all patients); 9.2.1 Primary 
endpoint (Phase 2 only); 
12.4.4.2 Further follow-up visits until 
12 months after LPI; 12.4.5 Post OS 
study cut-off date 
Follow-up procedures after the extended 
safety period of 90 days after last study 
treatment dose will not be performed 
anymore after amended protocol 05 
approval.  
The final OS analysis planned at 
24 months after LPI will not be 
performed. 
Patients benefiting from study treatment 
may continue receiving treatment beyond 
amended protocol 05 implementation. 
The addition to cemiplimab to 
SAR650984 only resulted in marginal 
additive efficacy. No safety concerns 
were observed during periodic DMC 
review. No further efficacy data 
collection at longer follow-up will be 
performed per DMC recommendation. 
1.1 Study Flowchart; 6.5.7 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. 
6.5.7 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. 
6.5.7 Guidance in case of hepatitis B 
reactivation occurring under study 
treatment; 12.4.1 Cycle 1 (Day 1, 
Day 8, Day 15 and Day 22 all ±1 day); 
12.4.2 Subsequent cycles (Day 1 and 
15 both ±2 days) 
Description of monitoring of alanine 
aminotransferase (ALT) and aspartate 
aminotransferase (AST) in case of viral 
reactivation. 
A risk of hepatitis reactivation has been 
identified. 
1.2.3 ISATUXIMAB QW/Q2W + 
CEMIPILIMAB Q2W (DL1) - End of 
treatment and follow-up periods; 
1.3.3 ISATUXIMAB QW/Q2W + 
CEMIPILIMAB Q4W (DL-1) - End of 
treatment and follow-up periods; 
9.1.5 Immunogenicity; 9.3.1 Sampling 
time 
Anti-drug antibodies (ADA) and 
pharmacokinetics (PK) collection was 
stopped at cutoff date for primary efficacy 
analysis 6 months after Last Patient In. 
Sufficient information on PK and 
immunogenicity of isatuximab is 
available. This change was already 
communicated through an 
administrative letter dated 10-Sep-2019 
effective on 04-Oct-2019 for patients 
still on treatment and is brought in the 
protocol at the occasion of this 
amendment. 
10.4.2 Timely handling of certain AEs 
Hospitalization and examination reports 
for serious adverse events (SAEs), 
adverse events of special interest (AESI), 
pregnancy, or overdose will not be 
systematically requested 
Only necessary copies of medical 
records are to be shared with the 
Sponsor. 
 
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Page 1
STATISTICAL ANALYSIS PLAN
A Phase 1/2 study to evaluate safety, pharmacokinetics and efficacy of isatuximab 
in combination with cemiplimab in patients with relapsed/refractory multiple 
myeloma
SAR650984-TCD14906
NCT03194867
STATISTICIAN:
DATE OF ISSUE: 05-Mar-2019
Total number of pages:
65
(electronic 1.0)


Statistical Analysis Plan
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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 ....................................................................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) .............................................15
2.1.3
Efficacy endpoints..........................................................................................................................16
2.1.3.1
Primary efficacy endpoint (Phase 2 only) ......................................................................................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............................................................................................................................................23
2.1.4.3
Laboratory safety variables............................................................................................................23
2.1.4.4
Vital signs variables .......................................................................................................................24
2.1.4.5
R code for conditional power and stopping boundary calculation Electrocardiogram 
variables.........................................................................................................................................24
2.1.4.6
Other safety endpoints...................................................................................................................24
2.1.5
Immunogenicity variables ..............................................................................................................24
2.1.6
Pharmacokinetic variables .............................................................................................................26
2.1.7
Biomarker endpoints ......................................................................................................................27
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2.1.7.1
Immune Genetic Determinants ......................................................................................................27
2.1.7.2
Immune phenotyping .....................................................................................................................28
2.1.7.3
Adaptive immune response ...........................................................................................................28
2.1.7.4
PD1-PDL1 expression ...................................................................................................................29
2.1.7.5
Blood typing interference test ........................................................................................................29
2.1.8
Health related quality-of-life (HRQL) endpoints .............................................................................29
2.1.9
Health economic endpoints............................................................................................................29
2.1.10
Further therapy after discontinuation of investigational medicinal product administration 
during the study..............................................................................................................................29
2.2
DISPOSITION OF PATIENTS .......................................................................................................29
2.2.1
Randomization and drug dispensing irregularities.........................................................................30
2.3
ANALYSIS POPULATIONS...........................................................................................................31
2.3.1
Intent to treat (ITT)/Randomized population (Phase 2 only)..........................................................31
2.3.2
All treated (AT)/safety population...................................................................................................31
2.3.3
Patients evaluable for DLT assessment (Phase 1 only)................................................................32
2.3.4
Pharmacokinetic population...........................................................................................................32
2.3.5
ADA evaluable population..............................................................................................................32
2.3.6
Biomarker population .....................................................................................................................32
2.4
STATISTICAL METHODS .............................................................................................................32
2.4.1
Demographics and baseline characteristics ..................................................................................33
2.4.2
Prior or concomitant medications (other than anticancer therapies) .............................................33
2.4.3
Extent of investigational medicinal product exposure and compliance .........................................33
2.4.3.1
Overall exposure............................................................................................................................34
2.4.3.2
Isatuximab exposure......................................................................................................................34
2.4.3.3
Cemiplimab exposure ....................................................................................................................36
2.4.4
Analyses of efficacy endpoints.......................................................................................................38
2.4.4.1
Analysis of primary efficacy endpoint(s) ........................................................................................38
2.4.4.2
Analyses of secondary efficacy endpoints.....................................................................................39
2.4.4.3
Multiplicity issues ...........................................................................................................................39
2.4.5
Analyses of safety data..................................................................................................................40
2.4.5.1
Dose-limiting toxicities (Phase 1 only) ...........................................................................................40
2.4.5.2
Analyses of adverse events ...........................................................................................................40
2.4.5.3
Deaths............................................................................................................................................47
2.4.5.4
Analyses of laboratory variables....................................................................................................47
2.4.5.5
Analyses of vital sign variables......................................................................................................48
2.4.5.6
Analyses of electrocardiogram variables .......................................................................................49
2.4.5.7
Analyses of other safety endpoints................................................................................................49
2.4.6
Analyses of immunogenicity variables...........................................................................................49
2.4.7
Analyses of pharmacokinetic variables..........................................................................................50
2.4.7.1
PK parameters ...............................................................................................................................50
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2.4.7.2
Immunogenicity impact on PK .......................................................................................................51
2.4.8
Analyses of Biomarker variables....................................................................................................51
2.4.8.1
Genetic variables ...........................................................................................................................51
2.4.8.2
Other variables...............................................................................................................................51
2.4.8.3
Potential interference of isatuximab in the M protein assessment ................................................52
2.4.9
Analyses of quality of life variables................................................................................................52
2.4.10
Further therapy after discontinuation of investigational medicinal product administration 
during the study..............................................................................................................................52
2.5
DATA HANDLING CONVENTIONS ..............................................................................................53
2.5.1
General conventions ......................................................................................................................53
2.5.2
Data handling conventions for secondary efficacy variables.........................................................53
2.5.3
Missing data...................................................................................................................................53
2.5.4
Windows for time points.................................................................................................................56
2.5.5
Unscheduled visits .........................................................................................................................56
2.5.6
Pooling of centers for statistical analyses......................................................................................56
2.5.7
Statistical technical issues .............................................................................................................56
3
INTERIM ANALYSIS .....................................................................................................................57
4
DATABASE LOCK........................................................................................................................58
5
SOFTWARE DOCUMENTATION .................................................................................................59
6
REFERENCES...............................................................................................................................60
7
LIST OF APPENDICES.................................................................................................................61
APPENDIX A
GENERIC RANGES FOR HEMATOLOGICAL AND BIOCHEMISTRY..............................62
APPENDIX B
SUMMARY OF STATISTICAL ANALYSES ........................................................................63
APPENDIX C
R CODE FOR CONDITIONAL POWER AND STOPPING BOUNDARY 
CALCULATION..............................................................................................................................64
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
ADA:
anti-drug antibody
ADI:
actual dose intensity
AE:
adverse event
AESI:
adverse event of special interest
ALT:
alanine aminotransferase 
AST:
aspartate aminotransferase 
AT:
all treated
ATC:
anatomic category class
BOR:
best overall response
BUN:
blood urea nitrogen
CBR:
clinical benefit rate
CR:
complete response
CTCAE:
common terminology criteria for adverse events
DFU:
duration of follow-up
DLT:
dose limiting toxicity
DOR:
duration of response
ECOG:
eastern cooperative oncology group, eastern cooperative oncology group
eCRF:
electronic case report form
EOT:
end of treatment
FCGR:
fc gamma receptor
FIH:
first in human
GFR:
glomerular filtration rate
HDAC:
histone deacetylase
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
IMP:
investigational medicinal product
IMWG:
international myeloma working group
irAE:
immune-related AE
IRT:
interactive response technology
ISS:
international staging system
ITT:
intent to treat
KIR:
killer-cell immunoglobulin-like receptor
KPS:
karnofsky performance status
LLT:
lower level term
MDRD:
modified diet in renal disease
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MedDRA:
medical dictionary of regulatory activities
MR:
minimal response
MRD:
minimal residual disease
NCI:
national cancer institue
NIMP:
non investigational medicinal product
ORR:
overall respnse rate
OS:
overall survival
PCSA:
potentially clinically significant abnormalities
PFS:
progression free survival
PK:
pharmacokinetic
PR:
partial response
PS:
performance status
PT:
preferred term
Q2W:
once every two weeks
QW:
once weekly
RDI:
relative dose intensity
RRMM:
relapsed/refractory multiple myeloma
SAE:
serious adverse event
SAP:
statistical analysis plan
SD:
standard deviation
SOC:
system organ class
TEAE:
treatment-emergent adverse event
TLS:
tumor lysis syndrome
TNF-α:
tumor necrosis factor alpha
TTR:
time to response
VGPR:
very good partial response
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1
OVERVIEW AND INVESTIGATIONAL PLAN
TCD14906 is the first in human study of isatuximab (SAR650984) in combination with 
cemiplimab (REGN2810) in patients with relapsed/refractory multiple meyloma. The study was 
originally designed as a dose de-escalation and expansion study (original protocol 12-Apr-2017). 
However, following comments from the FDA, the study design was subsequently modified, prior 
to enrollment of any patients, to evaluate the safety and clinical activity in relapsed/refractory 
multiple myeloma (RRMM) in 2 parts: dose de-escalation in Phase 1, followed by a three arm 
randomized Phase 2. This statistical analysis plan (SAP) describes the statistical methods to be 
used for the analyses of data collected during both Phase 1 and Phase 2 parts of the study. This 
SAP should be read in conjunction with the amended study protocol (Version 03 - 06-Aug-2018) 
and electronic case report form (eCRF).
1.1
STUDY DESIGN AND RANDOMIZATION
The study is conducted in 2 parts:

The Phase 1 (lead in) part was to confirm the feasibility of the isatuximab/cemiplimab 
combination using 3 + 3 dose de-escalation design. The Phase 1 part of the study was 
completed at time of writing of this SAP. Three patients were enrolled at DL1 
(isatuximab 10 mg/kg once weekly (QW) for four weeks followed by once every 
two weeks (Q2W) + cemiplimab 250 mg (Q2W) and no patient had DLT. 

