Repurposing Leflunomide to Delay Progression of Smoldering Multiple Myeloma in African Americans

重新调整来氟米特的用途以延缓非裔美国人闷烧性多发性骨髓瘤的进展

基本信息

批准号：
10225924
负责人：
Flavia Pichiorri
金额：
$ 71.89万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10225924
关键词：
Address Affect African American American Biological Bone Marrow CYP1A2 gene CYP2C19 gene Cell Culture Techniques Cells Clinical Color Correlative Study Custom Cytometry DHODH gene Data Diagnostic Disease Disease Outcome Disease Progression Drug Kinetics Drug Transport Drug usage Economic Burden Enzymes Epigenetic Process European FDA approved Family Genetic Genetic Polymorphism Health Health Benefit Hepatic Immune Immune system Immunocompetent Immunologics Immunomodulators Immunosuppressive Agents Incidence Inherited Leflunomide Mediating Messenger RNA Metabolism Molecular Molecular Target Monoclonal gammopathy of uncertain significance Multiple Myeloma Mus Oncogene Deregulation Oncogenes Oral Participant Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacodynamics Pharmacogenomics Pharmacology Phase Phase I Clinical Trials Phase II Clinical Trials Plasma Cells Population Prevalence Price Progression-Free Survivals Protein-Serine-Threonine Kinases Proteins Publishing Refractory Relapse Rheumatoid Arthritis Role Safety Sampling Serum Specimen Stable Disease Time Toxic effect Ursidae Family burden of illness c-myc Genes cancer cell cohort cost cytotoxicity design disorder control disorder risk drug metabolism experience health care availability high risk improved in vivo insight lenalidomide meetings neoplastic cell novel novel strategies novel therapeutics open label patient population phase II trial pre-clinical preclinical study premalignant prevent primary endpoint racial difference racial disparity response single-cell RNA sequencing standard care treatment response tumor

项目摘要

PROJECT SUMMARY Smoldering multiple myeloma (SMM) is an asymptomatic precursor of active multiple myeloma (MM), and 50 percent of patients meeting criteria for high-risk disease will develop active MM within 2 years. Despite recent advances in treatment for MM, African Americans have experienced racial disparities in disease outcome and bear significantly greater disease burden. The reasons for this racial disparity are unclear and may be due to biological differences, diagnostic and treatment delays, and/or unequal access to health care. Although some drugs used to treat MM have shown promise in improving progression free survival compared to observation, this advantage has not been established for African American participants. In addition, because these drugs carry a price in terms of toxicity and economic burden, their role in treating pre-myeloma conditions is controversial. This highlights the urgent need for new approaches with novel mechanisms of action that can be used successfully long-term to prevent disease progression. To meet this need, we propose to evaluate leflunomide, a commercially available oral immunosuppressive agent that has been FDA-approved since 1998 for the treatment of rheumatoid arthritis. Our preclinical data indicate that clinically achievable concentrations of leflunomide: a) induce favorable immunological changes able to delay MM progression in immunocompetent MM mice and b) downregulate expression of the master regulatory MM oncogene c-Myc at the mRNA and protein levels in MM cells. Moreover, we saw encouraging results in our recently completed phase I clinical trial of single agent leflunomide in relapsed/refractory MM patients in which safety and disease stabilization were seen in nine of eleven patients, including two African American patients who had stable disease lasting for over a year. Therefore, we hypothesize that leflunomide, as a single agent, will benefit patients with high-risk SMM by preventing or delaying progression to symptomatic MM. We propose to 1) Determine the anti-myeloma activity of single agent leflunomide in a phase 2 clinical trial in African American and European American patients with high-risk SMM; 2) Characterize the temporal relationship between serum concentration of teriflunomide, the active metabolite of leflunomide, and disease status and the impact of genetic polymorphisms on teriflunomide concentration; and 3) Determine the relationship between leflunomide, immunological changes, and disease status, and changes in c-Myc signature. Successful completion of these studies would provide the first insight into the underlying mechanism of how leflunomide modulates the immune systems of African American and European American patients with high-risk SMM and how these changes affect response to treatment and disease progression. Furthermore, showing leflunomide to be active in delaying or preventing progression of SMM to active disease would provide a well-tolerated alternative for patients with high-risk SMM, and results could be extrapolated to other patient populations.

项目概要冒烟型多发性骨髓瘤 (SMM) 是活动性多发性骨髓瘤 (MM) 的无症状前兆，50 符合高风险疾病标准的患者将在 2 年内发展为活动性 MM。尽管最近随着 MM 治疗的进步，非裔美国人在疾病结果方面经历了种族差异，承受更大的疾病负担。这种种族差异的原因尚不清楚，可能是由于生物学差异、诊断和治疗延误和/或获得医疗保健的机会不平等。虽然有些与观察相比，用于治疗 MM 的药物有望改善无进展生存期，对于非裔美国参与者来说，这一优势尚未确立。另外，由于这些药物就毒性和经济负担而言，它们是有代价的，但它们在治疗骨髓瘤前期病症中的作用是有争议的。这凸显了迫切需要具有新颖作用机制的新方法长期使用可成功预防疾病进展。为了满足这一需求，我们建议评估来氟米特，一种市售口服免疫抑制剂，自 1998 年起获得 FDA 批准用于治疗类风湿性关节炎。我们的临床前数据表明，临床上可达到的浓度来氟米特：a) 诱导有利的免疫学变化，能够延缓免疫功能正常的 MM 进展 MM 小鼠和 b) 下调主调节 MM 癌基因 c-Myc mRNA 和蛋白质的表达 MM 细胞中的水平。此外，我们在最近完成的单药 I 期临床试验中看到了令人鼓舞的结果来氟米特治疗复发/难治性 MM 患者，其中 9 例患者安全且病情稳定十一名患者，其中包括两名非裔美国患者，病情稳定持续一年多。因此，我们假设来氟米特作为单一药物，将通过以下方式使高危 SMM 患者受益：预防或延缓进展为有症状的 MM。我们建议 1) 确定抗骨髓瘤活性单药来氟米特在非裔美国人和欧洲裔美国人患者中进行的 2 期临床试验高风险SMM； 2) 表征特立氟胺血清浓度、来氟米特的活性代谢物、疾病状况以及基因多态性对特立氟米特的影响专注; 3) 确定来氟米特、免疫学变化和疾病之间的关系状态和 c-Myc 签名的变化。成功完成这些研究将提供第一个见解研究来氟米特如何调节非裔美国人和非裔美国人免疫系统的潜在机制患有高危 SMM 的欧洲裔美国患者以及这些变化如何影响对治疗和治疗的反应疾病进展。此外，表明来氟米特可有效延缓或预防疾病进展 SMM 治疗活动性疾病将为高风险 SMM 患者提供耐受性良好的替代方案，结果可以推断到其他患者群体。