Pathogenesis of MM. The orange round cell represents a normal B cell, whereas the yellow round cell is a mutated, post–germinal center (GC) B lymphocyte that later differentiates into a long-lived PC (yellow oval). In MM pathogenesis, the initial genetic event (red square) is thought to occur in the GC, facilitated by the processes of somatic hypermutation and isotype switching, and characterizes the founder clone (F). Later genetic mutations occur at the time of transformation to MM (red circle), with de novo mutations (red geometric shapes) acquired during disease evolution and heterogeneously present in different subclones (S1 and S2). The genetic, epigenetic, and biological events occurring in the cancer clones and BM microenvironment during the evolution of premalignant dyscrasia to MM are outlined in the pink, green, and blue boxes, respectively. ECM, extracellular matrix.