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Linvoseltamab monotherapy produced responses and was safe in newly diagnosed multiple myeloma.
Treatment with the BCMA/CD3-targeted bispecific antibody linvoseltamab (Lynozyfic) monotherapy led to responses and displayed a manageable safety profile in patients with newly diagnosed multiple myeloma, according to data from the phase 1/2 LINKER-MM4 trial (NCT05828511).
The study, which is the first to evaluate a bispecific antibody as a standalone agent in the frontline setting, showed an investigator-assessed ORR of 79% across all dose levels. In the 200 mg dose cohort—the approved dosage for relapsed/refractory disease—the ORR reached 86%. Notably, 95% of evaluable patients achieved minimal residual disease (MRD) negativity at a 10⁻⁵ threshold.
These findings, presented at the 2025 ASH Annual Meeting and Exposition, suggest that linvoseltamab could offer a simplified, highly effective alternative to the complex triplet and quadruplet regimens that currently define the standard of care for newly diagnosed myeloma.
The LINKER-MM4 trial enrolled 45 adult patients with previously untreated, symptomatic multiple myeloma. The cohort included both transplant-eligible (62.2%) and transplant-ineligible patients. As of the September 15, 2025, data cutoff, the median follow-up was 11.2 months for the phase 1a dose-escalation cohort and 4.8 months for the phase 1b dose-expansion cohort.
Responses were rapid, with a median time to partial response or better of 1.2 months.
Among the 43 patients evaluable for response:
The efficacy data indicated a dose-dependent response. Patients in the 200 mg cohort (n = 21) demonstrated higher response rates compared with the 50 mg cohort (n = 20), with 86% vs 70% ORR, respectively. At the time of analysis, all patients remained progression-free.
Safety data from LINKER-MM4 indicated a favorable toxicity profile compared with historical controls for bispecific antibodies. There were no dose-limiting toxicities observed in phase 1, and no grade 2 or higher cytokine release syndrome (CRS) events were reported.
CRS was the most common treatment-related adverse effect (AE) and occurred in 44.4% of patients (40% in the 50 mg cohort; 52% in the 200 mg cohort). All events were grade 1.
Only 1 case of immune effector cell-associated neurotoxicity syndrome (ICANS) was reported. It was grade 1 and subsequently resolved.
“Interestingly enough, [the case of ICANS] happened at the lowest dose level,” explained Robert Orlowski, MD, PhD, MD Anderson Cancer Center, during the presentation.
Infections of any grade were reported in 84.4% of patients, with 33.3% classified as grade 3 to 4. Most infections occurred within the first 3 months, with a decline in subsequent months of treatment.
“We only saw 2 cases of [cytomegalovirus (CMV)] reactivation, again, interestingly, at 50 mg,” Orlowski added. The cases were grade 1 and 2 with no organ involvement.
The most common hematologic treatment-emergent AEs were neutropenia (37.8% any grade; 33.3% grade 3/4) and anemia (26.7% any grade; 17.8% grade 3/4). Only 1 patient discontinued treatment due to a treatment-emergent AE (grade 3 pneumonia), which resolved.
The trial population reflected a diverse patient group. The median age was 67 years (range, 43–84). Regarding racial demographics, 18% of the participants identified as Black or African American. High-risk cytogenetics were present in 11.1% of evaluable patients, and 67% had bone marrow plasmacytosis of ≥50%.
Moving forward, the study will proceed with 200 mg as the recommended phase 2 dose.
“In general, we feel that this [study] does support a positive benefit-to-risk profile and there is further exploration of linvo[seltamab] as a foundation in frontline therapy in newly diagnosed multiple myeloma,” Orlowski concluded.
Reference
Orlowski R, Shah M, Chakraborty R, et al. Safety and efficacy of linvoseltamab as a simplified monotherapy first-line regimen in NDMM: Initial Results from the window of opportunity Phase 1/2 LINKER-MM4 trial. Presented at: 67th Annual ASH Meeting; December 6–9, 2025; Orlando, Florida. Abstract 697.
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