Isatuximab in Combination With Lenalidomide and Dexamethasone in High-risk Smoldering Multiple Myeloma

Running, not enrolling · Phase 3

Conditions studied: Plasma Cell Myeloma

In brief

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)

Key facts

Study ID

NCT04270409

Run by

Sanofi

People needed

337

Starts

2020-06-16

Expected to finish

2033-10-21

Last updated by the study team

2025-12-12

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: accepted.

You may qualify if…

• 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.

You may not qualify if…

• 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)

Where it is running

• Colorado Blood Cancer Institute Site Number : 8400007 — Denver, Colorado, United States
• Cancer Specialist of North Florida Site Number : 8400011 — Jacksonville, Florida, United States
• University of Miami Site Number : 8400012 — Miami, Florida, United States
• Dana Farber Cancer Institute Site Number : 8400001 — Boston, Massachusetts, United States
• Presbyterian Hospital Site Number : 8400015 — Charlotte, North Carolina, United States
• Novant Health Forsyth Medical Center Site Number : 8401015 — Winston-Salem, North Carolina, United States
• Tennessee Oncology Site Number : 8400006 — Nashville, Tennessee, United States
• ~University of Texas - MD Anderson Cancer Center Site Number : 8400002 — Houston, Texas, United States
• Investigational Site Number :0360008 — Liverpool, New South Wales, Australia
• Investigational Site Number :0360005 — Waratah, New South Wales, Australia
• Investigational Site Number :0360001 — Wollongong, New South Wales, Australia
• Investigational Site Number :0360002 — Fitzroy, Victoria, Australia
• Investigational Site Number :0360007 — Heidelberg West, Victoria, Australia
• Investigational Site Number :0360004 — Richmond, Victoria, Australia
• Investigational Site Number :0360006 — Nedlands, Western Australia, Australia
• Investigational Site Number :0760002 — São Paulo, São Paulo, Brazil
• Investigational Site Number :1240004 — Edmonton, Alberta, Canada
• Investigational Site Number :1240005 — Moncton, New Brunswick, Canada
• Investigational Site Number :1240001 — Montreal, Quebec, Canada
• Investigational Site Number :1560002 — Hangzhou, China
• Investigational Site Number :1560003 — Hangzhou, China
• Investigational Site Number :1560006 — Nanchang, China
• Investigational Site Number :1560004 — Shanghai, China
• Investigational Site Number :1560005 — Shenyang, China
• UCLA Site Number : 8400010 — Los Angeles, California, United States

Full record on ClinicalTrials.gov

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