The investigational bispecific antibody linvoseltamab (targeting B-cell maturation antigen [BCMA] and CD3) achieved high response rates with acceptable safety in heavily pretreated patients with relapsed or refractory multiple myeloma, according to results of the phase I/II LINKER-MM1 study reported at the American Association for Cancer Research (AACR) Annual Meeting 2024.1
At a median follow-up of 11.1 months, linvoseltamab achieved objective response rates of 71%, with 41% of treated patients achieving a stringent complete response, and 46% achieving a complete response. The investigators noted that responses deepened over time, including in patients who switched from every-2-week dosing to every-4-week dosing after 24 weeks.
“Linvoseltamab demonstrated high efficacy in patients with relapsed or refractory multiple myeloma, including those in prespecified high-risk subgroups. The safety profile of linvoseltamab is acceptable. The most common treatment-emergent adverse events were cytokine-release syndrome, neutropenia, and anemia,” said presenting author Sundar Jagannath, MD, of the Icahn School of Medicine and the Tisch Cancer Institute at Mount Sinai, New York.
Linvoseltamab demonstrated high efficacy in patients with relapsed or refractory multiple myeloma, including those in prespecified high-risk subgroups.— Sundar Jagannath, MD
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Linvoseltamab is a fully humanized bispecific antibody targeting BCMA and CD3. Bispecific antibodies represent an effective off-the-shelf option for the treatment of patients with heavily pretreated multiple myeloma. Linvoseltamab, which requires two 1-day hospitalizations and allows monthly dosing, has been shown to induce deep responses in patients, according to Dr. Jagannath.
Study Details
The phase I/II study assessed the safety and efficacy of the 200-mg dose of linvoseltamab in patients with active multiple myeloma that progressed on or after at least three prior lines of therapy, including the three cornerstones of treatment—a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody—or who had triple-class–refractory disease (ie, refractory to a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody).
Treatment was initiated with weekly infusions until week 14 and then given every 2 weeks. Patients who achieved a very good partial response or better after 24 weeks of treatment were transitioned to dosing every 4 weeks. The primary endpoints were safety and objective response rates, and secondary endpoints were duration of response, progression-free survival, and overall survival.
The data analysis included 117 patients. Median patient age was 70, and 26.5% of patients were aged 75 or older. More than half (54.7%) were male, 70.9% were White, and 71.8% had an Eastern Cooperative Oncology Group performance status of 1. The median treatment exposure was five prior lines of therapy (range = 2–16). About two-thirds of patients were refractory to at least four previous treatments, and 28%, to at least five. About two-thirds of patients (65%) had undergone a previous autologous transplant.
At a median follow-up of 11.1 months, the objective response rate was 71%, the complete response rate was 46%, and the stringent complete response rate was 41%. In addition, a very good partial response was seen in 16% and a partial response, in 9%. These percentages included 56% of patients who switched to every-4-week dosing.
Among 27 patients assessed for measurable residual disease (MRD), 25 had undetectable MRD. Subgroup analysis showed high response rates across most prespecified subgroups, including African Americans, patients aged 75 or older, and those with high-risk cytogenetics and stage III disease. The exceptions were patients with extramedullary disease at baseline, bone marrow plasma cell level > 50%, and soluble BCMA ≥ 400 ng/mL, where response rates between 48% and 56% were reported.
Median time to response was 1 month, 2.6 months with a very good partial response, and 7.9 months with a complete response or better. After switching to every-4-week dosing, 14 of 29 patients improved from a very good partial response to a complete response.
Median progression-free survival was not reached, and 68.8% of patients were estimated to be alive and free of disease at 1 year. Median overall survival was also not reached, and 74.5% of patients were estimated to be alive at 1 year.
Safety Assessment
Median exposure to linvoseltamab was 47.4 weeks. The most common treatment-related adverse events occurring in at least 20% of patients were neutropenia, anemia, cytokine-release syndrome, diarrhea, fatigue, arthralgia, hypokalemia, nausea, COVID-19 infection, and headache.
Among patients who experienced cytokine-release syndrome, only 1% had grade 3; no grade 4 cytokine-release syndrome events were reported. Median time to onset of cytokine-release syndrome was 11 hours, and the median duration was 14.8 hours. Dr. Jagannath noted that most cytokine-release syndrome events occurred during step-up dosing of linvoseltamab. About 25% of patients needed supportive treatment.
Immune effector cell–associated neurotoxicity syndrome occurred in nine patients (grade 3 in 26%). These events occurred concurrently with cytokine-release syndrome or infusion-related reactions. The severity of infections decreased over time.
There were six deaths within 30 days of the last dose of linvoseltamab. Five of those deaths were the result of infection, and one was from renal failure.
Linvoseltamab is currently being studied in a phase III trial of patients with relapsed or refractory multiple myeloma (LINKER-MM3).
DISCLOSURE: Dr. Jagannath has served as a consultant or advisor to Bristol Myers Squibb, Caribou, DMC Biotechnologies, Janssen, Karyopharm, Legend Biotech, Regeneron, Sanofi, and Takeda.
REFERENCE
1. Jagannath S, Richter J, Dhodakar MV, et al: Linvoseltamab, a B-cell maturation antigen-targeted T-cell engaging bispecific antibody in patients with relapsed or refractory multiple myeloma, including difficult-to-treat subgroups. AACR Annual Meeting 2024. Abstract CT001. Presented April 9, 2024.
