Smoldering Multiple Myeloma MedDRA version: 21.1 Level: PT Classification code 10035226 Term: Plasma cell myeloma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Sanofi-Aventis Recherche & Développement
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Participant must be at least 18 years of age inclusive or older - 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 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 Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 367 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 198
Exclusion criteria
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) 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 = 5mm in size *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 and localized amyloid light-chain (AL) amyloidosis, monoclonal gammopathy of undetermined significance (MGUS), standard risk smoldering myeloma, soft-tissue plasmacytoma, and 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 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 resistan
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: - 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 participants with high-risk SMM;Secondary Objective: 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 -Impact of abnormal cytogenetic subtype on participant outcome 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 biochemical progression *Time to first-line treatment for MM *Safety and tolerability *Pharmacokinetics (PK) *Potential of isatuximab immunogenicity *Clinical outcome assessments (COAs);Primary end point(s): 1. Safety assessment: adverse events (AEs): Number of participants with AEs Safety Run-in Part 2. Plasma concentration of isatuximab (Cmax): Maximum concentration observed after the first infusion Safety Run-in Part 3. Receptor density/receptor occupancy (Safety Run-in Part): Change in CD38 receptor occupancy from baseline 4. Progression-free survival (PFS)(Randomized Phase 3): Time from randomization to MM (SLiM CRAB criteria) or other related conditions based on independent review committee assessment according to 2014 Internati | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Overall response rate (ORR)-Safety Run-in Part and Randomized Phase 3: Proportion of participants with best overall response recorded as partial response or better according to 2016 IMWG criteria 2. Duration of response (DOR)-Safety Run-in Part and Randomized Phase 3: Time from the date of the first response to date of progressive disease or death, whichever happens first 3. Minimal residual disease (MRD) negativity Safety Run-in Part and Randomized Phase 3: Number of participants for whom MRD is negative 4. Time to diagnostic (SLiM CRAB) progression or death-Safety Run-in Part and Randomized Phase 3: Time from randomization to diagnosis of SLiM-CRAB or other related conditions, progression, or death from any cause 5. Time to first-line treatment for multiple myeloma (MM)-Safety Run-in Part and Randomized Phase 3: Time from randomization to first-line treatment for MM 6. Immunogenicity - Safety Run-in Part: Incidence of anti-drug antibodies (ADA): Number of participants with anti-drug antibodies against isatuximab 7. Sustained MRD negativity - Randomized Phase 3: Number of participants with sustained MRD negativity (sample is still negative at least 1 year after the first negativity assessment) 8. Second PFS (PFS2)- Randomized Phase3: Time from the date of randomization to the date of first documentation of PD (as reported by the Investigator) after initiation of further treatment for MM or the date of death from any cause, whichever happens first 9. Overall survival - Randomized Phase 3: Time from date of randomization to death from any cause 10. PFS and OS in participants with cytogenetic abnormalities- Safety Run-In and Randomized Part: Association of cytogenetic abnormalities with survival outcomes 11. Complete response rate - Randomized Phase 3: Percentage of participants with a CR as defined by 2016 IMWG response criteria 12. Time to biochemical progression - Randomized Phase 3: Time to biochemical progression is defined as the time | — |
Countries
Australia, Brazil, Canada, China, Czechia, Czech Republic, Denmark, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Japan, Korea, Republic of, Lithuania, New Zealand, Norway, Poland, Spain, Sweden, Turkey, United Kingdom, United States
Contacts
Public ContactClinical Study Unit
Sanofi-Aventis Deutschland GmbH
Outcome results
None listed