Abstract
BackgroundThrombocytopenia is a significant problem in patients with relapsed or refractory multiple myeloma, precipitating a need for supportive platelet transfusions and necessitating decreases in delivered doses of chemotherapy. Eltrombopag is a non-peptide, small molecule thrombopoietin (TPO) receptor agonist that promotes megakaryopoiesis similar to endogenous human TPO and may be an effective agent for thrombocytopenia in this patient population.MethodsWe examined the effects of eltrombopag on megakaryocyte colony-forming capacity in CD34+ cells in patients with multiple myeloma and investigated its impact on proliferation, viability, and apoptosis in primary CD138+ human myeloma cells and myeloma cell lines.ResultsEltrombopag at doses of 0.1 to 100 μM did not enhance proliferation of primary human CD138+ multiple myeloma cells from patients with relapsed disease or myeloma cell lines when used alone or in combination with erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF) and did not alter cell viability nor apoptosis of human myeloma cells exposed to bortezomib and lenalidomide. Eltrombopag stimulated megakaryopoiesis in human CD34+ cells from normal individuals and from patients with relapsed multiple myeloma via activation of Akt signaling pathways.ConclusionsThese results provide proof-of-principle supporting the design of future clinical studies examining eltrombopag for the treatment of thrombocytopenia in patients with advanced multiple myeloma.
Highlights
Thrombocytopenia is a significant problem in patients with relapsed or refractory multiple myeloma, precipitating a need for supportive platelet transfusions and necessitating decreases in delivered doses of chemotherapy
Multiple myeloma cells do not express MPL We examined whether c-mpl was expressed on human myeloma cell lines or primary CD138+ myeloma cells from patients with relapsed disease
Primary myeloma cells from each patient were found to be ≥95% CD138+/CD19−, as assessed by staining with CD138-PE and CD19-APC antibodies as previously described [18]. cDNA was prepared from the KMS-11 and OCI-My5 cell lines and from primary CD138+ myeloma cells from four subjects, and a specific 144 bp fragment of the human MPL gene and a 797 bp fragment of the GAPDH gene were amplified by polymerase chain reaction (PCR). cDNA prepared from normal CD34+ cells cultured in the presence of 100 ng/ml Recombinant human TPO (rhTPO) for 4 days or K562 cells [19] were used as positive and negative controls, respectively
Summary
Thrombocytopenia is a significant problem in patients with relapsed or refractory multiple myeloma, precipitating a need for supportive platelet transfusions and necessitating decreases in delivered doses of chemotherapy. Eltrombopag is a non-peptide, small molecule thrombopoietin (TPO) receptor agonist that promotes megakaryopoiesis similar to endogenous human TPO and may be an effective agent for thrombocytopenia in this patient population. Significant thrombocytopenia is a common problem in patients with relapsed or refractory multiple myeloma, resulting in increased bleeding complications, administration of supportive platelet transfusions, and necessitating reductions in delivered doses of chemotherapy. Eltrombopag is an orally bioavailable, non-peptide, small molecule c-mpl agonist that has been shown in both in vitro and in vivo studies to promote megakaryocyte proliferation and differentiation in a manner similar to that seen with endogenous human TPO [13]. Preclinical studies evaluating the effects of eltrombopag on bone marrow cells from patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) found that it promoted normal megakaryopoiesis without inducing clonal expansion of malignant cells [17]
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