Unexplored mutations in Plasma Cell Myeloma

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.

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.

Among 1167 PCM patients, 738 peripheral blood samples were analyzed, with CHIP mutations in 307 (41.6%). KRAS mutations were most frequent (15.2%; 120 driver, 1 VUS), followed by NRAS (8.5%; 65 driver, 1 VUS), DNMT3A (8.4%; 55 driver, 12 VUS), TP53 (7.2%; all driver), BRAF (5.3%; all driver), TET2 (4.9%; 32 driver, 6 VUS), and ASXL1 (2.8%; 17 driver, 4 VUS). Mutations <1.5% included BCOR, EGFR, CREBBP, CBL, GNAS, IDH2, JAK2, MPL, FLT3, SRSF2, CALR, ALK, SUZ12, PPM1D, PHF6, CSF3R, GNB1, PRPF8, and RUNX1 with mixed driver and VUS classifications.

Our analysis identified several potentially targetable mutations in PCM, including KRAS, NRAS, BRAF, IDH2, FLT3, JAK2, ALK, and EGFR for which FDA-approved therapies exist in other cancers (such as sotorasib, selumetinib, vemurafenib, enasidenib, midostaurin, ruxolitinib, crizotinib, erlotinib), though they remain largely unexplored in PCM. 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.