Deciphering the genetic underlying causes of sex differences in multiple myeloma incidence and mortality.

Multiple myeloma (MM) is a genetically complex cancer that has a higher incidence and mortality in males when compared to females. These sex differences are well documented epidemiologically, yet their biological mechanisms remain uncharacterized. We hypothesized that sex-specific genetic regulation by somatic mutations affects MM cell gene expression differently in each sex and subsequently leads to differential functional genetic dependencies between the two sexes. To test this, we first identified genes with sex-biased expression in MM, then identified sex-specific somatic regulators of these genes, evaluated their association with overall survival outcomes, and finally assessed their functional importance using CRISPR-Cas9 dependency screens in MM cell lines. Our findings provide systematic evidence that sex-differentiated somatic regulation underlies tumor-intrinsic mechanisms in MM, establishing the importance of incorporating sex-aware molecular analyses for improved biomarker discovery and precision medicine. Collectively, these results establish sex as a fundamental biological variable in MM with significant implications for disease outcomes.