Aplidin Prolongs Survival and Time to Disease Progression in Heavily Treated Multiple Myeloma Patients, Phase 3 Trial Shows

Aplidin (plitidepsin) in combination with dexamethasone significantly prolonged the survival and time to disease progression or death in heavily treated patients with relapsed or refractory multiple myeloma compared to patients taking dexamethasone alone, a Phase 3 trial shows.

The trial’s findings were reported in the study, “Randomized phase III study (ADMYRE) of plitidepsin in combination with dexamethasone vs. dexamethasone alone in patients with relapsed/refractory multiple myeloma,” which was published in the Annals of Hematology.

Aplidin is an experimental anti-cancer therapy that has been developed by PharmaMar. Its active ingredient, plitidepsin, is an anti-tumor compound that was originally isolated from the sea squirt (Aplidium albicans). The medication works by binding to the eEF1A2 protein that is found on the surface of malignant myeloma cells, thereby interfering with their growth and viability.

The therapy has received the status of orphan drug in the U.S., Europe, and Switzerland. In Australia, it was recently approved in combination with dexamethasone to treat multiple myeloma patients who failed or became resistant to other therapies.

The approval was largely based on findings from the multicenter, randomized, open-label ADMYRE Phase 3 trial (NCT01102426).

The study’s main goal was to compare the safety and efficacy of Aplidin in combination with dexamethasone to dexamethasone alone in a group of patients with relapsed or refractory multiple myeloma who had received between three to six prior therapies, including Velcade (bortezomib), and Revlimid (lenalidomide) or thalidomide.

The trial enrolled a total of 255 patients who were randomly assigned at a ratio of 2:1 to receive either the Aplidin-dexamethasone combo therapy (5 mg/m² of Aplidin on days 1 and 15 plus 40 mg of dexamethasone on days 1, 8, 15 and 22, every four weeks), or dexamethasone alone. The median number of prior therapies was four in both groups.

The trial allowed patients in the dexamethasone treatment group to switch to the combo therapy group if their disease progressed after eight weeks or more of taking dexamethasone.

The study’s primary outcome was to evaluate the time patients lived until disease progression (progression-free survival, or PFS). Secondary outcomes included patients’ response rate, duration of response, and overall survival.

Key findings from ADMYRE have shown that adding Aplidin to dexamethasone prolonged patients’ median PFS from 1.7 months to 2.6 months, which corresponded to a 35% reduction in the risk of disease progression or death.

While Aplidin treatment led to a median overall survival of 11.6 months, compared with 8.9 months for dexamethasone-treated patients, the difference did not reach statistical significance.

The effect of the combo therapy on overall survival, however, became significant after removing data from the 37 patients who had switched from the control group to the active treatment group: Median overall survival remained at 11.6 months and was estimated to be 6.4 months for the control group. In this analysis, Aplidin cut the relative risk of death by about 38%.

The researchers also showed that more patients responded to the Aplidin combination (13.8%) than to dexamethasone alone (1.7%) and that the combo therapy was generally considered safe and well-tolerated.

The most common severe (grade 3) and life-threatening (grade 4) treatment-related adverse events included fatigue, muscle pain, and nausea, and most were temporary and easily reversible. The percentage of patients who discontinued treatment due to adverse events was similar in the combo therapy group (9.0%) and the dexamethasone group (9.6%).

Two deaths were reported during the trial, one in each treatment group.

“In conclusion, efficacy data, the reassuring safety profile, and the novel mechanism of action of plitidepsin suggest that this combination can be an alternative option in patients with relapsed/refractory multiple myeloma after at least three prior therapy lines,” the investigators wrote in the study.

Of note, some of the researchers have links to PharmaMar.