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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：
10620113
负责人：
Flavia Pichiorri
金额：
$ 65.36万
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/10620113
关键词：
Address Affect African American African American population 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 Disparity Drug Kinetics Drug Transport Drug usage Economic Burden Enzymes Epigenetic Process European FDA approved Family Genes Genetic Genetic Polymorphism Health Benefit Hepatic Immune Immune system Immunocompetent Immunologics Immunosuppressive Agents Incidence Inherited Leflunomide Mediating Messenger RNA Metabolism Modality Molecular Molecular Target Monoclonal gammopathy of uncertain significance Multiple Myeloma Mus Oncogene Deregulation Oncogenes Oral Oral Administration Participant Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacodynamics Pharmacogenomics 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 Serine Serum Specimen Stable Disease Time Toxic effect burden of illness c-myc Genes cancer cell cohort cost cytotoxicity design disorder control disorder risk drug metabolism efficacy evaluation experience health care availability high risk immune modulating agents immunoregulation improved in vivo insight lenalidomide meetings neoplastic cell novel novel strategies novel therapeutics open label patient population pharmacologic 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 tumor-immune system interactions

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.

项目总结阴燃多发性骨髓瘤(SMM)是活动性多发性骨髓瘤(MM)的无症状先兆，50 符合高危疾病标准的患者中有百分比将在2年内发展为活动期多发性骨髓瘤。尽管最近多发性骨髓瘤的治疗进展，非裔美国人在疾病结局和承担明显更大的疾病负担。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/或获得卫生保健的机会不平等。尽管有些人与观察相比，用于治疗多发性骨髓瘤的药物在改善无进展存活率方面表现出了希望。这一优势还没有为非裔美国人的参与者建立起来。另外，因为这些药物在毒性和经济负担方面是有代价的，它们在治疗骨髓瘤前期疾病方面的作用是有争议的。这突显了迫切需要具有新的行动机制的新方法，这些机制可以长期成功地用于预防疾病的进展。为了满足这一需求，我们建议评估来氟米特，一种自1998年以来一直获得FDA批准的商业化口服免疫抑制剂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，可延缓免疫活性MM的进展 MM小鼠和b)下调主要调控的MM癌基因c-Myc的mRNA和蛋白的表达 MM细胞中的水平。此外，我们在最近完成的Single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/难治性MM患者，其中9例患者安全且病情稳定 11名患者中，包括两名病情稳定一年以上的非裔美国人。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患者受益防止或延缓进展为有症状的MM。我们建议：1)确定其抗骨髓瘤活性单药来氟米特在非洲裔美国人和欧洲裔美国人患者中的2期临床试验高危SMM；2)表征特氟米特的血药浓度、来氟米特的活性代谢物、疾病状况及基因多态性对特氟米特的影响浓度；以及3)确定来氟米特、免疫变化和疾病的关系状态，以及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和患有高危SMM的欧美患者以及这些变化如何影响治疗反应和疾病的发展。此外，来氟米特在延缓或预防癌症进展方面具有积极作用。 SMM到活动期疾病将为高危SMM患者提供一种耐受性良好的替代方案，结果可以推论到其他患者群体。