Abstract
Introduction
Linvoseltamab induced deep and durable responses with an acceptable safety profile in patients with relapsed/refractory multiple myeloma (RRMM) in the LINKER-MM1 study (NCT03761108) (Bumma et al. JCO 2024). Long-term outcomes in the overall population and in high-risk subgroups are critical for evaluating the efficacy and safety of linvoseltamab. Here we report additional analyses of efficacy, including duration of response (DOR), progression free survival (PFS), and overall survival (OS), in prespecified, high-risk subgroups at a median of 14.3-months' safety follow-up. Longer follow-up data will be presented at the meeting.
Methods
Eligible patients had triple-class exposed or refractory MM. Patients received intravenous linvoseltamab once a week through week 14-16, then once every 2 weeks (Q2W). In the 200 mg phase 2 expansion cohort, patients reaching a very good partial response or better received linvoseltamab Q4W after week 24. The primary endpoint was objective response rate (ORR). Key secondary endpoints included safety, DOR, PFS, OS, and minimal residual disease (MRD). We analyzed outcomes in patient subgroups defined by baseline bone marrow plasma cell (BMPC) percentage, disease refractoriness, and soluble B-cell maturation antigen (sBCMA) concentration.
Results
As of January 6, 2024, median duration of safety follow-up of the 117 patients with MM enrolled in the 200 mg dosing cohorts was 14.3 months. In the full population of patients treated with 200 mg linvoseltamab, ORR was 70.9%, with 49.6% reaching a complete response or better; median Kaplan-Meier (KM) estimated DOR was 29.4 months (95% confidence interval [CI] 19.2- non-evaluable [NE]); median PFS was not reached (NR; 95% CI 17.3 months-NE) with 70% estimated probability of PFS at 12 months; median OS was 31.4 months (95% CI 21.6-NE) (Bumma et al. JCO 2024). KM estimated median DOR in patients who transitioned to Q4W was NR (95% CI 19.2 months-NE). Efficacy per BMPC level was as follows: in patients with <50% BMPC (n=65), ORR was 78.5% and KM-estimated median DOR, PFS, and OS were NR (95% CI 29.4 months-NE), NR (95% CI NE-NE); and 31.4 months (95% CI 21.6-NE), respectively. In patients who had ≥50% BMPC (n=28), ORR was 50% and KM estimated median DOR, PFS, and OS were 19.2 months (95% CI 11.6-NE), 17.3 months (95% CI 2.5-NE); and NR (95% CI 10.2 months-NE), respectively. Efficacy per refractory status was as follows: in patients with triple-class refractory disease (n=19) ORR was 73.7% and KM-estimated median DOR, PFS, and OS were NR (95% CI 11.6 months-NE), NR (95% CI 7.6 months-NE), and 21.6 months (95% CI 12.2-NE), respectively. In patients with penta-class refractory disease (n=33) ORR was 66.7% and KM-estimated median DOR, PFS, and OS were 29.4 months (95% CI 11.2-NE), NR (95% CI 5.4 months-NE), and 31.4 months (95% CI 10.2-NE), respectively. Efficacy per sBCMA level was as follows: in patients with <400 ng/mL sBCMA (n=59), ORR was 83.1% and KM estimated median DOR, PFS, and OS were all NR with 95% CIs of 19.2 months-NE, 19.8 months-NE, and 21.6 months-NE, respectively. In patients with ≥400 ng/mL sBCMA (n=52) ORR was 55.8% and KM estimated median DOR, PFS, and OS were 29.4 months (95% CI 16.6-NE), 17.3 months (95% CI 3.0-NE), and 31.4 months (95% CI 11.7-NE), respectively.
Safety outcomes in the overall population have been previously reported (Bumma et al. JCO 2024). The most common treatment-emergent adverse event (TEAE) was cytokine release syndrome 46.2% any grade. Other common TEAEs were neutropenia (composite); 42.7% any grade, anemia (composite) 38.5% any grade, diarrhea 37.6% any grade, cough 36.8% any grade, and fatigue 33.3% any grade.
Conclusions
Linvoseltamab 200 mg induced prolonged response and survival in patients with RRMM, including those with difficult to treat refractory disease and high tumor burden (high sBCMA concentration or BMPC percentage), while maintaining a generally manageable safety profile. More mature safety and efficacy data with longer follow-up and including MRD data will be presented at the meeting.
Shah:Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding; Dedham Group: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Targeted Oncology: Consultancy. Richter:Karyopharm: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Johnson & Johnson - Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy, Speakers Bureau; Genentech: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Speakers Bureau. Lee:GlaxoSmithKline: Consultancy, Research Funding; Pfizer: Consultancy; Regeneron: Consultancy, Research Funding; Allogene: Consultancy; Amgen: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Abbvie: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Sanofi: Consultancy. Hoffman:Syndax: Other: stock and other ownership interests. Lentzsch:Janssen: Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria; Sanofi: Research Funding; Caelum Bioscience: Patents & Royalties: CAEL-101; Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Pfizer: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Clinical Care Options: Honoraria. Jagannath:Janssen: Consultancy; BMS: Consultancy; Caribou: Consultancy; Legend Biotech: Consultancy; Regeneron: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Posieda Therapeutics: Consultancy; Grail: Consultancy; IMS: Membership on an entity's Board of Directors or advisory committees; SOHO: Membership on an entity's Board of Directors or advisory committees. Zonder:BMS (employment of spouse): Current Employment; Regeneron: Consultancy; BMS, Janssen, RLL: Research Funding. Baz:Bristol-Myers Squibb: Research Funding; Cellectar: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Research Funding; Celgene: Research Funding; AbbVie: Research Funding; Regeneron: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Namburi:Pfizer: Honoraria; Janssen: Honoraria; GSK: Honoraria; Genentech: Honoraria; BMS: Honoraria. Dhodapkar:Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Lava Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees. Silbermann:Sanofi-Aventis, Janssen Oncology, and Oncopeptides: Consultancy; Sanofi: Research Funding. Pianko:AbbVie, Ascentage, Bristol Myers Squibb, Janssen, Nektar, Pfizer, Regeneron, Sanofi: Research Funding; Janssen, Pfizer: Consultancy; Janssen, Karyopharm, Oncopeptides, Pfizer, Sanofi: Honoraria. Vekemans:Amgen, BMS Celgen, Sanofi, Menarini, GSK, Sanofi, Takeda, Janssen, Pfizer: Other: advisory boards; Sanofi, Janssen: Other: travel grants. Munder:Janssen: Consultancy, Honoraria; Stemline therapeutics: Consultancy; Amgen: Consultancy, Other: Travel Expenses; Takeda: Consultancy; Sanofi: Consultancy, Honoraria; GSK: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: Travel expenses. Martínez-Lopez:Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Incity: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Kite: Consultancy, Honoraria. DeVeaux:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Chokshi:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Seraphin:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Boyapati:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Hazra:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Kroog:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Knorr:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Bumma:sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
Linvoseltamab, an investigational BCMAxCD3 bispecific antibody, for the treatment of patients with relapsed or refractory multiple myeloma.