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Myeloma

A gene expression signature for high-risk multiple myeloma

A Corrigendum to this article was published on 07 May 2014

Abstract

There is a strong need to better predict the survival of patients with newly diagnosed multiple myeloma (MM). As gene expression profiles (GEPs) reflect the biology of MM in individual patients, we built a prognostic signature based on GEPs. GEPs obtained from newly diagnosed MM patients included in the HOVON65/GMMG-HD4 trial (n=290) were used as training data. Using this set, a prognostic signature of 92 genes (EMC-92-gene signature) was generated by supervised principal component analysis combined with simulated annealing. Performance of the EMC-92-gene signature was confirmed in independent validation sets of newly diagnosed (total therapy (TT)2, n=351; TT3, n=142; MRC-IX, n=247) and relapsed patients (APEX, n=264). In all the sets, patients defined as high-risk by the EMC-92-gene signature show a clearly reduced overall survival (OS) with a hazard ratio (HR) of 3.40 (95% confidence interval (CI): 2.19–5.29) for the TT2 study, 5.23 (95% CI: 2.46–11.13) for the TT3 study, 2.38 (95% CI: 1.65–3.43) for the MRC-IX study and 3.01 (95% CI: 2.06–4.39) for the APEX study (P<0.0001 in all studies). In multivariate analyses this signature was proven to be independent of the currently used prognostic factors. The EMC-92-gene signature is better or comparable to previously published signatures. This signature contributes to risk assessment in clinical trials and could provide a tool for treatment choices in high-risk MM patients.

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Acknowledgements

We would like to thank John Shaughnessy for kindly providing the data. Peter Valk and Mathijs Sanders are acknowledged for insightful discussions. Financial support: This work was supported by the Center for Translational Molecular Medicine (BioCHIP), a clinical research grant from the European Hematology Association and an EMCR Translational Research Grant from Skyline Diagnostics, Janssen and MSCNET.

Author contributions

RK, AB, MVD and PS designed the research. AB, YDK performed the research and collected the data. RK developed the classifier, AB, RK, MVD analyzed and interpreted the data and wrote the manuscript. MVV, EVB analyzed and interpreted the data and critically reviewed the paper. BVDH and LEJ performed data management and statistical analyses. GM provided the CEL files from the APEX data set and critically reviewed the paper. GM and WG provided CEL files and clinical data from the MRC-IX data set and critically reviewed the paper. HG is principal investigator of the performed research in the German part of the H65/GMMG-HD4 and critically reviewed the paper. HL organized the trial and critically reviewed the paper. PS organized the trial, is principal investigator of the performed research in the Dutch part of the H65/GMMG-HD4 and critically reviewed the paper.

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Correspondence to P Sonneveld.

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Competing interests

GM has declared a financial interest in Millennium Pharmaceuticals Inc., whose product was an object of study in the HOVON 65/ GMMG-HD4. GM is currently employed by Millennium Pharmaceuticals Inc. HG has served on the advisory boards of Johnson & Johnson. HL is on the advisory Boards of Celgene and Genmab. EVB and MVV are employees of Skyline Diagnostics. PS is on the advisory boards of Skyline Diagnostics, Janssen and Celgene. The other authors declare no conflict of interest.

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Kuiper, R., Broyl, A., de Knegt, Y. et al. A gene expression signature for high-risk multiple myeloma. Leukemia 26, 2406–2413 (2012). https://doi.org/10.1038/leu.2012.127

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Keywords

  • multiple myeloma
  • gene expression
  • signature
  • prognosis
  • survival
  • comparison

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