Plitidepsin, a marine-derived drug, targets the eukaryotic elongation factor 1A2e (EF1A2), a protein which is overexpressed in multiple myeloma (MM). Plitidepsin plus dexamethasone (DXM) showed activity in a phase II trial conducted in relapsed and/or refractory MM. We report here the efficacy and safety of plitidepsin plus DXM vs. DXM alone found in the randomized phase III trial ADMYRE.
METHODS:
Patients with relapsed/refractory MM after at least three but not more than six prior therapeutic regimens, including at least bortezomib and lenalidomide or thalidomide, were included between June 2010 and May 2015. Patients were randomly assigned (2:1) to receive plitidepsin 5 mg/m2 D1 and 15 plus DXM 40 mg D1,8,15 and 22 (Arm A) or DXM 40 mg D1,8,15 and 22 (Arm B) every four weeks. Stratification factors were Eastern Cooperative Oncology Group performance status score (0 and 1 vs. 2) and Durie-Salmon stage (I/II vs. III). Crossover from Arm A to Arm B was allowed in case of progressive disease (PD) after a minimum of eight weeks from randomization. The primary endpoint was progression-free survival (PFS). Overall survival (OS) was a key secondary endpoint.
FINDINGS:
A total of 255 patients were randomly assigned to receive either plitidepsin plus DXM (Arm A, n=171) or DXM alone (Arm B, n=84). Thirty-seven patients (44%) from Arm B crossed over to the combination arm (Arm A). A total of 167 patients were treated in Arm A and 83 in Arm B. Median PFS with confirmation of PD by Investigator’s assessment (IA) was 3.8 months (95% CI, 2.9-5.6 months) in Arm A and 1.9 months (95% CI, 1.1-2.7 months) in Arm B (HR=0.611; p=0.0048). Median PFS with plitidepsin plus DXM without confirmation of PD according to Independent Review Committee (IRC) was 2.6 months (95% CI, 1.9-3.0 months) in Arm A and 1.7 months (95% CI, 1.1-2.0 months) in Arm B (HR=0.650; p=0.0062). A trend for longer OS was observed in Arm A, with a median of 11.6 months (95% CI, 9.2-16.1 months) and 8.9 months (95% CI, 6.0-15.4 months) in Arm B, (HR=0.797; p=0.1273). When the crossover is mitigated by a sensitivity analysis based on the two-stage method proposed by Latimer et al., a significant difference in OS was observed (median of 11.6 months in Arm A and estimated as 6.7 months in Arm B) (HR=0.667; p=0.0069). Subsequent therapies were similar in both treatment arms. Objective response rate (ORR; ≥partial response) according to the IRC in evaluable patients was 13.8% in Arm A and 1.7% in Arm B, with a median duration of response of 12.0 months in Arm A (1.8 months in the only patient with response in Arm B). Responding patients in Arm A had a median OS of 37.8 months (OS was 27.7 months in the patient with response in Arm B, who crossed over to Arm A).
The most common grade 3-4 treatment-related adverse events (% of patients in Arm A/Arm B) were fatigue (10.8%/1.2%), myalgia (5.4%/0%) and nausea (3.6%/1.2%). The most common grade 3-4 hematological/non-hematological laboratory abnormalities regardless of relationship (% of patients in Arm A/Arm B) were anemia (31.3%/35.4%), thrombocytopenia (21.9%/27.9%), neutropenia (15.7%/5.1%), CPK increase (20%/0%), ALT increase (14.5%/0%) and AST increase (8.9%/0%). Most of these events were transient and reversible. Fifteen patients (9%) discontinued treatment due to treatment-related adverse events in Arm A; 3 (6.5%) in Arm B, and 5 in crossover patients (13.5%). One treatment-related adverse event lead to death in Arm A (0.6%) and one in Arm B (1.2%).
CONCLUSIONS:
This phase III trial on plitidepsin in combination with DXM showed prolongation of both PFS and OS, with a remarkable duration of response.
These efficacy data, the reassuring safety profile and the novel mechanism of action of plitidepsin suggest that plitidepsin plus DXM can be considered as a new treatment option in patients with relapsed/refractory MM.