Clonal evolution in a permissive microenvironment. Progression from MGUS to SMM to symptomatic MM involves clonal evolution and heterogeneity, which is not only cell autonomous but also dependent on the interactions of the tumor cells with the bone marrow microenvironment. This includes immune cells such as T-regulatory cells (Tregs), myeloid derived suppressor cells (MDSCs), natural killer (NK) cells, osteoclasts, osteoblasts, angiogenesis, and MSCs.