I 01. Participant must be at least 18 years of age inclusive or older, at the time of signing the informed consent. or country’s legal age of majority if the legal age is more than 18 years.
I 02. Participant who are diagnosed within 5 years with SMM defined as:
• Serum M-protein ≥30 g/L or urinary M-protein ≥500 mg per 24 hour or both,
• And/or BMPCs 10% to <60%, • And absence of myeloma defining events or other related conditions. I 03. High-risk SMM including at least 2 of 3 following abnormalities, based on the central laboratory data obtained at screening: a) Serum M-protein >20 g/L.
b) Serum involved/uninvolved FLC ratio >20.
c) BMPC >20%.
Or Presence of ≥10% BMPC, based on the central laboratory data obtained at screening and at least one of the following:
• Serum M-protein ≥30 g/L (If IgA, IgA ≥20g/L), based on the central laboratory data obtained at screening.
• Serum involved/uninvolved FLC ratio ≥8 (but <100), based on the central laboratory data obtained at screening.
• Abnormal PC immunophenotype (≥95% of BMPCs are clonal) and reduction of ≥1 uninvolved Ig isotype, confirmed on the central laboratory data obtained at screening. (Only IgG, IgA and IgM will be considered).
• Progressive increase in Serum M-protein level (evolving type of SMM) defined as an increase of Serum M-protein ≥10% in the last 12 months before enrolment in the safety run-in/randomization in the phase 3. This increase must be consistent from one to another sample (ie, no decrease observed between 2 increased local Serum M-protein values) and profile of increase consistent with the central laboratory value obtained at screening.
I 04. ECOG Performance Status 0 or 1 or 2.
I 05. Absolute neutrophil count (ANC) ≥1000/μL (1 × 109/L). No granulocyte colony stimulating factor (G-CSF) is permitted during screening and within 2 weeks prior to screening ANC to reach this level).
I 06. Platelets ≥50,000/μL (50 × 109/L) (not permissible to transfuse a participant during screening and within 2 weeks prior to the screening platelet count to reach this level).
I 07. Total bilirubin ≤3 mg/dL (except Gilbert syndrome, in which direct bilirubin should be ≤5 mg/dL).
I 08. Alanine aminotransferase ≤3× upper limit of normal (ULN), aspartate aminotransferase ≤ 3 × ULN.
I 09. Male or Female
a) Male participants: A male participant must agree to use contraception as detailed in Appendix 4 Section 10.4 of this protocol for at least ≥4 weeks before the start of study intervention, during treatment (including dose interruptions), and up to 28 days after last lenalidomide administration or 5 months after the last isatuximab administration, whichever occurs last and refrain from donating sperm during this period.
b) Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
– Not a woman of childbearing potential (WOCBP) as defined in Appendix 4
– A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 for at least ≥4 weeks before the start of study intervention, during treatment (including dose interruptions), and up to 28 days after last lenalidomide administration or 5 months after the last isatuximab administration, whichever occurs last and refrain from donating oocytes during this period.
I 10. Capable of giving voluntary written informed consent as described in Appendix 1 of the protocol which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
E 01. Evidence of any of the following 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 GFR <40 mL/minute/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 of ≥5mm in size.
e) BMPCs ≥60%.
f) Serum involved/uninvolved FLC ratio ≥100 and an involved FLC ≥100mg/L
g) Whole body MRI or PET-CT with more than 1 bone focal lesion (≥5 mm in diameter by MRI).
E 02. Primary systemic and localized AL (amyloid light chain) amyloidosis, MGUS, standard risk smoldering myeloma, soft-tissue plasmacytoma, and symptomatic myeloma.
E 03. Uncontrolled infection within 28 days prior to randomization in Phase 3 or first study intervention administration in safety run-in.
E 04. Clinically significant cardiac or vascular disease within 3 months prior to randomization, eg, Myocardial Infarction; Unstable Angina; Coronary (eg, 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 E 05. 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 HBsAg and/or HBV DNA. • Active hepatitis C virus (HCV) infection: positive HCV RNA and negative anti-HCV E 06. Malabsorption syndrome or any condition that can significantly impact the absorption of lenalidomide. E 07. 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, and diverticulitis. E 08. Any severe acute or chronic medical condition which could impair the ability of the participant to participate to the study or interfere with interpretation of study results (eg, systemic infection unless anti-infective therapy is employed), or participant unable to comply with the study procedures. E 09. Received treatment (eg surgery, radiotherapy, medication) for a malignancy within 3 years of randomization (or first study intervention administration in safety run-in cohort). E 10. 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 IV bisphosphonate given for the treatment of osteoporosis is permitted. E 11. 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).
E 12. Individuals accommodated in an institution because of regulatory or legal order; prisoners or participants who are legally institutionalized.
E 13. Any country-related specific regulation that would prevent the participant from entering the study.
E 14. All participants who disagree to refrain from donating blood while on study intervention and for 5 months after discontinuation from this study intervention.
E 15. All participants who do not agree to keep study intervention for their personal use only.
E 16. Participants are dependent on the Sponsor or Investigator.
E 17. Participants are employees of the clinical study site or other individuals directly involved in the conduct of the study, or immediate family members of such individuals.
E 18. Hypersensitivity to dexamethasone, sucrose histidine (as base and hydrochloride salt), boron, mannitol, and polysorbate 80 or any of the components of study therapy that are not amenable to premedication with steroids, or H2 blockers that would prohibit further treatment with these agents.
E 19. Unable or unwilling to undergo to thromboprophylaxis as per local clinical practice (with the exception of patients with excessive risk of bleeding).
E 20. Vaccination with alive vaccine 4 weeks before the start of the study drug. Seasonal flu vaccines that do not contain live virus are permitted.
Hopital Maisonneuve-Rosemont ( CIUSSS de l’Est-de-l’Ile-de-Montréal)