"LEUKAEMIA": Possible early Rx MGUS

publication > 19 July 2013 Leukemia advance online publication 19 July 2013; doi: 10.1038/leu.2013.199 Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms B A Walker1,6, C P Wardell1,6, L Melchor1, A Brioli1,2, D C Johnson1, M F Kaiser1, F Mirabella1, L Lopez-Corral3, S Humphray4, L Murray4, M Ross4, D Bentley4, N C Gutiérrez3, R Garcia-Sanz3, J San Miguel3, F E Davies5, D Gonzalez1 and G J Morgan1 1Molecular Haematology, Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, London, UK 2Istituto di Ematologia Seràgnoli, Università degli Studi di Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy 3Department of Hematology, University Hospital of Salamanca, Centro de Investigacion del Cancer (CIC) de Salamanca, Instituto Biosanitario de Salamanca (IBSAL), Salamanca, Spain 4Illumina Cambridge Ltd, Chesterford Research Park, Little Chesterford, Saffron Walden, UK 5Targeted Myeloma Treatment, Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, London, UK Correspondence: Professor GJ Morgan, Molecular Haematology, Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, London SM2 5NG, UK. Email: gareth.morgan@icr.ac.uk 6These authors contributed equally to this work. Received 18 April 2013; Revised 23 June 2013; Accepted 24 June 2013 Accepted article preview online 2 July 2013; Advance online publication 19 July 2013 Top of page Abstract The mechanisms involved in the progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) to malignant multiple myeloma (MM) and plasma cell leukemia (PCL) are poorly understood but believed to involve the sequential acquisition of genetic hits. We performed exome and whole-genome sequencing on a series of MGUS (n=4), high-risk (HR)SMM (n=4), MM (n=26) and PCL (n=2) samples, including four cases who transformed from HR-SMM to MM, to determine the genetic factors that drive progression of disease. The pattern and number of non-synonymous mutations show that the MGUS disease stage is less genetically complex than MM, and HR-SMM is similar to presenting MM. Intraclonal heterogeneity is present at all stages and using cases of HR-SMM, which transformed to MM, we show that intraclonal heterogeneity is a typical feature of the disease. At the HR-SMM stage of disease, the majority of the genetic changes necessary to give rise to MM are already present. These data suggest that clonal progression is the key feature of transformation of HR-SMM to MM and as such the invasive clinically predominant clone typical of MM is already present at the SMM stage and would be amenable to therapeutic intervention at that stage.