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Despite advances in therapy, <jats:styled-content style=\"fixed-case\">MM<\/jats:styled-content> remains a largely incurable disease with a median survival of 6\u00a0years. In almost all cases, the development of <jats:styled-content style=\"fixed-case\">MM<\/jats:styled-content> is preceded by the benign <jats:styled-content style=\"fixed-case\">PC<\/jats:styled-content> condition Monoclonal Gammopathy of Undetermined Significance (<jats:styled-content style=\"fixed-case\">MGUS<\/jats:styled-content>). Recent studies show that the transformation of <jats:styled-content style=\"fixed-case\">MGUS<\/jats:styled-content> to <jats:styled-content style=\"fixed-case\">MM<\/jats:styled-content> is associated with complex genetic changes. Understanding how these changes contribute to evolution will present targets for clinical intervention. We discuss three models of <jats:styled-content style=\"fixed-case\">MM<\/jats:styled-content> evolution; the linear, the expansionist and the intraclonal heterogeneity models. Of particular interest is the intraclonal heterogeneity model. Here, distinct populations of <jats:styled-content style=\"fixed-case\">MM PC<\/jats:styled-content>s carry differing combinations of genetic mutations. Acquisition of additional mutations can contribute to subclonal lineages where \u201cdriver\u201d mutations may influence selective pressure and dominance, and \u201cpassenger\u201d mutations are neutral in their effects. Furthermore, studies show that clinical intervention introduces additional selective pressure on tumour cells and can influence subclone survival, leading to therapy resistance. This review discusses how Next Generation Sequencing approaches are revealing critical insights into the genetics of <jats:styled-content style=\"fixed-case\">MM<\/jats:styled-content> development, disease progression and treatment. <jats:styled-content style=\"fixed-case\">MM<\/jats:styled-content> disease progression will illuminate possible mechanisms underlying the tumour.<\/jats:p>","DOI":"10.1111\/bjh.14649","type":"journal-article","created":{"date-parts":[[2017,5,3]],"date-time":"2017-05-03T06:23:04Z","timestamp":1493792584000},"page":"196-208","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Cutting edge genomics reveal new insights into tumour development, disease progression and therapeutic impacts in multiple myeloma"],"prefix":"10.1111","volume":"178","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2535-3729","authenticated-orcid":false,"given":"Ankit K.","family":"Dutta","sequence":"first","affiliation":[{"name":"School of Medicine Adelaide Medical School Faculty of Health and Medical Sciences The University of Adelaide Adelaide SA Australia"},{"name":"Cancer Theme South Australian Health &amp; Medical Research Institute Adelaide SA Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6010-1116","authenticated-orcid":false,"given":"Duncan R.","family":"Hewett","sequence":"additional","affiliation":[{"name":"School of Medicine Adelaide Medical School Faculty of Health and Medical Sciences The University of Adelaide Adelaide SA Australia"},{"name":"Cancer Theme South Australian Health &amp; Medical Research Institute Adelaide SA Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2912-6048","authenticated-orcid":false,"given":"J. 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