Aplidin-Dexamethasone Combo Improves Survival in Advanced Multiple Myeloma Patients, Phase 3 Trial Reports

Combining Aplidin (plitidepsin) with dexamethasone significantly extends their survival in heavily pretreated multiple myeloma patients compared to dexamethasone alone, data from a Phase 3 trial show.

PharmaMar, Aplidin’s maker, presented these findings in an oral presentation at the recent 2018 American Society of Clinical Oncology (ASCO) Annual Meeting  in Chicago.  Details can be found in the abstract “Overall survival (OS) results of randomized phase III study (ADMYRE trial) of plitidepsin and dexamethasone (DXM) vs. DXM alone in patients with relapsed/refractory multiple myeloma (RRMM): Evaluation of the crossover impact.”

Aplidin is a synthetic chemical that was originally isolated from the marine invertebrate Aplidium albicans. It targets the cancer-causing gene eEF1A2, which is produced in excess by multiple myeloma cells.

The Phase 3 trial, called ADMYRE (NCT01102426), compared the safety and efficacy of Aplidin plus dexamethasone to dexamethasone alone in patients with relapsed or refractory multiple myeloma who had received three to six prior therapies, including Velcade (bortezomib), and Revlimid (lenalidomide) or thalidomide.

The trial, designed to assess the time a patient lived without disease worsening as its primary goal, randomly assigned patients in a 2:1 ratio, meaning that for each patient receiving dexamethasone, two would receive the combination.

The trial allowed patients in the dexamethasone arm to crossover to combination treatment if their disease progressed after eight or more weeks taking dexamethasone.

Results previously presented at the ASH meeting in December 2017 showed that patients receiving the Aplidin combo lived almost two month longer before their disease progressed, compared to those in the dexamethasone arm. This represented a 35 percent reduction in the risk of death or disease worsening.

More patients also responded to the combination treatment than to monotherapy — 13.8 percent versus 1.7 percent. The median duration of response were 12 months in patients taking Aplidin and 1.8 months in the only patient who had responded to dexamethasone.

At the time, researchers also saw a trend toward longer survival with the Aplidin combo, 11.6 months versus 8.9 months.

Now, researchers assessed survival rates taking into account those who crossed over to the combination arm after progressing on dexamethasone. This was achieved with two statistical models, the rank preserving structural failure time (RPSFT) and the two-stage methods.

Of the 84 patients treated with dexamethasone, 37 (44%) switched to the combination treatment after progression.

Using RPSFT, researchers found that patients treated with Aplidin survived a median of 11.6 months, compared to 7.2 months for those treated with dexamethasone alone.

With the two-stage methods, patients in the combination lived a median of 11.6 months, compared to 6.4 months in the single-agent group. This model showed a 37.8 percent reduction in the risk of death.

“Plitidepsin in combination with DXM [dexamethasone] demonstrated a clinically significant benefit in terms of overall survival in heavily pretreated RRMM, a disease where new therapeutic alternatives are still needed,” the researchers wrote.