Institute for Myeloma & Bone Cancer Research

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.

INTRODUCTION Financial support from pharmaceutical sponsors influences the design and outcomes and leads to the reporting of results that favor sponsor interests across many fields, including oncology.[1] Medical writing bias (MWB) is a byproduct of this influence that manifests in the exaggeration or duplication of positive results and omission of unfavorable results, which risks both misinforming physician decisions and compromising patient outcomes. The market size for multiple myeloma (MM) treatments is rapidly increasing and is estimated to be worth $21.6 billion in 2023 and over $33 billion by 2030,[2] making this topic both relevant and important. We analyzed MWB in MM clinical research papers published between 2000 and 2023 involving one or more of the following drugs: bortezomib, carfilzomib, daratumumab, elotuzumab, isatuximab, ixazomib, lenalidomide, panobinostat, pomalidomide, and selinexor. METHODS We accessed clinical trial data from PubMed using the following search criteria: “(multiple myeloma) AND (Bortezomib OR Carfilzomib OR Ixazomib OR Lenalidomide OR Pomalidomide OR Selinexor OR Daratumumab OR Isatuximab OR Elotuzumab OR Panobinostat).” We filtered results to only include the following article types: Clinical Study, Clinical Trial, Clinical Trial Protocol, Clinical Trial Phase I, Clinical Trial Phase II, Clinical Trial Phase III, and Clinical Trial Phase IV. Next, we used the software extension “Multiple Search and Highlight” to find keywords within each paper, including “fund,” “assist,” “manuscript,” “acknowledge,” “medical writ,” “writ,” “editorial,” “sponsor,” “support,” “contract,” “author,” and “finance.” For the paper to be considered containing MWB, it had to study one or more of our 10 observed drugs, have the drug manufacturer(s) sponsor the trial, and acknowledge that the medical writing was done by the manufacturer’s employees, or the company directly funded the medical writing group. RESULTS We determined the combined MWB percentage for all drugs since 2000. There was 0% bias reported up until 2006. In 2007 and 2008, 4% MWB occurred in both years (2/53 and 2/57, respectively), and increased to 12% (5/42) in 2009. From 2010 to 2014, 16% (54/328) of papers exhibited MWB, which increased to 29% (137/469) from 2015 to 2019. Between 2020 and 2022, 35% (114/330) of papers showed MWB. Through March, 44% (12/27) of the manuscripts published in 2023 exhibited MWB. Next, we determined average MWB percentage since 2000 for each drug, which showed the following: isatuximab 93% (26/28), ixazomib 77% (36/47), daratumumab 76% (63/83), elotuzumab 71% (17/24), selinexor 62% (8/13), pomalidomide 55% (27/49), panobinostat 50% (9/18), bortezomib 47% (47/100), lenalidomide 46% (75/163), and carfilzomib 32% (15/47). Since 2000, the Blood, British Journal of Haematology, and Haematologica contained the highest number of articles with MWB at 42, 30, and 20, respectively. The Blood Cancer Journal, Annals of Hematology and Oncology, and European Journal of Haematology each reported 11 papers with MWB. The highest-impact journals, such as the New England Journal of Medicine (NEJM) and Lancet, had comparatively lower MWB frequencies at 9 and 6, respectively. Fourteen journals had a single occurrence of MWB. We also analyzed percentages of MWB since 2000. The Journal of Clinical Pharmacology, Future Oncology, and Cancer Chemotherapy and Pharmacology showed high percentages at 86% (6/7), 57% (4/7), and 50% (6/12), respectively. NEJM and Lancet showed rates of 33% (9/27) and 46% (6/13), respectively. Most (140/190) journals contained 0% MWB, whereas nine contained 100% MWB although these all had only one evaluable manuscript. DISCUSSION Previous studies report how commercial sponsors are more likely to have control over data analysis and interpretation than noncommercial sponsors;[3] real-world examples, such as the hormone replacement therapy lawsuits against Wyeth Pharmaceuticals, demonstrate how dangerous sponsor influences can be.[4] By favoring sponsor interests, clinical research may compromise patient well-being for financial gain which may lead to misguided treatment decisions and damaged public trust. Strategies to decrease the risk of MWB include regulating conflicts of interest, expanding reviewer and editorial board independent oversight, and choosing medical writers without ties to companies whose drug(s) are being evaluated. This should be explored in future studies by comparing the reporting of each drug’s efficacy and safety information across manuscripts funded with those not funded by each drug’s manufacturer, evaluating the types and extent of involvement that investigators have in the development of manuscripts. Financial support and sponsorship Nil Conflicts of interest There are no conflicts of interest.

Multiple myeloma (MM) patients are at higher risk for severe COVID-19. Their mRNA vaccination response against SARS-CoV-2 is unknown. Thus, we analyzed responses to mRNA vaccination against COVID-19 among these patients. Using an ELISA-based assay that detects IgG antibodies to SARS-CoV-2 spike protein, we determined serum antibody levels prior to immunization and 12–21 and 14–21 days following the first and second vaccinations, respectively, with mRNA-1273 (Moderna) or BNT162b2 (Pfizer/BioNTech) among 103 MM patients (96 and 7 with active and smoldering disease, respectively). We stratified patients into clinically relevant responders (>250 IU/mL), partial responders (50–250 IU/mL, which was above pre-COVID-19 background), and nonresponders (<50 IU/mL). Smoldering MM patients responded better than those with active disease. Only 45% of active MM patients developed an adequate response, while 22% had a partial response. Lower spike antibody levels were associated with older age, impaired renal function, low lymphocyte counts, reduced uninvolved immunoglobulin levels, > second line of treatment, and among those not in complete remission. Patients who received mRNA-1273 vaccine had higher anti-spike antibody levels than those who were vaccinated with BNT162b2. Thus, most MM patients have impaired responses to mRNA vaccination against COVID-19, and specific clinical and myeloma-related characteristics predict vaccine responsiveness.

Multiple myeloma (MM) patients with smoldering (S) disease are defined by a lack of CRAB/SLiM criteria but may transform into disease requiring treatment. The International Myeloma Working Group risk stratification model for SMM uses serum M-protein, serum-free light chain ratio, and bone marrow plasma cell percentage. We investigated whether baseline serum B-cell maturation antigen (sBCMA) levels are predictive of disease progression among 65 patients with SMM. A receiver operating characteristic curve was used to establish a definition for high-risk baseline sBCMA. Mantel Byar analysis was used to examine whether high-risk sBCMA was correlated with shorter time to transformation, and a time-dependent cox proportional hazard was used to determine whether it is independent of other risk factors. A z test for proportions was used to compare the percentage of patients that progressed among high-risk versus low-risk sBCMA patients. A baseline sBCMA level ≥137.5mg/ml was found to be the optimal cutoff between high- and low-risk SMM patients. Patients with high-risk sBCMA levels had a shorter time to transformation (P=.000332). sBCMA was also higher at the time of transformation than baseline levels (P=.0116). sBCMA was the only variable found to be significantly predictive of time to transformation and additionally was found to be independent of other risk factors. In this study, we have shown for the first time that sBCMA levels predict transformation of SMM to active disease and that these levels increase at the time of transformation. These results are consistent with other studies showing that active MM patients undergoing therapy with higher baseline sBCMA levels are more likely to progress early and its levels increase at the time of disease progression.