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

Abstract

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.

Keywords: Circulating Plasma Cells (CPCs); Circulating Tumor Plasma Cells (CTPCs); Flow cytometry; Microenvironment; Monoclonal gammopathy; Multiple Myeloma (MM).

Figure 1. Multiple Myeloma (MM) cell trafficking events and its interaction with bone marrow mesenchymal stromal cells (BMMSC); (a) the myeloma cells in peripheral circulation home to bone marrow under the influence of CXCL12 chemokine secreted by cells comprising the bone marrow microenvironment. The interactions of myeloma cells with BM microenvironment are responsible for retention and growth of myeloma cells, which further influence activation of osteoclasts, causing lytic lesions. The myeloma cells exit into peripheral blood circulation under influence of CCL3 which may lead to extramedullary disease; (b) highlights the interaction of MM cells with BMMSCs: CXCR4 on surface of myeloma cells interacts with its ligand CXCL12 for homing into BM, this induces interaction with BMMSC and upregulation of adhesion molecules responsible for retention and growth of myeloma cells. Further, the interaction between CCR1 receptor on MM cells and its ligand CCL3 has a negative influence on CXCR4 & CXCL12 axis, causing the myeloma cells to exit BM. The figure has been created on BioRender.com.

Figure 2. Representative bi-axial dot-plots of flow cytometric data from peripheral blood sample of a patient of MM diagnosed in our institute. a, b, c: sequential gates for inclusion of uniformly acquired continuous events, non-aggregated and non-debris viable cells, respectively; d: gating of CD38 & CD138 variably-expressed events; e: gating of CD38 positive and CD45 variable (dim to moderately-bright) events; f: gating of nicely clustered CD38 positive & SSC-low events which include the CPCs; g: plasma cells divided in two distinct populations, i.e., CD 45 & CD19 positive events (blue dots) and CD45 & CD19 dim events (orange dots), in addition, non-plasma cells (green dots) have been excluded; h: CD45+CD19+ events displayed on CD81 vs. CD27 plot and show bright expression of CD81 and CD27; i: Circulating Normal Plasma Cells (CNPCs) have been gated based on absence of CD56 and CD200/CD28 expression (black dots); j: CNPCs divide into cytoplasmic kappa light chain and cytoplasmic lambda light chain expressing cells; k: CD45dimCD19dim events have been displayed on CD81 vs. CD27 plot and a cluster of cells with absence of CD81 and CD27 have been gated (violet dots); l: CTPCs have been gated based on CD56 & CD200/CD28 positive expression levels (red dots); m: CTPCs show cytoplasmic kappa light chain restriction. *The numbers mentioned along with gated population in some of the plots represent the number of events recorded for the respective gated population.