Two pathways for progression to plasma cell neoplasia. Defined stages of pathogenesis are depicted, with shaded triangles indicating the possible timing and frequency of known oncogenic events. The earliest changes include 2 partially overlapping pathways, indicated by primary IgH translocations (tx) and multiple trisomies. Deletion 13 (most often in nonhyperdiploid tumors) and p16 methylation might be included among the earliest changes, but might sometimes be involved in progression. Activating mutations of N- and K-RAS appear to mark, if not cause, the MGUS to MM transition in some tumors, but can also occur as later progression events. Late oncogenic changes include inactivation of p18 and p53, and also translocations that dysregulate c-myc. Inactivation of Rb, PTEN, and secondary translocations not involving c-myc are not depicted.