Bystander or perpetrator: Unravelling the significance and challenges of MGUS.

Monoclonal gammopathy of undetermined significance (MGUS) represents a premalignant clinical state with an evolving footprint beyond its established role as a precursor to multiple myeloma. This review is intended for hematologists, oncologists, and translational investigators involved in MGUS risk stratification and prevention research and confronts four unresolved controversies shaping modern MGUS management: (1) The debate surrounding population screening-weighing potential benefits against economic/psychological burdens; (2) Limitations of current risk-stratification models and the promise of dynamic genomic tools; (3) The contentious pathogenic role of MGUS in non-malignant conditions versus its frequent bystander status; and (4) The paradigm-shifting question of early intervention to prevent malignancy. We synthesize emerging evidence suggesting that while MGUS presents unique opportunities for myeloma prevention, significant knowledge gaps persist in risk prediction, disease biology, and therapeutic strategy. Future progress hinges on defining the right patient, right time, and right intervention through advanced biomarker discovery and carefully designed clinical trials.