Abstract
In a conceptual study of drug resistance we have used a preclinical model of malignant B-cell lines by combining drug induced growth inhibition and gene expression profiling. In the current report a melphalan resistance profile of 19 genes were weighted by microarray data from the MRC Myeloma IX trial and time to progression following high dose melphalan, to generate an individual melphalan resistance index. The resistance index was subsequently validated in the HOVON65/GMMG-HD4 trial data set to prove the concept. Biologically, the assigned resistance indices were differentially distributed among translocations and cyclin D expression classes. Clinically, the 25% most melphalan resistant, the intermediate 50% and the 25% most sensitive patients had a median progression free survival of 18, 32 and 28 months, respectively (log-rank P-value = 0.05). Furthermore, the median overall survival was 45 months for the resistant group and not reached for the intermediate and sensitive groups (log-rank P-value = 0.003) following 38 months median observation. In a multivariate analysis, correcting for age, sex and ISS-staging, we found a high resistance index to be an independent variable associated with inferior progression free survival and overall survival. This study provides clinical proof of concept to use in vitro drug screen for identification of melphalan resistance gene signatures for future functional analysis.
Highlights
Multiple Myeloma (MM) is an incurable B-cell malignancy that relapses due to resistant disease despite advances in therapeutic approaches [1,2]
We evaluated the impact of RI assignment on remission status following high dose melphalan (HDM) in the HOVON65/GMMGHD4 trial which revealed no significant difference with respect to obtained complete remission (CR), very good partial response (VGPR), PR, near complete remission (NCR) and progressive disease (PD) three months post transplant
This concept is based on recent work from the Myeloma Stem Cell Network (MSCNET) consortium making well characterized B-cell lines available for further studies, with the limitation that it only detects genetic resistance associated to oncogenesis and does not consider cell adhesion mediated drug resistance (CAMDR) or inherited genetic variations expected to contribute to the resistance phenotype
Summary
Multiple Myeloma (MM) is an incurable B-cell malignancy that relapses due to resistant disease despite advances in therapeutic approaches [1,2]. The ultimate goal for an individualized treatment strategy is to have diagnostic tests predicting drug specific resistance This is currently not state of the art in MM where a number of prognostic systems exist. It has been shown that ISS can be improved by the integration of cytogenetic findings, which are independently associated with poor prognosis [6,7,8,9,10] These observations underline the importance of genetic biomarkers in determining the optimal treatment approach in MM, and constitute the first step towards a personalised treatment approach, but do not constitute true prediction of the individual response to a single drug
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