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
John R. Jones,
Niels Weinhold,
Cody Ashby,
Brian A. Walker,
Chris Wardell,
Charlotte Pawlyn,
Leo Rasche,
Lorenzo Melchor,
David A. Cairns,
Walter M. Gregory,
David Johnson,
Dil B. Begum,
Sidra Ellis,
Amy L. Sherborne,
Gordon Cook,
Martin F. Kaiser,
Mark T. Drayson,
Roger G. Owen,
Graham H. Jackson,
Faith E. Davies,
Mel Greaves,
Gareth J. Morgan
Affiliations
John R. Jones
Department of Haematology, The Royal Marsden Hospital NHS Foundation Trust, London, UK;The Institute of Cancer Research, London, UK
Niels Weinhold
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Cody Ashby
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Brian A. Walker
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Chris Wardell
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Charlotte Pawlyn
Department of Haematology, The Royal Marsden Hospital NHS Foundation Trust, London, UK;The Institute of Cancer Research, London, UK
Leo Rasche
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Lorenzo Melchor
The Institute of Cancer Research, London, UK
David A. Cairns
Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, UK
Walter M. Gregory
Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, UK
David Johnson
The Institute of Cancer Research, London, UK
Dil B. Begum
The Institute of Cancer Research, London, UK
Sidra Ellis
The Institute of Cancer Research, London, UK
Amy L. Sherborne
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Gordon Cook
Leeds Institute of Cancer and Pathology, University of Leeds, UK
Martin F. Kaiser
Department of Haematology, The Royal Marsden Hospital NHS Foundation Trust, London, UK;The Institute of Cancer Research, London, UK
Mark T. Drayson
Clinical Immunology, School of Immunity and Infection, University of Birmingham, UK
Roger G. Owen
Leeds Institute of Cancer and Pathology, University of Leeds, UK
Graham H. Jackson
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
Faith E. Davies
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Mel Greaves
The Institute of Cancer Research, London, UK
Gareth J. Morgan
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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. Patients included were considered high risk, relapsing within 30 months of maintenance randomization. Patients achieving a complete response had predominantly branching evolutionary patterns leading to relapse, characterized by a greater mutational burden, an altered mutational profile, bi-allelic inactivation of tumor 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 seen at both time points. There were no significant differences between patients relapsing after lenalidomide maintenance versus observation. This study shows that the depth of response is a key determinant of the evolutionary patterns seen at relapse. This trial is registered at clinicaltrials.gov identifier: 01554852.
