Biological Characterization and Clinical Relevance of Circulating Tumor Cells: Opening the Pandora's Box of Multiple Myeloma

Simple Summary Bone marrow (BM) aspirates are mandatory for diagnosis and follow-up of patients with multiple myeloma (MM). However, they present two important caveats: Their invasiveness and limited scope to capture the broad tumor heterogeneity. Conversely, circulating tumor cells (CTCs) are detectable in the peripheral blood of patients with precursor and malignant disease states and have strong prognostic value. Moreover, the high genetic and transcriptomic overlap between both plasma cell compartments suggests that CTCs might reflect with notable precision the medullar clone. Furthermore, the study of CTCs could be used as a model to identify mechanisms favoring BM egression and disease spreading. Here, we summarize the state of the art on MM CTCs and provide insights on what they may offer in research and clinical scenarios. Bone marrow (BM) aspirates are the gold standard for patient prognostication and genetic characterization in multiple myeloma (MM). However, they represent an important limitation for periodic disease monitoring because they entail an aggressive procedure. Moreover, recent findings show that a single BM aspirate is unable to reflect the complex MM heterogeneity. Recent advances in flow cytometry, microfluidics, and "omics" technologies have opened Pandora's box of MM: The detection and isolation of circulating tumor cells (CTCs) offer a promising and minimally invasive alternative for tumor assessment and metastasis study. CTCs are detectable in premalignant and active MM states, and their enumeration has strong prognostic value, to the extent that it is challenging current stratification systems. In addition, CTCs reflect with high precision both intra- and extra-medullary disease at the phenotypic, genomic, and transcriptomic levels. Despite this high resemblance between tumor clones in distinct locations, some subtle (not random) differences might shed some light on the metastatic process. Thus, it has been suggested that a hypoxic and pro-inflammatory microenvironment could induce an arrest in proliferation forcing tumor cells to recirculate. Herein, we summarize data on the characterization of MM CTCs as well as their clinical and research potential.