The Phase 2 part is to further evaluate the safety, efficacy and PK of the combination 
versus isatuximab monotherapy. Based on the evaluation of the results from the 
Phase 1 part of the study, patients are randomized in the Phase 2 part of the study in 
1 of the 3 arms using an interactive response technology (IRT) in a 1:1:1 ratio:
-
Arm 1 (control): isatuximab 10 mg/kg QWx4 followed by Q2W (QW/Q2W),
-
Arm 2 (DL1): isatuximab 10 mg/kg QW/Q2W + cemiplimab 250 mg Q2W,
-
Arm 3 (DL-1): isatuximab 10 mg/kg QW/Q2W + cemiplimab 250 mg Q4W.
The duration of the study for a patient will include a period for screening of up to 21 days. 
Patients will continue treatment until disease progression, unacceptable adverse events, consent 
withdrawal, or any other reason. After the last dose of study treatment (isatuximab or 
cemiplimab), the post-treatment follow up period include an extended safety follow-up period of 
90 days, and further follow up beyond 90 days after last treatment until death or study cutoff date, 
whichever occur first.
A maximum of 105 patients (35 patients per arm) will be randomized in the Phase 2 
randomization part. Details on study design can be found in Protocol Section 6.
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1.2
OBJECTIVES
1.2.1
Primary objectives
The primary objectives are:

To determine the safety and tolerability of the combination of isatuximab and cemiplimab.

Phase 2 only: to compare the overall response rate (ORR, defined as complete 
response[CR] + very good partial response[VGPR] + partial response [PR]) of the 
combination of isatuximab and cemiplimab versus isatuximab alone in patients with 
RRMM based on International Myeloma Working Group (IMWG) criteria.
1.2.2
Secondary objectives
The secondary objectives are:

To determine the following efficacy measurements (Phase 2 part only): 
-
Clinical benefit rate (CBR, CR + VGPR + PR + Minimal response[MR]),
-
Duration of response (DOR),
-
Time to response (TTR),
-
Progression free survival (PFS),
-
Overall survival (OS).

To determine the pharmacokinetic (PK) profile of isatuximab and cemiplimab when given 
in combination.

To assess the immunogenicity of isatuximab and cemiplimab when given in combination.
1.2.3
Exploratory objectives

To explore the minimal residual disease (MRD) in patients achieving a CR.

To assess the relationship between immune phenotypes, immune regulatory marker 
expression, adaptive immune response and parameters of clinical response.

To explore central/effector memory T cell proliferation.
1.3
DETERMINATION OF SAMPLE SIZE
In Phase 1 part, the objective is to determine the recommended Phase 2 Dose (RP2D) based on 
DLT occurrence. The actual sample size will depend on DLTs observed and number of dose 
levels actually explored. It is anticipated that 3 to 18 DLT-evaluable patients will be treated in the 
Phase 1 part of the study.
In Phase 2 randomization part, the objective is to evaluate the efficacy and safety of the 
combination therapy. Assuming ORR=20% in control arm (isa alone arm) and ORR=50% in 
combination arms, using Fisher’s exact test to compare the ORR in control vs combination arms
and an overall 1-sided type I error of 5% for each combination arm, 35 patients per arm is 
required to achieve a 79% power for each combination arm. EAST 6.0 was used in the sample 
size calculation. The total expected number of patients treated in Phase 2 randomization part 
is 105.
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1.4
STUDY PLAN
Safety evaluations will be performed continuously throughout the study and will include the 
following: 

DLT at first cycle as defined in the protocol (Phase 1 only).

Adverse events (AEs) evaluation including immune related AEs. Severity grade 
determined according to the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03.

Laboratory tests in blood and urine.

Vital signs and physical exam. 

Eastern Cooperative Oncology Group (ECOG) performance status (PS).

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, 
lactate dehydrogenase [LDH].

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 in the protocol, and include:

M-protein quantification (serum and/or 24-hour urine), serum free light chain levels.

Immunoglobulins including IgG, IgA, IgD, IgE and IgM (except Cycle 1 Day 1).

Bone marrow biopsy/aspiration (at baseline, and to be performed to confirm a CR and as 
clinically indicated, and at the end of treatment (EOT) visit as clinically indicated).

Radiologic imaging of plasmacytoma (at baseline, and during the trial as clinically 
indicated and to confirm response according to IMWG criteria).

Bone skeletal survey (at baseline, and during the trial as clinically indicated and to confirm 
response according to IMWG criteria).
The following additional evaluations will also be performed:

Serum β2-microglobulin (except Cycle 1 Day 1).

Pregnancy test (except Cycle 1 Day 1).

Blood typing interference test (at baseline and Cycle 2 Day 1).

Adaptive immune response in blood and bone marrow aspirate (at baseline, Cycle 3 Day 1 
for blood only, and in case of CR).

Adaptive immune response (humoral and cellular response) (Prior to pre-medication and
IMP administration on Day 1 of Cycle 1, Cycle 2, Cycle 4, Cycle 7 and Cycle 10 and in 
disease progression patients at EOT). 

PD1-PDL1 expression in bone marrow biopsy (at baseline, at Cycle 3 Day 1, and at EOT).

MRD assessment in bone marrow aspirate (at baseline, and during the trial in case of CR).

Level of human anti-drug antibodies (ADA).

Immune phenotyping and molecular analysis on blood and bone marrow.

FISH bone marrow aspirate (at baseline).
PK samples will be collected in all patients receiving isatuximab and cemiplimab as depicted in
the PK study flowcharts included in the protocol.
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1.5
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL 

Change from first dose date to randomization date.
Secondary efficacy endpoints (Section 2.1.3.2) including progression free survival (PFS), time to 
response (TTR) and overall survival (OS) were defined starting from the first treatment date in the 
protocol, this is updated to the date of randomization in the analysis plan. The associated 
censoring rules are also updated.
This change is also applied to disease characteristics variables (Section 2.1.1), including time 
from diagnosis to randomization, time from last regimen to randomization, time from last 
transplant to randomization and time from last radiotherapy to randomization.
1.6
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN
Not applicable, as this is the 1st version.
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2
STATISTICAL AND ANALYTICAL PROCEDURES
2.1
ANALYSIS ENDPOINTS
Unless otherwise specified, analyses endpoints are defined for both Phase 1 and Phase 2 patients
and will be analyzed separately based on the analysis population defined in Section 2.3. 
The reference date is defined as the date of first dose for Phase 1 and date of randomization for 
Phase 2. 
2.1.1
Demographic and baseline characteristics
The baseline value is defined as the last value or measurement taken up to the date and time of the
first dose of study treatment. 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 (Phase 2 only), 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 (American Indian or Alaska Native, 
Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White,
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), 
weight (kg) and ECOG performance status.
Medical or surgical history
Medical (or surgical) history includes relevant history of previous/associated pathologies other 
than symptomatic multiple myeloma (MM), including respiratory medical history. This 
information will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) in 
effect at Sanofi at the time of database lock.
In addition, smoking habits including smoking status at study entry will be collected in a specific 
eCRF page.
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Disease characteristics at initial diagnosis
The following MM characteristics at initial diagnosis will be summarized: time from initial 
diagnosis to reference date (in years) and by category (<5 years and ≥5 years), International 
Staging System (ISS) stage, and subtype (heavy and light chain component as collected in the 
eCRF), biclonal status.
Disease characteristics at study entry
The following MM characteristics at study entry will be summarized: 

ISS stage (Table 1), 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).

Cytogenetic abnormalities from central FISH assessment:
-
Number and percentage of patients with cytogenetic abnormality for del (17p), t(4;14),
and t(14;16). Abnormality is defined as at least 15% of abnormal plasma cells for
t(4;14), and t(14;16), and at least 10% of abnormal plasma cells for del(17p13),
-
Type of risk: Standard risk, high-risk (defined as presence of del(17p) and/or
translocation t(4;14) and /or translocation t(14;16) abnormality) and unknown/missing,
-
Number of patients with 2 abnormalities: del(17p) and t(4,14); and, del(17p) and
t(14,16). 

MM type: Heavy and light chain components (as collected in eCRF).

Bi-clonal status (as collected in eCRF).

Refractory status
-
Relapsed and refractory: non-responsive while on salvage therapy or progresses within
60 days of last therapy in patients who have achieved minimal response or better at
some point previously to then progressing in their disease course,
-
Primary refractory: never achieve MR or better in any prior therapies,
-
Relapse: all cases not meeting the relapse and refractory or primary refractory
definition.

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.

Patients with bone lesions and number of lesion.
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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 disease)
Urine M-Protein
Urine M-protein ≥200 mg/24hours 
Serum and urine M-protein
Light chain
Not evaluable (neither serum 
neither urine)
Serum M-protein ≥1 g/dL (or 0.5 g/dL in case of IgA disease)
and 
urine M-protein ≥200 mg/24hours 
Serum immunoglobulin free light chain ≥10 mg/dL and abnormal
serum immunoglobulin kappa lambda free light chain ratio <0.26 or >1.65
Missing or not evaluable
Prior anti-myeloma therapies
Prior anti-myeloma treatment: 
Prior anti-myeloma treatments are collected by regimens on eCRF. A line of therapy consists of 
≥1 complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a 
planned sequential therapy of various regimens (eg, 3-6 cycles of initial therapy with 
bortezomib-dexamethasone followed by stem cell transplantation consolidation, and lenalidomide 
maintenance is considered 1 line; Amended protocol Version 3.0, Appendix E). An algorithm will 
be used to determine number of prior lines: a new line of therapy starts if:

There is an evidence of progression/relapse. OR,

A planned course of therapy is modified as a result of toxicity, progression/relapse, lack of 
response, inadequate response, or any other reasons indicative of incomplete treatment or 
change of plan.
The following analysis of prior anticancer treatment will be performed.

Prior anticancer treatments:
-
Number of prior lines (quantitatively and by category: 1, 2… 7 and ≥8),
-
Number of prior regimens (quantitatively and by category: 1, 2… 7 and ≥8),
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-
Main anticancer treatments:
-
Alkylating agents: including cyclophosphamide, melphalan, bendamustine, 
cisplatin,
-
Proteasome inhibitors: including bortezomib, carfilzomib, ixazomib,
-
Immunomodulators: including lenalidomide, thalidomide, pomalidomide,
-
Histone deacetylase (HDAC) inhibitors: panobinostat,
-
Corticosteroids: dexamethasone, prednisone,
-
Anthracyclines,
-
Vinca alkaloids,
-
Monoclonal antibodies: including elotuzumab, daratumumab and other 
anti CD38 agents,
-
Description of last regimen prior to study entry:
-
Time from completion of last regimen of treatment to reference date (months), 
-
Main treatments,
-
Best response to last regimen, 
-
Duration of last regimen of therapy (months).
In addition, the refractory status to main anticancer treatment (as listed above) and refractory 
status of the last prior anticancer treatment received before enrollment 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 (BOR) is SD or PD.
Reason for treatment discontinuation is “progressive disease”.

