Linvoseltamab Yields Favorable Safety Profile and Antimyeloma Activity in High-Risk Smoldering Myeloma

Linvoseltamab-gcpt (Lynozyfic) monotherapy was active and elicited a safety profile in patients with high-risk smoldering multiple myeloma that appeared more favorable than that seen with the agent in patients with relapsed/refractory multiple myeloma, according to first results from the phase 2 LINKER-SMM1 trial (NCT05955508), which were presented at the 22nd Annual International Myeloma Society Meeting and Exposition.1

Among 24 enrolled patients, any-grade and grade 3 or higher treatment-emergent adverse effects (TEAEs) were reported in 92% and 38% of patients, respectively. No patients discontinued treatment or died due to TEAEs. The most common hematologic TEAEs included neutropenia (any-grade, 46%; grade ≥ 3, 25%), anemia (25%; 0%), and COVID-19 (21%; 4.2%). The most common any-grade nonhematologic TEAEs were cytokine release syndrome (CRS; 42%), hypogammaglobulinemia (29%), and rash (29%); no grade 3 or higher nonhematologic TEAEs were reported.

Among all efficacy-evaluable patients enrolled across both parts of the study (n = 19), at a median follow-up of 3.9 months (range, 0-13), the overall response rate (ORR) was 100.0%, including stringent complete response (sCR), CR, very good partial response (VGPR), and PR rates of 15.8%, 21.1%, 36.8%, and 26.3%, respectively.

All 12 patients with minimal residual disease (MRD)–evaluable samples had MRD-negative disease at a sensitivity of 10–6 using EuroFlow (100%; n = 9/9) and/or clonoSEQ (90%; n = 9/10) testing. Among patients with a CR or better, the rates of MRD negativity per these respective assays were 100% (n = 6/6) and 86% (n = 6/7). Among patients with a VGPR, the rates of MRD negativity per these respective assays were 100% (n = 3/3) and 100% (n = 3/3).

“The data look encouraging, and we believe this could be a good platform to try to prevent the evolution from high-risk smoldering into active disease,” Paula Rodriguez-Otero, MD, PhD, said in an interview with OncLive® during the meeting.

Rodriguez-Otero is a consultant, deputy professor, and member of the Myeloma Unit at the University of Navarra, as well as medical responsible of the Clinical Trial Unit at Clinica Universidad de Navarra in Pamplona, Spain.

Where Does Linvoseltamab Currently Fit Into the Myeloma Treatment Paradigm?

On July 2, 2025, the FDA granted accelerated approval to linvoseltamab for the treatment of triple-class–exposed patients with relapsed/refractory multiple myeloma who have received at least 4 prior lines of therapy.2 This regulatory decision was backed by data from the phase 1/2 LINKER-MM1 trial (NCT03761108), in which the ORR was 70% (95% CI, 59%-80%).

What is the Design of the LINKER-SMM1 Study?

The open-label study enrolled adult patients with high-risk smoldering myeloma diagnosed within 5 years of enrollment who have received no prior treatment.1 Patients needed to have an ECOG performance status of 0 or 1 and adequate organ function.

Part 1 of the study was the safety run-in portion (n = 6). Following acceptable safety findings, part 2, the expansion portion (planned n = 34), was permitted to proceed. Patients received linvoseltamab in both parts at the same dosing schedule. The screening period was up to 28 days in length. Treatment began with a 3-week step-up dosing schedule of 1 mg in week 1, 4 mg in week 2, and 25 mg in week 3. In weeks 4 through 7 (cycle 1), patients received linvoseltamab at the full study dose of 200 mg, administered weekly. In cycles 2 through 5, patients receive linvoseltamab at 200 mg every 2 weeks. In cycles 6 through 24, patients received linvoseltamab at 200 mg every 4 weeks. Premedication is required during the step-up period and on cycle 1 day 1. Follow-up will be conducted for up to 5 years after the last dose.

In part 1, the primary end points were the frequency of AEs of special interest, and the frequency and severity of TEAEs. In part 2, the primary end points were CR rate per International Myeloma Working Group criteria, and MRD negativity rates at 12 and 24 months. Key secondary end points in both parts included ORR, MRD negativity rate, and duration of response (DOR).

