Key Points• Detailed characterization of myeloma circulating tumor cells shows that these represent a unique subpopulation of BM clonal PCs.• Myeloma CTCs are clonogenic, quiescent, and may represent an ancestral clone potentially driven by circadian rhythms.Circulating myeloma tumor cells (CTCs) as defined by the presence of peripheral blood (PB) clonal plasma cells (PCs) are a powerful prognostic marker in multiple myeloma (MM). However, the biological features of CTCs and their pathophysiological role in MM remains unexplored. Here, we investigate the phenotypic, cytogenetic, and functional characteristics as well as the circadian distribution of CTCs vs paired bone marrow (BM) clonal PCs from MM patients. Our results show that CTCs typically represent a unique subpopulation of all BM clonal PCs, characterized by downregulation (P < .05) of integrins (CD11a/CD11c/CD29/CD49d/CD49e), adhesion (CD33/CD56/CD117/CD138), and activation molecules (CD28/CD38/CD81). Fluorescence in situ hybridization analysis of fluorescence-activated cell sorter-sorted CTCs also unraveled different cytogenetic profiles vs paired BM clonal PCs. Moreover, CTCs were mostly quiescent and associated with higher clonogenic potential when cocultured with BM stromal cells. Most interestingly, CTCs showed a circadian distribution which fluctuates in a similar pattern to that of CD34 1 cells, and opposite to stromal cell-derived factor 1 plasma levels and corresponding surface expression of CXC chemokine receptor 4 on clonal PCs, suggesting that in MM, CTCs may egress to PB to colonize/metastasize other sites in the BM during the patients' resting period. (Blood. 2013;122(22):3591-3598)
IntroductionIn the late 2000s, 2 pivotal studies elegantly showed that monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM) in most, if not all myeloma patients.
1,2End-organ damage is the most important criterion to classify therapyrequiring MM patients, and the most common CRAB (hyperCalcemia, Renal failure, Anemia, Bone lesions) symptom is the presence of bone lesions detectable on a skeletal survey.3 Extramedullary disease is present in ;10% of newly diagnosed symptomatic patients, but it increases up to 20% in the relapse/refractory setting, 4 and typically anticipates a dismal outcome. Plasma cell (PC) leukemia is one of the most aggressive forms of the disease and even with novel drugs, the outcome is very poor with both short remission and survival rates.5 This landscape does not greatly differ from that of most solid tumors, in which the presence of metastasis is a key prognostic factor. 6 In fact, recent observations suggest that tumor cell dissemination is often an early event, 7 and the clinical sequel of circulating tumor cells (CTCs) has been the focus of extensive research.
8Interestingly, peripheral blood (PB) MM CTCs (morphologic and phenotypically defined as mature PCs) are also a common event throughout the spectrum of MM. [9][10][11][12][13] CTCs can only be detected in a small fraction of newly diagn...
