A Phase 3, Open-label, Controlled, Randomized Study of Newly Diagnosed Multiple Myeloma Treatment, Designed to Evaluate the Efficacy and Safety of the Elranatamab-lenalidomide Combination as a Replacement for Chemotherapy Followed by Autologous Stem Cell Transplant in the Consolidation Phase, and to Compare Elranatamab With Standard of Care in the Maintenance Phase
This study is designed as a multicenter, randomized, parallel groups, open-label, phase 3 study in subjects with untreated newly diagnoses Multiple Myeloma eligible for ASCT. 824 patients will be enrolled in this study from approximately 70 study sites. The 2 parts in the Treatment Phase are described below. Part 1: Induction/ASCT/Consolidation Phase (1:1 Randomization) After the screening period, patients will be randomly allocated (1:1) to either: * Arm A (standard of care arm): standard induction therapy with 4 cycles of D-VRd, followed by HDCT (Melphalan) + ASCT, D-VRd consolidation therapy * Arm B (experimental arm): standard induction therapy with 4 cycles of D-VRd, followed by elranatamab and lenalidomide consolidation therapy. Part 2: Maintenance Phase (1:1 Re-randomization) Patients will be re-randomized (1:1) and will enter the Maintenance Phase upon completion of consolidation therapy. • Arm C (standard of care arm): daratumumab + lenalidomide approx 2 years. Subjects with a negative MRD (for at least 12 months) after 24 cycles of daratumumab-lenalidomide will discontinue daratumumab and continue with lenalidomide monotherapy until disease progression, or study cut-off date (whichever occurs first). Subjects who did not achieve MRD negativity for at least 12 months after 24 cycles of daratumumab-lenalidomide will continue to receive daratumumab-lenalidomide until: * MRD negativity for at least 12 months is reached. Subjects will then continue with lenalidomide monotherapy until disease progression, or study cut-off date (whichever occurs first). * Disease progression * Or study cut-off date (whichever occurs first). * Arm D (experimental arm): elranatamab. Approx 2 years. Subjects with a negative MRD (for at least 12 months) after receiving M22 administration of elranatamab will discontinue study treatment with elranatamab. Subjects who did not achieve MRD negativity for at least 12 months after M22 elranatamab administration will continue to receive elranatamab, every 24 weeks, until MRD negativity for at least 12 months is reached, disease progression, or study cut-off date (whichever occurs first).
• Male or female subjects, aged over 18 but \< 70 years old
• Patients have provided voluntary written informed consent before performing any study-related procedure.
• Patients with newly diagnosed multiple myeloma (NDMM) eligible for high-dose chemotherapy (melphalan) and autologous stem cell transplantation (ASCT).
• 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 a biopsy-proven plasmacytoma. In addition, the patient must have ≥1 of the following myeloma defining events:
‣ \- Hypercalcemia: serum calcium \>0.25 mmol/L (\>1 mg/dL) higher than upper limits of normal (ULN) or \>2.75 mmol/L (\>11 mg/dL).
‣ \- Renal insufficiency: creatinine clearance \< 40mL/min/1.73 m2 using CKD-EPI or serum creatinine \>177 μmol/L (\>2 mg/dL).
‣ \- Anemia: hemoglobin \>2 g/dL below the lower limit of normal (LLN) or hemoglobin \<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 urine M-component ≥200 mg/24 h and/or serum FLC ≥100 mg/L.
• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2.
• Patients must have clinical laboratory values (within 15 days of initiating induction therapy) as follows:
• • Hemoglobin ≥7.5 g/dL (≥5 mmol/L). Prior red blood cell (RBC) transfusion or the use 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, such as 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 nucleated cells as plasma cells. If not, platelet count \>30 G/L (platelets transfusions done during the 15 days before initiating induction therapy are not permitted).
• Women of childbearing potential must have a negative serum or urine pregnancy test during the screening period before randomization AND within 3 days before of initiating induction therapy.
• Patients must be willing and able to comply with scheduled appointments, treatment plan, laboratory tests, and other study procedures (such as blood transfusion if required, ASCT, IVIG prophylaxis, etc.).