Published Ahead of Print on September 30, 2010, as doi:10.3324/haematol.2010.030296. Copyright 2010 Ferrata Storti Foundation.
Early Release Paper
Proliferation is a central independent prognostic factor and target for personalized and risk adapted treatment in multiple myeloma by Dirk Hose, Thierry Rème, Thomas Hielscher, Jérôme Moreaux, Tobias Meißner, Anja Seckinger, Axel Benner, John D. Shaughnessy Jr., Bart Barlogie, Yiming Zhou, Jens Hillengass, Uta Bertsch, Kai Neben, Thomas Möhler, Jean François Rossi, Anna Jauch, Bernard Klein, and Hartmut Goldschmidt Haematologica 2010 [Epub ahead of print] Citation: Hose D, Rème T, Hielscher T, Moreaux J, Meißner T, Seckinger A, Benner A, Shaughnessy JD Jr, Barlogie B, Zhou Y, Hillengass J, Bertsch U, Neben K, Möhler T, Rossi JF, Jauch A, Klein B, and Goldschmidt H. Proliferation is a central independent prognostic factor and target for personalized and risk adapted treatment in multiple myeloma. Haematologica. 2010; 95:xxx doi:10.3324/haematol.2010.030296 Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process. Haematologica (pISSN: 0390-6078, eISSN: 1592-8721, NLM ID: 0417435, www.haematologica.org) publishes peer-reviewed papers across all areas of experimental and clinical hematology. The journal is owned by the Ferrata Storti Foundation, a non-profit organization, and serves the scientific community with strict adherence to the principles of open access publishing (www.doaj.org). In addition, the journal makes every paper published immediately available in PubMed Central (PMC), the US National Institutes of Health (NIH) free digital archive of biomedical and life sciences journal literature.
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DOI: 10.3324/haematol.2010.030296
Proliferation is a central independent prognostic factor and target for personalized and risk adapted treatment in multiple myeloma Dirk Hose,1,2 Thierry Rème,3,4 Thomas Hielscher,5 Jérôme Moreaux,3,4 Tobias Meißner,1 Anja Seckinger,1 Axel Benner,5 John D. Shaughnessy Jr.,6 Bart Barlogie,6 Yiming Zhou,6 Jens Hillengass,1 Uta Bertsch,1 Kai Neben,1 Thomas Möhler,1 Jean François Rossi,3,4 Anna Jauch,7 Bernard Klein3,4 and Hartmut Goldschmidt1,2
1
Medizinische Klinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany; 2Nationales
Centrum für Tumorerkrankungen, Heidelberg, Germany; 3CHU Montpellier, Institute for Research in Biotherapy, Hôpital Saint-Eloi, Montpellier, France; 4INSERM U847, Montpellier, France; 5Abteilung für Biostatistik, Deutsches Krebsforschungszentrum Heidelberg, Heidelberg, Germany; 6Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA, and 7Institut für Humangenetik, Universitätsklinikum Heidelberg, Heidelberg, Germany
Correspondence Dirk Hose, Medizinische Klinik V, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Phone: +49 6221 56 39047; FAX: +49 6221 56 6238. Email:
[email protected]
Key words: gene-expression profiling, multiple myeloma, proliferation, survival, risk adapted treatment, risk score. Acknowledgments The authors would like to thank Véronique Pantesco, Katrin Heimlich, Maria Dörner and Gabriele Hoock for technical assistance.
DOI: 10.3324/haematol.2010.030296
Funding This work was supported in part by grants from the Hopp-Foundation, Germany, the University of Heidelberg, Germany, the National Center for Tumor Diseases, Heidelberg, Germany, the Tumorzentrum Heidelberg/Mannheim, Germany, the European Myeloma Stem Cell Network (MSCNET) funded within the 6th framework program of the European Community and the Ligue Nationale Contre Le Cancer, Paris, France.
2
DOI: 10.3324/haematol.2010.030296
Abstract Background Proliferation of malignant plasma cells is a strong adverse prognostic factor in multiple myeloma and simultaneously targetable by available (e.g. tubulin-polymerase inhibitors) and upcoming (e.g. aurora-kinase inhibitors) compounds. Design and Methods We assessed proliferation using gene-expression based indices in 757 samples including independent cohorts of 298 and 345 CD138-purified myeloma cells from previously untreated patients undergoing high-dose chemotherapy, together with clinical prognostic factors, chromosomal aberrations, and gene-expression based high-risk scores. Results In the two cohorts, 43.3% and 39.4% of myeloma cell samples show a proliferation-index above the median plus three standard-deviations of normal bone-marrow plasma cells. Malignant plasma cells of patients in advanced stages or those harboring disease-progression associated gain of 1q21 or deletion of 13q14.3 show significantly higher, patients with gain of chromosome 9, 15 or 19 (hyperdiploid samples) significantly lower proliferation-indices. Proliferation correlates with presence of chromosomal aberrations in metaphase cytogenetics. It is significantly predictive for event-free and overall survival in both cohorts, allows highly predictive risk stratification (e.g. event-free survival 12.7 vs. 26.2 vs. 40.6 months, P
