Abstract
<jats:p>Background: Multiple myeloma (MM) is a biologically heterogeneous plasma cell malignancy with variable responses to induction therapy that are not fully explained by current risk stratification systems. Mutations in RAS family genes are prevalent in MM, yet contemporary risk stratification systems do not include them despite their oncogenic potential. Our previous findings showed reduced tumor cell sensitivity to bortezomib-containing triplet induction regimens in the presence of RAS mutations. The aim of this study is to identify RAS pathway–related molecular targets and evaluate their relationship with clinical outcomes. Methods: Forty-four patients with newly diagnosed MM received bortezomib-based induction therapy (VCD or PAD/VCD). Bone marrow CD138+ plasma cells were isolated for transcriptome analysis. KRAS and NRAS gene mutations were identified by Sanger sequencing, and RNA sequencing was performed on the Illumina HiSeq 3000 platform. Gene expression was analyzed using Salmon and DESeq2. The clinical endpoints were depth of response, progression-free survival (PFS), and overall survival (OS). Results: Of 66 candidate RAS-pathway genes examined, five—CREM, NRL, IL-6, MMP14 and MEB2B—showed significantly higher expression in samples with KRAS and NRAS gene mutations (t-test, p &lt; 0.05). Lower NRL gene expression was associated with achieving a deep response (CR/VGPR; p = 0.02). Elevated IL6 gene expression correlated with poorer OS (HR 3.18; p = 0.05), while increased CREM gene expression was associated with shorter PFS (HR 2.62; p = 0.01). Conclusions: Increased expression of NRL, CREM, and IL6 genes could serve as potential prognostic biomarkers in MM and may reflect the molecular mechanisms underlying the adverse effects of KRAS and NRAS gene mutations.</jats:p>