Overview

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

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 first-line treatment for MM
• Safety and tolerability
• Pharmacokinetics (PK)
• Potential of isatuximab immunogenicity
• Clinical outcome assessments (COAs)

Eligibility

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
• 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 m (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
• Clonal BMPCs 60%
• Serum involved/uninvolved FLC ratio 100
• Whole body magnetic resonance imaging (WB-MRI) or positron emission tomography-computed tomography (PET-CT) with more than 1 focal lesion (>5 mm in diameter by MRI)
• Primary systemic amyloid light-chain (immunoglobulin light chain) amyloidosis, monoclonal gammopathy of undetermined significance (MGUS), standard risk smoldering myeloma, 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 HA antigen or positive IgM), hepatitis B (defined as either positive HBs antigen or positive hepatitis B viral DNA test above the lower limit of detection of the assay), or C infection (defined as a known positive hepatitis C antibody result or known quantitative hepatitis C [HCV] RNA results greater than the lower limits of detection of the assay)
• 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

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