Preclinical and a phase 1 study of purinostat mesylate, a novel hdac i/iib selective inhibitor, for the treatment of relapsed or refractory multiple myeloma

Introduction: Purinostat Mesylate (PM) is a uniquely potent and selective HDAC I/IIb inhibitor. This study evaluated the efficacy and safety of PM in preclinical studies and phase 1 clinical trial for the treatment of relapsed or refractory(R/R) Multiple Myeloma (MM). Methods: This open-label, non-randomized, first-in-human, phase 1 two-center trial enrolled adult patients with MM who were refractory to or relapsed after ≥1 prior regimens. PM was administered by 30-minute intravenous infusion ranging from 1.2 to 8.4 mg/m2 in a standard 3+3 dose escalation design. Eligible patients received a single dose (Day 1) and multiple doses (Day 8, 11, and 15) followed by extended doses (Day 1, 4, 8, 11 in 21-day cycles). MM cell lines and multiple mouse models were used to evaluate the antitumor activity of PM alone or in combination in vitro and in vivo. Additionally, various methods were used to study the mechanism of PM, such as Bulk RNA sequencing and single-cell RNA sequencing, Luminex high-throughput detection of cytokines, and others. Results: A total of 11 heavily pretreated MM patients were enrolled. All evaluable 11 patients achieved the disease control rate (DCR) of 72.7%. Eight patients had stable disease after the first cycle of administration and entered the extended stage with a maximum of 6 extended cycles, of which one patient achieved a minimal remission. No dose-limiting toxic effects were observed. At low nanomolar concentrations, PM exhibited superior antiproliferative activity and apoptosis induction compared to LBH589 in MM cell lines and patient-derived MM cells. In vivo studies demonstrated that PM alone was better than LBH589, or lenalidomide, bortezomib, and dexamethasone (DXM) triple-drug combinations in treating multiple MM mouse models. Mechanistically, PM significantly inhibited the key proteins for MM survival, including c-MYC, IRF4, EZH2, IKZF1, and IKZF3, and activated the innate and adaptive immune response in MM model mice. Combining PM with pomalidomide and DXM has strong antiproliferative effects and reduces key proteins for MM survival in MM1S and MM1R cell lines [CI index = 0.092]. In mouse models, this combination treatment is more effective than PM alone and other triple-drug combination therapies (selinexor, pomalidomide, and DXM, and daratumumab, pomalidomide, and DXM) without significant toxicity. Keywords: Molecular Targeted Therapies, Multiple Myeloma No conflicts of interests pertinent to the abstract.