Molecular pathogenesis of multiple myeloma: basic and clinical updates

Abstract

Multiple myeloma is divided into two distinct genetic subtypes based on chromosome content. Hyperdiploid myeloma is characterized by multiple trisomies of chromosomes 3, 5, 7, 9 11, 15, 19 and 21, and lacks recurrent immunoglobulin gene translocations. Non-hyperdiploid myeloma in contrast is characterized by chromosome translocations t(4;14), t(14;16), t(14;20), t(6;14) and t(11;14). A unifying event in the pathogenesis of multiple myeloma is the dysregulated expression of a cyclin D gene, either directly by juxtaposition to an immunoglobulin enhancer, as a result of ectopic expression of a MAF family transcription factor, or indirectly by as yet unidentified mechanisms. Secondary genetic events include rearrangements of MYC, activating mutations of NRAS, KRAS or BRAF, a promiscuous array of mutations that activate NFkB and deletions of 17p. Among the poor-risk genetic features are t(4;14), t(14;16), t(14;20), del 17p and gains of 1q. Available evidence supports the use of a risk-stratified approach to the treatment of patients with multiple myeloma, with the early and prolonged use of bortezomib particularly in patients with t(4;14) and del 17p.

Fig. 1

Distribution of genetic subtypes of untreated MM using the TC classification. A Pie chart shows the relative frequency of the different genetic subgroups of MM using the TC classification

Fig. 2

Cyclin Ds dysregulation in MM. MGUS and MM karyotypes can be divided into hyperdiploid and non-hyperdiploid based on chromosomal content. Almost all hyperdiploid tumors have biallelic cyclin D1 trans-dysregulation. Non-hyperdiploid tumors often have t(14q32) translocations affecting the indicated loci (frequency is shown). In about 25 % of them, one of the D type cyclin is cis-dysregulated by a 14q32 translocation, in the other non-hyperdiploid tumors cyclin D2 expression is trans-dysregulated

Fig. 3

mSMART recommendations for a risk-adapted approach to therapy. Clinical trials strongly recommended as the first option. *Note that a subset of patients with these factors will be classified as high-risk by GEP, LDH >ULN and beta-2 M >5.5 also may indicate worse prognosis, and prognosis is worse when associated with high beta-2 microglobulin and anemia. a Bortezomib containing regimens preferred in renal failure or if rapid response needed. b If age >65 or >4 cycles of Rd Consider G-CSF plus cytoxan or plerixafor. c Continuing Rd is option for patients responding to Rd and with low toxicities; Dex is usually discontinued after first year. d In patients treated with Rd, continuing treatment is an option for patients responding well with low toxicities; Dex is usually discontinued after first year