(OA-68) Safety and Efficacy of Linvoseltamab (LINVO) in Patients (Pts) with High-risk Smoldering Multiple Myeloma (HR-SMM): First Results from the Phase 2 LINKER-SMM1 Trial

LINVO, a BCMA×CD3 bispecific antibody, is approved for triple-class exposed relapsed/refractory multiple myeloma (RRMM) after ≥3 therapies (EU) or ≥4 prior lines of therapy (US). Early intervention in HR-SMM when the immune system is more functional could significantly delay or prevent progression to active MM. Here we report the preliminary safety and efficacy of LINVO in pts with HR-SMM from the LINKER-SMM1 study (NCT05955508).

Methods:

LINKER-SMM1 is an open-label study of LINVO monotherapy in adults with HR-SMM, defined as SMM diagnosis within 5 yrs of study entry and high-risk features by Mayo 2018 “20-2-20” or PETHEMA criteria. Treatment (tx) began with a 3-week step-up schedule of 1 mg (week [W]1), 4 mg (W2), and 25 mg (W3), followed by LINVO 200 mg in 28-day cycles: weekly for Cycle (C)1, every 2 wks for C2–5, and every 4 wks for C6–24.

Part 1 (P1) was a safety run-in of 6 pts. Primary endpoints were frequency of AEs of special interest, including Grade (Gr) ≥2 CRS and ICANS, and frequency and severity of tx-emergent AEs (TEAEs). In the ongoing Part 2 (P2) expansion, primary endpoints are complete response (CR) rate and MRD negativity at 12 and 24 months (mos). Key secondary endpoints for P1 and P2 include overall response rate (ORR), MRD negativity rate, and duration of response (DOR).

Results:

As of May 28, 2025, 24 pts were enrolled (Mayo criteria, n=18; PETHEMA criteria, n=6). Median age was 63 yrs (range 39–79), 29% male, and 92% ECOG PS 0. Median duration of exposure was 16.6 wks (range 1–57). Median duration of follow-up was 12.7 mos (P1) and 3.3 mos (P2). No safety concerns were observed in P1.

Overall, 92% of pts experienced ≥1 TEAE, and 38% (n=9) experienced a Gr ≥3 TEAE (all Gr 3 except neutropenia). Neutropenia was the only Gr ≥3 hematologic toxicity (Gr 3, n=4; Gr 4, n=2). Infections occurred in 79% of pts (n=19) and consisted of mostly low-grade respiratory tract infections ([RTI], n=6; upper RTI, n=3). Gr 3 infections were reported in 3 pts: COVID-19, Salmonella gastroenteritis, and Staphylococcus epidermidis bacteremia; the latter 2 were assessed as tx-related and rapidly resolved with IV antibiotics. Ig replacement was given to 95% of pts who received ≥1 cycle of therapy. CRS occurred in 10 pts (42%), and all events were Gr 1 except a single Gr 2 event after the 1 mg step-up dose. Tocilizumab was used in 2 pts. No ICANS events were observed. No pts discontinued tx.

After ≥1 cycle of LINVO (n=19), investigator-assessed ORR per IMWG criteria was 100% (≥VGPR 74%; ≥CR 37%). Among P1 pts with longer follow-up, 100% achieved ≥VGPR (1 VGPR; 5 ≥CR) and 100% achieved MRD negativity at 10^-6. All responses were ongoing at the time of data cutoff and showed evidence of deepening over time.

Conclusions:

LINVO in HR-SMM was highly active with 100% ORR, and the safety profile appeared more favorable compared to RRMM. These data support further investigation of LINVO as an early intervention for SMM.