Linvoseltamab Yields Deep, MRD-Negative Responses With Manageable Safety in High-Risk Smoldering Myeloma

Single-agent, fixed-duration linvoseltamab-gcpt (Lynozyfic) produced high rates of deep, ongoing response and minimal residual disease (MRD) negativity in patients with high-risk smoldering multiple myeloma (HR-SMM), according to updated data from the phase 2 LINKER-SMM1 study (NCT05955508) presented at the 23rd International Myeloma Society (IMS) Annual Meeting & Exposition.¹

Responses continued to deepen over time, with no biochemical or clinical progression to active multiple myeloma observed as of the data cutoff. The safety profile remained manageable, with no immune effector cell–associated neurotoxicity syndrome (ICANS) and no new safety signals identified.

At a median follow-up of 13.3 months (range, 1-26) across the full cohort (N = 40), the objective response rate (ORR) was 100% among the 39 response-evaluable patients (part 1 safety run-in, n = 6; part 2 expansion, n = 33). A very good partial response (VGPR) or better was achieved by 97% of patients, and a complete response (CR) or better was achieved by 85%. Among MRD-evaluable patients, 100% achieved MRD negativity at a sensitivity of 10^–5, including all 34 patients evaluable at initial VGPR or better and all 22 patients evaluable at the 12-month landmark; 19 of 22 patients (86%) were MRD negative at the deeper 10^–6 threshold at the 12-month landmark, with 3 indeterminate. All 21 patients with 2 consecutive MRD assessments maintained MRD-negative status.

“I think that linvoseltamab single-agent, fixed-duration [therapy] was highly active in patients with high-risk [smoldering multiple myeloma], with ongoing, deepening responses over time. In terms of safety profile, [it] is manageable—no new safety signal was observed,” said María-Victoria Mateos, MD, PhD, of the University Hospital of Salamanca and Instituto de Investigación Biomédica de Salamanca in Salamanca, Spain.

How was the LINKER-SMM1 trial designed?

LINKER-SMM1 is an open-label, phase 2 study assessing single-agent, fixed-duration linvoseltamab in adults with HR-SMM diagnosed within 5 years of enrollment who had received no prior treatment. High-risk status was defined by the “2-20-20” criteria (at least 2 of: serum M protein > 2 g/dL, serum involved:uninvolved free light chain ratio > 20, or bone marrow plasma cells [BMPCs] > 20%) and/or PETHEMA criteria (≥95% aberrant/clonal BMPCs and immunoparesis); patients also needed an ECOG performance status of 1 or less and adequate organ function. Of the 40 enrolled patients, 35 (88%) met the “2-20-20” criteria, 28 (70%) met PETHEMA criteria, 23 (58%) met both, and all 40 (100%) met at least 1.

The study enrolled in 2 parts: a part 1 safety run-in (n = 6) that proceeded to a part 2 expansion cohort (n = 34) once the safety profile was deemed acceptable. Linvoseltamab was given via step-up dosing (1 mg, 4 mg, 25 mg) followed by 200 mg intravenously weekly in cycle 1, every 2 weeks in cycles 2 through 5, every 4 weeks in cycles 6 through 13, and every 8 weeks in cycles 14 through 24, for a fixed duration of up to 24 cycles. The primary end points were safety (frequency of adverse effects of special interest, including grade ≥2 CRS and ICANS, and frequency/severity of treatment-emergent adverse effects [TEAEs]) in part 1, and CR rate per International Myeloma Working Group criteria plus MRD negativity at 12 and 24 months in part 2. Key secondary end points included ORR, MRD, duration of response, progression-free survival (PFS), overall survival, and safety.

Median patient age was 61.0 years (range, 39-84), and most patients had an ECOG performance status of 0 (n = 38 of 40; 95%). As of the June 26, 2026, data cutoff, 29 of 40 patients (73%) remained on treatment, 4 (10%) had completed the full fixed-duration course, and 7 (18%) had discontinued treatment; the study remained ongoing for 39 of 40 patients (98%), with 1 patient withdrawing consent during step-up dosing before a response assessment could be performed.

