Dynamic changes in cytogenetic abnormalities during treatment predict long-term outcomes in multiple myeloma

Abstract Cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH) at diagnosis are essential for risk stratification in multiple myeloma (MM), yet their prognostic value diminishes over time as the disease undergoes clonal evolution. In this retrospective study of 1,425 newly diagnosed MM patients—including 525 with serial FISH assessments prior to relapse—we demonstrate that cytogenetic features are dynamic and modifiable under treatment pressure. The prognostic significance of baseline high-risk cytogenetic abnormalities (HRCAs) waned in patients who remained event-free beyond 30 months, while risk trajectories defined by longitudinal FISH provided superior prognostic resolution. Notably, 62.3% of initially high-risk patients experienced cytogenetic regression during therapy, whereas 15.6% of standard-risk patients acquired new HRCAs. Following induction therapy, patients generally exhibited reduced cytogenetic burden, as reflected by declines in HRCA score. Patients who transitioned from high- to standard-risk profiles (HR→SR) achieved significantly longer progression-free and overall survival compared to those with persistent or newly acquired HRCAs. Cytogenetic regression was associated with deeper and more durable minimal residual disease (MRD) responses, and HRCA scores declined during treatment but rose again at relapse, mirroring dynamic clonal remodeling. These findings highlight the importance of integrating serial FISH testing into routine disease monitoring to better capture the evolving genomic landscape of MM and guide more personalized therapeutic strategies.