Abstract
Recent studies have shown that arsenic trioxide (Trisenox, ATO) can induce apoptosis in myeloma cells and overcomes anti-apoptotic effects of interleukin-6. Pre-clinical studies reported profound anti-myeloma effects when ATO, ascorbic acid (AA) and dexamethasone are combined. Single nucleotide polymorphism (SNP) in metabolic enzymes may influence susceptibility of a treatment and the prognosis of multiple myeloma (MM).
We performed a multicenter phase II trial of ATO in patients with advanced MM. Patients with progressive disease following more than one line chemotherapy were included. The treatment regimen consists of four 28-days cycles. In 1st cycle, during 1st week: a loading-dose with ATO 0,25mg/kg IV, AA 1000mg IV and Dex 40mg orally on day 1–5. During 2nd and 3rd week: a maintenance-dose of twice weekly ATO 0,25mg/kg IV, AA 1000mg IV and Dex 20mg orally. During the 4th week no treatment is given. In the 2nd, 3rd and 4th cycle: a maintenance-dose of twice weekly ATO 0,25mg/kg IV, AA 1000mg IV and Dex 20mg orally in 1st, 2nd and 3rd week was administered followed by the 4th week as a rest period. Patients with a clinical response after the 4th cycle received two additional treatment cycles.
Preliminary results: The ongoing study currently has enrolled 20 pts, median age 63 yrs (range 42–76), who had received a median of 4 lines of prior treatments (range 1–6). There were 2 early deaths from pneumonia and gastro-intestinal bleeding. Fifteen patients were evaluable for response; PR in 2 pts, MR in 3 pts, SD in 3 pts and 7 pts had PD. Six patients died from progressive disease. Grade 3 or 4 adverse events included fluid retention (3), thrombocytopenia (2), neutropenia (1), increased ALT (2), peripheral neuropathy (1), bacterial pneumonia (2). In addition to standard clinical observations we did an analysis for Genetic Single Nucleotide polymorphisms of relevant metabolic enzymes in order to assess the relevance for toxicity and effect of ATO. A polymerase chain reaction followed by restriction enzyme digestion for GSTP1, CYP3A4, CYP3A5, MDR-1, GSTT1 and GSTM1 was performed. Responding patients vs non-responding patients showed the following wild-type(ww) / mutant (mm) / heterozygous (wm/mm) haplotype: GSTP1 1 / 2 / 1 vs 2 / 3 / 3; CYP3A4 1 / 0 / 3 vs 1 / 0 / 7; CYP3A5 0 / 4 / 0 vs 0 / 8 / 0; MDR1 0 / 3 / 1 vs 0 / 1 / 7 and deletion / normal genotype: GSTT1 1 / 3 vs 2/ 6; GSTM1 1 / 3 vs 4 / 4.
Conclusion: These preliminary results suggest that the ATO-AA-Dex regimen shows efficacy, with limited toxicity in advanced MM patients. An extended genotype analysis will be performed to characterize the role of metabolic enzymes in the effect of this regimen.
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