LINKER-MM3, a phase 3, open-label, randomized study of linvoseltamab versus elotuzumab, pomalidomide, and dexamethasone (EPd) in relapsed/refractory multiple myeloma (RRMM)

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Frontline treatment for multiple myeloma (MM) often utilizes combinations of 2–4 active drugs, including an immunomodulatory drug, a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody (mAb). However, relapse remains a persistent problem and there is no single algorithm for the treatment of RRMM. Pomalidomide-based regimens are available in the RRMM setting, with those combinations that avoid re-use of anti-CD38 mAbs assuming greater importance following the positioning of these mAbs in frontline therapy. EPd is a recognized anti-CD38 mAb-free combination, although only about half of the patients responded to treatment in the pivotal study of EPd, and the efficacy of this regimen in patients previously exposed to anti-CD38 mAbs is yet to be determined. Expanding the anti-MM armamentarium with drugs that have new mechanisms of action is thus important, particularly for RRMM. Linvoseltamab (REGN5458) is a B-cell maturation antigen (BCMA)×CD3 bispecific antibody that induces T-cell-mediated cytotoxicity of BCMA-expressing MM cells. In the Phase 1/2 LINKER-MM1 study, linvoseltamab monotherapy achieved early, deep, and durable responses in patients with heavily pretreated RRMM, with a manageable safety profile (Bumma, et al. ASH, 2022). Aims: To conduct a Phase 3 study to compare the efficacy and safety of linvoseltamab monotherapy to EPd in patients with RRMM. Methods: LINKER-MM3 (NCT05730036) is a Phase 3, open-label, randomized study of linvoseltamab monotherapy versus EPd combination therapy in patients with RRMM. Eligible patients will have received 1–4 prior lines of therapy, including lenalidomide and a PI, and have progressed on/after the last therapy; prior anti-CD38 mAb treatment is permitted. Other key eligibility criteria include measurable disease per 2016 IMWG criteria; ≥18 years of age; adequate bone marrow reserves and hepatic, renal, and cardiac function; no prior treatment with elotuzumab, pomalidomide or BCMA-directed immunotherapies. All patients will provide consent. Linvoseltamab will be administered in 28-day cycles, with step-up dosing to the full dose undertaken during Cycle 1. EPd treatment will also be given in 28-day cycles, according to the package inserts. Both treatment regimens will be given until disease progression, intolerance, or another defined reason for drug discontinuation. The study will take place at approximately 130 sites globally. A total of 286 patients will be randomized (1:1) to intravenous linvoseltamab or EPd, with randomization between arms stratified according to prior anti-CD38 mAb exposure and a composite of International Staging System stage and extramedullary plasmacytoma status. Results: The primary endpoint is progression-free survival per IMWG criteria, determined by Independent Review Committee (IRC). Key secondary endpoints are objective response rate (including ≥very good partial response and ≥complete response, determined by IRC); minimal residual disease negative status; overall survival; and change in pain at Week 12 (Brief Pain Inventory-Short Form, Item 3). Incidence and severity of treatment-emergent AEs will also be assessed. Study enrollment is planned to begin in Q2 2023. Summary/Conclusion: The LINKER MM-3 study will determine the utility of linvoseltamab monotherapy as a novel alternative treatment relative to a standard pomalidomide-based triplet therapy for patients with RRMM. Keywords: Multiple myeloma, Relapse, Bispecific, B-cell maturation antigen