A phase 1 clinical trial of the repurposable acetyllysine mimetic, n-methyl-2-pyrrolidone (NMP), in relapsed or refractory multiple myeloma

Shortt Jake Shortt, Peter Galettis, Chan Y. Cheah, Joanne Davis, Mandy Ludford-Menting, Emma K. Link, Jennifer H. Martin, Rachel Koldej, David Ritchie

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Abstract

Background: N-methyl-2-pyrrolidone (NMP) is an epigenetically active chemical fragment and organic solvent with numerous applications including use as a drug-delivery vehicle. Previously considered biologically inert, NMP demonstrates immunomodulatory and anti-myeloma properties that are partly explained by acetyllysine mimetic properties and non-specific bromodomain inhibition. We therefore evaluated orally administered NMP in a phase 1 dose-escalation trial to establish its maximum tolerated dose (MTD) in patients with relapsed/refractory multiple myeloma (RR–MM). Secondary endpoints were safety, pharmacokinetics (PK), overall response rate and immunological biomarkers of activity. Results: Thirteen patients received NMP at starting doses between 50 and 400 mg daily. Intra-patient dose escalation occurred in five patients, with one attaining the ceiling protocolised dose of 1 g daily. Median number of monthly cycles commenced was three (range 1–20). Grade 3–4 adverse events (AEs) were reported in seven (54%; 95% CI 25–81%) patients. Most common AEs (> 30% of patients) of any grade were nausea and musculoskeletal pain. The only dose limiting toxicity (DLT) was diarrhoea in a patient receiving 200 mg NMP (overall DLT rate 8%; 95% CI 0–36%). Hence, the MTD was not defined. Median progression-free and overall survival were 57 (range 29–539) days and 33 (95% CI 9.7– > 44) months, respectively. The best response of stable disease (SD) was achieved in nine patients (69%; 95% CI 39–91%). PK analysis demonstrated proportional dose–concentrations up to 400 mg daily, with a more linear relationship above 500 mg. Maximum plasma concentrations (Cmax) of 16.7 mg/L at the 800 mg dose were below those predicted to inhibit BET-bromodomains. Peripheral blood immune-profiling demonstrated maintenance of natural killer (NK) cells, and a gene expression signature suggestive of enhanced T, B and NK cell functions; a subject with prolonged exposure manifested sustained recovery of B and NK cells at 12 months. Conclusions: NMP demonstrated potential disease stabilising and immunomodulatory activity at sub-BET inhibitory plasma concentrations and was well tolerated in RR–MM; an MTD was not determined up to a maximum dose of 1 g daily. Further dose-finding studies are required to optimise NMP dosing strategies for therapeutic intervention.

Original languageEnglish
Article number15
JournalClinical Epigenetics
Volume15
Issue number1
DOIs
Publication statusPublished - Dec 2023

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