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17-08-2016 | Hematologic cancers | Article

Genomic complexity of multiple myeloma and its clinical implications

Authors: Saloman Manier, Karma Z. Salem, Jihye Park, Dan A. Landau, Gad Getz, Irene M. Ghobrial

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Abstract

Multiple myeloma (MM) is a genetically complex disease that evolves from pre-malignant stages, such as monoclonal gammaopathy of undetermined significance and smouldering multiple myeloma, and progresses to symptomatic MM; this continuum provides a unique framework to study the sequential genomic evolution of MM. In the past 5 years, results from large-scale whole-exome sequencing studies have provided new insights into the clonal heterogeneity and evolution of the disease. Moreover, the recurrent co-occurrence of genomic events helps to dissect the genomic complexity underlying tumour progression. According to the primary genetic events involved in tumorigenesis, MM tumours are hierarchically subdivided into hyperdiploid and non-hyperdiploid subtypes; subsequently, secondary genetic events lead to tumour progression. In this Review, we describe the 'driver' gene alterations involved in the development and progression of MM, with a focus on the sequential acquisition of the main genomic aberrations. We also provide valuable insight into the clonal heterogeneity and clonal evolution of the disease, as well as into the therapeutic implications of a comprehensive understanding of the genomic complexity of MM.

Nat Rev Clin Oncol 2017; 14: 100–113. doi: 10.1038/nrclinonc.2016.122

Subject terms: Cancer genetics • Genome evolution • Myeloma • Tumour heterogeneity

Multiple myeloma (MM) is a haematological malignancy characterized by the clonal proliferation of plasma cells in the bone marrow1. In the USA, the prevalence of MM was estimated to be 89,650 people in 2012, with an annual incidence of 6.3 new cases per 100,000 individuals2 In 2012, MM represented 1.6% of all cancers and was the second most frequent haematological malignancy in the USA2. MM predominantly affects elderly people, and the median age at diagnosis is 69 years2. Traditionally, this disease was associated with a poor prognosis, with a 5-year overall survival of 48.5% (according to data from 2006–2012)2; however, the introduction of new-generation proteasome inhibitors and immunomodulatory drugs, as well as new potent monoclonal antibodies has greatly improved the clinical outcome of patients with MM.

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