Can be found in plasma cell myeloma, monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, plasma cell leukemia, and plasmacytoma.
Collectively, the term plasma cell neoplasms include a number of disorders characterized by monoclonal gammopathy. The most common of these disorders, monoclonal gammopathy of undetermined significance (MGUS), is characterized by the infiltration of clonal plasma cells into bone marrow (30% plasma cells, a non-systemic solitary plasmacytoma, or plasma cell leukemia with a peripheral blood plasmacytosis >20% [Rollig et al, 2015].

Post-germinal center, terminally differentiated plasma cell.
Plasma cells develop from hematopoietic stem cells that differentiate first into B-cells, then eventually after several rounds of differentiation into plasma cells. The final differentiation stage of B-cells occurs in bone marrow and involves rearrangement of the immunoglobulin heavy chain gene (IGH), followed by rearrangement of the light chain genes [IG kappa (IGK) and IG lambda [IGL)]. The mature B cell than exits the bone marrow to populate secondary lymphoid organs where it will continue its maturation. Somatic hypermutation occurs within the germinal centers of these secondary lymphoid organs, involving stochastic mutations within the VDJ segment. The final maturation stage involves class switch recombination, resulting in the mature B-cell expressing IgG, IgA, or IgE. The mature B-cell will now either differentiate into a memory B-cell or return to bone marrow as a long-lived plasma cell [Corre et al, 2015].

The cause of PCM is unknown, but potential environmental and occupational risk factors have been proposed. In addition, genetic risk factors have been elucidated through genome-wide association studies (GWAS) which have identified multiple susceptibility loci, as well as loci associated with inferior survival and with development of drug-induced toxicity (such as bortezomib-induced neuropathy) [Kumar et al, 2017].

PCM accounts for approximately 1.8% of all cancers and a little more than 17% of all hematologic malignancies in the United States. According to the American Cancer Society, an estimated 30,280 new cases will be diagnosed in the United States in 2017, with an estimated 12,590 deaths. The incidence of PCM is 2-3 times higher in African-American individuals compared with Caucasians. The prevalence has increased, likely because of better diagnostic techniques and increased survival as the result of novel therapeutic agents and autologous stem cell transplantation [Kumar et al, 2017].
Approximately 40-50% of myeloma cases demonstrate an IGH gene rearrangement. The t(14;20)(q32;q12) is the rarest of the five most common IGH-rearrangements, found in approximately 1% of cases [Manier et al, 2016].

After developing a primary genetic abnormality, either hyperdiploidy or an IGH gene rearrangement, plasma cells induce stromal cells to produce numerous cytokines, especially interleukin-6. Plasma cells undergo additional genetic alterations that prevent normal cell differentiation and apoptosis. The end result is the immortalization of a plasma cell clone. Recent DNA sequencing studies have identified two types of clonal evolution in plasma cell myeloma. Genetic heterogeneity appears to be acquired either through linear evolution with acquisition of secondary mutations over time in the original clone or through branching evolution, whereby multiple subclones diverge to produce greater genetic heterogeneity. Such subclones, it is theorized, coexist and compete for space and stromal support within the bone marrow microenvironment. The kinetics of this evolution has important implications for therapy [Coore et al, 2015; Pawlin et al, 2015].
Malignant plasma cells are positive by flow cytometry for CD138 and CD38, negative for CD19, and either positive or negative for CD45 and CD56. Immunohistochemical detection of CD138 (syndecan-1) helps to quantify plasma cell in tissue. Detection of CD56, cyclin-D1, and CD117 are also helpful.

Plasma cell myeloma cases with a t(14;20)(q32;q12) have a poorer prognosis; however, paradoxically, identification of the translocation in MGUS or SM may be associated with long-term stable disease [Ross FM et al, 2010]. This suggests that additional molecular events are necessary in those cases that progress to plasma cell myeloma, and that those secondary molecular events specifically associated with the rearrangement may be the factors actually responsible for the negative prognosis. A recent study demonstrated that cases of MGUS or SM that progress to overt myeloma do so through acquisition of mutations in APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) cytidine deaminases [Bolli N et al, 2018]. Some myeloma patients are found to have coexistent hyperdiploidy (a good prognostic marker) as well as a high-risk IGH rearrangement such as the t(14;20). Single cell analysis reveals that hyperdiploidy may precede IGH translocation. In such cases, coexistent hyperdiploidy does not change the otherwise poor prognosis associated with the t(14;20) [Pawlyn C et al, 2015].

The t(14;20)(q32;q12) is the rarest of the five most common translocations in myeloma that involve the IGH gene. It is found in about 1% of all myeloma cases, and in the few cases that have been reported, the translocation has been balanced. Unlike the other relatively uncommon IGH gene translocations t(4;14) and t(14;16) that are often undetectable by conventional cytogenetic analysis of bone marrow (which yields chromosomes of lower resolution and require FISH analysis), the t(14;20) can be observed in metaphase chromosome preparations. However, FISH utilizing an IGH/MAFB dual-color, dual-fusion translocation should still be performed to confirm the translocation, even in those cases which appear to demonstrate the translocation by karyotype.

The t(14;20)(q32;q12) results in upregulation of expression of the MAF paralogue MAFB. Gene expression studies have revealed that MAFB overexpression produces an expression profile similar to that observed in MAF overexpression, suggesting similar downstream targets [Zhan et al, 2006]. Using an inducible system to upregulate MAFB in multiple myeloma cell lines, fourteen upregulated genes were identified, including CCND1, CCND2, and NOTCH2. The same upregulated genes are, in fact, targets of the entire MAF group of transcription factors, suggesting similar pathogenic molecular mechanisms in both MAF and MAFB dysregulated myelomas [van Stralen et al, 2009].
Myeloma cases with either of the two poor prognosis translocations, t(14;16) (q32;q23) and t(14;20)(q32;q12) associated with MAF or MAFB gene dysregulation, respectively, have been shown to have a higher mutational burden than other cytogenetic groups of myeloma and to have an APOBEC gene signature resulting in overexpression of APOBEC3Aand APOBEC3B genes. ENCODE data demonstrates a maf transcription factor binding site in the promoter regions of both genes, providing the link between MAF or MAFB dysregulation and increased tumor load [Walker BA et al, 2015]. The t(14;16) and t(14;20) are known to be associated with long-term stable disease in MGUS and SM despite their poor prognostic indication in plasma cell myeloma. This raised the possibility that the APOBEC signature is acquired at a later stage in the disease, and only at that time does the condition transform to plasma cell myeloma. A very recent study has proven that APOBEC activity does, in fact, increase with disease progression from MGUS or SM to overt PCM [Bolli N et al, 2018].
Finally, genome-scale methylation profiling studies have shown that the MAFB protein establishes an epigenetic program in hematopoietic stem/progenitor cells which can reset the genome of such cells to a terminally differentiated tumor state [Vicente-Dueñas et al, 2012].

IGH/MAFB