Last fall, City of Hope scientists opened a clinical trial investigating the use of the arthritis drug leflunomide as an innovative treatment for cancer patients with COVID-19. Now, thanks to a $4 million, multiyear R01 grant from the National Cancer Institute (NCI), new research will study the efficacy of the drug in preventing or delaying the evolution of high-risk smoldering multiple myeloma (SMM) to overt multiple myeloma, a cancer that presents significantly more often in the Black population.
SMM is an early precursor to multiple myeloma, which is twice as common in African Americans and has double the mortality rate among this population.
“Despite the strides in the treatment of multiple myeloma in recent years, African Americans have experienced much smaller and less significant improvements in outcomes,” explained Provost and Chief Scientific Officer Steven Rosen, M.D., the Irell & Manella Cancer Center Director’s Distinguished Chair, who is a co-principal investigator for the study. “We’re comparing results in Black versus Caucasian populations and studying the use of leflunomide and its potential anti-myeloma activity.”
Steven Rosen, M.D.
Rosen said that his research team has previously shown the drug’s activity in refractory myeloma, with a more pronounced positive response in Black patients. Leflunomide was approved by the Food and Drug Administration (FDA) as a commercially available medication for rheumatoid arthritis in 1998. The leflunomide compound used in this study is the same compound currently being used in the COVID-19 therapy trial.
Rosen’s co-PIs in this study are Flavia Pichiorri, Ph.D., M.S., associate professor in the Judy and Bernard Briskin Center for Multiple Myeloma Research; and Michael Rosenzweig, M.D., M.S., associate clinical professor in the Department of Hematology & Hematopoietic Cell Transplantation.
Other members of the research team include Rick Kittles, Ph.D., director of the Division of Health Equities, who is leading the ancestry genetic research; Kimlin Tam Ashing, Ph.D., founding director of the Center of Community Alliance for Research & Education, who is spearheading recruitment for the study; and Timothy Synold, Pharm.D., who is overseeing the pharmacokinetics associated with the administration of leflunomide.
“We are examining the essential role that patients contribute to biomedical science, especially clinical trials,” Ashing said. “This will help guide our study so that our approach can be more patient responsive, and inform how we consider and ask about patient-reported outcomes as part of trials, including measuring and addressing health-related quality of life.”
“Leflunomide’s relatively low toxicity and markedly reduced cost as compared to treatments currently being investigated to delay progression of smoldering multiple myeloma could substantially benefit the health of African Americans,” said Rosenzweig. “This is true especially considering the greater prevalence of pre-myeloma conditions in this ethnic group compared to European Americans.”
In addition to the lack of standard treatments for SMM, Kittles said there are racial disparities that exist that contribute to the higher incidence of the disease in the Black community.
“African Americans are still bearing the greater burden with this disease,” said Kittles. “This could be due in part to biological differences, delays in diagnosis and treatment, and insufficient access to health care.”
Rosenzweig said that the research team’s preclinical data have already indicated that the drug has the ability to induce favorable immunological changes and delay the progression of multiple myeloma in mice and minimize the expression of myeloma cells. Funded by the NCI grant, the team’s next phase of research will seek to:
- Determine the anti-myeloma activity of single agent leflunomide in a Phase 2 clinical trial with both African American and European American patients.
- Characterize the temporal relationship between leflunomide, disease status and the impact of genetic polymorphisms in a concentration of the drug.
- Determine the relationship between leflunomide, immunological changes and disease status.
“If we’re successful, completion of these studies will give us our first look into the underlying mechanism of how leflunomide modulates the immune system in these two disparate ethnic groups, and how these changes affect response to treatment and disease progression,” Pichiorri said. “Furthermore, showing that the drug is active in delaying or preventing SMM would give us an alternative medication for patients who have high-risk SMM, which, when successful, could potentially then be introduced to other patients.”