Treatment with linvoseltamab (REGN5458) at 200 mg generated an objective response rate (ORR) of 71% in patients with relapsed/refractory multiple myeloma, according to the phase 2 LINKER-MM1 study (NCT03761108).1
In the study, 2 dose levels of linvoseltamab, a BCMA/CD3 bispecific antibody, were evaluated. The first cohort administered 104 patients linvoseltamab 50 mg, and the second consisted of 117 patients treated with the agent at 200 mg.
With the higher dose, the ORR was 71%, 14% of patients had a complete response (CR), and 16% had a stringent CR. A total of 29% of patients had a very good partial response and 12% had a partial response. The 6-month estimated progression-free survival was 72.7%, but the median PFS was not reached.
For safety, the most common treatment-emergent adverse events (TEAEs) seen among patients in the 200 mg cohort were hematologic, and the most common grade 3/4 events were neutropenia (30.8%), anemia (23.9%), thrombocytopenia (13.7%), and lymphopenia (11.1%). The most common non-hematologic TEAEs in this cohort were cytokine release syndrome (CRS; 45.3%), cough (33.3%), fatigue (32.5%), and diarrhea (32.5%).
“This supports the continued development of linvoseltamab in multiple myeloma. A phase 3 study evaluating linvoseltamab vs a standard of care pomalidomide triplet will be initiated shortly in an earlier relapsed refractory multiple myeloma patient population,” Hans C. Lee, MD, told Targeted OncologyTM, in an interview.
In the interview, Lee, associate professor, and director of multiple myeloma clinical research in the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, discussed the safety and efficacy results of the phase 2 LINKER-MM1 study.
Targeted Oncology: What was the rationale behind LINKER-MM1?
Lee: The LINKER-MM1 study was a phase 2 study about linvoseltamab, which is a bispecific antibody in relapsed/refractory multiple myeloma. Based on encouraging efficacy and safety data of the phase 1 part of the LINKER-MM1 study, the phase two parts of the study was launched, which basically evaluate two different dose cohorts, Illuma salts, MEB, at 50 milligrams and 200 milligrams to optimize the dose.
How were the dose levels used in the study decided upon?
In the phase one dose escalation, the maximum tolerated dose was not reached, and so there was efficacy seen at lower doses and higher doses of linvoseltamab. Really, a greater patient population was needed to fully evaluate or optimize the dose of the drug.
What were the methods and designed use in this phase of the study?
The key eligibility criteria of the phase 2 parts of the LINKER-MM1 study was basically, patients with relapsed/refractory multiple myeloma with at least 3 prior lines of therapy with exposure to a proven inhibitor, and an anti-CD38, monoclonal antibody, or who are triple class refractory, regardless of lines of prior therapy. The primary objective of the study was to evaluate overall response, and patients who were enrolled on the study then received linvoseltamab intravenously initially with to step-up doses of 5 milligrams and 25 milligrams one week apart with a 24 hour hospitalization after each step up dose for CRS monitoring.
Subsequently, patients then receive either 50 mg or 200 mg of linvoseltamab weekly for cycles 1 through 3 on a 20-day cycle. This was then de-escalated to every other week dosing for cycles 4 and 5, and patients enrolled on the 200 mg cohort could then further de-escalate their frequency of therapies every 4 weeks of attaining a very good partial response or better.
What were the efficacy findings reported at ASCO 2023?
At the 50 mg dose cohort, the overall response rate was 50%. In the recommended 200 mg dose of linvoseltamab, the overall response rate was 71% with a very good partial response rate or better of 59% and a complete response rate or better of 30%. Two thirds of patients who were dosed in the 200 mg cohort remain on study. Among patients who attained a complete response and complete response with available MRD data, 54% of patients were MRD-negative. The responses also seemed to be deep and durable. At 6 months, probability of response was at 4%, and at a median follow-up of 5.6 months, the median progression-free survival in the 200 mg cohort had not been reached. Six month progression-free survival rates were 73%.
Can you discuss the safety data?
The most common AE seen across the study was cytokine release syndrome, which occurred in 55% of patients in the 50 mg cohort and occurred in 45% of patients in the 200 mg cohort. In the 200 mg court, most [cases] of CRS were grade 1 in severity, [and] 35% of patients had grade 1 CRS, 9% of patients had grade 2 CRS, and there was a single grade 3 CRS event. When it did occur, CRS occurred typically within the same day of dosing and resolved typically within 24 hours of dosing, hence, the limited hospitalization required for the study with 24 hospitalizations required only for the initial 2 step-up doses of the drug.
Other AEs of interest are certainly infections with bispecific antibodies as a drug class. So, across the study, there was a similar rate of infection between the 50 mg and 200 mg cohorts. Infections occurred in about 60% of cases in either arm, and about 35% of cases were grade 3 or higher in severity.
What are the next steps for this research?
So overall, the phase 2 part of the LINKER-MM1 study demonstrated the high efficacy linvoseltamab may have in a heavily pretreated multiple myeloma patient population with rapid, deep, and durable responses seen particularly at the 200 mg dose cohort. Importantly, responses were seen in historically difficult to treat patient populations, patients of high-risk cytogenetics, and patients with high baseline disease burden. This supports the continued development of linvoseltamab in multiple myeloma. A phase 3 study evaluating linvoseltamab vs a standard of care pomalidomide triplet will be initiated shortly in an earlier relapsed/refractory multiple myeloma patient population.
Lee HC, Bumma N, Richter JR, et al. LINKER-MM1 study: Linvoseltamab (REGN5458) in patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2023;41(suppl 16):8006. doi:10.1200/JCO.2023.41.16_suppl.8006