A gene expression signature for high-risk multiple myeloma

• Published in: Leukemia Vol. 26; no. 11; pp. 2406 - 2413
• Main Authors: Kuiper, R, Broyl, A, de Knegt, Y, van Vliet, M H, van Beers, E H, van der Holt, B, el Jarari, L, Mulligan, G, Gregory, W, Morgan, G, Goldschmidt, H, Lokhorst, H M, van Duin, M, Sonneveld, P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-11-2012; Nature Publishing Group
• Subjects: 631/1647/2217/2018; 692/53/2422; 692/699/67/1990/804; Apexes; Biological and medical sciences; Bone marrow; Bortezomib; Cancer Research; Clinical trials; Confidence intervals; Critical Care Medicine; Drug therapy; Gene expression; Gene Expression Profiling; Gene mutations; Genetic aspects; Health aspects; Hematologic and hematopoietic diseases; Hematology; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; In Situ Hybridization, Fluorescence; Intensive; Internal Medicine; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical prognosis; Medical sciences; Medicine; Medicine & Public Health; Multiple myeloma; Multiple Myeloma - genetics; Oncology; original-article; Patients; Plasma; Principal components analysis; Prognosis; Risk assessment; Risk factors; Simulated annealing; Survival; United States; United Kingdom; Netherlands; United Kingdom > UK; multiple myeloma; comparison; signature; prognosis; gene expression; survival; Immunopathology; High risk; Prognosis; Hematology; Malignant hemopathy; Gene expression; Myeloma; Survival; Gene expression profile; Immunoglobulinopathy; Lymphoproliferative syndrome; Comparative study; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2012.127

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.