Signals in Peripheral Blood: Tracking Redox Status and DNA Damage Response During the Progression of Multiple Myeloma

Alterations in the redox status and the DNA damage response (DDR) parameters are early, mechanistically interconnected drivers of carcinogenesis. Herein, we investigated whether such alterations, arising during the progression of Multiple Myeloma (MM), are systemically reflected in peripheral blood mononuclear cells (PBMCs). Redox status, expressed as the GSH/GSSG ratio, and DDR-related parameters, including baseline DNA damage, efficiency of key DNA repair pathways, namely nucleotide excision repair (NER) and double-strand break repair (DSB/R), as well as apoptotic sensitivity, were evaluated in PBMCs from 17 patients with Monoclonal Gammopathy of Undetermined Significance (MGUS), 20 with smoldering MM (SMM), and 19 with MM. PBMCs from 20 healthy controls (HCs) were analyzed in parallel. Baseline DNA damage levels and DNA repair capacities across all examined pathways increased progressively in the following order: HC < MGUS < SMM < MM (p < 0.001). This progression was accompanied by a gradual increase in chromatin relaxation. Conversely, the GSH/GSSG ratio and apoptotic sensitivity declined during disease progression (p < 0.001). Collectively, malignant transformation in MM is associated with progressive dysregulation of DDR pathways and redox status in PBMCs. The identification of these molecular perturbations in an easily accessible tissue, such as peripheral blood, underscores their potential utility for early detection and prognostic assessment of MM.