Adding plitidepsin (Aplidin) to dexamethasone reduced the risk of disease progression by 35% versus dexamethasone alone in patients with relapsed/refractory multiple myeloma enrolled in the phase III ADMYRE trial.
Plitidepsin, which targets eukaryotic translation elongation factor 1 alpha 2 (eEF1A2), is an anticancer agent originally obtained from a marine organism, the ascidianAplidium albicans.
“These results are welcome as Aplidin appears to be another active agent with unique mechanisms of action in the management of multiple myeloma. While the outcomes for patients with multiple myeloma have improved greatly in recent years, they are still not ideal and this could pave the way for another treatment option for this difficult to manage disease. We are hopeful that Aplidin may soon provide another treatment option for those patients who have failed prior therapies and are running out of alternatives,” lead Australian investigator on the ADMYRE study Jeff Szer, director of haematology at the Royal Melbourne Hospital, said in a statement.
The open-label phase III ADMYRE trial (NCT01102426) included 255 patients with relapsed/refractory multiple myeloma (ECOG PS ≤2) enrolled at 83 locations across 19 countries, including centers in the United States, Europe, and Asia-Pacific. Patients had received 3 to 6 prior regimens.
Plitidepsin was administered at 5 mg/m2as a 3-hour IV infusion on days 1 and 15 every 4 weeks. Patients in both arms received 40 mg of dexamethasone orally (4 mg tablets) on days 1, 8, 15, and 22 every 4 weeks. In the experimental arm, dexamethasone was administered at least 1 hour before plitidepsin infusion.
The 35% reduction in the risk of progression observed with the plitidepsin combination met the trial’s primary endpoint of a statistically significant improvement in progression-free survival (P = .0054). Complete data from the trial will be presented at an upcoming medical meeting.
“Taking into account these positive results, we intend to submit a marketing authorization application to the European Medicines Agency during the last quarter of this year,” Luis Mora, managing director of the Oncology Business Unit of PharmaMar, said in a statement.
Carlo Montagner, CEO of ST Asia, added, “We look forward to working with PharmaMar to ensure this valuable multiple myeloma therapy is available as soon as possible to patients in key South East Asia regions, as well as in Australia and New Zealand.”
A previously published phase II trial evaluated both single-agent and combination plitidepsin therapy in multiple myeloma.1 In the study, 51 patients with relapsed/refractory multiple myeloma started treatment with plitidepsin monotherapy at the same dose administered in the ADMYRE trial. Patients who had a suboptimal response to single-agent plitidepsin were allowed to add 20 mg/day of oral dexamethasone on days 1 to 4 every 2 weeks.
Forty-seven patients were evaluable for efficacy. The overall response rate (complete response plus partial response plus minimal response) was 13% with plitidepsin monotherapy and 22% in the group of patients who added dexamethasone (n = 19, 18 evaluable).
Both Single-agent plitidepsin and the combination regimen were well tolerated. The most frequent grade 3/4 hematologic adverse events (AEs) were anemia (29%) and thrombocytopenia (18%). The most significant nonhematologic AEs included fatigue (16%), muscular toxicity (6%), and increased levels of ALT/AST (27%) and creatine phosphokinase (23%).
Plitidepsin has received an orphan drug designation from the FDA and the European Medicines Agency. Beyond the ADMYRE trial, the drug is also being evaluated in combination with bortezomib (Velcade) and dexamethasone in a phase Ib trial in relapsed/refractory multiple myeloma, as well as in a phase II study in relapsed or refractory angioimmunoblastic T-cell lymphoma.
In addition to its partnership with ST Asia, PharmaMar also has a licensing agreement to market and distribute plitidepsin with TTY Biopharm in Taiwan and a copromotion agreement in 8 European countries with Chugai Pharma Europe.