Elranatamab/Lenalidomide Consolidation and/or Elranatamab Maintenance Versus Standard of Care After D-VRd Induction in Transplant-eligible NDMM Patients

Inclusion Criteria:

1. Male or female subjects, aged over 18.

2. Patients have provided voluntary written informed consent before performing anystudy-related procedure.

3. Patients with newly diagnosed multiple myeloma (NDMM) eligible for high-dosechemotherapy (melphalan) and autologous stem cell transplantation (ASCT).

4. Patients with documented symptomatic NDMM according to CRAB and/or SLIM criteria,with measurable disease as defined by:

• Presence of ≥10% monoclonal plasma cells in the bone marrow OR presence of abiopsy-proven plasmacytoma. In addition, the patient must have ≥1 of thefollowing myeloma defining events:

• Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than upperlimits of normal (ULN) or >2.75 mmol/L (>11 mg/dL).

• Renal insufficiency: creatinine clearance < 40mL/min/1.73 m2 using CKD-EPIor serum creatinine >177 μmol/L (>2 mg/dL).

• Anemia: hemoglobin >2 g/dL below the lower limit of normal (LLN) orhemoglobin <10 g/dL.

• Bone lesions: ≥1 osteolytic lesion on skeletal radiography, CT or PET-CT.

• Clonal bone marrow plasma cell percentage ≥60%.

• Serum involved/uninvolved free light chain ratio ≥100.

• More than 1 focal lesion (≥5 mm diameter) on MRI.

• Measurable disease as defined by serum M-component ≥5 g/L, and/or urineM-component ≥200 mg/24 h and/or serum FLC ≥100 mg/L.

5. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2.

6. Patients must have clinical laboratory values (within 15 days of initiatinginduction therapy) as follows:

• Hemoglobin ≥7.5 g/dL (≥5 mmol/L). Prior red blood cell (RBC) transfusion or theuse of recombinant human erythropoietin is permitted.

• Absolute neutrophil count (ANC) ≥1.0 G/L (granulocyte colony stimulating factor [G-CSF] use is permitted).

• Aspartate aminotransferase (AST) ≤3 x ULN.

• Alanine aminotransferase (ALT) ≤ 3 x ULN.

• Total bilirubin ≤3 x ULN (except in subjects with congenital bilirubinemia, suchas Gilbert syndrome, that require a direct bilirubin ≤3 x ULN).

• Calculated creatinine clearance ≥40 mL/min/1.73 m².

• Albumin corrected serum calcium ≤14 mg/dL (<3.5 mmol/L); or free-ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L).

• Platelet count ≥50 Giga/L for subjects who have <50% of bone marrow nucleatedcells as plasma cells. If not, platelet count >30 G/L (platelets transfusions doneduring the 15 days before initiating induction therapy are not permitted).

7. Women of childbearing potential must have a negative serum or urine pregnancy testduring the screening period before randomization AND within 3 days before ofinitiating induction therapy.

Exclusion Criteria:

1. Subjects previously treated with any systemic therapy for multiple myeloma. Patientsare allowed corticosteroids during screening not >160 mg of dexamethasone (orequivalent). Patients with concurrent radiotherapy (localized) within the 14 daysbefore initiating induction therapy are not eligible (If possible, in these cases,enrolment should be deferred).

2. Subject with ongoing Grade ≥ 3 peripheral sensory or motor neuropathy.

3. Subject with history of GBS or GBS variants, or history of any Grade ≥3 peripheralmotor polyneuropathy.

4. Subject with a current diagnosis of primary amyloidosis, monoclonal gammopathy ofundetermined significance, smoldering multiple myeloma, or solitary plasmacytoma.

5. Subject has a diagnosis of Waldenström's macroglobulinemia, or other conditions inwhich IgM M-protein is present in the absence of a clonal plasma cell infiltrationwith lytic bone lesions.

6. The subject has had plasmapheresis within 14 days of initiating induction therapy.

7. Subject with clinical signs of meningeal involvement of multiple myeloma.

8. The subject has plasma cell leukemia (by WHO criterion: ≥5% of plasma cells in theperipheral blood) or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy,monoclonal protein, and skin changes).

9. Subject has any concurrent medical or psychiatric condition or disease (e.g., activesystemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonarydisease) that is likely to interfere with the study procedures or results, or thatin the opinion of the investigator, would constitute a hazard for participating inthis study.

10. Subject has clinically significant cardiac disease, including:

• Subject has had myocardial infarction within 1 year before initiating inductiontherapy, or currently has an unstable or uncontrolled disease/condition related toor affecting cardiac function (e.g., unstable angina, congestive heart failure, NewYork Heart Association [NYHA] class III IV).

• Subject has uncontrolled cardiac arrhythmia (common terminology criteria foradverse events [CTCAE] version 4 grade ≥2) or clinically significantelectrocardiography (ECG) abnormalities.

• Subject with a baseline QT interval as corrected by Fridericia's formula (QTcF) >470 msec (12-lead ECG).

11. Subjects taking 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 useof Ginkgo biloba or St. John's wort (millepertuis) within the 14 days beforeinitiating induction therapy.

12. Known intolerance to steroids, mannitol, pregelatinized starch, sodium stearylfumarate, histidine (as base and hydrochloride salt), arginine hydrochloride,poloxamer 188, sucrose or any of the other components of study intervention that arenot amenable to premedication with steroids and H2 blockers or would prohibitfurther treatment with these agents.

13. Known allergies to any of the study medications, their analogues, or excipients inthe various formulations.

14. Subjects who have had major surgery within 2 weeks before study inclusion (signingof the informed consent) OR will not have fully recovered from surgery beforeinitiating induction therapy OR have surgery planned during their studyparticipation. Kyphoplasty and vertebroplasty are not considered as major surgery.

15. Subjects with any prior or concurrent invasive malignancy (other than multiplemyeloma) within 10 years of study inclusion study, except for adequately treatedbasal cell or squamous cell carcinoma of the skin, in situ carcinoma of the cervix,or localized prostate adenocarcinoma diagnosed ≥3 years ago and without evidence ofbiological failure, or other cancers for which the subject has undergone potentiallycurative therapy and has without evidence of relapse/recurrence for ≥10 years.

16. Pregnant or breast-feeding women.

Women that refuse to abstain from heterosexual intercourse or refuse to use adequate contraceptives during heterosexual intercourse starting at least 4 weeks before initiating induction therapy and continually until at least 4 weeks after discontinuing lenalidomide,90 days after discontinuing daratumumab and 6 months after discontinuing elranatamab.

18. Men with partners of childbearing potential, even men with a successful vasectomy,that refuse to use a condom during intercourse, from initiating induction therapy to ≥4 weeks ys after discontinuing lenalidomide,. Furthermore, men must agree to notdonate sperm during this period.

19. Known positive for HIV or active hepatitis A, B or C: Uncontrolled or active HBVinfection: Patients with positive HBsAg and/or HBV DNA

Of note:

Patients can be eligible if anti-HBc IgG positive (with or without positive anti-HBs) but HBsAg and HBV DNA are negative.

o If anti-HBV therapy in relation to 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.

20. Patient with an active systemic infection or severe infections requiring parenteraladministration of antibiotics.

21. Patients with a gastrointestinal disease/disorder that may significantly impact theabsorption of oral treatments.

22. Patients unable or unwilling to undergo antithrombic prophylaxis.

23. A person under guardianship, trusteeship, or deprived of freedom by a judicial oradministrative decision.