Plasma cell myeloma with RAS/BRAF mutations is frequently associated with a complex karyotype, advanced stage disease, and poorer prognosis.

Background: Mutations in the RAS-MAPK pathway, such as KRAS, NRAS, and BRAF, are known as high-risk factors associated with poor prognosis in patients with various cancers, but studies in myeloma have yielded mixed results.

Methods: We describe the clinicopathologic, cytogenetic, molecular features, and outcomes of 68 patients with RAS/BRAF-mutated myeloma, and compare with 79 patients without any mutations.

Results: We show that KRAS, NRAS, and BRAF were mutated in 16%, 11%, and 5% of cases, respectively. RAS/BRAF-mutated patients had lower hemoglobin and platelet counts, higher levels of serum lactate dehydrogenase and calcium, higher percentage of bone marrow plasma cells, and more advanced R-ISS stage. RAS/BRAF mutations were associated with complex karyotype and gain/amplification of CKS1B. The median overall survival and progression-free survival were significantly shorter for RAS/BRAF-mutated patients (69.0 vs. 220.7 months, p = 0.0023 and 46.0 vs. 60.6 months, p = 0.0311, respectively). Univariate analysis revealed that KRAS mutation, NRAS mutation, lower hemoglobin, elevated lactate dehydrogenase, higher R-ISS stage, complex karyotype, gain/amplification of CKS1B, monosomy 13/RB1 deletion and lack of autologous stem cell transplantation were associated with poorer prognosis. Multivariate analysis showed that KRAS mutation, lower hemoglobin level, higher level of serum calcium, higher ISS stage, and lack of autologous stem cell transplantation predict inferior outcome.

Conclusions: RAS/BRAF mutations occur in 30%-40% of myeloma cases and are associated with higher tumor burden, higher R-ISS stage, complex karyotype, and shorter overall survival and progression-free survival. These findings support testing for RAS/BRAF mutations in myeloma patients and underscore the potential therapeutic benefits of RAS/BRAF inhibitors.