Prior transplant: patients with transplant, type of transplant, number of transplant by 
patient, time from last transplant to reference date (months).

Prior surgery: patients with any prior surgery related to cancer, type of surgery and time 
from last surgery to reference date (months).

Prior radiotherapy: number (%) of patients with any prior radiotherapy related to cancer, 
intent, and time from last radiotherapy to reference date (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 
Creatinine clearance, ie, glomerular filtration rate (GFR) in mL/min/1.73 m2 (qualitative 
variable: <15, [15-30[, [30-60[, [60-90[, ≥90) will be calculated from serum creatinine 
concentration measured at baseline using Modified Diet in Renal Disease (MDRD) formula
(Section 2.5.1).
2.1.2
Prior or concomitant medications (other than anticancer therapies)
All medications taken by the patient within 21 days prior to first study treatment, at any time 
during the study in addition to IMP 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, etc), 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.

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.

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).

Post-treatment medications (excluding post anticancer treatments) are those the patient 
took from 31 days after last study treatment administration up to the end of the study.
IR medications
As defined in Section 8.2 of the study protocol, 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.
Analysis of premedications will focus on those given for prophylaxis reason. Medication given in 
curative intent of IR will be also analyzed.
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 were to be performed on Day 1 of every cycle during treatment by 
investigators using the International Myeloma Working Group (IMWG) response criteria (1) and 
by considering the assessment included in Section 1.4.
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.
For Phase 1, best overall response, duration of response, progression free survival and overall 
survival will be derived and listed by patient.
2.1.3.1
Primary efficacy endpoint (Phase 2 only)
The primary efficacy endpoint is ORR, defined as the proportion of patients with CR
(including sCR), VGPR or PR as BOR as assessed by the investigator. BOR will be derived using 
disease assessments (overall response CRF page) from the start of treatment through the entire 
study excluding any assessments performed after disease progression (that is confirmed), the 
cutoff date or following the start of further therapies for MM (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 will be 
‘Not evaluable’. BOR will be the best sequential response based on the investigator’s disease
assessments as determined by the criteria in Table 3. In addition, the following rules will be 
applied:

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. 

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. 
Symptomatic deterioration will not be considered as progression in the primary analysis of ORR.
Table 3 - 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
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Overall response at Cycle n
Overall response at Cycle n+1a
Sequential response
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.
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 will be performed for the variables listed in Table 4.
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Table 4 - List of variables for subgroup analyses
Variable
Description 
Age
<70 years vs ≥70 years
Gender
Male vs female
Number of previous lines of therapy
≤3 vs >3
ISS staging at study entry
I vs II vs III
High risk cytogenetic
Yes vs No
Baseline creatinine clearance (MDRD)
<60 ml/min/1.73m2 vs ≥60 ml/min/1.73m2
Refractory to IMiD
Yes vs No
Refractory to PI
Yes vs No
Refractory to IMiD and PI
Yes vs No
Refractory to daratumumab
Yes vs No
Baseline PD-L1 level
≥50% vs <50%
2.1.3.2
Secondary efficacy endpoints
Secondary efficacy endpoints are defined below.

CBR: defined as the proportion of patients with CR (including sCR), VGPR, PR or MR as 
assessed by investigators using the IMWG response criteria.

DOR: DOR is defined as the time from the date of the first response (≥PR) that is 
subsequently confirmed, to the date of first documented PD or death (if reported before the 
analysis cutoff date or the date of initiation of a new anticancer treatment), whichever 
happens earlier. In the absence of the confirmation of subsequent disease progression or 
death before the analysis cut-off date or the date of initiation of a further anticancer 
treatment, the DOR will be censored at the date of the last valid disease assessment not 
showing disease progression performed prior to initiation of a further anticancer treatment 
and the analysis cut-off date, whichever is earlier. DOR will not be calculated for patients 
that do not achieve a PR or better.

TTR: defined as time from randomization to first response (PR or better) that is 
subsequently confirmed.

PFS: defined as the time interval from the randomization date to the date of the 
first documented disease progression that is subsequently confirmed or the date of death 
due to any cause, whichever comes first. For patients who did not experience documented 
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 comes first. 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 documented disease progression) 
and without any valid post-baseline disease assessments will be censored at the 
randomization date. Patients with death and time between the last post-baseline assessment 
and death >2 cycles will be censored at the date of last valid assessment (ie, not equal to 
NE). Subgroup analysis for variables defined in Table 4 will be performed.
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
OS: defined as the time interval from the date of randomization to death from any cause.
Patients without death prior to the analysis cutoff date will be censored at the last date the 
patient is known to be alive or the cut-off date whichever comes first.
Other efficacy endpoints include:

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). In case that
both serum and urine M proteins are measurable, change in serum M protein will be 
calculated. The calculation will exclude anytime point following the start of other 
anticancer therapy or cutoff date.

Duration of follow-up (DFU) (in months): DFU is defined as the time from randomization
to last disease assessment before start of other therapy or cut-off date or death, whichever 
comes first.

MRD: MRD will be assessed by sequencing and/or flow cytometry in bone marrow 
samples from CR patients. Method to measure MRD include multi-parametric flow 
cytometry (MFC) and more recently next generation sequencing to amplify and sequence 
immunoglobulin gene segments present in myeloma clone is a quantitative method for 
MRD detection. Bone marrow samples will be collected at CR.
Figure 2 - Date of PFS event/censoring relative to the date of further anti-myeloma therapies 
and the cutoff date using investigator’s assessment
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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, ECG and ECOG performance status (Section 1.4).
Observation period
The observation period will be divided into 3 periods: pre-treatment, on-treatment, and 
post-treatment including the extended safety follow-up period.

The pre-treatment period is defined as the time from when the patient gave informed 
consent and the start of study treatment administration.

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.

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).
-
The extended safety follow-up period is defined as the time period from 31 days 
after the last dose of study treatments to 90 days after the last dose of study treatments.
2.1.4.1
Adverse events variables
Adverse events occurring from signature of informed consent form up to 30 days after the last 
study treatment administration will be recorded in the eCRF. In addition, all study treatment 
related AEs and serious AEs (SAEs) ongoing at time of study treatment discontinuation will be 
followed during the follow-up period until resolution or stabilization.
All AEs (including 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:

Pre-treatment AEs: defined as any AE reported during the pre-treatment period.

Treatment-emergent AEs (TEAEs): defined as any AE developed, worsened (according 
to the Investigator’s opinion), or became serious during the on-treatment period.

Post-treatment AEs: defined as any AE developed, worsened (according to the 
Investigator’s opinion), or became serious during the post-treatment period.
-
Extended safety follow-up period AEs: defined as any AE developed, worsened 
(according to the Investigator’s opinion), or became serious during the extended safety 
follow-up period.
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In addition, deaths (Section 2.1.4.2), SAEs, AEs leading to withdrawal, and other significant AEs 
will be analyzed. Other significant events will include: 
Adverse events of special interest (AESIs):

Grade ≥2 acute infusion reactions (IRs).

Grade ≥3 immune-related TEAEs.

Any grade of treatment emergent immune-related AEs (irAE) in a patient previously 
treated with a Pi3K inhibitor.

DLTs (for Phase 1 part only).

Symptomatic overdose with IMP/NIMP.

Pregnancy occurring in a female patient or in a female partner of a male patient.
Infusion reactions
Infusion reactions typically occur within 24 hours from the start of each cemiplimab/isatuximab 
infusion. As described above, Grade ≥2 IRs are AESIs.
Whenever possible, a diagnosis of the IR (eg, Cytokine release syndrome, infusion related 
reaction, anaphylactic reaction, or any other teams chosen by the investigator) will be reported by 
the investigator on a specific AE page instead of individual symptoms. Each IR diagnosis will be 
reported as related to isatuximab, cemiplimab or NIMP (eg, premedication). In addition, 
symptoms of the IRs will be reported on a separate eCRF form.
The primary analysis of IR will include all events regardless of the relationship to isatuximab,
cemiplimab or NIMP.
One type of IR analysis will be performed based on the investigator’s reporting of IR (diagnosis
or symptoms).
Another type of IR analysis 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 
infusion of isatuximab and/or cemiplimab (ie, TEAEs with onset on the same calendar day of the 
cemiplimab/isatuximab infusion or on the following day). 
A similar type of analysis including TEAEs occurring within 24 hours from the start of each
infusion and within the within 24 hours in the “Hypersensitivity and CRS” CMQ will also be 
performed. 
Moreover, all the TEAEs (not only limited to those occurring within 24h of each infusion) from 
the above listed CMQ will also be analyzed.
If relevant (see Section 2.4.5.2), additional analyses of IR will be performed separately for IRs 
related to isatuximab or to cemiplimab. 
IRs related to NIMP (if any) will be reported in a listing.
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Immune-related AEs
Immune-related AEs are typically associated with immune checkpoint inhibitors (2). The 
symptoms of irAEs may be subtle (Amended Protocol Version 3.0, Section 6.5.4) and may
include, but not limited to, colitis, endocrine AE, pneumonitis, renal AE, dermatologic AE, 
hepatitis, ophthalmologic AE (Uveitis), nausea and vomiting. Because irAEs could occur long 
after exposure with immune checkpoint inhibitors, the irAE analysis will not be limited to the 
on-treatment period, but also include the extended safety follow up period.
Different types of irAE analysis will be performed.

Grade ≥3 irAEs reported as AESIs: include all AESIs and exclude IRs, pregnancy, 
symptomatic overdose and DLT (if any).

TEAEs plus extended safety follow-up AEs (related to cemiplimab; regardless of 
relationship).

TEAEs plus extended safety follow-up AEs from sponsor selected grouping of PTs 
(related to cemiplimab; regardless of relationship).
Respiratory AEs
Analysis of respiratory TEAEs will focus particularly on the following groupings: 

Lower Respiratory adverse events, selected using CMQ ‘Lower respiratory events’.

Respiratory infections, selected using CMQ ‘Respiratory infections’.
In addition, respiratory adverse events with late onset (ie, occurring, worsening or becoming 
serious more than 30 days after last dose) will be analyzed as part of the post-TEAEs analysis.
Cardiac AEs
Analysis of cardiac adverse events will focus particularly on SMQ “Cardiac failure” (narrow).
Neutropenia and neutropenic complications
Neutropenia, febrile neutropenia and neutropenic infections will be analyzed using the following
data source:

Neutropenia based on laboratory results.

Febrile neutropenia selected using CMQ ‘Febrile neutropenia’.

Neutropenic infections: defined as NCI-CTCAE Grade ≥2 infections from SOC Infections
and Infestations’ (selected using CMQ ‘GLB_SOC infections and infestations’) 
concomitant with NCI-CTCAE Grade 3-4 neutropenia from laboratory results. Infection 
and Grade 3-4 neutropenia will be considered as concomitant if one of the following 
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.
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Thrombocytopenia and hemorrhages

Thrombocytopenia will be analyzed based on laboratory results.

Hemorrhages will be selected using the TEAEs from the SMQ ‘Haemorrhage terms 
(excl laboratory terms)’.

