Phase II Clinical and Pharmacokinetic Study of Plitidepsin 3-Hour Infusion Every Two Weeks Alone or with Dexamethasone in Relapsed and Refractory Multiple Myeloma

Abstract

Purpose: This trial evaluated the antitumor activity and safety of the marine-derived cyclodepsipeptide plitidepsin in patients with relapsed/refractory multiple myeloma.Experimental Design: This was a prospective, multicenter, open-label, single-arm, phase II trial with plitidepsin at 5 mg/m 2 as a 3-hour i.v. infusion every two weeks. The protocol was amended to allow patients with suboptimal response to single-agent plitidepsin to add 20 mg/day on days 1 to 4 of oral dexamethasone every two weeks. Results: Fifty-one patients started treatment with plitidepsin and 47 were evaluable for efficacy. The overall response rate (complete response plus partial response plus minimal response) was 13% with plitidepsin alone and 22% in the cohort of patients with the addition of dexamethasone (n = 19, 18 evaluable). Both plitidepsin alone and with dexamethasone were feasible and well tolerated. Anemia (29%) and thrombocytopenia (18%) were the most frequent grade 3/4 hematologic toxicities. Fatigue (16%), muscular toxicity (6%), and transient alanine aminotransferase/aspartate aminotransferase (27%) and creatine phosphokinase (23%) increases were the most relevant nonhematologic side effects. A prolonged plasma half-life was observed in responding patients as compared with nonresponding patients (P = 0.009).Conclusions: Single-agent plitidepsin has limited but reproducible activity in relapsed/refractory multiple myeloma patients. Activity observed after dexamethasone addition merits further study. Both regimens were well tolerated in this heavily pretreated population. Clin Cancer Res; 16(12); 3260-9. ©2010 AACR.Multiple myeloma is the second most common hematologic malignancy after non-Hodgkin's lymphoma. In the Western hemisphere, about 1% of cancer-related deaths are due to myeloma. The disease primarily affects aged individuals, with a median age of 60 years at diagnosis. Despite recent advances in the treatment of multiple myeloma and the availability of novel agents, few patients, if any, can be considered cured, as the vast majority will eventually relapse (1). Thus, new active agents without known cross-resistance with other well-established anti-multiple myeloma agents are needed.Plitidepsin is a cyclodepsipeptide originally isolated from the Mediterranean tunicate Aplidium albicans and is currently produced by chemical synthesis. The doselimiting toxicities (DLT) at the phase II recommended dose of 5.0 mg/m 2 over a 3-hour i.v. infusion every two weeks (2-7) included myalgia, muscular weakness, transient and reversible transaminases increase, and fatigue both in patients with solid tumors and in those

Didemnins, tamandarins and related natural products

“…The activity observed after dexamethasone addition should be further investigated. 73 3.3.6 JAK2 inhibitors. The discovery of JAK2 mutations in Philadelphia-negative myeloproliferative neoplasms prompted investigators to evaluate mutation-targeted treatments to restore hematopoietic cell functions in these diseases.…”

Plitidepsin (Aplidin) is a potent inhibitor of diffuse large cell and Burkitt lymphoma and is synergistic with rituximab

“…41 A phase II study of plitidepsin with dexamethasone in relapse/refractory multiple myeloma reported a response rate of 13% with plitidepsin alone and 22% in the cohort of patients with the addition of dexamethasone. 18 In peripheral T-cell lymphoma, a response rate of 20% was recently reported. 27 In this study, we explored the efficacy of plitidepsin alone and in combination in two aggressive type lymphomas.…”

“…Plitidepsin is a marine derived antitumor agent currently in phase II/III clinical trials for solid and hematologic malignancies. 17,18 Plitidepsin has strong antiproliferative activity against different human cancer cell lines and tumors. 19,20 Importantly, little or no bone marrow toxicity has been detected in clinical trials.…”

How I treat relapsed myeloma

“…A newer exciting approach is immunotherapy with modified virus use, 74 natural killer cell therapy, 75,76 or chimeric antigen receptor strategies, 77 combining activity against malignant plasma cells and T-cell receptors. The above and other potential effective drugs in MM [78][79][80][81][82][83][84][85][86] are listed in Table 3. However, all of these newer agents are only used in clinical trials and are not yet available for most practitioners.…”