What Were the Baseline Characteristics of Patients Enrolled in LINKER-SMM1?

As of the data cutoff date of May 28, 2025, 24 patients have been enrolled (part 1, n = 6; part 2, n = 18). Linvoseltamab treatment is ongoing in all enrolled patients.

Among all enrolled patients, the median age was 63.0 years (range, 39-79); 42% and 13% of patients were older than 65 years of age and older than 75 years of age, respectively. Additionally, 29% of patients were male, and 92% of patients had an ECOG performance status of 0. Regarding high-risk criteria, 42% of patients were considered to have high-risk disease per “2-20-20” criteria only, 25% of patients were considered to have high-risk disease per PETHEMA criteria only, and 33% of patients were considered to have high-risk disease per both sets of criteria. Patients were also reported to have serum M protein levels higher than 20 g/dL (67%), serum free light chain ratios greater than 20 (83%), bone marrow plasma cell (BMPC) levels higher than 20% (75%), levels of aberrant or clonal BMPCs greater than 95% (71%), and immunoparesis (63%).

What Were Additional Safety Data From LINKER-SMM1?

All CRS events were grade 1 except for 1 grade 2 event that occurred after the 1-mg step-up dose. Among the patients who developed CRS, the median time to CRS from the most recent prior dose was 18.13 hours (range, –0.2 to 83.0), the median duration of CRS was 9.23 hours (range, 1.4-48.0), and 2 patients received tocilizumab (Actemra) to treat CRS. No immune effector cell–associated neurotoxicity syndrome events were reported.

Any-grade and grade 3 or higher infections were reported in 79% and 12.5% of patients, respectively. The most common infections were respiratory tract infection (any-grade, 25%; grade ≥ 3, 0%), COVID-19 (21%; 4.2%), tonsilitis (13%; 0%), and upper respiratory tract infection (13%; 0%). Other notable grade 3 or higher infections were salmonella gastroenteritis and staphylococcus epidermidis bacteremia, which each occurred in 1 patient; these were deemed treatment related and resolved with intravenous antibiotics.

In total, 89.5% of patients who received at least 1 cycle of therapy received immunoglobulin replacement.

What Were Additional Efficacy Data From LINKER-SMM1?

Among evaluable patients in part 1 (n = 6), at a median follow-up of 12.7 months (range, 11-13), the respective rates of sCR, CR, VGPR, and PR were 33.3%, 50.0%, 16.7%, and 0%. Among evaluable patients in part 2 (n = 13), at a median follow-up of 3.3 months (range, 0-7), the respective rates of sCR, CR, VGPR, and PR were 7.7%, 7.7%, 46.2%, and 38.5%.

The median time to first response was 1.7 months (range, 0.7-2.6). Responses deepened over time, and all responses were ongoing at the data cutoff date.

“These are still preliminary data, so we need to first fully enroll the study,” Rodriguez-Otero concluded. “We need more follow-up and a larger cohort of patients. The idea is to go into a phase 3 randomized trial of linvoseltamab compared with daratumumab. We know [linvoseltamab is] probably going to be a new standard in this population.”

Disclosures: Rodriguez-Otero reported serving in advisory roles for AbbVie, Bristol Myers Squibb, GSK, Johnson & Johnson—Janssen, Kite Pharma, Oncopeptides, Pfizer, Roche, Sanofi, and Takeda; owning stock and other ownership interests for Syndax; receiving honoraria from Amgen, Bristol-Myers Squibb, GSK, Johnson & Johnson—Janssen, Regeneron Pharmaceuticals, Inc., Sanofi, and Takeda; and receiving travel, accommodation, and expense support from Pfizer.

References

1. Rodriguez-Otero P, Lieonart JJB, Clavero ME, et al. 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. Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-68.
2. FDA grants accelerated approval to linvoseltamab-gcpt for relapsed or refractory multiple myeloma. FDA. July 2, 2025. Accessed September 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-linvoseltamab-gcpt-relapsed-or-refractory-multiple-myeloma