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.  
Hemolytic disorders
Hemolytic disorders will be selected using the TEAEs from the CMQ ‘Haemolytic disorders
Broad’.
Tumor lysis syndrome
Tumor lysis syndrome will be identified using CMQ ‘Tumour lysis syndrome’.
Second primary malignancies
Second primary malignancies will be selected using CMQ ‘Second primary malignancies’
2.1.4.2
Deaths
The deaths observation periods are per the observation periods defined in Section 2.1.4.

Death on-treatment: deaths occurring during the on-treatment period.

Death post-treatment: deaths occurring during the post-treatment period.
2.1.4.3
Laboratory safety variables 
Clinical laboratory data consists of blood and urine analysis, including hematology, biochemistry, 
and urinalysis.  Clinical laboratory values will be converted into standard international units and 
these international units will be used in all listings and tables.
The laboratory parameters will be classified as follows:

Hematology 
-
Red blood cells, platelets, and white blood cells: hemoglobin, hematocrit, red blood 
cell count, white blood cell with differential, and platelet count,
-
Coagulation: prothrombin time (expressed as international normalized ratio [INR]), 
activated partial thromboplastin time (aPTT).

Biochemistry 
-
Metabolism: fasting glucose, total protein, albumin,
-
Electrolytes: sodium, potassium, chloride, bicarbonate/carbon dioxide, calcium, 
corrected calcium (formula included in Section 2.5.1), magnesium, phosphate,
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-
Renal function: uric acid, creatinine, creatinine clearance (eGFR), urea or 
blood urea nitrogen (BUN),
-
Liver parameters: aspartate aminotransferase (AST), alanine aminotransferase
(ALT), bilirubin (total and direct), alkaline phosphatase, LDH,
-
Hormonal: thyroid stimulating hormore (TSH), and free T4.

Urinalysis
-
Qualitative analyses (dipstick),
-
Quantitative analyses: sodium, potassium, calcium, chloride, red blood cell, leukocytes, 
protein, glucose, ketone, pH, bilirubin, nitrate, and specific gravity.
Technical formulas are described in Section 2.5.1.
2.1.4.4
Vital signs variables
Vital signs include: systolic and diastolic blood pressure, heart rate, temperature, respiratory rate,
and weight.
2.1.4.5
R code for conditional power and stopping boundary calculation 
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:

Chest X-ray at screening and as clinically indicated.

Cytokines (TNF-α, IL-1-β, IL-6, IFN-γ), markers of complement (C3a, C4, CH50), 
serum tryptase.

Indirect antiglobuline test (IAT).
2.1.5
Immunogenicity variables
Anti-drug antibodies (ADA) against isatuximab and cemiplimab were collected according to the 
PK/PD flowcharts of the protocol.
Observation period
The observation period will be defined for isatuximab and cemiplimab separately, which are 
divided into 2 periods: ADA pre-treatment and ADA on-study observation.

ADA pre-treatment period: The ADA pre-treatment period is defined as the date from 
signed informed consent to the date and time of first study drug administration.

ADA on-study observation period: the ADA on-study observation period is defined as the 
date and time from the first study drug administration until the end of the study. 
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ADA attributes
Pre-existing ADA is defined as ADA that are present in samples drawn during the pre-treatment 
period.
Treatment boosted ADA is defined defined as pre-existing ADA with a significant increase in 
the ADA titer during the study compared to the baseline titer. A low serial dilution schema (2-fold 
or 3-fold) should be applied during titration. A difference in titer values of two titer steps between 
treatment or follow-up sample and its baseline sample is considered significant. For examples, at 
least a 4-fold increase in titers for 2-fold serial dilution schema (or 9-fold increase in titers for 
3-fold serial dilution schema). If no titer could be determined for a positive sample, the titer will 
be reported as the minimal required dilution of the assay.
Treatment-induced ADA is defined as 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). If the baseline ADA sample is missing or non-reportable and at 
least one reportable ADA sample is available during the treatment (including follow-up period) 
the baseline sample will be considered as “negative” for data analysis. This is considered being a 
conservative approach for ADA assessment.
Subject status
Among evaluable population for immunogenicity (described in Section 2.3.5), following patient 
status will be defined:

ADA-positive subject: A subject with at least one treatment induced or treatment boosted 
ADA-positive sample at any time following the first study treatment administration. 

ADA-negative subject: Subject without any treatment induced or treatment boosted
ADA-positive sample during the on-study observation period.

ADA-inconclusive subject: A subject who cannot irrefutably be classified as 
ADA-negative (eg, all post baseline samples inconclusive).
Overview of the ADA response
Two main categories can be reported for the epidemiology of an ADA immune response: 
ADA prevalence and ADA incidence:

ADA prevalence is defined as the proportion of all patients tested positive for ADAs 
(including preexisting antibodies, treatment boosted ADAs and treatment induced ADAs) 
at any point.

ADA incidence is defined as the proportion of subjects found to either have seroconverted 
(treatment induced ADAs) or boosted their pre-existing ADA response during the
on-study observation period. Only evaluable subjects (described in Section 2.3.5) are 
considered for computing ADA incidence.
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Kinetics of the immune response

Onset of ADA: refers to the time period between the initial drug administration and the 
first instance of treatment induced ADAs (in days). The “median time to ADA 
development” and the quartiles Q1 and Q3 will be reported.

Duration of ADA: ADA duration will be calculated as the date of last treatment induced.

ADA sample minus date of first treatment induced or treatment boosted ADA sample + 1.

ADA duration will be calculated only for patients with at least two ADA positive samples.
Median duration of an induced ADA response and the quartiles Q1 and Q3 should be 
reported.

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 the 
treatment (including follow-up period if any), where the first and last ADA-positive 
samples (irrespective of any negative samples in between) are separated by a period 
less than 16 weeks, and the patient’s last sampling time point is ADA negative.

Persistent ADA response is defined by:
-
Treatment induced ADA detected at two or more sampling time points during the 
ADA on-study observation period, where the first and last ADA-positive samples are 
separated by at least 16 weeks (irrespective of any negative samples in between).

Indeterminate ADA is defined by:
-
Treatment induced ADA detected only at the last sampling time point, OR
-
The last two samples being ADA-positive and separated by a period of less than 
16 weeks.
Treatment-boosted ADAs are excluded from the analysis of ADA kinetics.
2.1.6
Pharmacokinetic variables
The PK sampling times for isatuximab and cemiplimab were provided in the PK/PD flowcharts of 
the protocol.
The following PK parameters (listed in Table 5) will be calculated with pharmacokinetic data 
management system (PKDMS) software (Pharsight) V3.0; using non-compartmental analysis 
(NCA) from isatuximab and cemiplimab concentrations after the first administration on Cycle 1. 
The parameters will include, but may not be limited to the following:
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Table 5 - List of pharmacokinetic parameters and definitions after the first administration
Parameters
Analyte
Definition
Cemiplimab
Isatuximab
Ceoi
•
•
Concentration observed at the end of intravenous (IV) infusion
Cmax
•
•
Maximum concentration observed
tmax
•
•
Time to reach Cmax
Clast
•
•
Last concentration observed above the lower limit of quantitation
tlast
•
•
Time of Clast
AUC0-14d
or AUC0-28d
•
Area under the concentration versus time curve calculated using the 
trapezoidal method over the dosing interval 
(DL1=14 days and DL-1=28 days)
AUC0-7d
•
Area under the plasma concentration versus time curve calculated using the 
trapezoidal method over the dosing interval (7 days)
Ctrough are defined as sample collected just before treatment administration during repeated dosing.
In addition, Populations PK approaches may be used for both compounds and PK estimates may 
be used to conduct exploratory exposure-response analyses for safety and efficacy and 
PK/PD analyses for relevant biomarkers. If done, the data generated will be reported in 
stand-alone report(s). 
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:

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.

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

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, D1 of Cycle 3) and/or peripheral blood (baseline, 
D1 of Cycle 3 and EOT) will be assessed. The blast cells and immune cell populations include 
MDSC cell, B-cell, T-cell and NK-cell subsets and regulatory T cells (Treg)/CD8 effector ratio
will be determined by multiparametric flow cytometry based on the expression of different cell 
surface markers. 
2.1.7.3
Adaptive immune response
Adaptive immune response (TCR repertoire profiling) will be assessed in blood and bone marrow 
samples, which are collected at screening, D1 of Cycle 3 (blood only) and at CR.
Adaptive immune response (humoral and cellular immune responses to myeloma-related tumor 
antigens) will be assessed in blood prior to pre-medication and IMP administration on D1 of 
Cycle 1, Cycle 2, Cycle 4, Cycle 7 and Cycle 10 and in disease progression patients at EOT. 
Humoral response will be assessed in all sites. Cellular response will be assessed in patients at
selected sites.
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2.1.7.4
PD1-PDL1 expression
PD1-PDL1 expression will be assessed using archival bone marrow biopsy.
2.1.7.5
Blood typing interference test
Blood typing interference test will be done on blood sample.
2.1.8
Health related quality-of-life (HRQL) endpoints 
Not applicable following Protocol Amendment 3.
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: relapse/progression date, best response, 
drug/medication (brand or generic name), start date and end date (if available)/ongoing 
(otherwise).
2.2
DISPOSITION OF PATIENTS
This section describes patient disposition for both patient study status and the patient analysis 
populations. Disposition will be described separately for Phase 1 and Phase 2 patients, based on 
the analysis population defined in Section 2.3. 
Screened patients are defined as any patients who signed the informed consent. Randomized 
patients and all treated/safety patients are defined in Section 2.3.
For patient study status, patients in each of the following categories will be provided in a 
summary table or a flowchart diagram:

Screened patients.

Screen failure patients and reasons for screen failure (if any).

Randomized patients (Phase 2 only).

Randomized but not treated patients (Phase 2 only).

Randomized and treated patients (Phase 2)/treated (Phase 1).

Patients who discontinued study treatment.

Patients still on treatment.

Status at last study contact.
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A summary of the reasons for definitive and premature treatment discontinuation for any 
compound by arm will be provided. Definitive treatment discontinuation is defined as the 
discontinuation of all the study drugs. Premature treatment discontinuation (only for the 
combination arms) is defined as the discontinuation of at least one of the study drugs but at least 
one is continued. Listing of the reasons for treatment discontinuation at time of the analysis will 
be provided.
Patients in each country and center will be summarized using the randomized population.
All critical or major deviations potentially impacting efficacy analyses, randomization, and
drug-dispensing irregularities and other major or critical deviations will be summarized in tables
giving numbers and percentages of deviations by arm.
Additionally, the following analysis populations will be summarized:

ITT/randomized population.

Safety population.

Pharmacokinetics population.

