Repurposing leflunomide to delay progression of smoldering multiple myeloma in african americans

Active Project Grant Awarded Last action

Award ID
R01CA253545
Recipient
Awarding agency
Obligated
$5,479,171

Award facts

Assistance listing
93.395 Cancer Treatment Research
Completion date 91% complete
Originally
Funding
  • $4,760,255.00 Federal
  • $718,916.00 Non-federal
Place of performance
Irwindale, CA 91010, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
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.

Transactions

Action Federal Non-federal Date
Amendment $0 $0
Amendment $677,645 $0
Amendment $677,645 $0
Amendment $0 $0
Amendment $0 $0
Amendment $653,591 $0
Amendment $656,771 $0
Amendment $656,771 $0
Amendment $718,916 $0
Original award $718,916 $718,916

Subawards

Subrecipient Amount Awarded
The Charlotte-Mecklenburg Hospital Authority Levine Cancer Institute (LCI): Manisha Bhutani, MD will serve as PI at LCI-Main. Dr. Bhutani will be responsible for the management and integrity of the design,… $164,350
Barbara ANN Karmanos Cancer Institute For the study titled "Repurposing Leflunomide to Delay Progression of Smoldering Multiple Myeloma in African Americans," subrecipient will: 1. Collaborate… $0
Sloan-Kettering Institute For Cancer Research Saad Usmani, MD will serve as Site Principal Investigator (PI). Dr. Usmani will be responsible for the management and integrity of the design, conduct, and… $144,323
Barbara ANN Karmanos Cancer Institute For the study titled "Repurposing Leflunomide to Delay Progression of Smoldering Multiple Myeloma in African Americans," subrecipient will: 1. Collaborate… $17,635

Quick answers

Who received award R01CA253545?

R01CA253545 was awarded to Beckman Research Institute Of The City Of Hope by National Cancer Institute (National Institutes of Health) on May 1, 2021.

How much is award R01CA253545 worth?

$5,479,171 has been obligated on R01CA253545: $4,760,255 in federal funding and $718,916 in non-federal funding.

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