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 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)

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.