ADA evaluable population.
Definition of study populations are provided in Section 2.3.
2.2.1
Randomization and drug dispensing irregularities
For the Phase 2, randomization and drug-dispensing irregularities occur whenever:

A randomization is not in accordance with the protocol-defined randomization method, 
such as a) an ineligible patient is randomized, b) a patient is randomized twice. OR,

A patient is dispensed an IMP not allocated by the protocol-defined randomization, such 
as a) a patient at any time in the study is dispensed a different treatment IMP than as 
randomized (which may or may not contain the correct-as-randomized IMP), or
b) a non-randomized patient is treated with IMP reserved for randomized patients.
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report.  The irregularities will be categorized and summarized among randomized patients 
(number and percentages).  Non randomized and treated patients in Phase 2 (if any) will be 
described separately.
Randomization and drug-dispensing irregularities to be prospectively identified include but are 
not limited to: 

Study treatment administration without IRT transaction.

Patient randomized twice.

Treatment taken or schedule different from randomized treatment/schedule.
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2.3
ANALYSIS POPULATIONS
Unless otherwise specified, analysis population will be defined separately for Phase 1 and
Phase 2 patients. 
2.3.1
Intent to treat (ITT)/Randomized population (Phase 2 only)
The intent to treat/randomized population includes all patients from Phase 2 who gave their 
informed consent and were assigned a randomization number by the IRT, regardless of whether 
the patient was treated or not. In this population, patients will be analyzed according to the arm
allocated by IRT, regardless of whether patients received any study drug or receive a different 
study drug from which they were randomized.
For any patient randomized more than once, only the data associated with the first randomization 
will be used for analysis.
This population is the primary population for all efficacy analyses.
2.3.2
All treated (AT)/safety population
The all treated/safety population is defined by phases. 
For Phase 1, the all treated/safety population is defined as all screened patients who received at 
least one dose or a part of a dose of the study treatments (isatuximab or cemiplimab), regardless of 
the amount of treatment administered. 
For Phase 2, the all treated/safety population is defined as all randomized patients who received at 
least one dose or a part of a dose of the study treatments (isatuximab or cemiplimab), regardless of 
the amount of treatment administered. 

Patients who receive at least 1 cemiplimab dose (even incomplete) during the trial will be 
analyzed in the combination arms: 
-
Patient who receive at least 1 cemiplimab dose at Day 15 of any cycle will be analyzed 
in Q2W arm. Patient without any cemiplimab dose at Day 15 of any cycle will be 
analyzed in Q4W arm.

Patients who receive isatuximab only throughout the trial will be analyzed in isatuximab 
control arm. 
Randomized patients from whom it is unclear whether they took the IMP will be included in the 
safety population, and included in the treatment arms as randomized.
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 analysis of all exposure and safety parameters 
(except for DLT evaluation). Phase 1 and Phase 2 patients will be analyzed separately.
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2.3.3
Patients evaluable for DLT assessment (Phase 1 only)
The DLT evaluable population is defined as patients in the Phase 1 part receiving the planned 
doses of isatuximab and cemiplimab during Cycle 1, and who completed the DLT observation 
period of Cycle 1 after the first IMP administration, unless they discontinue the study treatment(s) 
due to DLT. Dose-limiting toxicity will be validated by the Study Committee. Patients not 
evaluable for DLT will be replaced.
2.3.4
Pharmacokinetic population
The PK population will be defined independently for isatuximab and cemiplimab, and includes 
patients from the all treated population with at least one reportable concentration after the study 
drug administration (whatever the cycle and even if dosing is incomplete).  
2.3.5
ADA evaluable population
The ADA evaluable population will be defined independently for isatuximab and cemiplimab, and 
includes subjects with at least one sample, taken post-baseline after drug administration during the 
treatment or follow-up observation period, that is appropriate for ADA testing with a reportable 
result (positive, negative or inconclusive).
2.3.6
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
unless otherwise specified. 
2.4
STATISTICAL METHODS
Unless otherwise specified, analyses will be descriptive and performed separately for Phase 1 and
Phase 2 patients, based on the analysis population defined in Section 2.3. 
For Phase 1 part, when the number of treated patient is small (<5), baseline information together 
with listings on response and adverse events will be provided. Summary tables might be presented 
if deemed appropriate.
In Phase 2 summary tables (except for demographics and baseline characterastics), treatment arms 
will be presented as follows:

Isatuximab 10 mg/kg QW/Q2W (Isa).

Isatuximab 10 mg/kg QW/Q2W + cemiplimab 250 mg Q2W (Isa + CemQ2W).

Isatuximab 10 mg/kg QW/Q2W + cemiplimab 250 mg Q4W (Isa + CemQ4W).
Parameters on demographics and baseline characterastics would be provided by treatment arms 
and overall. 
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Continuous data will be summarized using the number of available data, mean, standard deviation 
(SD), median, minimum, and maximum for each arm. Categorical and ordinal data will be 
summarized using the number and percentage of patients in each arm.
2.4.1
Demographics and baseline characteristics
Parameters described in Section 2.1.1 will be summarized using descriptive statistics on the 
AT/safety population in Phase 1 or ITT/randomized population in Phase 2. For Phase 2, analyses 
for the AT/safety population will be included in the appendices if the size of the randomized 
population is different (>10%) from the size of the all treated/safety population for any arm.
Past medical or surgical history will be summarized by primary SOC and PT (SOC will be sorted
according to the internationally agreed order and PT by decreasing frequency) for randomized 
population in Phase 2. 
2.4.2
Prior or concomitant medications (other than anticancer therapies)
The prior and concomitant medications will be presented for the AT/safety population in Phase 1 
and the randomized population in Phase 2. 
Medications will be summarized by arm and overall according to the WHO-DD dictionary, 
considering the first digit of the anatomic category class (ATC) (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 tables for prior, 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 
Isa + CemQ2W column. In case of equal frequency regarding ATCs (anatomic or therapeutic 
categories), alphabetical order will be used.
IR medications
Number (%) of patients with IR medications (including prophylaxis and curative intent) as 
defined in Section 2.1.2 will be provided. Number (%) of patients with prophylactic IR 
medications including acetaminophen, diphenhydramine (or equivalent) and steroids will be 
provided by infusions. A similar summary will be provided for IR medications of curative intent.
2.4.3
Extent of investigational medicinal product exposure and compliance 
The extent of study treatment exposure will be assessed and summarized on the AT/safety
populations. 
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2.4.3.1
Overall exposure
The dose information will be assessed by the following variables to summarize the overall study 
treatment exposure (all study treatments together):

Number of cycles started, defined by maximum of isatuximab/cemiplimab cycles started.

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 cemiplimab 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 dose of cemiplimab + 14 days if last cycle is Q2W cycle or date of last 
dose of cemiplimab + 28 days if last cycle is Q4W cycle (if applicable).
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:

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:

Patient level: 
-
Number of patients treated (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).

Cycle level:  
-
Number of cycles (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.
2.4.3.2
Isatuximab exposure
The isatuximab dose information will be assessed by the following:

Total number of cycles started.

Number of cycles started by patient.
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
Duration of isatuximab exposure (or time on-treatment) (in weeks) is defined depending 
on the isatuximab administration schedule as follows:
-
If drug 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 drug is discontinued at a cycle with Q2W isatuximab administration: [date of last 
dose of isatuximab + 14 days - date of first dose of isatuximab]/7.

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).

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.

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).

Relative dose intensity (RDI) in %: 
.
Planned dose intensities in mg/kg/week corresponds to the planned dose (10 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:

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.

Infusion interruption: An infusion will be considered to be interrupted (as collected 
on CRF) if the isatuximab administration is stopped during an infusion before it is 
completed regardless of whether it is further restarted or not.

Dose omission: a dose is considered omitted if the dose is not administered for the 
scheduled visit and there are positive dose(s) afterwards.
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Dose delayed/modification will be analyzed at the patient, cycle and the total number of 
isatuximab administration levels as follows:

Patient level (number of all treated patients will be used for % calculation):
-
Number (%) of patients with at least 1 dose delay,
-
Number (%) of patients with at least 1 dose omission,
-
Number (%) of patients with a least 1 infusion interrupted:
-
Number (%) of patients with a least 1 infusion interrupted and re-started,
-
Number (%) of patients with a least 1 infusion interrupted and not re-started,
-
Number (%) of patients with at least 2 infusions interrupted.

Infusion level
-
Total number of infusions (used for % calculation for this section),
-
Number (%) of infusions interrupted:
-
Number (%) of infusions interrupted and re-started,
-
Number (%) of infusions interrupted and not re-started,
-
Number (%) of 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, 31-60, 61-90, 91-120, >120).
Duration of isatuximab infusion (in hours) is defined as the time from the start (date/time) of
isatuximab infusion to the end (date/time) of isatuximab infusion in the same visit. It will be 
summarized for first and subsequent infusions.
2.4.3.3
Cemiplimab exposure
The cemiplimab dose information will be assessed by the following:

Total number of cycles started.

Number of cycles started by patient.

Duration of cemiplimab exposure (or time on-treatment) (in weeks) is defined depending 
on the cemiplimab administration schedule as follows:
-
Q2W cemiplimab administration: [date of last dose of cemiplimab + 14 days - date 
of first dose of cemiplimab]/7,
-
Q4W cemiplimab administration: [date of last dose of cemiplimab + 28 days - date of 
first dose of cemiplimab]/7.

Actual dose (mg): for a given cycle and day of administration.

Cumulative dose (mg): the cumulative dose is the sum of all actual cemiplimab doses.   
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
ADI in mg/week: defined as the cumulative dose (in mg) divided by the duration of 
cemiplimab exposure (in weeks).

RDI in %: 
.
Planned dose intensities in mg/week is 125 mg/week for Q2W schedule, and 62.5 mg/week for 
Q4W schedule.
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 cemiplimab exposure, cumulative dose, ADI and RDI will be summarized by 
descriptive statistics. 
The following variables will be derived to describe dose delays/modifications:

Dose delay (within a cycle, only applicable to Q2W schedule): A dose is deemed as 
delayed if the actual start date of the infusion – theoretical start date of an infusion is 
>2 days for Q2W administration. Dose delay does not apply to the first infusion of each 
cycle.

Infusion interruption: An infusion will be considered to be interrupted (as collected on 
CRF) if the cemiplimab administration is stopped during an infusion before it is completed 
regardless of whether it is further restarted or not.

Dose omission: a dose is considered omitted if the dose is not administered for the 
scheduled visit and there are positive dose(s) afterwards.
Dose delayed/modification will be analyzed at the patient, cycle and the total number of 
cemiplimab administration levels as follows:

Patient level (number of all treated patients will be used for % calculation):
-
Number (%) of patients with at least 1 dose delay,
-
Number (%) of patients with at least 1 dose omission,
-
Number (%) of patients with a least 1 infusion interrupted:
-
Number (%) of patients with a least 1 infusion interrupted and re-started,
-
Number (%) of patients with a least 1 infusion interrupted and not re-started,
-
Number (%) of patients with at least 2 infusions interrupted.

