Randomized phase III study (ADMYRE) of plitidepsin in combination with dexamethasone vs. dexamethasone alone in patients with relapsed/refractory multiple myeloma

Abstract

The randomized phase III ADMYRE trial evaluated plitidepsin plus dexamethasone (DXM) versus DXM alone in patients with relapsed/refractory multiple myeloma after at least three but not more than six prior regimens, including at least bortezomib and lenalidomide or thalidomide. Patients were randomly assigned (2:1) to receive plitidepsin 5 mg/m 2 on D1 and D15 plus DXM 40 mg on D1, D8, D15, and D22 (arm A, n = 171) or DXM 40 mg on D1, D8, D15, and D22 (arm B, n = 84) q4wk. The primary endpoint was progression-free survival (PFS). Median PFS without disease progression (PD) confirmation (IRC assessment) was 2.6 months (arm A) and 1.7 months (arm B) (HR = 0.650; p = 0.0054). Median PFS with PD confirmation (investigator’s assessment) was 3.8 months (arm A) and 1.9 months (arm B) (HR = 0.611; p = 0.0040). Median overall survival (OS, intention-to-treat analysis) was 11.6 months (arm A) and 8.9 months (arm B) (HR = 0.797; p = 0.1261). OS improvement favoring arm A was found when discounting a crossover effect (37 patients crossed over from arm B to arm A) (two-stage method; HR = 0.622; p = 0.0015). The most common grade 3/4 treatment-related adverse events (% of patients arm A/arm B) were fatigue (10.8%/1.2%), myalgia (5.4%/0%), and nausea (3.6%/1.2%), being usually transient and reversible. The safety profile does not overlap with the toxicity observed with other agents used in multiple myeloma. In conclusion, efficacy data, the reassuring safety profile, and the novel mechanism of action of plitidepsin suggest that this combination can be an alternative option in patients with relapsed/refractory multiple myeloma after at least three prior therapy lines.

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

“…6b ), which may suggest that the rate of translation elongation is critical for obtaining optimal levels of viral proteins. Of note, the eEF1A inhibitor Plitidepsin is used clinically in multiple myeloma patients 51 . Multiple SARS-CoV-2 proteins are predicted to undergo SRP- and Sec61-mediated co-translational insertion into the endoplasmic reticulum, and SRP19/54/72 were identified as Nsp8 interacting proteins ( Fig.…”

Repurposing anticancer drugs for the management of COVID-19

“…So far, the drug has been investigated in several clinical trials for multiple myeloma, lymphoma, liposarcoma, and prostate cancer ( El Bairi et al 2018 ). Only one phase III randomized and controlled trial has evaluated the clinical activity of plitidepsin combined to dexamethasone in relapsed/refractory multiple myeloma (NCT01102426/ADMYRE), showing mild improvements in survival outcomes ( Spicka et al 2019 ). The development of this drug has been halted or terminated because of the arrival of competitive targeted agents as well as the poor enrollment in clinical trials.…”

Epidrug Repurposing: Discovering New Faces of Old Acquaintances in Cancer Therapy

“…In cancer cell lines, reduced spiruchostatin A effectively inhibited HDAC1, an effect not observed when oxidized, and it showed an increase in the acetylation levels of specific lysine residues of histones H3 and H4 (228). Plitidepsin is currently in clinical trials to treat multiple myeloma (243,244) but it has also displayed interesting properties against hematological malignancies (245). Some depsipeptides display a greater affinity for HDAC1 than HDAC6 and class II HDACs, but this does not appear to limit their activity as anticancer agents judging by in vitro effects in cancer cells (208,226,228).…”