Phase 2 LINKER-SMM1 Trial Supports Linvoseltamab in Smoldering Myeloma

Paula Rodríguez-Otero, MD, consultant and deputy professor at the University of Navarra, Spain, discusses the findings from the Phase 2 LINKER-SMM1 study (NCT05955508) she presented at the International Myeloma evaluated linvoseltamab (Lynozyfic), a BCMA × CD3 bispecific antibody, as a single agent in 40 patients diagnosed with high-risk smoldering multiple myeloma (HR-SMM) over the preceding 5 years. All enrolled participants met stringent high-risk criteria defined by either the 2/20/20 or PET-CT standards. The trial included a safety lead-in (n = 6) followed by an expansion cohort (n = 34). Treatment was administered for a fixed 2-year duration (22 cycles) featuring a response-adapted and time-decaying schedule: 3 initial step-up doses, weekly administration in cycle 1, biweekly in cycles 2-5, monthly in cycles 6-13, and bimonthly from cycle 14 onward.

Linvoseltamab demonstrated exceptional efficacy among response-evaluable patients with a 100% overall response rate, with 97% achieving a very good partial response or better and 85% attaining a complete response (CR) or better. At the time of achieving , all 34 evaluable patients reached minimal residual disease (MRD) negativity at 10^-5, with 31 of 34 (91.2%) also achieving MRD negativity at 10^-6. Among 22 evaluable patients at 12 months, 100% maintained MRD negativity at 10^-5, and 19 of 22 (86.4%) were negative at 10^-6.

Linvoseltamab demonstrated a manageable safety profile consistent with BCMA-targeted bispecifics, with grade or higher treatment-emergent adverse events occurring in 70% of patients, primarily driven by neutropenia. Any-grade infections occurred in 92% of participants, but grade 3 infections were limited to 20%, with 0 grade 4 or 5 infectious events. Cytokine release syndrome was reported in 45% of patients (all grade 1 except for a single grade 2 event; no grade or higher), with only 7 patients requiring tocilizumab (Actemra).

Four patients discontinued treatment in CR due to physician decision regarding recurrent low-grade infections, and 3 discontinued due to adverse events. Overall, Rodríguez-Otero says these robust depth-of-response and manageable safety data support the fixed-duration use of linvoseltamab in HR-SMM and provide a strong rationale for the ongoing phase 3 LINKER-SMM2 trial (NCT07393282) against daratumumab (Darzalex).