title: Bone marrow infiltration by multiple myeloma causes anemia by reversible disruption of erythropoiesis.
abstract: Multiple myeloma (MM) infiltrates bone marrow and causes anemia by disrupting erythropoiesis, but the effects of marrow infiltration on anemia are difficult to quantify. Marrow biopsies of newly diagnosed MM patients were analyzed before and after four 28-day cycles of non-erythrotoxic remission induction chemotherapy. Complete blood cell counts and serum paraprotein concentrations were measured at diagnosis and before each chemotherapy cycle. At diagnosis, marrow area infiltrated by myeloma correlated negatively with hemoglobin, erythrocytes, and marrow erythroid cells. After successful chemotherapy, patients with less than 30% myeloma infiltration at diagnosis had no change in these parameters, whereas patients with more than 30% myeloma infiltration at diagnosis increased all three parameters. Clinical data were used to develop mathematical models of the effects of myeloma infiltration on the marrow niches of terminal erythropoiesis, the erythroblastic islands (EBIs). A hybrid discrete-continuous model of erythropoiesis based on EBI structure/function was extended to sections of marrow containing multiple EBIs. In the model, myeloma cells can kill erythroid cells by physically destroying EBIs and by producing proapoptotic cytokines. Following chemotherapy, changes in serum paraproteins as measures of myeloma cells and changes in erythrocyte numbers as measures of marrow erythroid cells allowed modeling of myeloma cell death and erythroid cell recovery, respectively. Simulations of marrow infiltration by myeloma and treatment with non-erythrotoxic chemotherapy demonstrate that myeloma-mediated destruction and subsequent reestablishment of EBIs and expansion of erythroid cell populations in EBIs following chemotherapy provide explanations for anemia development and its therapy-mediated recovery in MM patients.
authors.affiliation: Institut Camille Jordan, UMR 5208 CNRS, University Lyon 1, Villeurbanne, 69622, France.
authors.forename: Anass
authors.initials: A
authors.lastname: Bouchnita
authors.affiliation: Institut Camille Jordan, UMR 5208 CNRS, University Lyon 1, Villeurbanne, 69622, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Eymard
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Tamara K
authors.initials: TK
authors.lastname: Moyo
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Koury
authors.affiliation: Institut Camille Jordan, UMR 5208 CNRS, University Lyon 1, Villeurbanne, 69622, France.|INRIA Team Dracula, INRIA Antenne Lyon La Doua, Villeurbanne 69603, France, and European Institute of Systems Biology and Medicine, Lyon, 69007, France.
authors.forename: Vitaly
authors.initials: V
authors.lastname: Volpert
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015415:Biomarkers; D001853:Bone Marrow / Q000473:pathology* / Q000503:physiopathology; D000069286:Bortezomib / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D004909:Erythrocyte Indices; D041905:Erythroid Cells / Q000473:pathology; D004920:Erythropoiesis / Q000187:drug effects; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D009101:Multiple Myeloma / Q000150:complications* / Q000188:drug therapy / Q000473:pathology*; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; D000077269:Lenalidomide