Breaking the Balance: Baseline Oxidative Stress and DNA Repair Capacity in Multiple Myeloma Therapy

Background/Objectives: Disruption of cellular redox balance and DNA damage response (DDR) signals represents a key driver of cancer development, influencing tumor progression and therapeutic response. Here, we investigated the interplay between DDR-related parameters and oxidative stress in relation to treatment response in patients with multiple myeloma (MM). Methods: Oxidative stress and DDR signals were evaluated in primary cells, including peripheral blood mononuclear cells (PBMCs) and bone marrow plasma cells (BMPCs), collected at diagnosis from MM patients who were subsequently classified as responders (n = 35) or non-responders (n = 41) to melphalan-based therapy. Results: PBMCs and BMPCs from non-responders exhibited a distinct biological profile characterized by lower baseline DNA damage, reduced oxidative stress, increased nucleotide excision repair and double-strand break repair capacity, and reduced apoptotic sensitivity compared with responders (all p < 0.001). In addition, non-responders displayed increased chromatin relaxation. Differential gene expression patterns involving DDR-related pathways further distinguished BMPCs between the two clinical outcome groups. Conclusions: Collectively, these findings indicate that alterations in oxidative stress and DDR signals play a crucial role in determining response to melphalan-based therapy in MM. The identification of these molecular alterations in an easily accessible tissue, such as peripheral blood, underscores their potential clinical relevance and warrants further validation.