MM is a low proliferative, malignant post-germinal center tumor of somatically mutated, isotype-switched plasma cells that accumulate in the bone marrow. It is often preceded by a premalignant state known as monoclonal gammopathy of undetermined significance (MGUS). Five recurrent primary translocations involving the immunoglobulin heavy locus (IGH) have been identified in 40% of MGUS and MM tumors. They include t(11;14)(q13.3;q32.3), t(6;14) (p21.1;q32.3), t(4;14)(p16.3;q32.3), t(14;16)(q32.3;q23), and t(14;20) (q32.3;q12), which involve the genes CCND1, CCND3, FGFR3 and NSD2, MAF, and MAFB, respectively. All of these translocations lead to the deregulation and overexpression of the target genes as a consequence of their juxtaposition to regulatory sequences of the IGH locus. The t(14;20) occurs in approximately 1-2% of MM patients and is associated with an adverse prognosis. Thus, currently, detection of t(14;20) by FISH is a reliable prognostic tool and may sustain therapeutic decision making in MM.