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 tRFHisGTG (mt-i-tRFHisGTG) in MM versus sMM/MGUS. The screening cohort of the study consisted of 147 MM patients, and mt-i-tRFHisGTG 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-tRFHisGTG 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-tRFHisGTG-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-tRFHisGTG loss as a powerful independent
indicator of post-treatment progression of MM patients, leading to superior risk stratification of patients' treatment outcome.