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Background: 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. Methods: We 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. Results: Eltrombopag 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. Conclusions: These 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. [ABSTRACT FROM AUTHOR]

Haploinsufficiency of ribosomal proteins ( RPs) and upregulation of the tumour suppressor TP53 have been shown to be the common basis for the anaemia observed in Diamond Blackfan anaemia and 5q- myelodysplastic syndrome. We previously demonstrated that treatment with L-Leucine resulted in a marked improvement in anaemia in disease models. To determine if the L-Leucine effect was Tp53-dependent, we used antisense MOs to rps19 and rps14 in zebrafish; expression of tp53 and its downstream target cdkn1a remained elevated following L-leucine treatment. We confirmed this observation in human CD34+ cells. L-Leucine thus alleviates anaemia in RP-deficient cells in a TP53-independent manner. [ABSTRACT FROM AUTHOR]