Circulating Tumor Cells in Multiple Myeloma: From Peripheral Clues to Central Insights

ABSTRACT Circulating tumor cells (CTCs) have emerged as a key component of liquid biopsy in multiple myeloma (MM), reflecting the ability of malignant plasma cells to escape the bone marrow (BM) niche, disseminate systemically, and contribute to disease progression. Their detection in peripheral blood is now feasible across the disease spectrum, from MGUS and smoldering myeloma to solitary plasmacytoma, symptomatic MM, and plasma cell leukemia, providing a dynamic window into tumor biology. Technological advances, including high‐sensitivity flow cytometry and next‐generation single‐cell sequencing, have enabled accurate enumeration and molecular interrogation of CTC. Beyond their biological significance, CTC quantification has consistently demonstrated independent prognostic value at diagnosis, with even low levels predicting inferior survival outcomes. Recent proof‐of‐concept studies, such as MinimuMM‐seq and SWIFT‐seq, established that genomic and transcriptomic profiling of CTC can recapitulate canonical myeloma lesions, reveal clonal heterogeneity and track evolutionary dynamics under therapy. Importantly, persistent or reemergent CTC after are occasionally observed and, when present, may signal relapse, particularly, in patients with BM‐MRD positivity, highlighting their potential as complementary biomarkers alongside established BM MRD assessment. Although methodological challenges remain—particularly, standardization, sensitivity, and integration into clinical workflows—CTC analysis holds the promise of transforming from a surrogate biomarker to a clinically actionable tool, advancing precision medicine in MM.