Safety and efficacy of linvoseltamab as a simplified monotherapy first-line regimen in NDMM: Initial Results from the window of opportunity Phase 1/2 LINKER-MM4 trial

Abstract Introduction Treatment of NDMM relies on complex quads and triplets, highlighting a need for a simpler, improved regimen. LINVO, a human B-cell maturation antigen (BCMA)×CD3 bispecific antibody (bsAb), monotherapy demonstrated deep, durable responses and a generally manageable safety profile in LINKER-MM1 (NCT03761108) and is approved in Europe and the US for pts with relapsed/refractory multiple myeloma (RRMM) after ≥3 prior therapies (EU) or ≥4 prior lines of therapy (US) . Building on RRMM results, LINVO monotherapy is being evaluated in pts with NDMM. In the Phase (Ph) 1 dose-escalation part (Part A [Ph 1A]) of the open-label Ph 1/2 LINKER-MM4 study (NCT05828511), LINVO showed promising preliminary efficacy and safety in autologous stem cell transplantation (ASCT) eligible (TE) or ineligible (TIE) pts with NDMM (Ferreri et al. IMS 2025). Here we report longer safety and efficacy follow-up in Ph 1A and in the Ph 1 dose-expansion (Ph 1B) cohorts. Methods Adults with previously untreated, symptomatic MM were enrolled. TE pts received LINVO induction, ASCT, and two cycles of LINVO consolidation, followed by standard of care maintenance therapy; TIE pts (and TE pts deferring ASCT) received LINVO until disease progression. Ph 1A dose escalation included modified step-up dosing (1/4/25 mg on Cycle [C]1 Day [D]1, C1D4, and C1D8, respectively) and evaluated 3 full doses (50, 100, 200 mg). Ph 1B expanded the 50/200 mg dose levels to determine the recommended Ph 2 dose in NDMM. Ph 1 primary endpoints: incidences of dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), and adverse events of special interest. Secondary endpoints: ORR, progression-free survival, and minimum residual disease (MRD) negativity (10−5 threshold). Results By Apr 28, 2025, 45 pts had received LINVO (50 mg, n=20; 100 mg, n=4; 200 mg, n=21). Median follow-up was 11.2 months (mo; range 1.6–15.7) in Ph 1A and 4.8 mo (range 1.6–6.5) in Ph 1B. Among all Ph 1 pts: median age was 67.0 years (range 43–84); 60% were male, 18% were Black or African American, 67% had bone marrow plasmacytosis ≥50%, 2% had extramedullary plasmacytomas, 47%/4% were Revised International Staging System (R-ISS) Stage II/III, 15% (4/27 evaluable pts) had high cytogenetic risk by R-ISS, and 62% were TE. No DLTs were observed in Phase 1. The most common non-hematologic TEAE was cytokine release syndrome, reported in 44% of pts; all events were Gr 1 (50 mg, 40%; 200 mg, 52%). The most common hematologic TEAEs (composite terms) were neutropenia (any Gr, 31%; Gr 3–4, 29%) (any Gr/Gr3–4: 50 mg, 25%/20%; 200 mg, 29%/29%) and anemia (any Gr, 27%; Gr 3–4, 16%) (any Gr/Gr3–4: 50 mg, 30%/25%; 200 mg, 24%/5%). A single immune effector cell-associated neurotoxicity syndrome (ICANS) event was observed and resolved (Gr 1: 50 mg). Infections occurred in 82% of pts (any Gr/Gr 3–4: 82%/31%; 50 mg, 85%/40%; 200 mg, 81%/19%). There was 1 tx discontinuation due to a TEAE (Gr 3 pneumonia: 200 mg) that resolved. No TEAEs resulted in death. Among 43 response-evaluable pts, investigator-assessed ORR was 79% (very good partial response or better [≥VGPR], 56%; ≥CR, 26%). Among evaluable pts receiving 200 mg or 50 mg, ORR was 86% (≥VGPR, 48%; ≥CR, 24%) and 72% (≥VGPR, 61%; ≥CR, 22%), respectively. Based on the results of longer follow-up RRMM studies, deeper responses may occur with longer follow-up. Median time to partial response or better was 1.2 mo (range 1.15–1.43) and 9/11 CRs were within 6 mo of tx initiation. Of 24 MRD-evaluable pts by clonoSEQ or Euroflow, 22/24 (92%) are MRD negative at or below the 10-5 threshold. All were progression-free at data cutoff. Exposure of LINVO was dose-dependent and overall pharmacokinetic profile was consistent with RRMM. ConclusionsTo our knowledge, this is the first bsAb evaluated as monotherapy in NDMM, where current therapies are burdensome. In this larger, longer follow-up analysis, LINVO monotherapy continues to have high ORR and a generally manageable safety profile in NDMM, with no Gr ≥2 CRS events and 1 Gr 1 ICANS event observed. Responses may deepen over time, especially in the 200 mg cohort, supporting the further exploration of LINVO as a foundational drug in NDMM front-line regimens.