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Clonal evolution in myeloma: the impact of maintenance lenalidomide and depth of response on the genetics and sub-clonal structure of relapsed disease in uniformly treated newly diagnosed patients


ABSTRACT: The emergence of treatment resistant sub-clones is a key feature of relapse in multiple myeloma. Therapeutic attempts to extend remission and prevent relapse include the maximisation of response and use of maintenance therapy. We used whole exome sequencing to study the genetics of paired presentation and relapse samples from 56 newly diagnosed patients, following induction therapy, randomised to receive either lenalidomide maintenance or observation as part of the Myeloma XI trial. Patients included were considered high risk, relapsing within 30 months of maintenance randomisation. Patients achieving a complete response had predominantly branching evolutionary patterns leading to relapse, characterised by a greater mutational burden, an altered mutational profile, bi-allelic inactivation of tumour suppressor genes, and acquired structural aberrations. Conversely, in patients achieving a partial response the evolutionary features were predominantly stable with a similar mutational and structural profile. There were no significant differences between patients relapsing after maintenance lenalidomide vs observation. This study shows that the depth of response is a key determinant of the evolutionary patterns seen at relapse.

PROVIDER: EGAS00001003539 | EGA |

REPOSITORIES: EGA

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Clonal evolution in myeloma: the impact of maintenance lenalidomide and depth of response on the genetics and sub-clonal structure of relapsed disease in uniformly treated newly diagnosed patients.

Jones John R JR   Weinhold Niels N   Ashby Cody C   Walker Brian A BA   Wardell Chris C   Pawlyn Charlotte C   Rasche Leo L   Melchor Lorenzo L   Cairns David A DA   Gregory Walter M WM   Johnson David D   Begum Dil B DB   Ellis Sidra S   Sherborne Amy L AL   Cook Gordon G   Kaiser Martin F MF   Drayson Mark T MT   Owen Roger G RG   Jackson Graham H GH   Davies Faith E FE   Greaves Mel M   Morgan Gareth J GJ  

Haematologica 20190207 7


The emergence of treatment resistant sub-clones is a key feature of relapse in multiple myeloma. Therapeutic attempts to extend remission and prevent relapse include maximizing response and the use of maintenance therapy. We used whole exome sequencing to study the genetics of paired samples taken at presentation and at relapse from 56 newly diagnosed patients, following induction therapy, randomized to receive either lenalidomide maintenance or observation as part of the Myeloma XI trial. Patie  ...[more]

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