MajesTEC-7: A Phase 3, Randomized Study of Teclistamab + Daratumumab + Lenalidomide (Tec-DR) Versus Daratumumab + Lenalidomide + Dexamethasone (DRd) in Patients with Newly Diagnosed Multiple Myeloma Who Are Either Ineligible or Not Intended for Autologous Stem Cell Transplant

Background: Recent advances in the treatment of patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for autologous stem cell transplant (ASCT) have led to improved outcomes, as evidenced by the increases in overall and progression-free survival (PFS) that were demonstrated with the combination of daratumumab (D) plus lenalidomide (R) and dexamethasone (DRd) in the phase 3 MAIA trial. Some patients who are eligible for ASCT also choose to defer transplant, as studies have shown that deferral does not adversely affect survival. There is thus a broad population of patients with NDMM who stand to benefit from improvements in frontline therapies that do not include ASCT, but new therapeutic regimens with alternative mechanisms of action are needed. MM remains incurable for most patients; the majority of patients relapse, and with each relapse, the duration of response decreases. Attrition rates between first and second lines of therapy can also be as high as 50%. Teclistamab (Tec) is a B-cell maturation antigen (BCMA) × CD3 bispecific antibody that redirects CD3+ T cells to induce cytotoxicity of BCMA-expressing MM cells. In the phase 1/2 MajesTEC-1 study (NCT03145181), Tec monotherapy was well tolerated, yielding durable responses that deepened over time in heavily pretreated patients with relapsed/refractory MM (RRMM). In the phase 1b TRIMM-2 study (NCT04108195), Tec + D showed manageable safety, with promising efficacy in patients with heavily pretreated RRMM, and the combination of Tec + D + R (Tec-DR) is being investigated in the MajesTEC-2 study in patients with newly diagnosed disease or MM who have received 1–3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) (NCT04722146). Here we report the design of the randomized, open-label, multicenter, phase 3 MajesTEC-7 trial, which will compare the efficacy of Tec-DR versus DRd in patients with NDMM who are ineligible or not intended for ASCT as initial treatment.

Study Design and Methods: Eligible patients will be aged ≥18 years with NDMM and are either ineligible or not intended for ASCT as initial therapy, have measurable disease, and an ECOG performance status score 0–2. A safety run-in phase for Tec-DR will precede the randomized phase. Approximately 1000 patients will be randomized 1:1 to receive Tec-DR or DRd. Treatment will continue until progressive disease, death, intolerable toxicity, loss to follow-up, withdrawal of consent, or end of study, whichever occurs first. The dual primary endpoints are PFS and minimal residual disease (MRD)-negative complete response (CR) sustained for at least 12 months. Secondary endpoints include rate of CR or better, overall survival, rate of MRD-negative CR, rate of very good partial response or better, PFS2, patient-reported outcomes, and adverse events (AEs). Response will be assessed using 2016 International Myeloma Working Group 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 will open for enrollment in Q4 2022. Results from this trial will provide insights into a possible new treatment regimen (Tec-DR) for patients with NDMM, which may provide improved outcomes.