International Myeloma Working Group molecular classification of multiple myeloma: spotlight review

Abstract

Myeloma is a malignant proliferation of monoclonal plasma cells. Although morphologically similar, several subtypes of the disease have been identified at the genetic and molecular level. These genetic subtypes are associated with unique clinicopathological features and dissimilar outcome. At the top hierarchical level, myeloma can be divided into hyperdiploid and non-hyperdiploid subtypes. The latter is mainly composed of cases harboring IgH translocations, generally associated with more aggressive clinical features and shorter survival. The three main IgH translocations in myeloma are the t(11;14)(q13;q32), t(4;14)(p16;q32) and t(14;16)(q32;q23). Trisomies and a more indolent form of the disease characterize hyperdiploid myeloma. A number of genetic progression factors have been identified including deletions of chromosomes 13 and 17 and abnormalities of chromosome 1 (1p deletion and 1q amplification). Other key drivers of cell survival and proliferation have also been identified such as nuclear factor- B-activating mutations and other deregulation factors for the cyclin-dependent pathways regulators. Further understanding of the biological subtypes of the disease has come from the application of novel techniques such as gene expression profiling and array-based comparative genomic hybridization. The combination of data arising from these studies and that previously elucidated through other mechanisms allows for most myeloma cases to be classified under one of several genetic subtypes. This paper proposes a framework for the classification of myeloma subtypes and provides recommendations for genetic testing. This group proposes that genetic testing needs to be incorporated into daily clinical practice and also as an essential component of all ongoing and future clinical trials.

Figure 1

Relationship between clonal evolution of plasma cells and time of diagnosis. The picture depicts the biology and genetic heterogeneity of patients with a clinical diagnosis of ‘new diagnosis myeloma.’ In some cases (a) the situation involves a slow progression from MGUS with gradual development of mild anemia, incipient evidence of bone disease and slowly emerging need for treatment. In some other individuals (b) myeloma presents with frank clinical features of aggressive disease (for example, bone lesions, anemia and other). Furthermore, in some individuals (c) the disease presents with very aggressive features, including extramedullary disease, multiple plasmacytomas and other complicating features. In these three scenarios the clinical diagnosis is of ‘new diagnosis myeloma’, yet the biological and genetic features are quiet different.