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 (ITHACA)

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.