Phase I clinical trial of the inosine monophosphate dehydrogenase inhibitor mycophenolate mofetil (cellcept) in advanced multiple myeloma patients.
OBJECTIVE
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.


METHODS
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.
Takebe
Naoko
N
University of Maryland Greenebaum Cancer Center, Baltimore, Maryland 21201, USA. ntakebe@som.umaryland.edu
Cheng
Xiangfei
X
Wu
Suhlan
S
Bauer
Kenneth
K
Goloubeva
Olga G
OG
Fenton
Robert G
RG
Heyman
Meyer
M
Rapoport
Aaron P
AP
Badros
Ashraf
A
Shaughnessy
John
J
Ross
Douglas
D
Meisenberg
Barry
B
Tricot
Guido
G
D000368:Aged; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010954:Plasmacytoma / Q000473:pathology; D016879:Salvage Therapy
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid