Multiple myeloma is a plasma cell malignancy characterized by complex heterogeneous cytogenetic abnormalities. The bone marrow microenvironment promotes multiple myeloma cell growth and resistance to conventional therapies. Although multiple myeloma remains incurable, novel targeted agents, used alone or in combination, have shown great promise to overcome conventional drug resistance and improve patient outcome. Recent oncogenomic studies have further advanced our understanding of the molecular pathogenesis of multiple myeloma, providing the framework for new prognostic classification and identifying new therapeutic targets.

Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets

Variation in gene expression is an important mechanism underlying susceptibility to complex disease. The simultaneous genome-wide assay of gene expression and genetic variation allows the mapping of the genetic factors that underpin individual differences in quantitative levels of expression (expression QTLs; eQTLs). The availability of systematically generated eQTL information could provide immediate insight into a biological basis for disease associations identified through genome-wide association (GWA) studies, and can help to identify networks of genes involved in disease pathogenesis. Although there are limitations to current eQTL maps, understanding of disease will be enhanced with novel technologies and international efforts that extend to a wide range of new samples and tissues.

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Mapping complex disease traits with global gene expression

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.

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

Based on the clinical features of myeloma and related malignancies of plasma cells, it has been possible to generate a model system of myeloma progression from a normal plasma cell through smouldering myeloma to myeloma and then plasma cell leukaemia. Using this model system we can study at which points the genetic alterations identified through whole-tumour molecular analyses function in the initiation and progression of myeloma. Further genetic complexity, such as intraclonal heterogeneity, and insights into the molecular evolution and intraclonal dynamics in this model system are crucial to our understandings of tumour progression, treatment resistance and the use of currently available and future treatments.

The genetic architecture of multiple myeloma

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

Integration of global SNP-based mapping and expression arrays reveals key regions, mechanisms, and genes important in the pathogenesis of multiple myeloma.

http://www.bloodjournal.org/content/bloodjournal/early/2007/07/03/blood-2007-02-075069.full.pdf

Article title: Gene Mapping and Expression Analysis of 16q Loss of Heterozygosity Identifies

Article Title: A compendium of myeloma associated chromosomal copy number abnormalities and their prognostic value Short Title: SNP-based genome mapping in myeloma

online June 7, 2011doi:10.1182/blood-2011-02-338665 originally published2011€118: 1231-1238€€for the NCRI Haematological Oncology Study GroupRudin, Mark T. Drayson, Roger G. Owen, Fiona M. Ross, Graham H. Jackson, J. Anthony Child andSzubert, Nuria Navarro Coy, Gordon Cook, Sylvia Feyler, Jenny L. Byrne, Huw Roddie, Claudius Gareth J. Morgan, Faith E. Davies, Walter M. Gregory, Nigel H. Russell, Sue E. Bell, Alexander J.€

Fiona M. Ross

Papers

Integration of global SNP-based mapping and expression arrays reveals key regions, mechanisms, and genes important in the pathogenesis of multiple myeloma.

Article title: Gene Mapping and Expression Analysis of 16q Loss of Heterozygosity Identifies

Article Title: A compendium of myeloma associated chromosomal copy number abnormalities and their prognostic value Short Title: SNP-based genome mapping in myeloma

transplantation therapy for patients with multiple myeloma unsuitable for autologous Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial