Tumor and microenvironment in natural history of gammopathies. Emerging data suggest that much of the genomic complexity and intraclonal heterogeneity is already well established by MGUS stage. The mechanism underlying the origins of this instability is not clear but may involve a big bang followed by clonal evolution. Clinical dormancy of MGUS or AMM lesions depends in part on interactions with the tumor microenvironment, and alteration of these signals can promote changes in growth kinetics at the population level, manifested as malignant transformation. Genetic complexity of MGUS also points to the presence of proximate, potentially less complex lesions termed pre-MGUS. We hypothesize that these lesions emerge from an initial polyclonal response to endogenous or exogenous antigens. Tumor evolution is driven by both tumor-intrinsic and tumor-extrinsic events that may be interdependent.