Final Results of a Phase II Trial with Plitidepsin (Aplidin) Alone and in Combination with Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma

Background: Plitidepsin (Aplidin - APL) is a cyclic depsipeptide isolated from the marine tunicate, Aplidium albicans. In vitro studies have shown potent activity against multiple myeloma (MM) cell lines and fresh cells obtained from MM patients, including cells resistant to conventional anti-MM agents and novel drugs (bortezomib, thalidomide, etc.). APL is ongoing clinical development in both, solid tumors and hematological malignancies, being muscle and liver (transient transaminases elevations) the main dose limiting toxicities. No significant hematological toxicity has been observed at the recommended dose of 5 mg/m² (administered over 3 hours by intravenous infusion) every two weeks. A prospective multicenter phase II study to evaluate the activity of APL in patients with relapsed/refractory MM has been recently completed and the final results are reported. On August 2005 the protocol was amended allowing the addition of dexamethasone (DXM) (20 mg on days 1–4) in those pts progressing after 3 cycles or remaining in SD after 4 cycles of APL alone.

Patients and Methods: Between Jun04 and Apr08, 53 relapsed/refractory MM pts were enrolled and 51 pts received treatment. Median age at the time of inclusion was 64 years (range: 47–86). The median number of prior lines of therapy was 4 (range: 1–8): 57% had undergone autologous stem cell transplant, 54% IMIDs-based therapy and 64% prior bortezomib. 47 pts were evaluable for response according to Bladé criteria. During the first study-phase, 24 patients were included and 21 received APL as monotherapy; 1 pt (5%) achieved PR, 1 pt (5%) MR and 5 pts remained in SD (24%) which makes an overall response rate (ORR) of 10%. During the second study-phase, 29 additional patients were included being 24 evaluable for response. ORR to APL as monotherapy in this second cohort was 21%, including 1 PR (4,3%) and 4 MR (17%); in addition, 15 pts remained in SD. DXM was subsequently added in 19 pts, 18 of them evaluable for efficacy, and response was upgraded as follows: 2 pts (11%) achieved PR, 2 pts MR (11%), and 9 pts (50%) remained in SD. Overall, pooled data of all evaluable patients (n=47) receiving APL as monotherapy in the two stages resulted in an ORR of 15% (2 PR, 5 MR). Median time to progression (TTP) was 3 months (mo) (95%CI: 2–5) and median overall survival (OS) was 17 mo. The addition of DXM increased the global ORR up to 19% (4 PR, 5 MR; n=47); in addition, in 28 pts disease was stabilized without progression. Median TTP increased up to 4.7 mo (95%CI: 3–8). Median OS has not been reached in this group and 82% of patients receiving APL plus DXM remained alive at 6 mo (95%CI: 63–100). All treated patients (n=51) were evaluated for safety (NCI criteria). The most common G3–4 drug-related adverse events were fatigue in 9 pts (18%), muscle events (weakness, myalgia, myopathy) in 5 pts (12%), serum creatine phosphokinase increase in 4 pts (8%) and liver enzyme disorders in 2 pts (4%). Neither significant APL-related hematologic toxicity nor neuropathies were observed.

Conclusion: APL has promising activity in this heavily treated subset of patients resulting in an ORR of 15%, which is upgraded up to 19% when DXM is added. This benefit was also translated in terms of TTP and OS. Toxicity profile is acceptable and the very low hematological toxicity of APL makes it an ideal agent in this disease setting. Further studies to determine the role of APL in combination with bortezomib and IMIDs are planned.