Linvoseltamab (Lynozyfic, Regeneron Pharmaceuticals, Inc) plus carfilzomib (Kyprolis; Onyx Pharmaceuticals) induced deep, durable responses in patients with heavily pretreated relapsed refractory multiple myeloma (RRMM) with prior exposure to a proteasome inhibitor (PI).
These results are according to data from the phase 1b LINKER-MM2 trial (NCT05137054) and were presented at the 2025 International Myeloma Society Annual Meeting in Toronto, Canada.1
Linvoseltamab is a humanized bispecific antibody targeting BCMA and CD3 that yields deep durable responses in patients with a manageable safety profile. The agent is most notable for its simple, gentle step-up dosing regimens, which benefit older or frail patients.
Linvoseltamab received accelerated approval as a monotherapy by the FDA in July 2025 for adults with RRMM who have received at least 4 prior lines of therapy, including a PI, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The decision was based on data from the open-label, multi-center, multi-cohort LINKER-MM1 trial (NCT03761108), where linvoseltamab demonstrated overall response rates of 70% (95% CI: 59, 80). The duration of response (DOR) was also notable at 89% at 9 months.2-4
Other trials have also yielded data supporting the clinical benefit of linvoseltamab. In the ongoing LINKER-MM2 trial, researchers are evaluating linvoseltamab as a combination regimen with carfilzomib in patients with RRMM. All patients received 1 or more prior lines of PIs and 52% were refractory to 1 or more (median number of prior LoT 3 [range 2–6]). Ninety-one percent of patients were triple-class exposed and 43% had triple-class refractory disease. The population had a median age of 70 years (range 53–83), and 48% were male, 4% had ISS stage 3 at study entry, 17% had high-risk cytogenetics, and 22% had sBCMA greater than or equal to 400 ng/mL.2
Patients started treatment with linvoseltamab alone in 2 step-up doses (5 mg and 25 mg) and 3 full doses (dose level [DL] 1 at 100 mg; DL1b at 150 mg; and DL2 at 200 mg) prior to initiation of carfilzomib (20/56 mg/m² on days 1, 2, 8, 9, 15, and 16) at cycle 1. Patients received linvoseltamab once weekly (QW) in cycles 1 through 4 and once every 2 weeks after. Carfilzomib dosing could be switched to QW after cycle 2. Patients were premedicated with dexamethasone at cycles 0 and 1.2
The primary end points of the study are dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs), with secondary end points of objective response rate (ORR), DOR, and progression-free survival (PFS).2
Of the total population (n = 23), 12 were treated at DL1, 6 at DL1b, and 5 at DL2. The median duration of follow-up for each group was 22.3 in DL1, 13.2 in DL1b, and 5.6 months in DL2, with 42%, 83% and 80% of patients still receiving treatment, respectively.2
The ORR was 91% at DL1 (10/11; ≥ very good partial response [VGPR], 91%), 100% at DL1b (5/5; ≥VGPR, 100%), and 80% at DL2 (3/5; ≥VGPR, 60%). Of the 7 patients evaluable for minimal residual disease (MRD), 5 achieved MRD negativity at the 10⁻⁵ threshold. At 12 months, the DOR rate was 87% (95% CI, 56–97) with a PFS of 83% (95% CI, 55–94).2
The most frequent TEAEs included neutropenia (any grade, 61%; grade 3–4, 52%), cytokine release syndrome (61%; no grade ≥3 events), thrombocytopenia (52%; grade 3–4, 30%), and diarrhea (52%; grade 3–4, 4%). One patient experienced grade 1 ICANS. Infections occurred in 91% of patients, with grade 3 or higher infections in 43%. A single dose-limiting toxicity (DLT) was observed at DL1 (grade 4 thrombocytopenia associated with tumor lysis syndrome), which resolved completely, allowing treatment to resume at the same dose.2
In patients with heavily pretreated RRMM and prior PI exposure, linvoseltamab plus carfilzomib induced a high rate of deep and durable responses with a safety profile generally consistent with that expected based on the individual drug profiles,” the authors concluded in their abstract. “These preliminary data support continued development of linvoseltamab plus carfilzomib for the treatment of patients with heavily pretreated RRMM.”2