Abstract 7175: <i>STAT3/STAT5</i> mutation predicts shorter overall survival in patients with plasma cell myeloma

Abstract Plasma cell myeloma is a heterogeneous hematological neoplasm characterized by clonal expansion of malignant plasma cells in the bone marrow. Mutations in the RAS-MAPK pathway, such as KRAS, NRAS, and BRAF, have been identified as high-risk factors associated with poor prognosis. However, the clinical impact of STAT3/STAT5 mutations in plasma cell myeloma has not been well studied. We assessed the clinicopathologic and molecular genetic features and clinical outcomes of 16 myeloma patients with STAT3/STAT5 mutations identified by next-generation sequencing, including 9 with STAT3 mutation, 5 with STAT5A mutation, and 2 with STAT5B mutation, and compared with 32 matched patients without any mutation. STAT3/STAT5 mutations were detected at initial diagnosis in all 8 patients with initial mutation status available, suggesting STAT3/STAT5 mutation is an early event in pathogenesis in plasma cell myeloma. STAT3/STAT5 mutation was the sole mutation in 5 cases and accompanied by other co-existing mutations in 10 cases, with KRAS/NRAS (n=5) and TP53 (n=3) being the most common; in the latter group, STAT3/STAT5 represented the dominant clone in 4 cases and co-dominant clone in 6 cases. All were missense mutations, with 10 of 16 (63%) located at the SH2 domain. The median variant allele frequency was 9.1%. STAT3/STAT5-mutated patients had higher level of serum lactate dehydrogenase, lower level of serum albumin, higher proportion of IgA type paraprotein, and more advanced R-ISS stage. STAT3/STAT5 mutations were associated with complex karyotype and gain/amplification of CKS1B. The median overall survival was significantly shorter for STAT3/STAT5-mutated patients (42 months vs 72 months, p&amp;lt;0.0001). In summary, STAT3/STAT5 mutations are often early events and represent dominant clones in plasma cell myeloma. These mutations are associated with a complex karyotype, more advanced R-ISS stage, and shorter overall survival. Our findings support the routine testing for STAT3/STAT5 mutations in patients with plasma cell myeloma, highlighting their role in disease pathogenesis and their potential as therapeutic targets. Citation Format: Matthew T. Ye, Zhuang Zuo, Steliana Calin, Yaling Yang, M. James You. STAT3/STAT5 mutation predicts shorter overall survival in patients with plasma cell myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7175.