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Clinical Trial
. 2023 Feb;12(4):3999-4009.
doi: 10.1002/cam4.5250. Epub 2022 Sep 20.

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

María Victoria Mateos  1 , Felipe Prosper  2   3 , Jesús Martin Sánchez  4 , Enrique M Ocio  1   5 , Albert Oriol  6 , Cristina Motlló  6 , Jean-Marie Michot  7 , Isidro Jarque  8 , Rebeca Iglesias  9 , María Solé  4 , Sara Martínez  10 , Carmen Kahatt  10 , Salvador Fudio  10 , Gema Corral  10 , Ali Zeaiter  10 , Lola Montilla  10 , Vincent Ribrag  7
Affiliations
Clinical Trial

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

María Victoria Mateos et al. Cancer Med. 2023 Feb.

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.

Keywords: bortezomib; dexamethasone; multiple myeloma; phase I study; plitidepsin.

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Conflict of interest statement

María Victoria Mateos has received honoraria for lectures and participation in advisory boards from Janssen, Celgene, Takeda, Amgen, GSK, AbbVie, Pharma Mar, Pfizer, Regeneron, Roche, Sanofi, Oncopeptides, and Seagen. Enrique M. Ocio has received honoraria or consultation fees from Janssen, BMS/Celgene, Sanofi, GSK, Oncopeptides, Takeda, Amgen, Pfizer, Karyopharm, and Pharma Mar. Jean‐Marie Michot has declared Principal/sub‐Investigator role of clinical trials from AbbVie, Agios, Amgen, Argen‐x, Astex, AstraZeneca, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Seattle Genetics, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, and Xencor. He has also received personal fees such as honoraria, royalties or fees for consulting, lectures, speakers bureau, expert testimony, employment, advisory boards, among others from Roche, AstraZeneca, and Amgen. In addition, he has also received non‐financial support such as, equipment supplied by the entity, travel paid by the entity, writing support, administrative support, among other from Celgene, Bristol‐Myers Squibb, and GSK. Isidro Jarque has declared speakers bureau and consultancy role by AbbVie, Amgen, AstraZeneca, Bristol‐Myers Squibb, Gilead, Janssen, Novartis, Pfizer, Roche and Takeda. Carmen Kahatt, Salvador Fudio, Gema Corral and Ali Zeaiter report personal fees for salary as full time employee and stock ownership from Pharma Mar, outside the submitted work. Sara Martínez and Lola Montilla report personal fees for salary as full time employee from Pharma Mar, outside the submitted work. No disclosures were reported by the other authors.

Figures

FIGURE 1
FIGURE 1
Typical plitidepsin exposure in patients with in relapsed/refractory multiple myeloma patients and observed plitidepsin concentrations. Dots represent observations from the current study, lines represent the 5th, 50th, and 95th percentile of the simulated concentrations, and the shaded area represents the 90% prediction interval of plitidepsin whole blood concentrations
See this image and copyright information in PMC

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