Genomic Landscape of Multiple Myeloma with Elevated Lactate Dehydrogenase

Abstract

Background Multiple Myeloma (MM) is a malignant clonal plasma cell disorder. Elevated Lactate Dehydrogenase (LDH) has been associated with drug resistance and short survival. The biologic basis of this observation is uncertain. In this study, we sought to define the genomic landscape of MM patients with high LDH. Methods Utilizing data from the Multiple Myeloma Research Foundation (MMRF) CoMMpass database, we identified a cohort of patients with baseline LDH values and RNA-seq data available for inclusion. The RNA-seq data was analyzed to predict differentially expressed genes. We evaluated for enrichment of high risk cytogenetic changes within the high LDH group. Overall survival (OS) was estimated by Kaplan Meier method and a log-rank test. Results We identified 871 patients who met inclusion criteria (High LDH N = 143; Normal LDH N = 728). LDH continued to remain a poor prognostic factor consistent with prior literature, with median survival 660 days vs 795 days (p = 0.02852). There was no difference in the non-synchronous mutations between high vs normal LDH group. Hypergeometric test revealed Del(17p13) was significantly enriched (p = 0.011) in the high LDH subset compared to normal LDH. While there was no statistically significant difference in the presence of t(4;14) (p = 0.16) and t(14;16) (p = 0.21). GSEA detected 572 gene sets significantly up-regulated in the high LDH group (FDR q The ClueGO analysis using two separate sets of up-regulated DEGs revealed upregulation of different molecular signatures. The first gene set (fold > 1.5x) showed significant enrichments (p 2x) was strongly associated (p Conclusion Elevated LDH was confirmed as a poor prognostic factor in the MMRF CoMMpass cohort. Overrepresentation of Del17p likely contributes to poor prognosis. In MM, overexpression of proteolytic and cell adhesion signatures, evasion/suppression of host immune system along with hyper-proliferative signatures via cell division and RTK pathways in MM patients with high LDH offers insight into the aggressive disease in these patients. Targeting tumor microenvironment and RTK pathways may provide novel therapeutic strategies in this subtype of MM.