Infusion level
-
Total number of infusions (used for % calculation for this section),
-
Number (%) of infusions interrupted:  
-
Number (%) of infusions interrupted and re-started,
-
Number (%) of infusions interrupted and not re-started,
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-
Number (%) of 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- 60, 61-90, 91-120, >120).
Duration of cemiplimab infusion (in hours) is defined as the time from the start (date/time) of 
cemiplimab infusion to the end (date/time) of cemiplimab infusion in the same visit. It will be 
summarized for first and subsequent infusions.
2.4.4
Analyses of efficacy endpoints
All analyses described in this section are applicable to the Phase 2 part of the study only. For 
Phase 1, a listing of response data including duration of response on the all treated population will 
be provided instead of summary table.
In Phase 2, all primary, secondary and exploratory analyses will be performed using the 
randomized population in Phase 2. 
The cutoff date for the primary analysis of ORR will be 6 months after the date of the first dose of 
the last patient. In this analysis, hypothesis test(s) will be performed (Section 2.4.4.1).
Final analysis cutoff date for OS analysis and updated analysis of ORR and other secondary 
endpoints will be approximately 12 months after the date of the first dose of the last patient.
An interim analysis of response rate (including confirmed and unconfirmed responses) will be 
conducted when the first 15 randomized patients in each arm have completed 2 cycles of 
treatment or definitively discontinued the treatment. A combination arm will be stopped early for 
futility (Section 3). 
2.4.4.1
Analysis of primary efficacy endpoint(s)
The ORR will be summarized by treatment arms with descriptive statistics. A 95% two-sided 
confidence interval(s) will be computed using Clopper-Pearson. BOR will also be summarized 
descriptively.
The Fisher’s exact test will be performed to compare the ORR in control arm vs each of the 
combination arm, using a 1-sided significance level of 0.10 with Hochberg adjustment (at time of 
primary analysis of ORR; ie, cutoff date 6 months after last patient first dose). If the maximum 
p-value (of two p-values) is less than 0.1, the null hypothesis for both combination arms will be 
rejected; else if minimal p-value is less than 0.05, the null hypothesis will be rejected for this 
corresponding arm only. If only one combination arm is continued after the interim analysis in
addition to the control arm, then ORR will be tested using an 1-sided significant level of 0.05.
ORR and BOR will also be summarized descriptively for subgroups variable defined in Table 4.
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2.4.4.2
Analyses of secondary efficacy endpoints
No hypothesis testing will be performed on secondary efficacy endpoints. The following analyses 
will be performed:

CBR: will be summarized with descriptive statistics.

VGPR or above rate: will be summarized with descriptive statistics.

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 patients who 
achieve a response ≥PR. DOR will be also summarized with statistics in the subset of 
patients with BO ≥PR.

PFS and OS: PFS and OS will be analyzed using the Kaplan-Meier method. The 
Kaplan-Meier estimates of the 25th, 50th and 75th percentiles and their associated
95% confidence interval will be computed. The Kaplan-Meier curves will be plotted.

DFU and TTR will be summarized with descriptive statistics. Best percent 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. Percent change >100% will be displayed as 
100% increases. A swimmer plot of time on treatment (ie, duration of exposure) will also be 
provided. The patients will be ordered by BOR and duration of exposure. Patients with the 
best BOR and longest duration will be presented at the top of the plot.
A listing of response data will be provided for the randomized population and second listing will 
be provided for patients who are ADA positive (Section 2.1.6), and will include the following 
variables: high risk status, number of prior lines of anti-myeloma treatment, selected prior 
treatments given (alkylating agent, IMid, PI, mAb), 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 provided 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.
Number (%) of patients with MRD negative will be provided. This may be replaced by a listing if 
the number of MRD negative patient is small (≤5).
Subgroup analyses for secondary endpoints may be performed if relevant.
2.4.4.3
Multiplicity issues
For the primary efficacy analysis in Phase 2, one hypothesis is to be tested on each of the 
2 dose arms. To control overall type I error, Hochberg procedure will be used. The procedure is 
described in Section 2.4.4.1. An interim analysis is included to stop a dose arm for futility only, 
thus the type I error rate is not inflated.
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2.4.5
Analyses of safety data
All safety analyses will be performed on the AT/safety population as defined in Section 2.3.2.
2.4.5.1
Dose-limiting toxicities (Phase 1 only)
The DLTs will be listed by patient on the patients evaluable for DLT population for Phase 1.
2.4.5.2
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, on-treatment and post-treatment), the maximum severity grade will be used.
Summaries will be provided for all grades and for Grade ≥3 (including Grade 5). Missing grade 
handling is provided in Section 2.5.3. 
The following adverse events analyses will be performed. The presentation strategy (eg, by all 
grades and Grade ≥3 and by PT etc) are included in Table 7.

Overview of TEAEs.

TEAEs (regardless relationship to study treatment).

Drug related TEAEs.

Deaths (Section 2.4.5.3).

SAEs.

Adverse events leading to withdrawal.
-
Analysis of all treatment-emergent adverse event(s) leading to definitive treatment 
discontinuation. Analysis of all treatment-emergent adverse event(s) leading to 
premature isatuximab discontinuation. Analysis of all treatment-emergent adverse 
event(s) leading to premature cemiplimab 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. 

TEAE leading to dose modification
-
Separate analysis for each type of modification: dose reduction of any drug, dose 
interruption of any drug, dose delay of any drug.
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
Other significant adverse events 
-
IR and IR symptoms (details are included below),
-
Immune related AEs (details are included below), 
-
Respiratory AEs(details are included below), 
-
Hematological adverse events(details are included below; not included in Table 7),
-
Second primary malignancies,
-
Other AESIs: 
Pregnancy and symptomatic overdose. Data will be listed if ≤5 patients,
-
Pre- and Post-treatment AE/SAEs.
Sorting within tables will ensure the same presentation for the set of all AEs within the 
observation period (pre-treatment, on-treatment, and post-treatment). For that purpose, the table of 
all TEAEs presented by SOC and PT sorted by 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 of the isatuximab 
QW/Q2W plus cemiplimab Q2W arm.
Overview of TEAEs
An overview of TEAEs including the number (%) of patients with the following treatment 
emergent events will be provided:

TEAE.

TEAE of Grade ≥3.

TEAE of Grade 3-4.

TEAE of Grade 5 (any TEAE with fatal outcome during the on-treatment period).

Treatment emergent SAE.

TEAE leading to definitive study treatment discontinuation, ie, discontinuation of 
isatuximab in control arm, and discontinuation of isatuximab and cemiplimab in 
combination arms.

TEAE leading to premature discontinuation (only applicable to combination arms)
-
TEAE leading to premature isatuximab discontinuation, ie, discontinuation of 
isatuximab before cemiplimab,
-
TEAE leading to premature cemiplimab discontinuation, ie, discontinuation of 
cemiplimab before isatuximab.

AESI
-
IR of Grade ≥2.

Treatment-related TEAE (related to either isatuximab or cemiplimab).

Treatment-related TEAE of Grade ≥3.

Serious treatment-related TEAE.
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Other significant adverse events
Infusion reactions
IR analyses will be done by including all the adverse events regardless of relationship to 
isatuximab, cemiplimab or NIMP. Unless otherwise described, the presentation strategy is
described in Table 7.

Number (%) of patients experiencing IRs (as a diagnosis, no symptoms) according to 
investigator reported AEs presented by primary SOC and PT (both sorted by decreasing 
order of frequency) will be summarized by grades (all grades and Grade ≥3).

Description of the IR diagnoses (using the diagnosis reported and excluding symptoms)
-
Worst grade,
-
Action taken with isatuximab and cemiplimab,
-
Number (%) of patients with only 1, ≥1, ≥2, ≥3, ≥4 and ≥5 episodes,
-
Number (%) of patients with first occurrence of IR at the first infusion and subsequent 
infusions,
-
Number (%) of patients with IR at the first and subsequent infusions,
-
Number (%) of patients with at least two episodes of IRs at the same infusion,
-
Day of onset from infusion,
-
Duration (in days).

Number of patients with symptoms of IRs (as reported by investigator).

Number (%) of patients experiencing TEAEs (related and regardless of causal 
relationship) within 24 hours from the start of each infusion.

Similar tables including all TEAEs within 24 hours from the start of each infusion from 
the selected list of CMQ (see Section 2.1.4.1).

Number (%) of patients experiencing TEAEs (related and regardless of causality), (not 
only limited to those occurring within 24h of each infusion) from the selected list of CMQ
(see Section 2.1.4.1).
If the IR rate is much higher (≥20%) in combination arms than in the control arm, additional 
analyses of IR might be performed separately for isatuximab and cemiplimab. 
A listing of IRs that are related to NIMP will be provided.
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Immune related AEs:
Because irAEs could occur long after exposure with immune checkpoint inhibitors, the 
irAE analysis will include both on-treatment period and extended safety follow up period. As 
noted in Table 7, the analysis will include:

Number (%) of patients experiencing irAEs reported as AESI by investigator: include all 
AESI and exclude IRs, pregnancy, symptomatic overdose and DLT (if any).

Number (%) of patients experiencing AEs from selected grouping of PTs occurring during 
the treatment emergent and extended safety follow up periods (one analysis for events 
related to cemiplimab; another analysis for regardless of relationship).

Number (%) of patients experiencing AEs occurring during the treatment emergent and 
extended safety follow up periods (one analysis for events related to cemiplimab; another 
analysis for events regardless of relationship).
Respiratory TEAEs: 
Respiratory TEAEs will be analyzed using selection defined in Section 2.1.4.1 and will be
presented by PT.
Cardiac TEAEs 
Cardiac TEAEs will be analyzed using selection defined in Section 2.1.4.1 and will be presented 
by PT, sorted by decreasing incidence. 
Analysis of pre-treatment and post-treatment adverse events 
The following frequency distributions of AEs (incidence tables) will be provided for the safety 
population, for all grades combined and Grade ≥3: 

All pre-treatment AEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 pre-treatment AE, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC. 

All pre-treatment SAEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 pre-treatment SAE, sorted by the internationally agreed SOC order and 
decreasing incidence of PTs within each SOC. 

All post-treatment AEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 post-treatment AE, sorted by the internationally agreed SOC order and 
decreasing incidence of PTs within each SOC. 

