P-365: Genetic Profiling and Drug Response Analysis in Multiple Myeloma: Insights for Personalized treatment approaches.

Introduction: Multiple myeloma (MM) is a genetically complex disease characterized by driver events at diagnosis and precursor stages. Disease progression involves a complex interplay of genetic, epigenetic, and biochemical mechanisms, especially in extensively treated patients. We and others have recently shown that relapsed/refractory MM (RRMM) is characterized by impaired DNA damage response (DDR) and increased genomic instability resulting in drug resistance. To address this challenge, we aimed at exploring the therapeutic vulnerabilities conferred by these mechanistic hallmarks of RRMM using a high-throughput combinatorial drug screening approach in correlation with genetic markers. Additionally, we aimed to explore any potential associations between DDR deregulation and aberrations in the MAPK pathway, considering its known prevalence in drug-refractory MM.

Methods: Human Myeloma Cell Lines (HMCLs) were used as a disease model. A panel of 26 HMCLs underwent panel Next Generation Sequencing (NGS) to characterize genomic alterations in the MAPK pathway and DDR genes. The high-throughput drug screening was conducted to investigate the single drug response of 29 drugs and 54 drug combinations. The data obtained from the drug screening were analysed using Bayesian Synergy, Synergy finder, and Drug Sensitivity Score (DSS) R packages.

Results: The molecular characterization of the 26 HMCLs revealed a total of 242 genetic alterations. Mutations in tp53 (71%), KMT2C (42%), CDKN2C (38%), and RAS family proteins (38%) were commonly observed in our study. Three distinct groups were identified based on tumour mutational burden (TMB) scores. Sensitivity to Trametinib (MEK1/2 inhibitor) and SCH772984 (ERK inhibitor) were significantly associated with lower TMB values (p < 0.05). Ruxolitinib demonstrated higher effectiveness in IL-6 dependent myeloma cell lines (p < 0.003). Presence of DDR genes (tp53, ATR, ATM) mutations were associated with lower Drug Sensitivity scores in Nutlin-3a, UMI77, and Doxorubicin (p < 0.05). Among the drug combinations evaluated, BTK or PI3K inhibitors combined with PARP inhibitors, as well as DNA damage checkpoint inhibitors with ATM/ATR inhibitors exhibited the highest bayesynergy and Bliss scores for synergistic efficacy. Interestingly, combined BTK/PARP inhibition showed best efficacy in IKZF mutant cell lines, indicating a potential role in IMID-refractory disease.

Conclusions: Our study underscores the significance of establishing ex vivo drug response panels in addition to NGS and immunochemistry data to advance precision medicine approaches in multiple myeloma. Addressing potential vulnerabilities created by common mechanisms of resistance may be more widely applicable than targeting rare activating mutations in RRMM. Therefore, by leveraging targeted therapy, patients can achieve favourable treatment responses, thus enabling them to gain access to subsequent immunotherapy options and maximize their therapeutic benefits.