Underexplored mutations in plasma cell myeloma

Abstract Background: Mutation testing with Next Generation Sequencing (NGS) is routinely used for risk stratification at the time of diagnosis in most hematologic malignancies, but its role in Plasma Cell Myeloma (PCM) is underexplored and not well defined. In this study, we aim to assess the prevalence of mutations associated with Clonal Hematopoiesis (CH or CHIP) and other potentially druggable mutations in a cohort of PCM. Many FDA-approved therapies exist in other cancers (such as sotorasib, selumetinib, vemurafenib, enasidenib, midostaurin, ruxolitinib, crizotinib, erlotinib), though these remain largely unexplored in PCM. Methods We conducted a descriptive study using data from the AACR GENIE v17.0 (cBioPortal) on patients with PCM. The analysis was limited to a single distinct sample per patient to avoid duplication. Mutations were categorized as driver or Variant of Unknown Significance (VUS). Mutations with a frequency of more than 1.5% were classified as significant. Results Among 1167 patients with PCM, 738 unique peripheral blood samples were analyzed, comprising 398 males, 314 females, and 26 with unknown gender. The median age range was 60- 65 years. Race distribution included 516 White, 103 Black, 26 Asian, 1 Native American, and 1 Pacific Islander, with the remainder reported as other or unknown. CHIP mutations were detected in 307 samples (41.6%). The most common somatic mutations were KRAS in 112 cases (15.2%) with 121 mutations (120 driver, 1 VUS); NRAS in 66 (8.5%) with 66 mutations (65 driver, 1 VUS); DNMT3A in 63 (8.4%) with 67 mutations (55 driver, 12 VUS); TP53 in 57 (7.2%) with 64 mutations (all drivers); BRAF in 40 (5.3%) with 41 mutations (all drivers); TET2 in 36 (4.9%) with 38 mutations (32 driver, 6 VUS); and ASXL1 in 22 (2.8%) with 21 mutations (17 driver, 4 VUS). Less frequent mutations (<1.5%) included BCOR (10 cases, 1.2%; 9 VUS), EGFR (9, 1.1%; 2 driver, 6 VUS), CREBBP (9, 0.8%; 3 driver, 3 VUS), CBL (8, 0.9%; 1 driver, 6 VUS), GNAS (7, 0.9%; 5 driver, 2 VUS), IDH2 (7, 0.7%; 4 driver, 1 VUS), JAK2 (6, 0.5%; 1 driver, 3 VUS), MPL (5, 0.4%; 1 driver, 2 VUS), SRSF2 (4, 0.5%; 3 driver, 1 VUS), CALR (4, 0.5%; 2 driver, 2 VUS), ALK (4, 0.5%; all VUS), SUZ12 (4, 0.5%; 1 driver, 3 VUS), PPM1D (3, 0.4%; all drivers), PHF6 (3, 0.3%; 2 VUS), CSF3R (2, 0.1%; 1 driver), and GNB1, PRPF8, and RUNX1 (each in 1 case, 0.1%). Conclusions CHIP mutation burden in MM / PCM was 40%, Our analysis identified several potentially targetable mutations in pts with PCM, including KRAS, NRAS, BRAF, IDH2, FLT3, JAK2, ALK, and EGFR. Clonal hematopoiesis (CH/CHIP) mutations, such as DNMT3A, TET2, ASXL1, and SRSF2, were also observed. Although the lineage origin of several targetable mutations remains unclear, the likely high plasma cell burden in PCM cases suggests that many may originate within the malignant plasma cell clone. This hypothesis warrants systematic investigation in future studies. Overall, our findings highlight the potential utility of early, lineage-specific NGS at diagnosis and relapse to guide risk stratification and uncover actionable targets.