Multi-Omic Profiling Reveals Epigenetic Drivers of Immunotherapy Resistance in Multiple Myeloma

Targeted immunotherapies against B-cell maturation antigen (BCMA) have transformed the treatment landscape of Multiple Myeloma (MM). Fc receptor-like 5 (FCRL5) has emerged as an alternative target. However, resistance frequently emerges within months, posing a significant clinical challenge. Structural alterations and mutations in BCMA only account for the minority of cases and insights into BCMA antigen escape remain largely unknown. This study investigates novel (epi)genetic mechanisms of antigen escape through comprehensive multi-omic Oxford Nanopore profiling of sequential pre-treatment and relapse samples. We identify acquired DNA-hypermethylation across the entire BCMA gene, and hypermethylation of the FCRL5 promoter, both resulting in epigenetic gene silencing as novel resistance mechanisms through which MM cells evade therapy. These findings underscore the dynamic clonal evolution of MM under therapeutic pressure and highlight the critical role of epigenetic modifications in resistance. Furthermore, we demonstrate the potential of advanced sequencing technologies for capturing epigenetic and complex genomic alterations in clinical settings, paving the way for personalized treatment strategies and predictive biomarkers for early resistance detection. Statement of significanceAcquired DNA hypermethylation of BCMA and FCRL5 regulatory regions, leading to gene expression downregulation, represent novel epigenetic resistance mechanisms to anti-BCMA and anti-FCRL5 immunotherapies. Furthermore, DNA methylation marks serve as a molecular memory of therapeutic pressure, capturing the treatment history of cancer cells.