Primary Objectives:

• Safety run-in Part: 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 Part: 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 Part:

• 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 chromosomal subtype on participant outcome

Randomized Phase 3 Part:

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
• Impact of abnormal chromosomal subtype on participant outcome
• Safety and tolerability
• Pharmacokinetics (PK)
• Potential of isatuximab immunogenicity
• Clinical outcome assessments (COAs)

Study duration is expected to be approximately 12 years, including a 42-day screening period, followed by an up to 36-month treatment period, and a follow-up period of approximately 9 years.

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
• Absolute neutrophil count (ANC) ≥1000/µL (1 × 10^9/L)
• Platelets ≥50,000/µL (50 × 10^9/L)
• Total bilirubin ≤3 mg/dL (except Gilbert syndrome, in which direct bilirubin should be -≤5 mg/dL).
• Alanine aminotransferase ≤3× upper limit of normal (ULN), aspartate aminotransferase ≤ 3 × ULN.

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 or vascular disease within 3 months prior to randomization, e.g. Myocardial Infarction; Unstable Angina; Coronary (e.g. Coronary Artery Bypass Graft, Percutaneous Coronary Intervention) or peripheral artery revascularization, Left Ventricular Ejection Fraction <40%, Heart Failure NYHA III-IV, Stroke, Transient Ischemic Attack, Pulmonary Embolism, other thromboembolic event, cardiac arrhythmia (Grade 3 or higher by NCI-CTCAE Version 5.0)

• 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 hepatitis B virus (HBV) infection: Patients with positive Hepatitis B surface antigen (HBsAg) and/or HBV Deoxyribonucleic acid (DNA)

Of note:

• Patient can be eligible if anti-HBc Immunoglobulin G (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 hepatitis C virus (HCV) infection: positive HCV ribonucleic acid (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 multiple myeloma (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.

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org