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

• 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
• 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

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.

项目摘要 郁积型多发性骨髓瘤（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中有20%将在2年内发展为活动性MM。尽管最近 随着MM治疗的进展，非裔美国人在疾病结局方面经历了种族差异， 承担着更大的疾病负担。造成这种种族差异的原因尚不清楚，可能是由于 生物差异、诊断和治疗延误和/或获得保健的机会不平等。尽管一些 与观察相比，用于治疗MM的药物显示出改善无进展生存期的前景， 非裔美国人的这种优势尚未确立。此外，由于这些药物 尽管它们在毒性和经济负担方面有一定的代价，但它们在治疗骨髓瘤前病症中的作用是 争议这突出表明迫切需要具有新作用机制的新方法， 长期成功使用以预防疾病进展。为了满足这一需求，我们建议评估 来氟米特是一种市售的口服免疫抑制剂，自1998年以来已获得FDA批准 用于治疗类风湿性关节炎。我们的临床前数据表明， 来氟米特：a）在免疫功能正常的人中诱导能够延迟MM进展的有利的免疫学变化， MM小鼠和B）在mRNA和蛋白水平下调主要调节MM癌基因c-Myc的表达 MM细胞中的水平。此外，我们在最近完成的单药治疗的I期临床试验中看到了令人鼓舞的结果。 来氟米特治疗复发性/难治性MM患者，其中在9例患者中观察到安全性和疾病稳定 11名患者，包括两名非洲裔美国人，他们的病情稳定持续了一年多。 因此，我们假设来氟米特作为单药，通过以下方式使高危SMM患者获益： 预防或延迟进展为症状性MM。我们建议：1）确定抗骨髓瘤活性 在非裔美国人和欧洲裔美国人患者中进行的2期临床试验中， 2）描述特立氟胺血清浓度、 来氟米特的活性代谢物、疾病状态和遗传多态性对特立氟胺的影响 浓度;和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洞察力， 来氟米特如何调节非裔美国人的免疫系统的潜在机制， 具有高风险SMM的欧洲裔美国患者以及这些变化如何影响对治疗的反应， 疾病进展。此外，显示来氟米特在延迟或预防肿瘤进展方面具有活性， 活动性疾病的SMM将为高风险SMM患者提供耐受性良好的替代方案， 可以外推到其他患者群体。