A Phase 2/3, multicenter, randomized, open-label study evaluating the efficacy and safety of etentamig and daratumumab compared to daratumumab, lenalidomide, and dexamethasone in frailer transplant-ineligible patients with newly diagnosed multiple my

Abstract Background: For newly diagnosed (ND) patients with multiple myeloma (MM), treatment selection is influenced by transplant eligibility and patient fitness. Triplet or quadruplet regimens, such as daratumumab, lenalidomide, and dexamethasone (DRd) or anti-CD38 monoclonal antibodies + bortezomib, lenalidomide, and dexamethasone are considered standard of care (SoC) in transplant-ineligible (TI) patients. However, among TI patients, elderly and/or frail patients have been shown to have suboptimal outcomes with current SoC regimens as well as being excluded from clinical studies with quadruplet regimens. Therefore, an unmet medical need exists for innovative treatment regimens that can deliver robust efficacy and a tolerable safety profile in elderly and/or frail patients. The cell-surface receptor B-cell maturation antigen (BCMA) is highly expressed on malignant plasma cells in patients with MM, making it a promising therapeutic target. Etentamig is a fully human bispecific monoclonal immunoglobulin G4 antibody that targets BCMA on MM cells and CD3 on the surface of T-cells, resulting in T-cell activation and selective destruction of BCMA-positive MM cells. Etentamig may offer a promising tolerable treatment option for older and frailer patients, given its low-affinity CD3 binding—which may reduce cytokine release—and a silenced Fc region that supports extended half-life and convenient monthly dosing. Aims: The primary objectives of this study are to determine the efficacy and safety of etentamig+daratumumab (etentamig+D) versus DRd for TI patients with NDMM. Methods: This global, IFM/PETHEMA collaborative study (NCT07095452) is a Phase 2/3 multicenter, randomized, open-label study and will enroll patients (aged ≥18 years) with NDMM who, based on investigator judgment, are ineligible for high-dose chemotherapy and autologous stem cell transplant (SCT) due to factors likely to negatively impact tolerability of high-dose chemotherapy and SCT. The study will include patients with an International Myeloma Working Group (IMWG) Myeloma Frailty Index Score of ≥1 (intermediate-fitness to frail). In the Phase 2 part of the study, patients will be randomized to receive 1 of 3 dose levels of etentamig (IV) every 4 weeks (Q4W) with 1800 mg of daratumumab (subcutaneous) every week (cycles 1–2), Day 1 and Day 15 (cycles 3–6), and Q4W (cycle 7+). From these data, the safety and tolerability, efficacy, pharmacokinetics and pharmacodynamics, and exposure-response analyses will inform the optimal recommended Phase 3 dose (RP3D) of etentamig+D. The Phase 3 part of the study will randomize patients 1:1 to receive the standard-of-care (DRd] administered per the local label), or etentamig+D at the RP3D found in the Phase 2 portion of the study. Etentamig+D will be administered based on a 28-day cycle, and will be given at the RP3D regimen. The primary endpoint in the Phase 2 part of the study is clinical activity per IMWG 2016 criteria, including overall response rate, complete response or better, very good partial response, and partial response. In Phase 3, measurable residual disease negativity (10−5 threshold) and progression-free survival are dual primary endpoints. Approximately 54 sites across the United States, Canada, Japan, France, Norway, and Spain will participate in Phase 2, and additional countries contributing approximately 101 sites will be added for Phase 3.