The Bone Marrow Microenvironment: Novel Targets to Circumvent Minimal Residual Disease and Drug Resistance in Multiple Myeloma

Abstract

The bone marrow micro environment has long been appreciated to support multiple myeloma cell pathogenesis. It is evident that this niche may be as important a therapeutic target as the malignant myeloma cells. This stems from research over the last one to two decades demonstrating that determinants of the bone marrow milieu are integral in myeloma pathogenesis, survival, immune surveillance, and resistance to both traditional and novel therapeutic agents. Early studies elucidating drug resistance in this disease focused on the myeloma cells and found that genetic, acquired changes, in the expression or function of specific gene products mediated cell survival. Subsequently, dynamic, de novo mechanisms coordinated by the tumor microenvironment have been shown to confer an environmental mediated- drug resistance (EM-DR). Appreciation of EM-DR has spawned an exciting path of preclinical and clinical research focused on attenuating the pro-myeloma aspects of the tumor microenvironment. Within this chapter we will provide an overview of the bone marrow microenvironment in the context of multiple myeloma and how these determinants contribute to minimal residual disease and subsequent treatment failure. With increased understanding of the bone marrow niche and EM-DR, numerous novel therapies are under development targeting the microenvironment with the anticipation of improved clinical outcomes.