title: Proof of the concept to use a malignant B cell line drug screen strategy for identification and weight of melphalan resistance genes in multiple myeloma.
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.
authors.affiliation: Department of Haematology, Aalborg Hospital Science and Innovation Center (AHSIC), Aalborg University Hospital, Aalborg, Denmark ; Department of Mathematical Sciences, Aalborg University, Aalborg, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Bøgsted
authors.affiliation: Department of Haematology, Aalborg Hospital Science and Innovation Center (AHSIC), Aalborg University Hospital, Aalborg, Denmark ; Department of Mathematical Sciences, Aalborg University, Aalborg, Denmark.
authors.forename: Anders E
authors.initials: AE
authors.lastname: Bilgrau
authors.affiliation: Haemato-Oncology Research Unit, Division of Molecular Pathology, Institute of Cancer Research, London, United Kingdom.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Wardell
authors.affiliation: Department of Internal Medicine V and National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Bertsch
authors.affiliation: Department of Haematology, Aalborg Hospital Science and Innovation Center (AHSIC), Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmitz
authors.affiliation: Department of Haematology, Aalborg Hospital Science and Innovation Center (AHSIC), Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Julie S
authors.initials: JS
authors.lastname: Bødker
authors.affiliation: Department of Haematology, Aalborg Hospital Science and Innovation Center (AHSIC), Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Malene K
authors.initials: MK
authors.lastname: Kjeldsen
authors.affiliation: Department of Internal Medicine V and National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
authors.affiliation: Haemato-Oncology Research Unit, Division of Molecular Pathology, Institute of Cancer Research, London, United Kingdom.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
authors.affiliation: Department of Haematology, Aalborg Hospital Science and Innovation Center (AHSIC), Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Karen
authors.initials: K
authors.lastname: Dybkaer
authors.affiliation: Department of Haematology, Aalborg Hospital Science and Innovation Center (AHSIC), Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Hans E
authors.initials: HE
authors.lastname: Johnsen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D056741:Cyclin D / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D008558:Melphalan / Q000494:pharmacology*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D014178:Translocation, Genetic
chemical_list: D000970:Antineoplastic Agents; D056741:Cyclin D; D009363:Neoplasm Proteins; D008558:Melphalan