Early oncogenic events in MM. The earliest oncogenic changes, which involve 3 overlapping pathways, probably occur in germinal center B cells and appear to be already present in premalignant MGUS tumors. Two partially overlapping pathways, indicated by IgH translocations (tx) and multiple trisomies, usually generate nonhyperdiploid and hyperdiploid tumors, respectively. A third pathway that leads to monosomy of chromosome 13 or deletion of 13q14 can be present in both types of tumors but occurs with a higher prevalence in nonhyperdiploid tumors, where it occurs in almost all tumors with t(4;14) and t(14;16) but infrequently in tumors with t(11;14). The essentially invariant dysregulation of a cyclin D gene appears to be associated with these early oncogenic changes. The identification of 5 recurrent IgH translocations and the dysregulated expression of a cyclin D gene by expression profiling forms the basis for assignment of MGUS and MM tumors into TC groups as depicted.