Single-agent, fixed-duration linvoseltamab (Lynozyfic) produced deep and durable responses in patients with high-risk smoldering multiple myeloma, according to updated results from the phase 2 LINKER-SMM1 trial (NCT05955508) presented in a poster session at the 23rd Annual International Myeloma Society (IMS) Meeting & Exposition.¹
What was the efficacy of linvoseltamab in high-risk smoldering myeloma?
At a median follow-up of 13.3 months among efficacy-evaluable patients (n = 39), linvoseltamab produced an ORR of 100%, including a stringent CR (sCR) in 59%, a CR in 26%, a very good partial response (VGPR) in 13%, and a PR in 3%. Additionally, 85% of patients achieved a CR or better, and 97% achieved a VGPR or better.
In the safety run-in cohort of part 1 of the study (n = 6), all patients achieved a CR or better, and in the expansion cohort of part 2 (n = 33), 82% achieved a CR or better. The median time to response across the overall population was 1.7 months (range, 0.7-4.5), and the median time to a VGPR or better was 3.9 months (range, 1.6-10.8). No patients experienced biochemical progression or progression to active multiple myeloma as of the data cutoff, and responses deepened over time. One enrolled patient who left during step-up dosing was not evaluable for efficacy.
What were the MRD results?
All 40 patients were enrolled and treated as of the June 26, 2026, data cutoff, and 100% of those who were evaluable for measurable residual disease (MRD) achieved MRD negativity at a sensitivity of 10–5. Among 34 patients evaluable at the time of initial VGPR or better, all 34 were MRD negative at 10–5, and 31 were MRD negative at 10–6; 3 had indeterminate results. At the 12-month landmark, all 22 evaluable patients were MRD negative at 10–5, and 19 were MRD negative at 10–6, with 3 having indeterminate results. Among 21 patients evaluable across 2 consecutive MRD assessments, all 21 had ongoing MRD-negative status.
What was the safety profile of linvoseltamab?
Among all 40 treated patients, the median exposure to linvoseltamab was 56.4 weeks (range, 3-113). Treatment-emergent adverse events (TEAEs) of any grade occurred in all patients, and grade 3/4 TEAEs occurred in 70%, with no grade 5 events. Neutropenia was the most common grade 3 or higher TEAE (grade 3, 28%; grade 4, 20%). Cytokine release syndrome (CRS) occurred in 45% of patients and was mostly grade 1, with a single grade 2 event and no grade 3 or higher events. Additionally, 18% of patients were managed with tocilizumab (Actemra), and the median time to CRS onset was 10.4 hours.
No immune effector cell–associated neurotoxicity syndrome (ICANS) was observed. Infections of any grade occurred in 93% of patients, with grade 3 infections in 20% and no grade 4 or higher infections. Seven patients (18%) discontinued treatment, including 3 due to TEAEs, including grade 3 pancreatitis during step-up dosing, grade 2 salmonellosis, and a grade 4 chronic obstructive pulmonary disease exacerbation with respiratory failure from which the patient recovered. The other 4 patients discontinued due to physician decision related to recurrent grade 1/2 infections after reaching a CR.
“Single-agent fixed-duration linvoseltamab was highly active in [high-risk smoldering multiple myeloma], with ongoing [and] deepening responses over time,” Paula Rodriguez-Otero, MD, a consultant and deputy professor at the University of Navarra, wrote with coauthors in the poster.1 “The safety profile of linvoseltamab in [high-risk smoldering multiple myeloma] remains manageable, with no new safety signal observed.”
What is the LINKER-SMM1 trial design, and what comes next?
LINKER-SMM1 is a phase 2 trial evaluating single-agent, fixed-duration linvoseltamab in adults with high-risk smoldering multiple myeloma diagnosed within 5 years, with high-risk features defined by the “2-20-20” criteria and/or PETHEMA criteria. Patients received linvoseltamab at 200 mg for up to 24 cycles with decreasing frequency following step-up dosing.
The primary end points were safety in the part 1 safety run-in portion of the study and CR rate per International Myeloma Working Group criteria and MRD negativity at 12 and 24 months in the part 2 expansion portion. The median patient age was 61 years (range, 39-84), 60% were female, and 58% met both the “2-20-20” and PETHEMA high-risk criteria.
A phase 3 trial, LINKER-SMM2 (NCT07393282), comparing linvoseltamab with daratumumab (Darzalex), the only currently approved therapy for smoldering multiple myeloma, in patients with high-risk smoldering multiple myeloma has begun enrollment.2
“Single-agent, fixed-duration linvoseltamab was highly active with deep and durable responses in LINKER-SMM1, supporting further evaluation as early intervention strategy for [high-risk smoldering multiple myeloma],” the investigators concluded.1
References
- Rodríguez-Otero P, Amer Salas N, Clavero ME, 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 Annual International Myeloma Society (IMS) Meeting & Exposition; September 23-26, 2026; Glasgow, Scotland. Poster PA-517.
- A study to compare linvoseltamab and daratumumab treatment in high-risk moldering multiple myeloma (HR-SMM) (LINKER-SMM2). ClinicalTrials.gov. Updated September 15, 2026. Accessed September 23, 2026. https://tinyurl.com/3r52my2e
