Phase I study of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma

Abstract

Previous studies showed antitumor activity for plitidepsin plus dexamethasone (DXM) in relapsed/refractory multiple myeloma (r/r MM), and in vitro synergism with bortezomib (BTZ) or DXM against MM cells.

This phase I trial evaluated plitidepsin (3-h intravenous infusion Day 1 and 15), BTZ (subcutaneous bolus Day 1, 4, 8, and 11), and DXM (orally Day 1, 8, 15, and 22), every 4 weeks in 36 r/r MM patients.

Twenty-two patients were treated using a standard dose escalation design (10 at the recommended dose [RD] cohort), and 14 additional patients were treated to expand the RD cohort. No dose-limiting toxicities (DLTs) occurred during dose escalation. The highest dose level evaluated (plitidepsin 5.0 mg/m2 , BTZ 1.3 mg/m2 , DXM 40.0 mg) was the RD for phase II studies. Results shown herein are focused on this RD. Two patients had DLTs (grade 3 diarrhea, and grade 3 nausea/vomiting refractory to antiemetic therapy). Grade ≥ 3 hematological toxicity (thrombocytopenia 46%, anemia 33%, and neutropenia 17%) was manageable and did not result in treatment discontinuation. Transient and manageable grade 3 ALT increase (26%) was the most common biochemical abnormality.

At the RD cohort, overall response rate was 22.2% (95%CI, 6.4%-47.6%), including one stringent complete response, one very good partial response, and two partial responses in r/r patients to BTZ and/or lenalidomide. The clinical benefit rate was 77.8% (95%CI, 52.4-93.6%). No major pharmacokinetic drug-drug interaction was found.

In conclusion, the triple combination of plitidepsin, BTZ, and DXM showed an acceptable safety profile and had moderate activity in adult patients with r/r MM.

CITA DEL ARTÍCULO  Cancer Med. 2023 Feb;12(4):3999-4009.  doi: 10.1002/cam4.5250. Epub 2022 Sep 20.