Small RNA‐seq and clinical evaluation of tRNA‐derived fragments in multiple myeloma: Loss of mitochondrial i‐tRFHisGTG results in patients' poor treatment outcome

Summary Despite the substantial progress in multiple myeloma (MM) therapy nowadays, treatment resistance and disease relapse remain major clinical hindrances. Herein, we have investigated tRNA‐derived fragment (tRF) profiles in MM and precursor stages (smoldering MM/sMM; monoclonal gammopathy of undetermined significance/MGUS), aiming to unveil potential MM‐related tRFs in ameliorating MM prognosis and risk stratification. Small RNA‐seq was performed to profile tRFs in bone marrow CD138 + plasma cells, revealing the significant deregulation of the mitochondrial internal tRF HisGTG (mt‐i‐tRF HisGTG ) in MM versus sMM/MGUS. The screening cohort of the study consisted of 147 MM patients, and mt‐i‐tRF HisGTG levels were quantified by RT‐qPCR. Disease progression was assessed as clinical end‐point for survival analysis, while internal validation was performed by bootstrap and decision curve analyses. Screening cohort analysis highlighted the potent association of reduced mt‐i‐tRF HisGTG levels with patients' bone disease ( p = 0.010), osteolysis ( p = 0.023) and with significantly higher risk for short‐term disease progression following first‐line chemotherapy, independently of patients' clinical data (HR = 1.954; p = 0.036). Additionally, mt‐i‐tRF HisGTG ‐fitted multivariate models led to superior risk stratification of MM patients' treatment outcome and prognosis compared to disease‐established markers. Notably, our study highlighted mt‐i‐tRF HisGTG loss as a powerful independent indicator of post‐treatment progression of MM patients, leading to superior risk stratification of patients' treatment outcome.