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Ferrata Storti Foundation
Haematologica 2019 Volume 104(7):1440-1450
Plasma Cell Disorders
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,1,2 Niels Weinhold,3 Cody Ashby,3 Brian A. Walker,3
Chris Wardell,3 Charlotte Pawlyn,1,2 Leo Rasche,3 Lorenzo Melchor,2
David A. Cairns,4 Walter M. Gregory,4 David Johnson,2 Dil B. Begum,2
2 3 5 1,2 Sidra Ellis, Amy L. Sherborne, Gordon Cook, Martin F. Kaiser,
Mark T. Drayson,6 Roger G. Owen,5 Graham H. Jackson,7 Faith E. Davies,3 Mel Greaves2 and Gareth J. Morgan;3 on behalf of the NCRI Haemato- Oncology CSG
1Department of Haematology, The Royal Marsden Hospital NHS Foundation Trust, London, UK; 2The Institute of Cancer Research, London, UK; 3Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 4Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, UK; 5Leeds Institute of Cancer and Pathology, University of Leeds, UK; 6Clinical Immunology, School of Immunity and Infection, University of Birmingham, UK and 7Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
ABSTRACT
The emergence of treatment resistant sub-clones is a key feature of relapse in multiple myeloma. Therapeutic attempts to extend remis- sion 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 sim- ilar 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.
Introduction
Multiple myeloma (MM) results from the malignant transformation of a normal plasma cell and has a mutational load which lies in an intermediate position between genetically simple malignancies, such as chronic myelogenous leukemia, and the more complex solid cancers.1,2 As such, MM provides an excellent model system through which to understand the mutational and evolutionary processes underlying disease relapse. MM is a genetically diverse condition, which is mani- fested by variations in clinical outcome even in uniformly treated populations.3,4
The treatment of newly diagnosed (ND) MM has improved over the last decade following the introduction of immunomodulatory drugs and proteasome inhibi- tion, which, together with autologous stem cell transplantation, have increased the median overall survival from three to eight years.5-7 However, patients frequently
Correspondence:
GARETH J. MORGAN gjmorgan@uams.edu
Received: August 31, 2018. Accepted: January 30, 2019. Pre-published: February 7, 2019.
doi:10.3324/haematol.2018.202200
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/7/1440
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