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.