PURPOSE: Inosine monophosphate dehydrogenase (IMPDH) inhibitors have been used to induce leukemia blast cell differentiation but have not been tested in multiple myeloma for activity. Currently, available IMPDH inhibitor, mycophenolate mofetil (MMF), which is known as an immunosuppressant, was shown to induce apoptosis in myeloma cell lines. On the basis of our preclinical studies, we designed a clinical study to test our hypothesis that MMF has antimyeloma activity. EXPERIMENTAL DESIGN: A Phase I MMF dose escalation study was conducted in relapsed and refractory myeloma patients who had documented disease progression by myeloma markers or bone marrow plasmacytosis to determine the maximum tolerated dose, toxicities, and efficacy of the drug. To assess the activity of IMPDH inhibition in the myeloma cells of patients, we measured intracellular nucleotide triphosphate levels by high-performance liquid chromatography-based analysis and examined the correlation with clinical response. RESULTS: Among the 11 study patients, MMF was generally well tolerated and was administered up to a maximum dose of 5 g/day. The most common toxicity was grade 1 fatigue (n = 4, 36%). One patient had a partial response (3 g/day), four patients had stable disease, and six patients had progression of disease. There was a statistically significant difference in the intracellular dGTP level changes between the stable disease/partial response group versus progression of disease. CONCLUSIONS: MMF at 1 to 5 g/day daily dose is well tolerated by patients with relapsed and refractory multiple myeloma patients. Positive correlation between clinical response and depletion of intracellular dGTP level was shown. Future drug development to target this enzyme maybe useful in treating myelomas.
PURPOSE: Inosine monophosphate dehydrogenase (IMPDH) inhibitors have been used to induce leukemia blast cell differentiation but have not been tested in multiple myeloma for activity. Currently, available IMPDH inhibitor, mycophenolate mofetil (MMF), which is known as an immunosuppressant, was shown to induce apoptosis in myeloma cell lines. On the basis of our preclinical studies, we designed a clinical study to test our hypothesis that MMF has antimyeloma activity. EXPERIMENTAL DESIGN: A Phase I MMF dose escalation study was conducted in relapsed and refractory myelomapatients who had documented disease progression by myeloma markers or bone marrow plasmacytosis to determine the maximum tolerated dose, toxicities, and efficacy of the drug. To assess the activity of IMPDH inhibition in the myeloma cells of patients, we measured intracellular nucleotide triphosphate levels by high-performance liquid chromatography-based analysis and examined the correlation with clinical response. RESULTS: Among the 11 study patients, MMF was generally well tolerated and was administered up to a maximum dose of 5 g/day. The most common toxicity was grade 1 fatigue (n = 4, 36%). One patient had a partial response (3 g/day), four patients had stable disease, and six patients had progression of disease. There was a statistically significant difference in the intracellular dGTP level changes between the stable disease/partial response group versus progression of disease. CONCLUSIONS:MMF at 1 to 5 g/day daily dose is well tolerated by patients with relapsed and refractory multiple myelomapatients. Positive correlation between clinical response and depletion of intracellular dGTP level was shown. Future drug development to target this enzyme maybe useful in treating myelomas.
Authors: Kan Chen; Wanlu Cao; Juan Li; Dave Sprengers; Pratika Y Hernanda; Xiangdong Kong; Luc Jw van der Laan; Kwan Man; Jaap Kwekkeboom; Herold J Metselaar; Maikel P Peppelenbosch; Qiuwei Pan Journal: Mol Med Date: 2015-10-13 Impact factor: 6.354
Authors: Tse-Yu Wu; Brooke L Fridley; Gregory D Jenkins; Anthony Batzler; Liewei Wang; Richard M Weinshilboum Journal: Int Immunopharmacol Date: 2011-03-23 Impact factor: 4.932
Authors: T-Y Wu; Y Peng; L L Pelleymounter; I Moon; B W Eckloff; E D Wieben; V C Yee; R M Weinshilboum Journal: Br J Pharmacol Date: 2010-12 Impact factor: 8.739
Authors: Abigail Koehler; Aniruddha Karve; Pankaj Desai; Jack Arbiser; David R Plas; Xiaoyang Qi; Renee D Read; Atsuo T Sasaki; Vaibhavkumar S Gawali; Donatien K Toukam; Debanjan Bhattacharya; Laura Kallay; Daniel A Pomeranz Krummel; Soma Sengupta Journal: Pharmaceuticals (Basel) Date: 2021-01-28