Dichloroacetate (DCA) is a pyruvate dehydrogenase kinase (PDK) inhibitor that can reverse the glycolytic phenotype. Phase 1/2 trials of DCA in cancer have demonstrated it is well tolerated, but there is limited efficacy information. DCA is metabolised by hepatic GSTZ1, which has common polymorphisms that may alter patient drug levels. Multiple myeloma (MM) is a B-cell malignancy with a glycolytic phenotype. In vitro, DCA can inhibit MM proliferation and increase apoptosis, and DCA improved survival of MM-bearing mice when combined with bortezomib. DiCAM is the first trial to test the efficacy of DCA in plateau phase MM.
DiCAM is a prospective two-stage, non-randomised phase 2 trial ongoing at The Canberra Hospital. Oral DCA (25 mg/kg bid for 3 days followed by 6.25 mg/kg bid for 12 weeks) was given in addition to standard maintenance therapies. Disease was monitored by monthly serum free light chain/paraprotein levels, DCA serum levels were determined by LC/MS, and GSTZ1 genotypes by PCR-RFLP.
MM patients tolerated DCA well despite baseline neuropathy. At 1 month, 3/6 patients had a partial response, but it was not sustained. Trough serum levels of DCA on the maintenance dose (0.1-0.15 mM) were approaching levels necessary for on-target inhibition of constitutive PDK2 (0.2 mM), but not sufficient to inhibit hypoxia-induced PDK1 and PDK3. Patients with unusual pharmacokinetics corresponded with patients having uncommon GSTZ1 genotypes.
We have demonstrated the safety of using DCA in MM patients with baseline neuropathy, but higher doses personalised according to GSTZ1 genotypes are required to achieve better outcomes.