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

7513 Background: LINVO, a T-cell redirecting BCMA×CD3 bispecific antibody, has demonstrated high efficacy and generally manageable safety in triple-class exposed (TCE: anti-CD38 Ab + immunomodulatory drug [IMiD] + proteasome inhibitor [PI]) pts with RRMM. Combination treatment (tx) with CFZ, a potent second-generation PI, may enhance clinical activity via rapid cytoreduction and complementary immunostimulatory mechanisms like immunogenic cell death and antigen spreading. We report safety and preliminary efficacy from dose escalation in the LINVO + CFZ cohort of the phase 1b, open-label LINKER-MM2 trial (NCT05137054). Methods: Eligible pts were ≥18 years with RRMM that progressed after ≥3 lines of therapy (LoT), or ≥2 LoT if either TCE or double-class refractory (IMiD + PI). Prior CFZ was allowed if previously tolerated and ≥6 months had elapsed since last exposure. CFZ-refractory pts were allowed during dose escalation. Tx began with LINVO alone (Cycle [C] 0) consisting of 2 step-up doses (5 mg and 25 mg) and 2 full doses (dose level [DL] 1 = 100 mg or DL1b = 150 mg) before initiation of CFZ (20/56 mg/m 2 on days 1, 2, 8, 9, 15, 16) at C1. LINVO was given once weekly (QW) in C1–4, and Q2W thereafter. CFZ dosing could be switched to QW after C2. Dexamethasone premedication was limited to C0–1. Primary endpoints were dose limiting toxicities (DLTs) and tx-emergent adverse events (TEAEs). Secondary endpoints included objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Results: As of Sep 30, 2024, 18 pts were treated at DL1 (n = 12) or DL1b (n = 6). Median duration of follow-up was 16.9 (DL1) and 7.7 months (DL1b), with 67% and 83% of pts still receiving tx, respectively. Median age was 68 years (range 53–79), 50% were male, 6% had ISS stage III, 50% had extramedullary or paraskeletal disease, and 17% had high-risk cytogenetics. Median prior LoT was 3 (2–6), including 83% of pts with TCE and 33% with triple-class refractory disease. Among evaluable pts, ORR was 91% at DL1 (10/11; ≥VGPR 91%) and 100% at DL1b (6/6; ≥VGPR 80%). Median DOR was not reached at either DL. For DL1, the PFS rate was 91% (95% CI 51–99) at 6 months and 73% (95% CI 37–90) at 12 months. No PFS events had occurred at DL1b. PK analysis found LINVO concentrations were not affected by addition of CFZ. The most common TEAEs were neutropenia (any Grade [Gr] 78%; Gr 3–4 61%), thrombocytopenia (61%; 39%), and cytokine release syndrome (61%; Gr ≥3 0%). One pt experienced ICANS (Gr 1). Infections were reported in 89% of pts (Gr ≥3 44%). One DLT was observed at DL1, Gr 4 thrombocytopenia in the setting of tumor lysis syndrome, from which the pt recovered and afterward resumed tx. Conclusions: LINVO + CFZ induced a high rate of deep and durable responses with a safety profile consistent with the individual drugs, supporting further development. Enrollment at 200 mg LINVO in combination with CFZ is ongoing. Clinical trial information: NCT05137054 .