MInimal Residual Disease Adapted Strategy

Inclusion Criteria:

1. Male or female subjects, 18 years of age or older, younger than 66 years (\< 66 years)
2. Voluntary written informed consent must be given before performance of any study-related procedure not part of normal medical care, with the understanding that the subject may withdraw consent at any time without prejudice to future medical care.
3. Subject must have documented multiple myeloma satisfying the CRAB and measurable disease as defined by:

   1. Monoclonal plasma cells in the bone marrow ≥ 10% or presence of a biopsy proven plasmacytoma AND any one or more of the following myeloma defining events:

      * Hypercalcemia: serum calcium \> 0.25 mmol/L (\> 1 mg/dL) higher than ULN or \> 2.75 mmol/L (\> 11 mg/dL)
      * Renal insufficiency: creatinine clearance \< 40mL/min or serum creatinine \> 177 μmol/L (\> 2 mg/dL)
      * Anemia: hemoglobin \> 2 g/dL below the lower limit of normal or hemoglobin \< 10 g/dL
      * Bone lesions: one or more osteolytic lesions on skeletal radiography, CT or PET-CT
      * Clonal bone marrow plasma cell percentage ≥ 60%
      * Involved: uninvolved serum free light chain ratio ≥ 100
      * Superior 1 focal lesion on MRI studies
   2. Measurable disease as defined by the following:

      * M-component ≥ 5g/L, and/or urine M-component ≥ 200 mg/24h and/or serum FLC ≥ 100 mg/L
4. Newly diagnosed subjects eligible for high dose therapy and autologous stem cell transplantation
5. Karnofsky performance status score ≥ 50% (eastern cooperative oncology group performance status ECOG score ≤ 2)
6. Subject must have pretreatment clinical laboratory values meeting the following criteria during the Screening Phase (Lab tests should be repeated if done more than 15 days before C1D1):

   1. Hemoglobin ≥ 7.5 g/dL (≥ 5mmol/L). Prior red blood cell \[RBC\] transfusion or recombinant human erythropoietin use is permitted;
   2. Absolute neutrophil count (ANC) ≥ 1.0 Giga/L (GCSF use is permitted);
   3. ASAT ≤ 3 x ULN;
   4. ALAT ≤ 3 x ULN;
   5. Total bilirubin ≤ 3 x ULN (except in subjects with congenital bilirubinemia, such as Gilbert syndrome, direct bilirubin ≤ 1.5 x ULN);
   6. Calculated creatinine clearance ≥ 40 mL/min/1.73 m²;
   7. Corrected serum calcium ≤ 14 mg/dL (\< 3.5 mmol/L); or free ionized calcium ≤6.5 mg/dL (≤ 1.6 mmol/L);
   8. Platelet count ≥ 50 Giga/L for subjects in whom \< 50% of bone marrow nucleated cells are plasma cells; otherwise platelet count \> 50 Giga/L (transfusions are not permitted to achieve this minimum platelet count).
7. Women of childbearing potential must have a negative serum or urine pregnancy test within 10 to 14 days prior to therapy and repeated within 24 hours before starting study drug. They must commit to continued abstinence from heterosexual intercourse or begin 2 acceptable methods of birth control (One highly effective method and one additional effective method) used at the same time, beginning at least 4 weeks before initiation of Lenalidomide treatment and continuing for at least 30 days after the last dose of Lenalidomide, Iberdomide and 5 months after last dose of Isatuximab. Women must also agree to notify pregnancy during the study.
8. Men must agree to not father a child and agree to use a latex condom during therapy and during dose interruptions and for at least 90 days after the last dose of study drug including Lenalidomide and Iberdomide and 5 months after last dose of Isatuximab, even if they have had a successful vasectomy, if their partner is of childbearing potential. Patient must also refrain from donating sperm during this period.

Exclusion Criteria:

1. Subjects must not have been treated previously with any systemic therapy for multiple myeloma. Prior treatment with corticosteroids or radiation therapy does not disqualify the subject (the maximum dose of corticosteroids should not exceed the equivalent of 160 mg of dexamethasone in a 2-week period). Two weeks must have elapsed since the date of the last radiotherapy treatment. Enrolment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 2 weeks have elapsed since the last date of therapy.
2. Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or solitary plasmacytoma.
3. Subject has a diagnosis of Waldenström's macroglobulinemia, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
4. Subject has had plasmapheresis within 14 days of C1D1.
5. Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma.
6. Myocardial infarction within 4 months prior to enrolment according to NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
7. Uncontrolled hypertension
8. Subjects with a history of moderate or severe persistent asthma within the past 2 years, or with uncontrolled asthma of any classification at the time of screening (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).
9. Intolerance to hydration due to pre-existing pulmonary or cardiac impairment.
10. Subject has plasma cell leukemia (according to WHO criterion: ≥ 20% of cells in the peripheral blood with an absolute plasma cell count of more than 2 × 109/L) or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
11. Any clinically significant, uncontrolled medical conditions that, in the Investigator's opinion, would expose the patient to excessive risk or may interfere with compliance or interpretation of the study results.
12. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort within 14 days before the first dose of study treatment.
13. Known intolerance to steroid therapy, mannitol, pregelatinized starch, odium stearyl fumarate, histidine (as base and hydrochloride salt), arginine hydrochloride, poloxamer 188, sucrose or any of the other components of study intervention that are not amenable to premedication with steroids and H2 blockers or would prohibit further treatment with these agents.
14. History of allergy to any of the study medications, their analogues, or excipients in the various formulations
15. Subject has had major surgery within 2 weeks before study inclusion (informed consent signature) or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study. Kyphoplasty or Vertebroplasty are not considered major surgery.
16. Clinically relevant active infection or serious co-morbid medical conditions
17. Prior malignancy except adequately treated basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer free of disease since 5 years.
18. Female subject who is pregnant or breast-feeding
19. Serious medical or psychiatric illness likely to interfere with participation in study
20. Uncontrolled diabetes mellitus
21. Known HIV infection; Known active hepatitis A, B or C viral infection
22. 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.
23. 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.
24. Active systemic infection and severe infections requiring treatment with a parenteral administration of antibiotics.
25. Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs
26. Subjects unable or unwilling to undergo antithrombotic prophylactic treatment
27. Person under guardianship, trusteeship or deprived of freedom by a judicial or administrative decision