A review on pathobiology of circulating tumour plasma cells: The sine qua non of poor prognosis in plasma cell neoplasms

Circulating plasma cells (CPCs) in patients of plasma cell neoplasm have been an area of intense research in recent decades. Circulating tumor plasma cells (CTPCs) might represent a sub-clone of tumor cells that have exited into peripheral blood as a result of the dynamic interactions between the bone marrow (BM) microenvironment and neoplastic plasma cells. Chemokine receptors like chemokine receptor 4 (CXCR4) and integrins are known to play a role in homing and migration of plasma cells (PCs). The hypoxic microenvironment in the BM niche also contributes to their circulation through various mechanisms. In addition, the CCL3–CCR1 axis probably competes with the retention signals from the CXCR4–α4β1 (VLA-4) interaction and actively promotes the exit of PCs from the BM. CTPCs, even in extremely low numbers, can be detected and quantified by high-sensitivity techniques like multi-color flow cytometry and next-generation sequencing. High load of CTPCs noted in patients of plasma cell neoplasm; monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), multiple myeloma (MM) is a strong predictor of shorter progression free survival (PFS) as well as overall survival (OS). In newly diagnosed patients of MM, a load of CTPCs correlates with the outcomes, i.e., OS and PFS. With more studies collaborating on the results of previous reports, assessment of the burden of CTPCs may become a complimentary approach for non-invasive risk stratification of MM patients and evaluating the response to therapy. Future research on larger cohorts and longer follow-ups may help to improve the existing staging system by incorporating the load of CTPCs as one of the prognostic indicators. Further studies based on isolation and genetic characterization of CTPCs may help in understanding the pathophysiology of the progression of the disease and may open avenues for newer treatment modalities. This review discusses the pathobiological aspects leading to circulation of neoplastic/tumor plasma cells in peripheral blood and provides a summary of research work done in last two decades on its prognostic importance in various plasma cells neoplasms.