Abstract 2437: A comparative scoring framework for BCMA-, GPRC5D- and CD38-targeted therapies in multiple myeloma

Abstract Selecting patients for T-cell engager (TCE) and CAR-T therapy in multiple myeloma (MM) relies on prior therapy lines, lacking predictive biomarkers. No tools guide target (e.g., BCMA vs GPRC5D) or modality (e.g., CAR-T vs TCE) selection. We developed an NGS-based framework computing a “Target Readiness” score (ReadyScore, RS) to predict response using malignant and tumor microenvironment (TME) features. Public MM cohorts, including bulk (n=715, n=290) and scRNA-seq (n=6, n=5), were used to develop the framework. RS was developed for anti-BCMA CAR-T and TCE, anti-GPRC5D TCE, and anti-CD38 monoclonal antibodies (mAb). RS is a normalized, weighted score integrating expression activity of related genes (e.g., targets TNFRSF17, GPRC5D, CD38; resistance STAT3, γ-secretase; immune factors CD274 (PD-L1), CD55, CD59, ICAM1) and relevant TME signatures (e.g., T-cell exhaustion, T-reg fraction). We observed heterogeneous profiles in MM (CoMMpass): 36% of patients (pts) had high RSBCMA-CAR-T/TCE, 33% high RSCD38-mAb, and 31% high RSGPRC5D-TCE, reflecting potential treatment benefit. Notably, 21% of pts had a low RS (< 0.5) for all tested immunotherapies. Within this 'low-RS' group, the tool identified other actionable pathways potentially linked to resistance (e.g., 2% high γ-secretase, 3% high STAT3), highlighting intervention opportunities. To illustrate the tool's predictive utility, we applied it to anti-BCMA CAR-T treated pts (Table 1 Table 1. Target ReadyScore applied to the GSE210079 dataset Patient PFS RSBCMA-CAR-T RSBCMA-TCE RSGPRC5D-TCE RSCD38-mAb Pt 1 long 0.69 0.23 0.01 1 Pt 19 long 1 0.66 0.48 0 Pt 33 long 0.71 0 0 0.3 Pt 8 short 0 1 0.51 0.16 Pt 16 short 0.6 0.38 0.56 0.61 Pt 32 short 0.09 0.29 1 0.24 ). All 3/3 pts with a high RSBCMA-CAR-T had long PFS. For pts with short PFS on CAR-T, the tool highlighted potential alternative therapies: pt 8 had a high value for RSBCMA-TCE, pt 32 for RSGPRC5D-TCE, and pt 16 for RSCD38-mAb. This work introduces a molecular stratification framework with potential to support biomarker-driven selection of MM pts for TCE and CAR-T therapies. While validation in expanded cohorts is needed, this approach could help prioritize predictive profiles that can enhance trial design and translational decision-making. Citation Format: Konstantin Chernyshov, Stanislav Kurpe, Maria Kuzmicheva, Kseniia Fede, Sargis Margaryan, Daria Goncharova, Anastasiya Evdokimova, Dmitry Grachev, Oleg Baranov, Polina Turova, Alexander Nesmelov, Andrey Kravets, Eduardo Shugaev-Mendosa, Nikita Kotlov. A comparative scoring framework for BCMA-, GPRC5D- and CD38-targeted therapies in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2437.