Model for the mechanisms that contribute to the development of primary and secondary plasma cell leukemia. Primary immunoglobulin heavy chain (IgH) translocations with 5 recurrent chromosomal partners (4p16, 6p21, 11q13, 16q23, and 20q11) and hyperdiploidy (typically with trisomies of chromosomes 3, 5, 7, 9, 11, 15, 19, and 21) are early events and associated with the initiation of limited clonal plasma cell proliferation in MGUS. Acquisition of secondary chromosomal abnormalities (such as deletions of [parts of] chromosomes or secondary chromosomal translocations) and mutations involving individual genes results in the stepwise progression from MGUS to newly diagnosed symptomatic MM and, finally, aggressive forms of MM, such as sPCL or extramedullary MM. During this process, there is a progressive replacement of normal/polyclonal plasma cells (red) by clonal plasma cells (green). Progression of the plasma cell disorder is also accompanied by altered interactions of the tumor cells with various components of their microenvironment, such as osteoclasts, endothelial cells, and cells of the immune system. On the other hand, the immortalized cell may accumulate various genetic aberrations in a short period of time, resulting in de novo pPCL or rapid progression of MGUS to PCL, without preceding MM. Importantly, in pPCL, hyperdiploidy is very uncommon, whereas primary IgH translocations have a higher incidence compared with the incidence of these primary genetic events in newly diagnosed MM.