All post-treatment SAEs by primary SOC and PT, showing the number (%) of patients
with at least 1 post-treatment SAE, sorted by the internationally agreed SOC order and
decreasing incidence of PTs within each SOC.
Neutropenia and neutropenic complications
Neutropenia (from laboratory abnormalities) will be displayed along with febrile neutropenia and
neutropenic infections (see Section 2.1.4.1).
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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.
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.
Overdose
A listing of patients who reported symptomatic overdose with study treatment during the study 
will be provided. This listing will include drug with overdose.
Pregnancy
Moreover, a listing of pregnancies (pregnancy as well as pregnancy of partner) will be provided. 
Tumor lysis syndrome (TLS)
A listing of patients with TLS reported in eCRF AE forms (using a CMQ: Tumor lysis syndrome) 
during the study will be provided. The clinical chemistry parameters regarding hyperkalemia, 
hyperphosphatemia, hypocalcemia, and hyperuricemia might be listed to corroborate any report of
TLS identified with the above CMQ.
Second primary malignancies
A listing of patients who reported second primary malignancies during the study will be provided
(as per the CMQ).   
This listing will include the diagnosis, type of second priamry malignancies, study day of the 
diagnosis (from the first dose), number of days from the last study treatment to the diagnosis, 
prior exposure to anti-myeloma treatments, and whether the patient received subsequent 
anti-cancer treatment. 
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Table 7 - Description of summary tables to be provided for the analysis of TEAEs
MedDRA variables
Sorting
Layout
Events
PT

PT: Decreasing order of 
frequency of 
Isa + CemQ2W arm
By treatment arms (and all patients if 
Phase 1): n (%) of patients with any 
event and n (%) of patients with event of 
Grade ≥3

TEAEs occurring in ≥5% of the patients (in any group for Phase 2)

Cardiac TEAEs

Respiratory TEAEs
SOC, HLGT, HLT, and PT

Primary SOC: 
internationally agreed order

HLGT, HLT, PT: 
alphabetical order
By treatment arms(and all patients if 
Phase 1): n (%) of patients with any 
event and n (%) of patients with event of 
Grade ≥3

All TEAEs

Serious TEAEs

Drug-related serious TEAEs

TEAEs leading to definitive treatment discontinuation
SOC and PT

Primary SOC: 
internationally agreed order

PT: decreasing order of 
frequency of 
Isa + CemQ2W arm
By treatment arms (and all patients if 
Phase 1): n (%) of patients with any 
event and n (%) of patients with event of 
Grade ≥3

All TEAEs

TEAEs occurring in ≥5% of the patients (in any group for Phase 2)

Drug-related TEAEs

Serious TEAEs

Drug related serious TEAEs

TEAEs leading to isatuximab discontinuation

TEAEs leading to cemiplimab discontinuation

TEAEs leading to dose interruption of isatuximab

TEAEs leading to dose interruption of cemiplimab

TEAEs leading to dose delay of isatuximab

TEAEs leading to dose delay of cemiplimab

TEAEs leading to dose reductiona of isatuximab

TEAEs leading to dose reductiona of cemiplimab

Pre-treatment AEs; Serious pre-treatment AEs

Post-treatment AEs; Serious post-treatment AEs
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MedDRA variables
Sorting
Layout
Events
SOC and PT

Primary SOC: 
internationally agreed order

PT: decreasing order of 
frequency of 
Isa + CemQ2W arm
By treatment arms (and all patients if 
Phase 1): n (%) of patients with any 
event and n (%) of patients with event of 
Grade ≥3
IR analysis:

IR diagnosis (as reported by investigator)

Symptoms of IR (as reported by investigator)

TEAEs (related; regardless of relationship) within 24 hours from the 
start of each infusion

TEAEs (related; regardless of relationship) from the selected CMQ
within 24 hours from the start of each infusion

TEAEs (related; regardless of relationship) from the selected CMQ 
(not limited to those occurring within 24 hours from the start of each 
isatuximab infusion) 
SOC and PT

Primary SOC: 
internationally agreed order

PT: decreasing order of 
frequency of 
Isa + CemQ2W arm
By treatment arms (and all patients if 
Phase 1): n (%) of patients with any 
event and n (%) of patients with event of 
Grade ≥3
irAE analysis:

irAE reported as AESI by investigator

AEs as defined by irAE selected grouping of AEs occurring during 
the treatment emergent and extended safety follow up periods 
(related to cemiplimab; regardless of relationship)  

AEs occurring during the treatment emergent and extended safety 
follow up periods (related to cemiplimab; regardless of relationship) 
a
Dose reduction is corresponding to action taken to any study treatment, as “Dose reduced”, “Dose delayed and reduced”.
AE=adverse event; AESI=adverse event of special interest; HLGT=high-level group term; HLT=high-level term; IR=infusion reaction; MedDRA=Medical Dictionary for Regulatory Activities; n (%)=number and 
percentage of patients; PT=preferred term; SOC=system organ class; TEAE=treatment-emergent adverse event.
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2.4.5.3
Deaths
Number (%) of patients who died by study period (on-treatment and post-treatment, within 
60 days from first dose of study treatment), 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 to death, preferred term, and causal relationship to isatuximab/cemiplimab
(when applicable) will be provided.
2.4.5.4
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 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.
The denominator used for percentage calculation is the number of patients with at 
least 1 evaluation of the laboratory test during the considered observation period. 
When appropriate, the summary table will present the frequency of patients with any grade of 
abnormal laboratory tests and with Grade 3-4 abnormal laboratory tests. 
For eGFR, urea acid, 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 8) 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 arm and overall, irrespective of the baseline level. 
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 parameters (eg, anemia, thrombocytopenia, 
neutropenia and other tests as appropriate). 
For creatinine clearance using MDRD formula, the number (%) of patients by category (<15, 
[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. 
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Table 8 - 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
2.4.5.5
Analyses of vital sign variables
The incidence of PCSAs prior to study treatment administration at any cycle during the 
on-treatment period will be summarized by arm whatever the baseline level and/or according to 
the following baseline categories:

Normal/missing.

Abnormal according to PCSA criterion or criteria.
The incidence of PCSA during and after study treatment administration at any cycle during the
on-treatment period will also be summarized
Table 9 - 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 arm
(and all patients for Phase 1).
A listing of patients with at least one PCSA will be provided.
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2.4.5.6
Analyses of electrocardiogram variables
The number (%) of patients with normal/abnormal ECG result during the on-treatment period will 
be summarized by arm (and all treated patients for Phase 1). 
2.4.5.7
Analyses of other safety endpoints
A shift table of baseline ECOG PS versus best and worst ECOG PS on treatment will be provided. 
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum
and maximum) of baseline values, peak values, change from baseline and relative change from
baseline will be calculated for Cytokines (TNF-α, IL-1-β, IL-4, IL-6, IFN-γ), markers of
complement (C3a, C4, CH50) and serum tryptase when available.
For IAT, a summary of patients with indirect Coombs test during the on-treatment period will be 
provided, including number (%) of patients with:

All tests negative.

At least one positive test.
And among patients with at least one positive test during study treatment, number (%) of patients
with:

Negative indirect Coombs test at baseline.

Missing indirect Coombs test at baseline.
A listing of chest x-ray results will be provided.
2.4.6
Analyses of immunogenicity variables
Immunogenicity analysis will be done separately for isatuximab and cemiplimab. 
Number of evaluable patients, number (%) of pre-existing ADA and negative patients at baseline, 
number (%) of boosted and induced patients (either transient, persistent or indeterminate) will be 
reported, along with descriptive statistics of titer, by arm and overall. Prevalence and incidence 
will also be presented.
In addition, for positive ADA patients, time to onset, duration of ADA response, and the 
characterization of the immune response (transient, persistent, indeterminate) will be provided. 
An individual data listing with ADA samples status (positive, negative or inconclusive), the titer if 
applicable, date of first/last dose, duration of exposure, study period, cycle/day, time point and 
date/time of sampling along with Ctrough value of the drug will be provided for all patients.
The impact on safety and efficacy endpoints may be further explored by graphical methods or 
descriptively, depending on the ADA prevalence.
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2.4.7
Analyses of pharmacokinetic variables
PK analysis will be done separately for isatuximab and cemiplimab. 
2.4.7.1
PK parameters 
2.4.7.1.1 Cycle 1
Following the first administration, individual concentrations and PK parameters of drug will be 
listed and summarized by descriptive statistics (such as the number of observations, arithmetic 
and geometric mean, median, SD, standard error (SE), coefficient of variation (CV)%, minimum, 
and maximum) by arm and possibly overall.
Individual and mean concentration profiles over time will be plotted by arm and possibly overall
under the responsibility of Sanofi, Pharmacokinetic, Dynamic and Metabolism (PKDM), 
Translational Medicine and Early Development (TMED) department.
A comparison between isatuximab PK parameters (Cmax and AUC0-7d) obtained after 
monotherapy (control arm) and isatuximab combined treatment with cemiplimab (DL1 and 
DL-1 arms) based on geometric mean ratio will be provided.
2.4.7.1.2 Overall treatment: Ctrough and Ceoi
Ctrough defined as a sample collected before dosing, and in a time window of 12 to 16 days after
the previous infusion for the Q2W administration, or in a time window of 6 to 8 days after the
previous infusion for the QW administration will be included in the descriptive analysis 
irrespectively of infusion interruption. However Ctrough drawn outside collection of time window 
described in the PKPD flowchart of the protocol or collected after dose deviation higher than 
±50% from intended dose will be excluded from the analyses.
Ceoi collected after significant infusion interruption, drawn outside collection of time window 
described in the PKPD flowchart of the protocol or collected after dose deviation higher than 
±50% from intended dose will be excluded from the analyses.
Individual Ctrough and Ceoi will be listed and summarized with same descriptive statistics as above 
by arm and possibly overall. 
Mean (±SE) of Ctrough will be plotted over treatment phase by arm and possibly overall.
Individual Ctrough ratio and Ceoi ratio (described in Table 10) will be listed and summarized by 
descriptive statistics by arm and possibly overall as described above. 
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Table 10 - Ctrough and Ceoi ratio
Analyte
Ctrough
Ceoi
Isatuximab
C2D1 vs C1D8
C2D1 vs C1D1
C4D1 vs C1D8
C4D1 vs C1D1
cemiplimab
C4D1 vs C1D15 (DL1)
C4D1 vs C2D1 (DL-1) 
C4D1 vs C1D1
2.4.7.2
Immunogenicity impact on PK 
Immunogenicity impact on PK analysis may be explored, depending on the ADA prevalence. 
A descriptive statistics of Ctrough as described above will be provided at each cycle in the subset of 
negative patients by arm and possibly overall where positive or inconclusive patients will be 
observed. 
A graphical representation of individual Ctrough profile will be provided throughout the course of 
treatment by arm and possibly overall where positive or inconclusive patients will be observed. 
Positive patients profile will be highlighted (eg, color or bold) and the concentration of the 
administered drug at the same time as ADA positive result will be notified.
2.4.8
Analyses of Biomarker variables
2.4.8.1
Genetic variables
Summary of BOR will be provided for the following patients:

High risk cytogenetic markers (del17p and/or t(4;14) and/or t(14;16)).

FcGR3A types: F/F, F/V, V/V and missing.

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
Graphs showing ORR/non-responder rate by biomarker levels will be provided for the following 
parameters at baseline:

CD38 mRNA.

Immune cell level (B-cell, T-cell and NK-cell subsets respectively in blood and bone 
marrow samples).
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Bone marrow and blood samples will be collected for the following biomarker analyses:

Correlation of immunophenotype in bone marrow and/or peripheral blood with parameters 
of clinical response. Blast cells and immune cell populations (including MDSC cell, 
T-cell, NK-cell subsets and Treg/CD8 effector ratio) will be characterized by 
multiparametric flow cytometry analysis 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 and blood 
will be collected at baseline and Day 1 of Cycle 3 and blood samples only will be 
collected at EOT.

Whenever possible, PD-L1 expression in malignant plasma and immune cells will be 
determined and correlated with clinical response. Access to archival bone marrow biopsy 
material will be requested at screening and if available, retrospective expression analysis 
will be performed by IHC assay. 

Correlation of adaptive immune response (TCR repertoire profiling) with parameters of 
clinical response. Blood and bone marrow samples will be collected at screening, D1 of 
Cycle 3 (blood only) and at CR. 

