Isatuximab in combination with lenalidomide and dexamethasone in high-risk smoldering multiple myeloma

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 300

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

Participants are excluded from the study if any of the following criteria apply:
- 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):
a) Increased calcium levels: Corrected serum calcium >1 mg/dL above the ULN or >11 mg/dL
b) 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
c) 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
d) >=1 bone lytic lesion
e) BMPCs >=60%
f) Serum involved/uninvolved FLC ratio >=100 and an involved FLC >= 100mg/L
g) 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, 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 randomiza

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
1. Safety assessment: adverse events (AEs) - Safety Run-in Part [ Time Frame: Up to approximately 63 months ]<br>Number of participants with AEs<br><br>2. Plasma concentration of isatuximab: Cmax - Safety Run-in Part [ Time Frame: After first infusion in Cycle 1 in safety run-in part. 1 cycle = 28 days ]<br>Maximum concentration observed after the first infusion (Cmax)<br><br>3. Receptor density/receptor occupancy Safety Run-in Part [ Time Frame: Baseline to Cycle 2 Day 1 (each cycle is 28 days) ]<br>Change in CD38 receptor occupancy from baseline<br><br>4. Progression-free survival (PFS) Randomized Phase 3 [ Time Frame: Up to approximately 114 months ]<br>Time from randomization to MM (SLiM CRAB criteria) or other related conditions based on independent review committee assessment according to 2014 International Myeloma Working Group (IMWG) criteria or death from any cause, whichever happens first

Secondary Outcome Measures

Name	Time	Method

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