From Spatial Heterogeneity to Real-Time Monitoring: Liquid Biopsy for Genomic Profiling and MRD Assessment in Multiple Myeloma

Multiple myeloma (MM) is a malignancy of plasma cells that is characterized by a complex and spatially heterogeneous genomic landscape. Despite this complexity, clinical monitoring remains largely dependent on localized bone marrow (BM) assessments. This dependence creates a significant diagnostic gap, as the primary monitoring tools fail to account for the spatial and temporal heterogeneity that drives tumor relapse. Liquid biopsy can serve as an adjunctive approach in assessing the pan-clonal landscape in MM through the molecular profiling of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs). In this review, we examine the clinical utility of liquid biopsy components in capturing mutational profiles, clonal evolution, treatment resistance mechanisms, and minimal residual disease (MRD), including early detection of relapse and extramedullary progression. We will further discuss current limitations, including variability in assay sensitivity, lack of standardization, and the need for prospective validation.