Linvoseltamab Yields High Response in Newly Diagnosed Multiple Myeloma

Initial results from the phase 1/2 LINKER-MM4 trial (NCT05828511) demonstrated that monotherapy with the BCMAxCD3 bispecific antibody linvoseltamab (Lynozyfic) led to a high response rate in newly diagnosed multiple myeloma. These results were shared at the 2025 American Society of Hematology Annual Meeting and Exposition.

The study, which is the first to evaluate a bispecific antibody as a standalone agent in the frontline setting, showed an investigator-assessed overall response rate (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 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.

Robust Efficacy and Rapid Response

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:

• 56% achieved a very good partial response (VGPR) or better.
• 26% achieved a complete response (CR) or better.
• 82% of patients who achieved a CR did so within 6 months of treatment initiation.

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 Profile and Demographics

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 event (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: 67^th Annual ASH Meeting; December 6–9, 2025; Orlando, Florida. Abstract 697.