Real-world comparison of anti-GPRC5D bispecific therapy versus anti-BCMA treatment in relapsed/refractory multiple myeloma after prior BCMA-directed therapy.

e19509 Background: In relapsed/refractory multiple myeloma (RRMM), B-cell maturation antigen (BCMA)-directed therapies (BDT), such as CAR-T, antibody-drug conjugates, and bispecifics, have shown promising results. However, relapse is common, and optimal sequencing post-BCMA therapy remains uncertain. The immediate second BDT after relapse had shown lower response rates. GPRC5D-directed bispecific therapy (talquetamab) post-BDT had an overall response rate (ORR) of 67% in the MonumenTAL-1 trial. No direct head-to-head comparisons of talquetamab vs repeat BDT in BCMA-exposed RRMM patients are available so far. Methods: We conducted a retrospective cohort study using the TriNetX Global Health Network. MM patients aged ≥18 years who had received prior BDT (Ide-cel, Cilta-cel, Teclistamab, Elranatamab) were selected. Defined into two cohorts as those who received (1) talquetamab (n=368) and (2) sequential BDT (N= 1118) after prior BCMA therapy. Propensity score matching (1:1) was done to balance demographics, comorbidities, and prior therapies. Follow-up period was 1 year. Survival was assessed using Kaplan-Meier analysis. Hazard ratios (HR) and log-rank p-values were calculated. Results: After matching, each cohort had 282 patients. Mean age was 67 ± 10 years, with 56% male and 64% white in both groups. Treatment patterns showed a heavily pretreated population: proteasome inhibitors (bortezomib 44.7%), IMiDs (lenalidomide 65%, pomalidomide 56%), anti-CD38 therapy (daratumumab 49%), CAR T (20%), autologous stem cell transplant (44.3%), belantamab (5.7%), elranatamab (6%), and teclistamab (74%). Mean follow-up was 206 vs 239 days in talquetamab and sequential BDT groups, respectively. All-cause mortality was slightly higher in the talquetamab group (HR = 1.101, 95% CI: 0.8–1.5), with survival probabilities of 63.79% vs 66.92% in the BDT group, but this difference was not statistically significant (P = 0.548). ER visits (HR = 0.716), anemia (HR = 0.915), sepsis (HR = 0.803), and pneumonia (HR = 0.641) were numerically lower in the talquetamab group but were not statistically significant (p > 0.05). Neutropenia (HR = 1.082), thrombocytopenia (HR = 1.301), and CRS (HR = 1.617) did not differ significantly (p > 0.05). Hospitalization, MM relapse, and neurotoxicity were not analyzable due to low events. Conclusions: This real-world study showed no significant difference in mortality, toxicities, infectious or healthcare outcomes between talquetamab and BDT in RRMM patients with prior BCMA exposure. This suggests that antigen escape is less common than anticipated. While these results need to be further evaluated in prospective studies, future research should focus on outcomes based on timing or type of prior BCMA therapy, biomarker-driven treatment selection, and optimal sequencing based on resistance mechanisms.