Abstract A098: Nuvisertib shows single-agent anti-tumor activity in multiple myeloma nonclinical models

Abstract This study evaluated the anti-myeloma activity of nuvisertib using in vitro and in vivo preclinical models. Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells within the bone marrow, leading to the production of monoclonal immunoglobulin and progressive marrow failure. Despite significant therapeutic advances, MM remains largely incurable, with many patients eventually relapsing or developing resistance to treatment. PIM-1 is frequently overexpressed in hematologic malignancies and contributes to malignant cell growth and resistance mechanisms. Nuvisertib (TP-3654), an oral PIM-1 kinase inhibitor currently under clinical investigation for myelofibrosis (NCT04176198), may be a potential therapeutic candidate for MM due to its role in modulating cell survival and proliferation pathways, particularly through the JAK/STAT signaling axis. While pan-PIM inhibitors have demonstrated anti-tumor activity in relapsed/refractory MM patients with acceptable tolerability, there are no published preclinical or clinical data on the anti-MM effects of nuvisertib. In this study, in vitro assays were conducted using bone marrow cells from MM patients and human MM LAGλ-1 cells. Cells were treated with nuvisertib alone or in combination with standard MM therapies. Cell viability was assessed using MTS assays after 48 hours of treatment. In vivo efficacy was evaluated in SCID mice implanted with LAGκ-2 or LAGλ-1 MM patient-derived xenografts (PDXs) in the gluteal muscle of the left hind limb. Once tumors became palpable, mice were randomized (n=10 per group) and treated orally with nuvisertib or vehicle control and tumor volumes measured during treatment. After 2–4 weeks, depending on tumor progression, mice were sacrificed and tumors harvested for weight analysis. Nuvisertib demonstrated potent, dose-dependent cytotoxicity in vitro, with an IC30 value of 1.11 µM, comparable to those of established MM drugs including dexamethasone (1.32 µM), cyclophosphamide (1.01 mM), lenalidomide (95.1 µM), and pomalidomide (16.5 µM). When combined with other agents, nuvisertib exhibited additive anti-proliferative effects, particularly in samples from patients with progressive disease (>50% malignant plasma cells). In contrast, samples from patients in complete response (<5% plasma cells) showed less pronounced effects. These findings suggest nuvisertib may be potentially active in drug-resistant or relapsed/refractory MM patients. In vivo, nuvisertib reduced tumor volume in both LAGκ-2 and LAGλ-1 models compared to controls, with final tumor volumes of 1385 mm3 and 2838 mm3 in treated groups versus 2789 mm3 and 6258 mm3 in vehicle groups, respectively (p<0.013). Tumor weights were also lower in nuvisertib-treated mice (p<0.04). These results support nuvisertib as a potential therapeutic agent for MM, both as a monotherapy and in combination with currently used treatments. Further studies using preclinical human MM PDX models are warranted to evaluate drug interactions and impact on overall survival. Citation Format: Zakir Khan, Stacy Behare, Mingjie Li, Jason M. Foulks, Steven L. Warner, James R. Berenson. Nuvisertib shows single-agent anti-tumor activity in multiple myeloma nonclinical models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A098.