Introduction

The interactions of clonal cells with the bone marrow begin with the initial establishment of transformed precursor MM cells in specialized niches, and their survival and persistence in such niches during the disease stage termed MGUS. During this stage, which can last for years, the bone marrow is gradually “re-modeled” to provide a permissive environment for the self-renewal of these (pre)malignant PC, with acquisition of (further) genetic lesions that trigger progression from MGUS to MM, accompanied by clonal expansion. Release of clonal cells into the circulation, and their homing to and establishment in other sites of hemopoietic bone marrow, with disruption of the bone homeostasis and angiogenesis, characterize the mature malignancy we call multiple myeloma (MM).

A multitude of players feature in these interactions (Table 6.1). Soluble factors direct migration and homing into bone marrow, upregulate anti-apoptotic pathways for drug resistance, modulate immune responses, act as mitogens to induce self-renewal and clonal expansion and function in many autocrine and paracrine loops to maintain survival, angiogenesis and bone destruction. Reciprocal interactions between MM cells and other cell types in the BM such as osteoblasts, osteoclasts, stromal cells and endothelial cells are mediated by some of these soluble factors, as well as by cell–cell contact dependent mechanisms such as adhesion molecules. Cell contact is also important for interactions with extracellular matrix proteins resulting in anti-apoptotic signaling and consequent drug resistance. This chapter will discuss these players in the context of each stage or component of disease pathogenesis, highlighting key players, and will consider in more detail the biochemical pathways that orchestrate survival and drug resistance of MM cells.