Preliminary Report from an Exploratory Phase II Trial with Plitidepsin (Aplidin®) in Patients with Refractory/Relapsed Multiple Myeloma.

Introduction and objectives :

Plitidepsin is a cyclic depsipeptide originally isolated from the marine tunicate, Aplidium albicans. It appears very potent against multiple myeloma (MM) cells. Specifically, it was observed that it was active against a broad panel of 35 human MM cell lines, which included MM cells resistant to conventional anti-MM agents and novel agents (i.e. thalidomide, bortezomib). Plitidepsin also induced cell death in primary MM tumor cells freshly isolated from patients resistant to thalidomide or its analogs and/or proteasome inhibitors. Phase I has been completed exploring 4 different schedules of administration. Muscle and liver (transaminases and/or alkaline phosphatase) toxicities were the main DLTs. Hematological toxicity was not observed at the recommended dose. The aim of this trial was to explore the activity of plitidepsin in patients with previously treated refractory/relapsed MM.

Material and Methods:

This is a non-randomized two-stage Phase II, multicenter, clinical and pharmacokinetic trial, with Aplidin® (APLD) 5 mg/m² as a 3 h intravenous infusion every 2 weeks, with antiemetic and antihistaminic prophylaxis. In the first stage 16 patients evaluable for efficacy were included. At least one response was requested in order to proceed with the second stage, in which a total of 37 patients will be included.

Results:

Between June’04 and June’05, 19 patients have been enrolled and data are available for 18 patient (7 men and 11 women, median age was 65.7y, range 48–82). Patients were previously relapsed/refractory. Prior treatments included: stem cell transplantation 64.7%, thalidomide 35.28% and bortezomib 17.64%. The median previous chemotherapy lines received were 3, range 1–6. The APLD median number of cycles received 4, range 1–16. Thirteen patients are currently evaluable for efficacy. One patient (7.7%) achieved a partial response (PR) with a 70% reduction in M-component lasting 8 months. Stable disease lasting between 3–5 months was observed in 3 patients (23.0%). In 2 patients (15.38%) a stabilization lasting 2.5 months was stated and the remaining 7 patients (53.8%) progressed. NCI-CTC grade 3–4 related toxicities were reported for n=17 patients and were mainly fatigue in 2 patients (11.8%), myalgia in 1 patient (5.9%), elevation of CPK in 1 patient (5.9%) and transient transaminases increase in 9 patients (52.9%). Significant hematological toxicity did not occurred in spite of 2 patients included and treated with thrombopenia grade 3–4 and 2 patient with neutropenia grade 3.

Conclusions:

First stage data shows that APLD presents hints of activity in patients with refractory/relapsed MM, with acceptable toxicity profile, thus meeting the criteria for proceeding to second stage recruitment. The absence of significant hematological toxicity is a well known feature of this drug and is being confirmed in this trial.