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    Keywords: PROGNOSTIC-FACTORS ; chemotherapy ; HIGH-RISK ; PLASMA ; gene expression ; CHROMOSOMAL-ABERRATIONS ; treatment ; BONE-MARROW ; STAGE ; score ; TARGET ; DELETION ; multiple myeloma ; HIGH-DOSE CHEMOTHERAPY ; PROGNOSTIC FACTORS ; TRANSLOCATION ; MULTIPLE-MYELOMA ; CELL ; SURVIVAL ; proliferation ; EXPRESSION ; CELLS ; PATIENT ; COHORT ; RISK ; SAMPLE ; SAMPLES ; GENE-EXPRESSION ; GENE ; BONE ; PROGNOSTIC-FACTOR ; methods ; DISEASE PROGRESSION ; MARROW ; PLASMA-CELLS ; chromosomal aberration ; A ; D ; Plasma cells
    Abstract: Introduction: Proliferation of malignant plasma cells - currently rarely measured - has been described as strong adverse prognostic factors in multiple myeloma. Methods. We assessed proliferation using gene expression based indices in 757 samples including two 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 all myeloma cell samples show a proliferation-index above the median plus three standard deviations of normal bone marrow plasma cells. Within myeloma cell samples, malignant plasma cells of patients in advanced stages or those harboring a disease-progression associated gain of 1q21 or deletion of 13q14.3 show a significantly higher, those with gain of chromosome 9, 15 or 19 (hyperdiploid samples) a significantly lower proliferation-index. Proliferation correlates with presence of chromosomal aberrations in metaphase cytogenetics. It is significantly predictive for event-free and overall survival in both cohorts of patients, largely independent of clinical prognostic factors, e.g. serum-ß2-microglobulin, ISS stage,high-risk associated chromosomal aberrations, e.g. translocation t(4;14), and gene expression based high-risk scores. Conclusion. Proliferation is a central prognostic factor in multiple myeloma. Using gene expression based assessment anti-proliferative treatment could be personalizedand risk-adaptedly administered.Gemeinsame Jahrestagung der Deutschen, Österreichischen und Schweizerischen Gesellschaften für Hämatologie und Onkologie, 2.-6. Oktober 2009, Heidelberg/Mannheim
    Type of Publication: Meeting abstract published
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    Keywords: HIGH-RISK ; quality control ; affymetrix ; microarrays ; gene expression ; TARGET ; score ; TRIAL ; IDENTIFICATION ; multiple myeloma ; TARGETS ; STRATEGIES ; PREDICTION ; RISK ASSESSMENT ; MULTIPLE-MYELOMA ; CLINICAL-TRIAL ; GENERATION ; CLASSIFICATION ; proliferation ; EXPRESSION ; INDEX ; PATIENT ; DNA ; TIME ; RISK ; SAMPLE ; microarray ; GENE ; GENES ; GENE-EXPRESSION ; prospective ; RISK STRATIFICATION ; MOLECULAR CLASSIFICATION ; SOFTWARE ; methods ; A ; D ; WELL ; THERAPEUTIC TARGET ; therapeutic ; STRATEGY
    Abstract: Introduction: In addition to current clinical and cytogenetic risk factors,several highly predictive gene expression based risk stratifications have been proposed in multiple myeloma. At the same time, putative drugable targets have been identified which are only expressed in a subpopulationof myeloma patients (e.g. AURKA). Whereas assessment of both works well within a clinical trial or an experimental setting, they can currently not readily be applied to clinical routine. Methods. As reference, a groupof 233 Affymetrix U133 Plus 2.0 DNA microarrays from patients with multiple myeloma is preprocessed using GC-RMA. Quality control of the DNA microarrays is implemented according to the MACQ-Project. Gene expression based prediction of sex, immunoglobulin- and light chain typeis used as sample identity-test within a multicenter-setting. Gene expression based risk stratification (IFM-score, 70-gene high risk score, gene expression based proliferation index) and molecular classifications areassessed as published, as are individual target genes e.g. AURKA. To classifya patient within a prospective clinical routine setting, the documentationby value strategy (Kostka & Spang, 2008) was adapted for GC-RMA preprocessing and is used for documenting the quantitative preprocessinginformation of the reference group. The gene expression based reportis developed in the open source language R, containing a GUI based onGtk2, and the final report is created as a PDF-file. Results. The developedpublicly available software (GEP-R) allows creating a gene expressionbased report based on Affymetrix raw-data for the risk stratification of anindividual patient based on saved preprocessing information of a referencecohort by treating the individual patient's expression data as beingpart of this group, assuring comparable risk stratification. Results can beinterpreted and commented within the report and a PDF based documentbe created. The generation of the report can be performed within short time on a standard computer. Conclusion. Gene expression reportingallows validated assessment of risk and individual therapeutic targetsin myeloma patients within a clinical routine setting.Gemeinsame Jahrestagung der Deutschen, Österreichischen und Schweizerischen Gesellschaften für Hämatologie und Onkologie, 2.-6. Oktober 2009, Heidelberg/Mannheim
    Type of Publication: Meeting abstract published
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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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