The Converging Roles of DNA Damage Resolution and Redox Dysregulation in Plasma Cell Transformation During the Evolution of Multiple Myeloma

Increasing evidence indicates that dysregulated DNA damage response (DDR) pathways and persistent oxidative stress contribute to genomic instability, increase mutational burden, and promote disease progression. This study investigated the interplay between DDR-related parameters and redox status throughout Multiple Myeloma (MM) evolution. Bone marrow plasma cells (BMPCs) from 16 patients with monoclonal gammopathy of undetermined significance (MGUS), 18 with smoldering multiple myeloma (SMM) and 15 with MM, were analyzed. Measurements included redox status, assessed by the reduced-to-oxidized glutathione (GSH-to-GSSG) ratio, abasic sites, and DDR-related parameters. Baseline DNA damage, abasic site burden, and the kinetics of UVC-induced DNA damage resolution and melphalan-induced γH2AX signal removal were progressively altered across disease stages. Moreover, disease progression was associated with a gradual decrease in chromatin condensation, apoptotic sensitivity, and the GSH-to-GSSG ratio. Multivariate statistical analyses identified distinct DDR-associated patterns that effectively discriminated among patients at different disease stages. Together, the transition from MGUS to SMM and ultimately to MM is characterized by progressive alterations in DNA damage processing, DDR-related signaling, chromatin organization, and redox status. A deeper understanding of these interconnected processes may yield valuable insights into disease progression, improve risk stratification, and guide the development of targeted therapeutic strategies for MM.