Background: Malignant cells display distinct metabolic phenotypes, including the glycolytic phenotype (prominent glycolysis even in the presence of adequate oxygen). Some multiple myeloma (MM) demonstrates this phenotype. Dichloroacetate (DCA) is an investigational drug that reverses the glycolytic phenotype by inhibiting pyruvate dehydrogenase kinases (PDK), redirecting metabolism of pyruvate away from lactate production towards mitochondrial oxidation. Several phase 1/2 trials in solid cancers suggest DCA shows promise as synergistic with chemotherapy.
Methods: DiCAM, a phase 2 study at The Canberra Hospital, aims to determine efficacy of DCA in ‘plateau phase MM’ as indicated by a >25% fall in paraprotein and/or free light chain difference. DCA was administered as a novel loading dose of 25mg/kg BD for 5 doses, followed by a standard 6.25mg/kg BD for 3 months, based on previously reported dosing regimens. Peak and trough levels were correlated with tolerability and GSTZ1 genotype, the liver enzyme responsible for DCA’s metabolism.
Results: To date, six patients have completed treatment. Three showed a partial response after the first month; not sustained at 2 months. Two maintained a stable plateau, one patient progressed. Trough DCA levels on maintenance dosing (0.1-0.15 mM) approached the level for on-target inhibition of constitutive PDK2 (0.2 mM), but not hypoxia-induced PDK1 and PDK3. A 25mg/kg dose resulted in sustained (>6 hr) levels of 0.4-0.6 mM.
Minor sensory neuropathy was the most common adverse effect. One patient with prominent neuropathy showed higher DCA troughs, and possessed an uncommon GSTZ1 promoter genotype (11%) associated with reduced promoter activity.
Conclusion: DCA shows modest efficacy with low toxicity making it suitable for combination myeloma therapy. Dosing regimens used in prior trials may not be adequate to inhibit PDK, particularly with varying GSTZ1 promoter genotypes. Further trials with higher dose regimens and expanded inclusion criteria encompassing patients with smouldering myeloma are planned.