Linvoseltamab (LINVO) + bortezomib (BTZ) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): First results from the LINKER-MM2 trial.

7510 Background: LINVO, a BCMA×CD3 bispecific antibody, has shown high efficacy and generally manageable safety in triple-class exposed (TCE: anti-CD38 Ab + immunomodulatory drug [IMiD] + proteasome inhibitor [PI]) pts with RRMM. PIs such as BTZ have direct anti-MM activity and may enhance LINVO activity by improving immune function. We report safety and preliminary efficacy data from dose escalation and expansion in the LINVO + BTZ cohort of the phase 1b, open-label LINKER-MM2 trial (NCT05137054). Methods: Eligible pts were ≥18 yrs with RRMM that progressed after ≥3 lines of therapy (LoT), or ≥2 LoT if either TCE or double-class refractory (IMiD + PI). Prior BTZ was allowed if previously tolerated and ≥6 months (mos) had elapsed since last exposure. BTZ-refractory pts were allowed during dose escalation. Treatment (tx) began with LINVO alone (Cycle [C] 0: 2 step-up doses [5 and 25 mg] and ≥1 full dose [dose level [DL] 1 = 100 mg or DL2 = 200 mg]) before initiating standard dose BTZ (1.3 mg/m 2 twice weekly over 21-day cycles) at C1. LINVO was given once weekly (QW) in C1–4, then Q3W thereafter. BTZ dosing could be switched to QW after C3 and ended after a total of 8 cycles. Dexamethasone premedication was limited to C0–1. Primary endpoints were dose-limiting toxicities (DLTs; dose-finding portion) and incidence/severity of tx-emergent AEs (TEAEs). Secondary endpoints included objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Results: As of Sept 30, 2024, 22 pts had received tx (DL1: n=6; DL2: n=16). Median follow-up duration was 6.3 mos (range 1–21), with 55% of pts still receiving tx. Median age was 68.5 yrs (range 45–77), 68% were male, 23% had ISS stage III, and 55% had extramedullary or paraskeletal disease. Median prior LoT was 3 (range 2–9), including 86% of pts with TCE and 41% with triple-class refractory disease; 59% were refractory to ≥1 PI (9% BTZ-refractory). Among evaluable pts, ORR was 79% (11/14; DL1 80% [4/5]; DL2 78% [7/9]). The 6-month DOR rate was 90% (95% CI 47–99) and 6-month PFS rate was 79% (95% CI 47–93). PK analysis found LINVO concentrations were not affected by addition of BTZ. The most common TEAEs were neutropenia (any Grade [Gr] 59%; Gr 3–4 45%), thrombocytopenia (50%; 36%), and cytokine release syndrome (55%; 0%). ICANS was reported in 4 pts (all Gr 1–2 with onset during step-up dosing). Infections were reported in 82% of pts (Gr 3–4 36%); 1 pt died of pneumonia ≤30 days after last dose before start of combination tx. One DLT occurred at DL2 (Gr 3 CMV colitis on day 48; resolved with tx delay and ganciclovir). Conclusions: LINVO + BTZ induced high response rates, with encouraging early DOR and PFS, in a population that was mostly PI-refractory. Safety was consistent with the known profile of each drug, and risk of Gr 3–5 infection was similar to LINVO monotherapy. These data will inform LINVO combination strategies for earlier LoT. Clinical trial information: NCT05137054 .