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

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 , gamma-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 RS BCMA-CAR-T/TCE , 33% high RS CD38-mAb , and 31% high RS GPRC5D-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 gamma-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). All 3/3 pts with a high RS BCMA-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 RS BCMA-TCE , pt 32 for RS GPRC5D-TCE , and pt 16 for RS CD38-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. Table 1. Target ReadyScore applied to the GSE210079 dataset Patient PFS RS BCMA-CAR-T RS BCMA-TCE RS GPRC5D-TCE RS CD38-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