A Phase 3 randomized, open label, multicenter study of isatuximab (SAR650984) in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with high-risk smoldering multiple myeloma

Primary Objectives:

- Safety run-in: To confirm the recommended dose of isatuximab when combined with
lenalidomide and dexamethasone in participants with high-risk smoldering multiple
myeloma (SMM)

- Randomized Phase 3: To demonstrate the clinical benefit of isatuximab in combination
with lenalidomide and dexamethasone in the prolongation of progression-free survival
when compared to lenalidomide and dexamethasone in subjects with high-risk SMM

Secondary Objectives:

Safety run-in

- To assess overall response rate (ORR)

- To assess duration of response (DOR)

- To assess minimal residual disease (MRD) negativity in participants achieving very
good partial response (VGPR) or complete response (CR)

- To assess time to diagnostic (SLiM CRAB) progression or death

- To assess time to first-line treatment for multiple myeloma (MM)

- To assess the potential immunogenicity of isatuximab

- Impact of abnormal cytogenetic subtype on participant outcome

Randomized Phase 3 - Key Secondary Objectives:

To compare between the arms

- MRD negativity

- Sustained MRD negativity

- Second progression-free survival (PFS2)

- Overall survival

Other Secondary Objectives:

To evaluate in both arms

- CR rate

- ORR

- DOR

- Time to diagnostic (SLiM CRAB) progression

- Time to biochemical progression

- Time to first-line treatment for MM

- Safety and tolerability

- Pharmacokinetics (PK)

- Potential of isatuximab immunogenicity

- Clinical outcome assessments (COAs)

Inclusion criteria:

- Participants who are diagnosed within 5 years with SMM (per International Myeloma
Working Group [IMWG] criteria), defined as serum M-protein ≥30 g/L or urinary
M-protein ≥500 mg per 24 hour or both, and/or clonal bone marrow plasma cells
(BMPCs) 10% to <60%, and absence of myeloma defining events or other related
conditions and with high-risk SMM

- Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 or 2

- Capable of giving voluntary written informed consent

Exclusion criteria:

- Evidence of any of the following calcium, renal failure, anemia, bone lesions (CRAB)
criteria or Myeloma Defining Events (SLiM CRAB) detailed below (attributable to the
participants SMM involvement):

- Increased calcium levels: Corrected serum calcium >1 mg/dL above the ULN or >11
mg/dL

- Renal insufficiency: Determined by glomerular filtration rate (GFR) <40
mL/min/1.73 m² (Modification of Diet in Renal Disease [MDRD] Formula) or serum
creatinine >2 mg/dL

- Anemia (hemoglobin 2 g/dL below lower limit of normal or <10 g/dL or both)
transfusion support or concurrent treatment with erythropoietin stimulating
agents is not permitted

- ≥ 1 bone lytic lesion

- BMPCs ≥60%

- Serum involved/uninvolved FLC ratio ≥100 and an involved FLC ≥100mg/L

- Whole body magnetic resonance imaging (WB-MRI) or positron emission
tomography-computed tomography (PET-CT) with more than 1 bone focal lesion (≥5
mm in diameter by MRI)

- Primary systemic amyloid light-chain (AL) amyloidosis, monoclonal gammopathy of
undetermined significance (MGUS), standard risk smoldering myeloma, soft tissue
plasmacytoma, symptomatic myeloma

- Uncontrolled infection within 28 days prior to randomization in Phase 3 or first
study intervention administration in safety run-in

- Clinically significant cardiac disease, including:

- Myocardial infarction within 6 months with left ventricular dysfunction or
uncontrolled ischemic cardiac disease before Cycle 1 Day 1, or unstable or
uncontrolled disease/condition related to or affecting cardiac function (eg,
unstable angina, congestive heart failure, New York Heart Association Class
III-IV)

- Uncontrolled cardiac arrhythmia (Grade 2 or higher by NCI-CTCAE Version 5.0) or
clinically significant electrocardiogram (ECG) abnormalities

- Known acquired immunodeficiency syndrome (AIDS)-related illness or known human
immunodeficiency virus (HIV) disease requiring antiviral treatment or active
hepatitis A (defined as positive hepatitis A antigen or positive IgM). HIV serology
at screening will be tested for German participants and any other country where
required as per local regulations and serology hepatitis B and C at screening will
be tested for all participants

- Uncontrolled or active HBV infection: Patients with positive HBsAg and/or HBV
DNA

Of note:

Patient can be eligible if anti-HBc IgG positive (with or without positive anti-HBs) but
HBsAg and HBV DNA are negative. If anti-HBV therapy in relation with prior infection was
started before initiation of IMP, the anti-HBV therapy and monitoring should continue
throughout the study treatment period.

Patients with negative HBsAg and positive HBV DNA observed during screening period will
be evaluated by a specialist for start of anti-viral treatment: study treatment could be
proposed if HBV DNA becomes negative and all the other study criteria are still met.

Active HCV infection: positive HCV RNA and negative anti-HCV

Of note:

Patients with antiviral therapy for HCV started before initiation of IMP and positive HCV
antibodies are eligible. The antiviral therapy for HCV should continue throughout the
treatment period until seroconversion.

Patients with positive anti-HCV and undetectable HCV RNA without antiviral therapy for
HCV are eligible

- Malabsorption syndrome or any condition that can significantly impact the absorption
of lenalidomide

- Any of the following within 3 months prior to randomization (or first study
intervention administration in safety run-in cohort): treatment resistant peptic
ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel
disease, diverticulitis, pulmonary embolism, or other uncontrolled thromboembolic
event

- Received treatment (eg surgery, radiotherapy, medication) for a malignancy within 3
years of randomization (or first study intervention administration in safety run-in
cohort)

- Prior exposure to approved or investigational treatments for SMM or MM (including
but not limited to conventional chemotherapies, immunomodulatory imid drugs, or
Proteasome inhibitors); concurrent use of bisphosphonates or receptor activator of
nuclear factor kappa-B ligand (RANKL) inhibitor denosumab is not permitted; however,
prior bisphosphonates or once-a-year intravenous bisphosphonate given for the
treatment of osteoporosis is permitted

- Ongoing treatment with corticosteroids with a dose >10 mg prednisone or equivalent
per day at the time of randomization (or first study intervention administration in
safety run-in cohort)

- Women of childbearing potential or male participant with women of childbearing
potential who do not agree to use a highly effective method of birth control

- Vaccination with a live vaccine 4 weeks before the start of the study drug. Seasonal
flu vaccines that do not contain live virus are permitted

The above information is not intended to contain all considerations relevant to a
potential participation in a clinical trial.