Correlation of adaptive immune response (humoral and cellular immune responses to
myeloma-related tumor antigens) with parameters of clinical response. Blood will be
collected prior to pre-medication and IMP administration on D1 of Cycle 1, Cycle 2,
Cycle 4, Cycle 7 and Cycle 10 and in disease progression patients at EOT. Humoral
response will be assessed in all sites. Cellular response will be assessed in patients at
selected sites.
Additional analysis, not specified in the protocol but related to the drug action and/or effect of 
isatuximab/cemiplimab, may be conducted on remaining samples pending evolving literature.
2.4.8.3
Potential interference of isatuximab in the M protein assessment
Number (%) of patients with M protein interference and with potential impact on the BOR will be
explored.
2.4.9
Analyses of quality of life variables
Not applicable as no quality of life variable is collected.
2.4.10 Further therapy after discontinuation of investigational medicinal product 
administration during the study
Further therapies will be descriptively summarized by arm and overall.
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2.5
DATA HANDLING CONVENTIONS
2.5.1
General conventions
The following formulas will be used for computation of parameters.
Creatinine clearance (eGFR) using the equation of MDRD formula:
with serum creatinine in mg/dL and age in year.
Corrected calcium formula:
Corrected Calcium (mmol/L) = Serum Calcium (in mmol/L) + 0.8*0.25 (4 - serum albumin 
[in g/dL])
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 (if not otherwise specified below)

If the day is missing, it will be imputed to be 1.

If the month is missing, it will be imputed to be 1 (only for medical history variables).

If the year is missing, no imputation will be performed.
Handling of medication (other than anticancer treatment) 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.
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Handling of post anti-myeloma treatment missing/partial dates
For post anti-myeloma treatments, if the anticancer treatment start date is missing, it will be 
imputed as follows:

If the medication start day and month are missing and the medication start year is the same 
as treatment end year, the medication start date will be set equal to treatment end date + 1. 

If the medication start day and month are missing and the medication start year is after the 
treatment end year, the medication start day and month will each be set to 01. 

If the medication start day is missing and medication start year and month is the same as 
the treatment end year and month, the medication start day will be set equal to the 
treatment end day + 1. 

If the medication start day is missing and medication start month is before the treatment 
end month and the medication start year is the same as treatment end year, the medication 
start day will be set to 01. 

If the medication start day is missing and the medication start month is after the treatment 
end month and the medication start year is the same as treatment end year, the medication 
start day will be set to 01. 

If the medication start day is missing and the medication start month is not missing and the 
medication start year is after the treatment end year, the medication start day will be set 
to 01. 

If the medication start day, start month and start year is missing, the medication start date 
will be set equal to the treatment end date + 1. 
No imputation will be done for the missing/partial end date.
Handling of adverse events with missing or partial date of onset
Missing or partial adverse event onset dates (occurrence or becoming serious) will be imputed so 
that if the partial adverse event onset date information or visit number does not indicate that the 
adverse event started prior to or after treatment, the adverse event will be classified as 
treatment-emergent.  In case of AEs worsening during the study, the emergence will also be based 
on the cycle of worsening. No imputation of adverse event end dates will be performed. These 
data imputations are for categorization purpose only and will not be used in listings.  No 
imputation is planned for date of adverse event resolution.  
Handling of death with missing or partial date of death
The imputation for missing or partial death date will proceed as follows:

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.

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.
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
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.

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 adverse events with missing grade
If the grade is missing for one of the treatment emergent occurrences of an AE, the maximal 
severity on the remaining occurrences will be considered. If the severity is missing for all the 
occurrences, no imputation will be done and missing grades will be summarized in the 
“all grades” category.
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product 
If the assessment of the relationship to study treatment (isatuximab or cemiplimab) is missing, 
then the relationship to isatuximab/cemiplimab 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.
No imputation will be done for relationship to NMIP.
Handling of parameters expressed as inequality or approximation
For some parameters (such as laboratory parameters), if the value is expressed as “<xx”,
“≤xx, half of the numeric portion of the entry or limit of quantification will be used in 
calculations.
Handling of missing date/time in duration of infusion calculation
When both cemiplimab and isatuximab are given to a patient on the same visit:

Missing cemiplimab end date/time will be imputed by isatuximab start date/time 
(if available).

Missing isatuximab start date/time will be imputed by cemiplimab end date/time 
(if available).
Other types of missing date/time will not be imputed, and data will be excluded from the analysis 
of duration of infusion. 
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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. 
2.5.5
Unscheduled visits
Unscheduled visit measurements of laboratory data, vital signs and ECG will be used for 
computation of 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
For Phase 2 part, a formal interim analysis of response rate (including confirmed and unconfirmed 
responses) will be performed when the first 15 randomized patients in each arm completed 
2 cycles of treatment or permanently discontinue treatment. The purpose of the analysis is to stop 
combination arm early for futility. 
The analysis will include the first 15 randomized patients from each arm in the ITT population. 
Given the observed response rate (including confirmed and unconfirmed responses) from each 
combination arm, and assuming the numbers of response follow binomial distribution with 
response rate=20% in control arm, and 50% in combination arm for the remaining 20 patients in 
each arm, the conditional power can be calculated based on 1-sided Fisher’s exact test at 
0.05 significance level (for each combination arm vs. control arm separately) at the end of the 
trial. If the conditional power is <30% for a combination arm, the arm will be stopped early for 
futility. The detailed decision rule of whether to continue or stop the arm is included in
Appendix B. R-code for calculating conditional power is included in Appendix C.
The analysis will include the following parameters/analyses (defined in Section 2): response rate 
(including confirmed and unconfirmed responses), demographics and baseline characteristics, 
prior or concomitant medication, AEs (TEAE, death, SAE, TEAE leading to discontinuation and 
IR), laboratory variables (abnormality of hematological and chemistry test), PK NCA after first 
adminsitration and ADA based on available data. 
In addition, formal safety review by data monitoring committee (DMC) are planned 
approximately every 3 months to regularly monitor unblinded patient safety data (all meetings), 
unblinded efficacy data (except the 1st DMC meeting) and quality of trial conduct. More details on 
formal safety reviews and on interim analyses are given in the DMC charter.
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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 
SAS® Version 9.4 or higher. Biomarker analyses will be performed using 
R software Version 3.4.0 or above.
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6
REFERENCES
1.
Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P et al. International 
Myeloma Working Group consensus criteria for response and minimal residual disease 
assessment in multiple myeloma. Lancet Oncol. 2016;17(8):328-46.
2.
Chen TW, Razak AR, Bedard PL, Siu LL, Hansen AR. A systematic review of immune-
related adverse event reporting in clinical trials of immune checkpoint inhibitors. Ann Oncol. 
2015;26(9):1824-9.
3.
Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Laboratory reference values.
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7
LIST OF APPENDICES
Appendix A: Generic ranges for hematological and biochemistry 
Appendix B: Interim analysis decision boundary
Appendix C: R code for conditional power and stopping boundary calculation
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Appendix A
Generic ranges for hematological and biochemistry
Table 11 - Generic ranges for hematological parameters
Test
Gender
Unit
Lower/Upper limit of normal
Hemoglobin
F
g/L
120 - 160
Hemoglobin
M
g/L
135 - 175
Lymphocytes
109/L
1 - 2
Neutrophils
109/L
1.8 - 3.15
Platelets
109/L
150 - 350
Leukocytes
109/L
4.5 - 11
Eosinophils
109/L
0 - 0.4
Basophils
109/L
0 - 0.15
Monocytes
109/L
0.18 - 0.5
Hematocrit
M
ratio
0.41 - 0.53
Hematocrit
F
ratio
0.36 - 0.46
Erythrocytes
F
1012/L
4 - 5.2
Erythrocytes
M
1012/L
4.5 - 5.9
INR
ratio
0.8 -1.2
Based on Kratz et al. (3)
The current list of generic ranges for biochemistry parameters (for adults) is provided in the table 
below:
Table 12 - 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
Chloride
mmol/L
80 - 115
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
Summary of statistical analyses
Assuming there are 15 patients per arm included in the combination and control arms. The action 
to either continue or stop the combination arm depends on the number of responder in the 
combination and control arms respectively. The detailed decision is included below. The x axis 
represents number of responders in the control arm. The y axis represents number of responders in 
the combination arm. When action=“Continue”, the combination arm is recommended to 
continue; otherwise, it is recommended to stop the combination arm due to lack of confidence to 
achieve a positive results if the arm is continued.
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Appendix C
R code for conditional power and stopping boundary calculation
## conditional power function; output conditional power
getcp = function( r0, r1 ,m0, m1 ,n0=35, n1=35, SIG.LEVEL = 0.05){
# r0, r1 – number of response in control arm and combination arm at IA, respectively; 
# m0, m1 - number of randomized patient in control and combination arm at IA, respectively
# n0, n1 - planed final sample size if the trial is continued for control and combination arm;
# SIG.LEVEL - 1-sided significant level for Fisher’s exact test
p0 = 0.2 #r0/m0
p1 = 0.5 #r1/m1
ilow <- 0
ihigh <- n0 - m0
jlow <- 0
jhigh <- n1-m1
prob.reject = 0
for (i in ilow:ihigh) {
for (j in jlow:jhigh) {
x <- matrix(c(j+r1, n1-(j+r1),i+r0, n0-(i+r0)), 2, 2)
pval <- fisher.test(x, alternative="greater")$p.value
if (pval <= SIG.LEVEL) {
prob.reject <- prob.reject + dbinom(i, n0-m0, p0) * dbinom(j, n1-m1, p1)
}
}}
prob.reject
}
# Stopping boundary; for each combination of responders, calculation the decision rule.
pcut = 0.3
n1size = 15
n0size=15
type = "CP"
alter = "less"
res = NULL
for(trt.1 in 0:n1size){
for(con.1 in 0:n0size){
trt.data = rep(0, n1size)
con.data = rep(0, n0size)
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if(trt.1) trt.data[1:trt.1] = 1
if(con.1) con.data[1:con.1] = 1
cp = getcp(con.1, trt.1, m0 = n0size, m1 = n1size)
if (alter == "less" & cp< pcut) {action = "Stop"
}else if(alter == "greater" & cp >pcut){
action = "Stop"
}else {
action ="Continue"
}
res.temp = data.frame(type, trt.1, con.1, action)
res = rbind(res, res.temp)
}
}
colnames(res) = c("Type", "Treatment", "Control", "Action")
if (alter == "greater") {direction = 1}else {direction = -1}
# graphic presentation of the stopping rule
library(ggplot2)
txt = paste(type, "stopping rule (cp,", pcut,")")
ggplot(res, aes(x = Control, y = Treatment, fill =Action))  + geom_tile() +
scale_x_continuous(breaks = 0:n0size) +  scale_y_continuous(breaks = 0:n1size) +
theme(axis.text=element_text(size=12),
axis.title=element_text(size=16,face="bold"),
plot.title = element_text(size = 18, face = "bold"),
legend.title=element_text(size=15) , legend.text=element_text(size=12) ) +
ggtitle(txt) +  scale_fill_brewer(palette  = "Paired", direction = direction)
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TCD14906 16.1.9 Statistical analysis plan