Marizomib
The novel, highly potent proteasome inhibitor marizomib, which irreversibly binds and inhibits all 3 proteasome subunits, is being studied in a phase 1 trial in combination with pomalidomide and dexamethasone in patients with relapsed and refractory disease, as well as in a phase 1/2 trial as monotherapy.5,6
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Preliminary findings of the phase 1 study evaluating the agent administered intravenously with pomalidomide and low-dose dexamethasone showed that 62% of patients achieved an overall response. In terms of safety, no dose-limiting toxicities were observed at the 4 dose levels evaluated. Marizomib is also in early clinical trials to evaluate an oral formulation.5
“A small study of 16 myeloma patients, which was part of a larger phase 1 trial, showed an overall response rate of 38% including minor responses with marizomib and an additional 38% had stable disease,” Dr Manasanch noted. “Although these results reflect a very small numbers of patients, marizomib is something to look out for.”7
Plitidepsin
Pitidepsin, an investigational marine-derived anticancer agent, is being evaluated with dexamethasone for relapsed/refractory multiple myeloma in a phase 3 trial and in combination with bortezomib and dexamethasone in a phase 1b trial.8,9 The drug works by binding to eEF1A2, thereby blocking the role of this protein and causing cell death.
In the multicenter, open-label, phase 3 ADMYRE trial, researchers have completed enrollment of patients with relapsed/refractory multiple myeloma who have received between 3 and 6 prior regimens for their disease. Participants were randomly assigned to receive plitidepsin 5 mg/m2 intravenously over 3 hours on days 1 and 15 plus dexamethasone 4 mg orally on days 1, 8, 15, and 22 of each 28-day cycle, or dexamethasone alone. The primary outcome measure is progression-free survival, with response rate, duration of response, and overall survival as secondary endpoints.
Preliminary data have shown that the addition of plitidepsin to dexamethasone resulted in a significant 35% reduction in the risk of progression or death compared with dexamethasone alone (P=.0054), thus meeting the study’s primary endpoint.10
A multicenter, open-label, dose-escalating, phase 1 study assessing plitidepsin plus bortezomib and dexamethasone is still recruiting patients who have received at least 1 previous treatment line. The primary goal is to determine a recommended dose of plitidepsin in this treatment combination.9
Of note, the FDA has granted orphan drug designation to plitidepsin.
