MajesTEC-4 (EMN30): A Phase 3 Trial of Teclistamab + Lenalidomide Versus Lenalidomide Alone As Maintenance Therapy Following Autologous Stem Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma

Background: Multiple myeloma (MM) is a malignant plasma cell disorder that is characterized by osteolytic lesions, increased susceptibility to infections, hypercalcemia, anemia, and renal failure. For patients with newly diagnosed MM (NDMM), autologous stem cell transplant (ASCT) is an important treatment strategy and has demonstrated significant improvement in progression-free survival (PFS). Maintenance treatment after ASCT has offered prolonged disease control and improved outcomes, and lenalidomide (Len) is now considered the standard of care as recommended by NCCN and ESMO guidelines. However, median PFS on Len maintenance (mean duration of treatment: approximately 2–3 years) is only 52.8 months, long-term tolerability is poor, and most patients eventually relapse. Therefore, there is a need for new therapeutic options in the maintenance setting that may provide improved PFS and overall survival (OS). Teclistamab (Tec) is a B-cell maturation antigen (BCMA) × CD3 bispecific antibody that redirects CD3+ T cells to induce cytotoxicity towards BCMA-expressing MM cells. In the phase 1/2 MajesTEC-1 study (NCT03145181), Tec monotherapy was well tolerated and showed encouraging efficacy, yielding durable responses that deepened over time in heavily pretreated patients with relapsed/refractory MM. The combination of Tec + Len (Tec-Len) is being investigated in the MajesTEC-2 study in patients with MM who have received ≥2 prior lines of therapy (LOT), including exposure to a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody (NCT04722146). Here we report the design of the randomized, open-label, multicenter, phase 3 MajesTEC-4 trial (NCT05243797), which will compare the efficacy of Tec-Len versus Len alone as maintenance therapy in patients with NDMM who have completed induction treatment followed by ASCT, with or without consolidation. As studies have suggested that IMiDs may enhance or improve the efficacy of immunotherapies, it is anticipated that the combination of Tec-Len in the maintenance setting will provide greater efficacy than Len alone.

Study Design and Methods: Eligible patients will be aged ≥18 years with NDMM (per International Myeloma Working Group [IMWG] criteria) who received 4–6 cycles of 3 or 4 drug-induction treatments (only 1 LOT, including a PI and/or IMiD with or without an anti-CD38 monoclonal antibody and achieved ≥partial response [PR]), had a single or tandem ASCT, and had an Eastern Cooperative Oncology Group performance status score 0–2. Patients who received any prior BCMA-directed treatment or have progressive disease will be excluded. As the combination of Tec-Len has not been previously evaluated in patients with NDMM, a safety run-in will be performed. If no safety signal is observed, randomization will begin. Approximately 1000 patients will be randomized 1:1 to receive 28-day cycles of Tec-Len or Len. The study will continue until ~380 deaths have occurred or a maximum of 8 years after the last patient is randomized. The primary endpoint is PFS. Secondary endpoints include complete response (CR) conversion from PR/very good PR, minimal residual disease (MRD) negative conversion, ≥CR, MRD negative CR, sustained MRD negativity, OS, PFS2, time to next treatment, patient-reported outcomes, and incidence and severity of adverse events (AEs). Response will be assessed using 2016 IMWG criteria. AEs will be graded by Common Terminology Criteria for AEs v5.0, except for cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, which will be graded by American Society for Transplantation and Cellular Therapy guidelines. The study opened for enrollment in May 2022. Results from this trial will provide insights into a possible new synergistic combination that could improve response and prolong survival versus current maintenance regimens for patients with NDMM.