Monday, August 18, 2025 8/18/2025

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

Award Number: R01CA253545
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $677,645 )
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	4	7/24/2025	NON-COMPETING CONTINUATION	$677,645
														Subtotal = $677,645

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	3	8/12/2024	NON-COMPETING CONTINUATION	$0
2024	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	3	8/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $653,591 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	3	4/28/2023	NON-COMPETING CONTINUATION	$653,591
														Subtotal = $653,591

Issue Date FY: 2022 ( Subtotal = $656,771 )
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	2	5/10/2022	NON-COMPETING CONTINUATION	$656,771
														Subtotal = $656,771

Issue Date FY: 2021 ( Subtotal = $718,916 )
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	1	3/30/2021	NEW	$718,916
														Subtotal = $718,916

Grand Total All Awards = $2,706,923

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

Award Number: R01CA253545

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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