STAT3/STAT5 Mutations Predict Shorter Overall Survival in Patients with Plasma Cell Myeloma

Introduction: Plasma cell myeloma is a heterogeneous hematologic malignancy characterized by clonal expansion of plasma cells. While RAS-MAPK pathway mutations are known high-risk features, the clinical relevance of STAT3/STAT5 mutations remains unclear. Method: We analyzed 16 myeloma patients with STAT3/STAT5 mutations identified by next-generation sequencing (9 STAT3, 5 STAT5A, 2 STAT5B) and compared them with 32 mutation-negative controls. Results: STAT3/STAT5 mutations were present at initial diagnosis in all eight patients with available initial sequencing data, suggesting these are early events in pathogenesis. STAT3/STAT5 mutations were the sole mutations in five patients, while 10 had co-mutations, most frequently in KRAS/NRAS (n = 5) and TP53 (n = 3). In co-mutated cases, STAT3/STAT5 represented the dominant clone in 4 and co-dominant in 6. All mutations were missense, with 63% involving the SH2 domain. Compared with controls, STAT3/STAT5-mutated patients had higher serum lactate dehydrogenase levels, higher incidence of IgA paraprotein, higher R-ISS stage, more complex karyotype, and frequent CKS1B gain/amplification. Overall survival was significantly shorter in patients with STAT3/STAT5 mutations (median 42 vs. 72 months, p < 0.0001). Conclusion: STAT3/STAT5 mutations are early, dominant, and potentially pathogenic events in plasma cell myeloma. Their association with adverse clinical features and inferior survival supports their routine assessment and potential therapeutic targeting.