Lactate metabolism in clonal plasma cells and its therapeutic implications in multiple myeloma patients with elevated serum LDH levels.

INTRODUCTION: This study aimed to evaluate the metabolic differences between MM cells derived from patients with elevated serum LDH levels and those without elevated serum LDH levels to identify biological differences that could be exploited for therapeutic purposes. METHODS: We performed transcriptome assessments of CD138 + MM cells derived from patients with elevated serum LDH levels compared to those without elevated serum LDH levels and validated the findings in a larger public dataset. Functional metabolic assessments of our findings were performed using a combination of stable isotope resolved metabolomics (SIRM), bioenergetic flux measurement assays, and live cell analysis in human myeloma cell lines and primary MM patient cells. RESULTS: We identified SLC16A1, responsible for the formation of MCT1, a well-defined bi-directional transporter of lactate in and out of a cell with a predilection to importing extracellular lactate, as differentially expressed between the two groups. This finding was functionally confirmed by higher membranous MCT1 protein expression and SIRM on MM cells derived from patients with elevated serum LDH levels compared to those without elevated serum LDH levels. Finally, disrupting lactate transport in and out of CD138 + MM cells was maximally achievable only with dual inhibition of MCT1 and its partner, MCT4, which was preferentially more cytotoxic in MM cells derived from patients with elevated serum levels of LDH. CONCLUSION: MCT1 mRNA and protein expression distinguish MM cells derived from patients with elevated serum LDH levels from those without elevated serum LDH levels. However, only dual inhibition of MCT1 and MCT4 can disrupt lactate transport in multiple myeloma (MM) cells, with preferential cytotoxicity in MM cells from patients with high serum LDH levels.