Model of clonal evolution. Myelomagenesis is hypothesized to begin with an initiating event in a germinal center B cell that differentiates into a defected PC carrying chromosomal aberrations and gene-expression and epigenetic signatures that separate it from benign PCs. In the progression from MGUS to SMM, the defected PC clone acquires additional chromosomal aberrations and genetic mutations. This is accompanied by a permissive microenvironment in the BM niche that involves bidirectional crosstalk between the malignant clones and surrounding cells that induces immune suppression and clonal expansion to overt MM. MIP-1α, macrophage inflammatory protein 1α; Rb, retinoblastoma protein; TH17, T helper 17; TNFα, tumor necrosis factor α; VEGF, vascular endothelial growth factor.