P-036: BCMA after GPRC5D: Efficacy of BCMA-directed therapy on patients with relapsed/refractory multiple myeloma (RRMM) progressing after GPRC5D-directed therapy

Introduction: T-cell redirecting therapy (TCRT; chimeric antigen receptor T cells and bispecific antibodies) has revolutionized the treatment landscape of RRMM. However, the optimal sequencing of available TCRT is unclear. With the development of BCMA TCRT before GPRC5D TCRT, the safety, efficacy and feasibility of BCMA-directed, then subsequent GPRC5D TCRT is relatively well established. However, outcomes of patients who experience disease relapse on a GPRC5D TCRT and subsequently receive BCMA TCRT is unknown.

Methods:
We reviewed all patients who received TCRT at a single large high volume academic multiple myeloma program. We included patients who received a GPRC5D TCRT in an investigational or commercial setting and followed longitudinally. We identified patients who evolved with disease progression and received subsequent BCMA TCRT.

Results: Between 1/2020 and 5/2024, we identified 77 patients who received a GPRC5D TCRT. Of those, 42 have not progressed, 5 died without progression and 30 had progression. Of the 30, 21 started subsequent treatment and 12 received subsequent BCMA TCRT in the immediate or subsequent next line of therapy (5 post GPRC5D TCE; 7 post CART) and had ≥6 months of follow up. The cohort consists of 75% male, 41% racial and ethnic minorities, 25% with ISS stage III disease, 41% with high risk FISH abnormalities [t(4;14), t(14;16), del17p and gain/amp 1q], 25% EMD. All patients had triple class refractory MM, 75% were penta-refractory and 92% received prior ASCT. At time of post-GPRC5D TCRT progression, 9 of the 12 received BCMA TCRT directly following GPRC5D (5 BCMA TCE, 4 BCMA CART) and 3 received BCMA targeted therapy in subsequent line of treatment (all BCMA TCE). Of the 12 patients, 5 were BCMA naïve. For the 7 BCMA exposed patients, the BCMA TCRT used prior to GPRC5D TCRT was CART in 6 patients and TCE in 1 and produced overall response rate (ORR) 86% with median PFS 12.8 months, justifying re-exploring BCMA after failure of GPRC5D TCRT. The ORR to subsequent BCMA TCRT was 50% (80% BCMA naïve, 29% BCMA exposed). With median follow up of 12.23 mos (95% CI 0-37.6), the median PFS of patients with subsequent BCMA TCRT was 7.06 months [8.2 mos BCMA naïve (95% CI 2.34-NR), 1.38 mos BCMA exposed (95% CI 0.36-NR)]. ORR according to type of BCMA TCRT is 75% for CART and 38% for TCE. The median PFS according to type of BCMA TCRT was 7.07 mos (95% CI 1.25-NR) for CART and 2.39 mos (95% CI 0.26-NR) for TCE.

Conclusions: GPRC5D and BCMA are promising, independent immunotherapeutic targets for MM therapy. Our dataset is one of the first reports showing favorable outcomes of BCMA directed TCRT following initial GRPC5D TCRT. Although limited by small sample size, these findings suggest that target switching in either direction may be feasible with deep and durable responses. Therefore, optimal sequencing is best guided by patient and disease characteristics as well as treatment availability.