Description:
<jats:title>Summary</jats:title><jats:p>Multiple myeloma (<jats:styled-content style="fixed-case">MM</jats:styled-content>) is a plasma cell neoplasm that presents with a major biological and clinical heterogeneity. We here investigated the spectrum of clonal and subclonal mutations of <jats:italic><jats:styled-content style="fixed-case">DIS</jats:styled-content>3</jats:italic>, an active part of the exosome complex, that may play a role in the development or progression of <jats:styled-content style="fixed-case">MM</jats:styled-content>. The whole coding sequence of <jats:italic><jats:styled-content style="fixed-case">DIS</jats:styled-content>3</jats:italic> was subjected to deep sequencing in 81 uniformly‐treated <jats:styled-content style="fixed-case">MM</jats:styled-content> patients and 12 <jats:styled-content style="fixed-case">MM</jats:styled-content> cell lines and the overall occurrence of <jats:italic><jats:styled-content style="fixed-case">DIS</jats:styled-content>3</jats:italic> mutations as well as the presence of <jats:italic><jats:styled-content style="fixed-case">DIS</jats:styled-content>3</jats:italic> mutations in minor and major subclones were correlated with cytogenetic alterations and clinical parameters. Our study identified <jats:italic><jats:styled-content style="fixed-case">DIS</jats:styled-content>3</jats:italic> mutations in 9/81 patients that were associated with 13q14 deletions and <jats:italic><jats:styled-content style="fixed-case">IGH</jats:styled-content></jats:italic> translocations on the cytogenetic level. Specifically, we detected seven novel somatic <jats:italic><jats:styled-content style="fixed-case">DIS</jats:styled-content>3</jats:italic> single nucleotide variants (<jats:styled-content style="fixed-case">SNV</jats:styled-content>s) and defined three hot spot mutations within the <jats:styled-content style="fixed-case">RNB</jats:styled-content> domain. Lastly, we found a trend towards a shorter median overall survival for patients with <jats:italic><jats:styled-content style="fixed-case">DIS</jats:styled-content>3</jats:italic> mutations, and patients carrying <jats:italic><jats:styled-content style="fixed-case">DIS</jats:styled-content>3</jats:italic> mutations in minor subclones of their tumours showed a significantly worse response to therapy compared to patients with <jats:italic><jats:styled-content style="fixed-case">DIS</jats:styled-content>3</jats:italic> mutations in the major subclone.</jats:p>