Abstract 3994: Differences in the mutational landscape across race and sex highlight distinct TP53-associated risk in multiple myeloma

Abstract Background: Complex health disparities involving race, sex, and genomics have been described in multiple myeloma (MM) (Tebuka E et al. Blood Gl. Hem. 2025). Large genomic studies have highlighted the impact of the mutational landscape (Maura F et al. JCO 2024; Schavgoulidze A et al. Blood 2024); however, the role of gene-gene interactions, including those involving TP53 alterations, has not yet been extensively examined by race and sex. Methods: Using a large, multi-institutional targeted sequencing dataset from the AACR GENIE v18 cohort, we analyzed 1,020 patients with MM (White n=839; Black n=181). Patients with at least one successfully profiled gene were included. Co-occurrence analyses were restricted to mutation-bearing patients. Clinical features, mutation burden, and fraction of genome altered were compared using Wilcoxon and Fisher tests. Differences in co-occurrence distributions were evaluated with Mann-Whitney U tests. Overall survival was assessed using multivariate Cox models, including interaction terms for TP53 with race and sex. Results: Age differed between Black and White patients (median 63.5 vs 66 years; p=0.002) but not between males and females. Mutation burden and fraction of genome altered were comparable across groups (p0.16). No individual mutation frequency differences remained significant after correction for multiple testing. In contrast, the landscape of gene-gene interactions with TP53 varied substantially by race (p=0.027) and sex (p=0.038). White patients showed numerous TP53-associated co-mutations, including TP53-TET2 (11.1% vs 0%), -FAT1 (10.2% vs 0%), -KRAS (8.3% vs 0%), -DNMT3A (7.4% vs 0%), -DIS3 (6.5% vs 0%), -BRAF (5.6% vs 0%), and TP53-TRAF3 (4.6% vs 0%). Black patients exhibited more NRAS-centered co-mutations, including NRAS-KRAS (7.41% vs 1.35%) and NRAS-CYLD (6.17% vs 1.57%). The NRAS-centered pattern was present in both sexes, with females showing slightly higher NRAS frequency and stronger clustering with DNMT3A and TET2. Examination of sex subgroups also showed the highest proportion of TP53 co-mutations among White males (16.6%) compared with White females (10.3%, p=0.009). Overall survival did not differ by race (p=0.83) or sex (p=0.11). TP53 mutation was associated with significantly shorter survival (p=0.0018), with a significant interaction between TP53 status and sex (p=0.0078). TP53-mutated males had the poorest outcomes. Conclusions: These findings underscore the importance of gene-gene interactions in MM and their relevance to understanding health disparities. The absence of TP53 co-mutational patterns among Black patients is notable and may have implications for future trial design and risk-stratification strategies. Citation Format: Chidiebube Ugwu, Nneoma Ubah, Muluken Megiso, Angimar Uriepero Palma, Tarfa Verinumbe, Ana Chachua, Sam King, Ariana Neely, Elvis Obomanu, Alankrita Taneja, Amin Turki. Differences in the mutational landscape across race and sex highlight distinct TP53-associated risk 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 3994.