Background: Marizomib has a novel, non-peptide based, bicyclic structure and compared to other proteasome inhibitors, unique properties of clinical relevance. Specifically, marizomib produces rapid, broad and prolonged inhibition of all 3 20S proteasome catalytic activities, and markedly different safety and efficacy profiles, including activity against MM resistant to bortezomib (BZ) both in vitro and in vivo.
Materials and Methods: Marizomib was given IV over 1-120 minutes on days 1, 4, 8 and 11 of 21-day cycles in 2 separate and parallel dose escalation studies performed in Australia and the United States in patients with relapsed and refractory MM. In addition to standard safety and efficacy monitoring, pharmacokinetics (PK) and proteasome inhibition as part of pharmacodynamics (PD) were assessed. Dexamethasone (20 mg) was given the day prior to and day of treatment in one study and could be added for patients who did not achieve a minimal response (MR) or better after 2 cycles in the other study. Toxicity evaluation was performed using CTCAE v3.0 and response was assessed by modified European Group for Blood and Marrow Transplantation (EBMT) and Uniform Criteria (UC).
Results: 34 patients (16 men and 18 women) have been treated at doses of 0.075 to 0.6 mg/m2/dose BIW with a median age of 62.5 years, in both studies. Patients received a median of 6 prior regimens; 30 patients (88%) had been exposed to prior BZ, including 24 (71%) who were BZ -refractory. The maximum tolerated dose of marizomib was found to be 0.4 mg/m2 over a 60 minute infusion time and 0.5 mg/m2 over a 120 minute infusion. Dose limiting toxicities included transient hallucinations, cognitive changes and loss of balance, all of which proved reversible. The most common drug-related adverse events were fatigue, nausea, vomiting, dizziness, headache, diarrhea, constipation, insomnia, anorexia, and dyspnea, which proved manageable with supportive care and/or dose reduction. Importantly, marizomib did not appear to induce myelosuppression, peripheral neuropathy (PN) or thrombocytopenia. PK analysis demonstrated a rapid elimination half-life (< 20 minutes) and large volume of distribution, with PD analyses of packed whole blood (PWB) and peripheral blood mononuclear cells (PBMC) confirming dose dependent proteasome inhibition. At interim analysis, of 22 patients with evaluable disease for best response to marizomib +/- dexamethasone, 3 had achieved partial response (PR) by EBMT/UC (14%). In the active dose range of 0.4-0.6 mg/m2, 15 pts were evaluable with PR in 3 pts (20%), all of whom were refractory to prior BZ. Median time on treatment was 1.5 months, with stable disease or better documented in 16 pts (73%).
Conclusions: The safety profile of marizomib clearly differs from BZ, without significant treatment–emergent PN or myelosuppression described. Preliminary results suggest anti-myeloma activity, with responses seen in patients in whom BZ had previously failed, as well as interesting PK/PD characteristics and tissue distribution supporting a possible role in patients with different disease characteristics (such as extramedullary spread). The efficacy and safety of 0.5 mg/m2 of marizomib given twice weekly, alone or with low dose dexamethasone, warrants further study, and continues to be investigated. Future directions will include combination approaches with lenalidomide and dexamethasone.