Daratumumab (Darzalex) is currently the only approved therapy for smoldering multiple myeloma; in previously reported data, it delayed disease progression but with a low CR rate (5-year PFS rate of 63.1% and CR or better rate of 8.8% at a median follow-up of 65.2 months).² BCMA-directed immunotherapies, including bispecific antibodies and CAR T-cell therapies, are being investigated in HR-SMM based on their potential to achieve high rates of CR and MRD negativity. Linvoseltamab, a BCMA×CD3 bispecific antibody, is approved for triple-class–exposed relapsed/refractory multiple myeloma after at least 3 prior lines of therapy in the European Union or at least 4 prior lines in the United States, with an ORR of 71% (≥CR rate, 52%) and a median PFS that was not reached at a median follow-up of 21.3 months in the pivotal phase 1/2 LINKER-MM1 study (NCT03761108).³ Earlier results from LINKER-SMM1, in the first 24 enrolled patients, showed acceptable safety and promising efficacy and were presented in 2025.⁴

What did the safety analysis show?

Grade 3/4 TEAEs occurred in 70% of patients (n = 28 of 40), with neutropenia the most common grade 3 or higher TEAE; no grade 5 events were reported.¹ CRS occurred in 45% of patients (n = 18 of 40), predominantly grade 1, with a single grade 2 event and no grade 3 or higher events; 7 CRS events (17%) were managed with tocilizumab (Actemra). No ICANS events were observed. Infections of any grade occurred in 93% of patients (n = 37 of 40), with grade 3 infections in 20% (n = 8 of 40) and no grade 4 infections.

Seven patients (18%) discontinued treatment. Three discontinuations were due to TEAEs: grade 3 pancreatitis during step-up dosing, grade 2 salmonellosis after the patient had achieved CR, and a grade 4 COPD exacerbation resulting in respiratory failure (the patient subsequently recovered). Four patients discontinued by physician decision because of recurrent grade 1/2 infections; all 4 had already achieved CR at the time of discontinuation.

What are the next steps for linvoseltamab in HR-SMM?

Investigators concluded that single-agent, fixed-duration linvoseltamab was highly active in HR-SMM, with deep and durable responses that deepened over time and a safety profile considered manageable with no new safety signals. Based on these findings, a phase 3 trial, LINKER-SMM2 (NCT07393282), comparing linvoseltamab with daratumumab in HR-SMM has begun enrollment as an early-intervention strategy for this population.

References

1. Rodríguez-Otero P, Amer Salas N, Esther Clavero M, et al. Updated safety and efficacy results for linvoseltamab in patients with high-risk smoldering multiple myeloma: phase 2 LINKER-SMM1 trial. Presented at: 23rd International Myeloma Society Annual Meeting & Exposition; September 23-26, 2026; Glasgow, Scotland. Abstract PA-517.
2. Dimopoulos MA, Vorhees PM, Schjesvold F, et al. Daratumumab or active monitoring for high-risk smoldering multiple myeloma. N Engl J Med. 2025;392(18):1777-1788. doi:10.1056/NEJMoa2409029
3. Lee HC, Zonder JA, Dhodapkar MV, et al. Linvoseltamab in patients with relapsed/refractory multiple myeloma in the LINKER-MM1 study: longer follow-up and subgroup analyses. Clin Lymphoma Myeloma Leuk. 2026;26(2):e201-e212.e8. doi:10.1016/j.clml.2025.11.004
4. Wahner A. Linvoseltamab yields favorable safety profile and antimyeloma activity in high-risk smoldering myeloma. OncLive. Published September 19, 2025. Accessed September 23, 2026. https://www.onclive.com/view/linvoseltamab-yields-favorable-safety-profile-and-antimyeloma-activity-in-high-risk-smoldering-myeloma