Disease stages and timing of oncogenic events. The earliest oncogenic changes are present in monoclonal gammopathy of undetermined significance (MGUS) and involve two minimally overlapping pathways, primary IgH translocations (black triangle) and multiple trisomies (white triangle), each of which can include a del 13 pathway (grey triangle). Other karyotypic abnormalities, including secondary (Ig) TLC, and epigenetic changes can occur at all stages. Activating mutations of K- or N-RAS appear to mark, if not cause, the MGUS to multiple myeloma (MM) transition in some cases, but sometimes occur during subsequent progression of MM. Late oncogenic events that occur at a time when tumors are becoming more aggressive include MYC dysregulation by secondary (Ig) TLC, bi-allelic deletion of p18, inactivation of Rb, and loss or mutation of p53.