Real-World Safety and Early Efficacy of Talquetamab in Patients with Heavily-Pretreated Relapsed/Refractory Multiple Myeloma

Introduction: Talquetamab, a G protein-coupled receptor, class C group 5 member D (GPRC5D)-directed bispecific antibody (BsAb), was approved in August 2023 for patients with relapsed/refractory multiple myeloma (RRMM) who have received ≥4 prior lines of therapy, based on the results of the phase 1/2 MonumenTAL-1 trial. Here, we evaluated the real-world safety and efficacy of talquetamab in a heavily pretreated patient population including individuals who would have been considered ineligible for the MonumenTAL-1 trial.

Methods: This retrospective cohort study included patients with RRMM who received standard-of-care talquetamab monotherapy at Memorial Sloan Kettering Cancer Center between August 2023 and March 2024. Only patients who received ≥1 therapeutic doses were included, and all patients had at least one month of follow up available at data cut off. Responses were determined per IMWG response criteria. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT guidelines, while other toxicities were graded per version 5.0 of Common Terminology Criteria for Adverse Events. Kaplan-Meier analysis was used to assess progression free survival (PFS) and overall survival (OS).

Results: Among the 28 patients analyzed (61% female, 18% black), median age was 65 years (range, 43-85) and median number of prior lines of therapy was 7 (range, 4-14). All patients were triple class exposed, 36% were penta refractory, 50% had high-risk cytogenetics, 50% had extramedullary disease, and 11% had ≥5% circulating plasma cells at baseline. ECOG performance status was 0-1 in 89% of patients. Notably, more than one-third (43%) of the patients would not have met eligibility criteria for MonumenTAL-1 trial, primarily due to baseline grade 3-4 cytopenias (36%). Furthermore, 75% had received a prior T-cell-redirecting therapy and 82% had received a prior BCMA-directed therapy.

Immune-related adverse events (AEs) included CRS in 57% (1 grade 3 event occurring after first full dose) and ICANS in 14% (1 grade 3 event occurring after step-up dose one). Rates of grade 3-4 hematologic toxicities were 11% for anemia, 25% for thrombocytopenia, 11% for neutropenia, and 43% for lymphopenia. The incidence of any grade infections was 36% (grade ≥3 events in 18%), predominantly involving the upper or lower respiratory tract. Other non-hematologic toxicities of interest included skin/rash-related AEs in 79% (1 grade 3 event), nail-related AEs in 43% (grade 1-2 only), weight loss in 68% (1 grade 3 event), dysgeusia in 64% (grade 1-2 only), dry mouth in 54% (grade 1-2 only), anorexia in 54% (grade 1-2 only), nausea in 36% (grade 1-2 only), diarrhea in 32% (grade 1-2 only), and dysphagia in 29% (grade 1-2 only). While dysphagia and diarrhea resolved in virtually all affected patients, dysgeusia persisted in 84% and dry mouth persisted in 71% throughout the course of talquetamab therapy. Two patients (7%) each had dose reduction and treatment discontinuation due to toxicities. No treatment-related mortality was observed, although 4/28 (14%) patients had died at data cut-off due to disease progression.

For response-evaluable patients (n=26, 2 patients with non-secretory disease), overall response rate (ORR) was 62% (CR 15%, VGPR 31%, PR 15%). Median time to initial response and best response were 1.3 months (range, 0.4-7.0) and 1.3 months (range, 0.4-10.8), respectively. With a median follow-up of 7.7 months (range, 1.1-11.2) for the entire patient population, the median PFS was 7.0 months (range, 1-NR) with median duration of response (for those with ≥ PR) of 7.0 months (range, 3.4-NR). Estimated 6-month PFS and OS were 51% (95% CI, 29-NR) and 89% (95% CI, 70-NR), respectively. For specific subgroups of interest, ORR corresponded to 77% in patients with high-risk cytogenetics, 46% in patients with extramedullary disease, 62% in patients with prior BCMA-directed therapy, and 58% in patients with any prior T-cell-redirecting therapy.

Conclusion: This single-center analysis represents one of the first real-world experiences of talquetamab for RRMM. While there were considerable rates of dermatologic and oral toxicities, no major life-threatening AEs were observed. Despite aggressive disease biology and a significant proportion of patients being MonumenTAL-1 ineligible, early efficacy results are encouraging.

Tan:Takeda: Research Funding; Sanofi: Honoraria; Janssen: Honoraria, Research Funding. Shekarkhand:Roche-Genentech: Consultancy. Lesokhin:Pfizer: Consultancy, Honoraria, Research Funding; Serametrix, Inc.: Patents & Royalties; Arcellx: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd, Janssen, SVB Leerink: Consultancy, Honoraria; Memorial Sloan Kettering Cancer Center: Current Employment. Shah:Janssen, Amgen, Beyond Spring, BMS, GPCR, DSMB with ArcellX.: Research Funding. Korde:Janssen: Membership on an entity's Board of Directors or advisory committees; Remedy Health 8/2022: Other: part of (Patient Power); CCO, OncLive, and Intellisphere: Consultancy; Amgen, Janssen, Epizyme, and AbbVie: Research Funding. Landau:Janssen, Alexion, Protego, Prothena: Research Funding; Abbvie, Immix Biopharma, Legend Biotech, Alexion, Prothena: Consultancy. Scordo:Amgen: Research Funding; Angiocrine Biosciences, Inc.: Research Funding; Miltenyi Biotec: Consultancy; IDEOlogy: Honoraria; Sanofi: Research Funding; Medscape: Honoraria; Kite - A Gilead Company: Consultancy; MJH Life Sciences (Cancer Network): Honoraria; Omeros Corporation: Consultancy, Research Funding. Hassoun:Janssen, Takeda: Research Funding. Shah:Bristol Myers Squibb: Research Funding; Janssen: Honoraria, Research Funding; Sanofi: Honoraria. Hultcrantz:Curio Science LLC, Intellisphere LLC, Janssen, Bristol Myers Squibb, and GlaxoSmithKline: Consultancy, Honoraria; Abbvie, GlaxoSmithKline, SpringWorks Therapeutics, Daiichi Sankyo, Cosette Pharmaceuticals: Research Funding. Mailankody:BMS, J&J, GSK, Springworks Therapeutics: Research Funding. Usmani:Abbvie: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Gracell: Consultancy; Pfizer: Consultancy; Genentech: Consultancy; Gilead: Research Funding; Oncopeptides: Consultancy; EdoPharma: Consultancy; SecuraBio: Consultancy; Merck: Research Funding; Pharmacyclics: Research Funding; GSK: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb - Celgene:: Consultancy, Research Funding; Array Biopharma: Research Funding; Sanofi: Consultancy, Research Funding; SeaGen: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; TeneoBio: Consultancy; Bristol-Myers Squibb - Celgene: Consultancy, Research Funding; Johnson & Johnson - Janssen: Consultancy, Research Funding.