The evolutionary biology leading to SMM. The post–germinal B cell acquires a primary genetic defect at the MGUS stage, which triggers a dominant clone. The secondary genetic events that incite the transition to SMM include the development of chromosomal copy number alterations, translocations and single-nucleotide variants, and epigenetic changes. Some of the key high-risk secondary genomic events triggering the transition to SMM are RAS oncogene activation, MYC overexpression and dysregulation, and APOBEC-mediated mutations. Several theories are proposed for the clonal evolution from MGUS to MM. The dominant theory is the branching pattern of evolution, where generations of subclones develop from the parent clone. With stable clonal evolution, there is no major change in the clonal architecture throughout the monoclonal continuum to MM. Progressive changes in the stromal and cellular compartments of the bone marrow microenvironment facilitate expansion of the plasma cell clone and loss of immune surveillance.