title: Lenalidomide consolidation treatment in patients with multiple myeloma suppresses myelopoieses but spares erythropoiesis.
abstract: New drugs for the treatment of multiple myeloma (MM) comprise immunomodulatory substances such as lenalidomide and related compounds. While lenalidomide has found its way into first-line treatment as well as into relapse therapy, little is known about lenalidomide effects on normal hematopoietic stem and progenitor cells (HSPCs). In this study, we investigated whether HSPCs are influenced by lenalidomide on a phenotypic, functional and gene expression level. For that purpose, samples from patients with MM were obtained who underwent equivalent first-line treatment including induction therapy, cytotoxic stem cell mobilization and high-dose melphalan therapy followed by autologous blood stem cell transplantation and a subsequent uniform lenalidomide consolidation treatment within a prospective clinical trial. We found that after six months of lenalidomide therapy, the number of CD34(+) HSPCs decreased. Additionally, lenalidomide affects the numerical composition of hematopoietic cells in the bone marrow while it does not affect long-term HSPC proliferation in vitro. We found a significant amplification of fetal hemoglobin (HbF) expression on a transcriptional level and can confirm a stimulated erythropoiesis on a phenotypic level. These effects were accompanied by silencing of the TGF-β signaling pathway on the gene expression and protein level that is known to be amplified in active MM. However, these pleiotropic effects gave no evidence for mutagenic potential. In conclusion, lenalidomide does not exert long-term effects on proliferation of HSPCs but instead promotes erythropoiesis by shifting hemoglobin expression toward HbF and by silencing the TGF-β signaling pathway.
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf and Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.|Hematology, University and University Hospital Zurich, Zurich, Switzerland.
authors.forename: Christian Matthias
authors.initials: CM
authors.lastname: Wilk
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf and Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.|Department of Diagnostic and Interventional Radiology, University Hospital Duesseldorf and Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Heinzler
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf and Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
authors.forename: Amelie
authors.initials: A
authors.lastname: Boquoi
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf and Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
authors.forename: Ron-Patrick
authors.initials: RP
authors.lastname: Cadeddu
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf and Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.|Division of Emergency Care, Helios Klinikum Wuppertal, Wuppertal, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Strapatsas
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf and Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
authors.forename: Ariane
authors.initials: A
authors.lastname: Dienst
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf and Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Majidi
authors.affiliation: Biologisch-Medizinisches Forschungszentrum (BMFZ), Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Deenen
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Ingmar
authors.initials: I
authors.lastname: Bruns
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf and Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schroeder
authors.affiliation: Biologisch-Medizinisches Forschungszentrum (BMFZ), Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Köhrer
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf and Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Haas
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf and Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Kobbe
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf and Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany. fenk@med.uni-duesseldorf.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Fenk
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects; D060830:Consolidation Chemotherapy; D004920:Erythropoiesis / Q000187:drug effects*; D005319:Fetal Hemoglobin / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D000077269:Lenalidomide; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood* / Q000188:drug therapy*; D038042:Myelopoiesis / Q000187:drug effects*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D020533:Angiogenesis Inhibitors; D013792:Thalidomide; D005319:Fetal Hemoglobin; D000077269:Lenalidomide
keywords: hematopoietic stem cells; lenalidomide; multiple myeloma