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    Keywords: EXPRESSION ; proliferation ; SURVIVAL ; KINASE ; SYSTEM ; RISK ; GENE-EXPRESSION ; IN-SITU HYBRIDIZATION ; gene expression profiling ; multiple myeloma ; STAGING SYSTEM ; MOLECULAR CLASSIFICATION ; INTERGROUPE FRANCOPHONE ; CELL LABELING INDEX ; CYCLIN-D DYSREGULATION ; EVENT-FREE SURVIVAL ; MALIGNANT PLASMA-CELLS ; MONOCLONAL GAMMOPATHIES ; risk score ; risk-adapted treatment
    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. Thereby, 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〈.001) of patients, and is largely independent of clinical prognostic factors, e.g. serum-beta2-microglobulin, ISS-stage, high-risk associated chromosomal aberrations, e.g. translocation t(4;14), and gene-expression based high-risk scores. Conclusions. Proliferation assessed by gene-expression-profiling, being independent of serum-beta2-microglobulin, ISS-stage, t(4;14), and gene-expression-based risk-scores, is thus a central prognostic factor in multiple myeloma. Surrogating a biological targetable variable, gene-expression-based assessment of proliferation allows selection of patients for risk-adapted anti-proliferative treatment in the background of conventional and gene expression based risk factors.
    Type of Publication: Journal article published
    PubMed ID: 20884712
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