title: IKAROS expression in distinct bone marrow cell populations as a candidate biomarker for outcome with lenalidomide-dexamethasone therapy in multiple myeloma.
abstract: Immunomodulatory drugs (IMiDs) are a cornerstone in the treatment of multiple myeloma (MM), but specific markers to predict outcome are still missing. Recent work pointed to a prognostic role for IMiD target genes (e.g. CRBN). Moreover, indirect activity of IMiDs on immune cells correlated with outcome, raising the possibility that cell populations in the bone marrow (BM) microenvironment could serve as biomarkers. We therefore analysed gene expression levels of six IMiD target genes in whole BM samples of 44 myeloma patients treated with lenalidomide-dexamethasone. Expression of CRBN (R = 0.30, P = .05), IKZF1 (R = 0.31, P = .04), IRF4 (R = 0.38, P = .01), MCT-1 (R = 0.30, P = .05), and CD147 (R = 0.38, P = .01), but not IKZF3 (R = -0.15, P = .34), was significantly associated with response. Interestingly, IKZF1 expression was elevated in BM environmental cells and thus selected for further investigation by multicolor flow cytometry. High IKAROS protein levels in total BM mononuclear cells (median OS 83.4 vs. 32.2 months, P = .02), CD19+B cells (median OS 71.1 vs. 32.2 months, P = .05), CD3+CD8+T cells (median OS 83.4 vs 19.0 months, P = .008) as well as monocytes (median OS 53.9 vs 18.0 months, P = .009) were associated with superior overall survival (OS). In contrast, IKAROS protein expression in MM cells was not predictive for OS. Our data therefore corroborate the central role of immune cells for the clinical activity of IMiDs and built the groundwork for prospective analysis of IKAROS protein levels in distinct cell populations as a potential biomarker for IMiD based therapies.
authors.affiliation: Department of Medicine I, Center for Oncology and Hematology, Wilhelminen Cancer Research Institute, Wilhelminenspital, Vienna, Austria.
authors.forename: Arnold
authors.initials: A
authors.lastname: Bolomsky
authors.affiliation: Department of Laboratory Medicine, Wilhelminenspital, Vienna, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hübl
authors.affiliation: Division of Haematology and Haemostaseology, University of Torino, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Spada
authors.affiliation: Department of Medicine I, Center for Oncology and Hematology, Wilhelminen Cancer Research Institute, Wilhelminenspital, Vienna, Austria.
authors.forename: Ercan
authors.initials: E
authors.lastname: Müldür
authors.affiliation: Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Schlangen
authors.affiliation: Department of Medicine I, Center for Oncology and Hematology, Wilhelminen Cancer Research Institute, Wilhelminenspital, Vienna, Austria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Heintel
authors.affiliation: Department of Haematology, Manchester Royal Infirmary, Central Manchester University Hospital NHS Foundation Trust, Manchester, UK.|School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
authors.forename: Alberto
authors.initials: A
authors.lastname: Rocci
authors.affiliation: Department of Medicine I, Center for Oncology and Hematology, Wilhelminen Cancer Research Institute, Wilhelminenspital, Vienna, Austria.
authors.forename: Adalbert
authors.initials: A
authors.lastname: Weißmann
authors.affiliation: Department of Medicine I, Center for Oncology and Hematology, Wilhelminen Cancer Research Institute, Wilhelminenspital, Vienna, Austria.
authors.forename: Veronique
authors.initials: V
authors.lastname: Fritz
authors.affiliation: Department of Laboratory Medicine, Wilhelminenspital, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Willheim
authors.affiliation: Department of Medicine I, Center for Oncology and Hematology, Wilhelminen Cancer Research Institute, Wilhelminenspital, Vienna, Austria.
authors.forename: Niklas
authors.initials: N
authors.lastname: Zojer
authors.affiliation: Division of Haematology and Haemostaseology, University of Torino, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Palumbo
authors.affiliation: Department of Medicine I, Center for Oncology and Hematology, Wilhelminen Cancer Research Institute, Wilhelminenspital, Vienna, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Ludwig
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D001854:Bone Marrow Cells / Q000737:chemistry*; D003907:Dexamethasone / Q000627:therapeutic use; D015870:Gene Expression; D006801:Humans; D051740:Ikaros Transcription Factor / Q000032:analysis* / Q000378:metabolism; D007155:Immunologic Factors / Q000235:genetics / Q000627:therapeutic use*; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D013792:Thalidomide / Q000031:analogs & derivatives / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; C497239:IKZF1 protein, human; D007155:Immunologic Factors; D051740:Ikaros Transcription Factor; D013792:Thalidomide; D003907:Dexamethasone; D000077269:Lenalidomide