Advances in the pathogenesis and diagnosis of multiple myeloma.

Multiple myeloma (MM) is a tumor of indolent, bone marrow (BM) localized, isotype-switched plasma cells. Recently, the diagnostic criteria have been amended to include some patients who would previously have been diagnosed with ultra-high-risk smoldering MM and benefit from immediate treatment. Genetically it can be divided into tumors with different recurrent immunoglobulin heavy chain gene translocations (4p16, 11q13, 6p21, 16q23, 20q11) and tumors characterized by hyperdiploidy with multiple trisomies. Recent genomic studies have shown that almost half of untreated patients have a genetic rearrangements of the MYC locus that result in juxtaposition of ectopic super-enhancers adjacent to MYC, as well as somatic mutations that activate the RAS/MAPK pathway (NRAS, KRAS, BRAF, FGFR3). Mutations that result in constitutive activation of the NFkB pathway and that inactivate TP53, CDKN2C, KDM6A, FAM46C, and DIS3 are also recurrent. A major insight from these studies has been the recognition of the high degree of subclonal heterogeneity in MM, which is more frequent in patients with high-risk genetics. The subclones may alternate in dominance under alternating therapeutic pressure, a phenomenon known as 'clonal tides'. The identification of marked subclonal heterogeneity argues in those patients for the use of therapeutic strategies to maximize response, and long-term suppressive therapies to prevent tumor regrowth and development of additional subclones.