The Route of the Malignant Plasma Cell in Its Survival Niche: Exploring "Multiple Myelomas"

Abstract

Growing evidence points to multiple myeloma (MM) and its stromal microenvironment using several mechanisms to subvert effective immune and anti-tumor responses. Recent advances have uncovered the tumor-stromal cell influence in regulating the immune-microenvironment and have envisioned targeting these suppressive pathways to improve therapeutic outcomes. Nevertheless, some subgroups of patients include those with particularly unfavorable prognoses. Biological stratification can be used to categorize patient-, disease- or therapy-related factors, or alternatively, these biological determinants can be included in a dynamic model that customizes a given treatment to a specific patient. Genetic heterogeneity and current knowledge enforce a systematic and comprehensive bench-to-bedside approach. Given the increasing role of cancer stem cells (CSCs) in better characterizing the pathogenesis of solid and hematological malignancies, disease relapse, and drug resistance, identifying and describing CSCs is of paramount importance in the management of MM. Even though the function of CSCs is well-known in other cancer types, their role in MM remains elusive. With this review, we aim to provide an update on MM homing and resilience in the bone marrow micro milieu. These data are particularly interesting for clinicians facing unmet medical needs while designing novel treatment approaches for MM.

Keywords: adhesion molecule; bone marrow homing; bone marrow immune-microenvironment; cancer stem cells; cell of origin; multiple myeloma.

Figure 1

The route of the malignant plasma cell in its survival niche. Multiple myeloma disease trajectory is schematized. Upper panel, left, clinical C.R.A.B. (hypercalcemia, renal failure, anemia, and bone disease; additional diagnostic criteria S.Li.M.—sixty percent clonal bone marrow infiltration, ratio light chains involved/uninvolved greater than 100, more than one focal lesion detected with MRI) results from cell-extrinsic and MM-intrinsic factors, driving disease progression. Left side, bottom: germinal center with B cells, plasma cells, and follicular dendritic cells; top: immune-microenvironment infiltration (left) and scheme of multiple alterations building heterogeneous genomic architecture (right). MM: multiple myeloma; PMN: neutrophil granulocytes; BMSC: bone marrow stromal cell; EC: endothelial cell; MGUS: monoclonal gammopathy of undetermined significance; SMM: smoldering multiple myeloma; EMD: extramedullary disease; PCL: plasma cell leukemia. Created with BioRender.com.