Associate Professor City of Hope National Comprehensive Cancer Center, United States
Introduction: Patients with relapsed/refractory multiple myeloma (RRMM) are in need of new and effective therapies. Many treatments today pose a high burden in terms of cost, toxicity, and route of administration. Leflunomide is an inexpensive, commercially available, oral immunosuppressive approved for treating rheumatoid arthritis. Our published preclinical data (Buettner et al., Blood Adv vol. 3, pp. 1027-1032) suggested a a therapeutic benefit of using leflunomide for MM as well as synergy with immunomodulatory drugs. We then assessed the clinical translation of these findings by opening a phase 2 trial of leflunomide in combination with pomalidomide and dexamethasone for the treatment of RRMM.
Methods: Primary
Objective: To estimate the overall response rate (ORR) of the three-drug combination in patients (pts) with RRMM. Secondary objectives: 1) to characterize and evaluate toxicities; 2) to obtain estimated duration of response (DoR) and time to progression, clinical benefit, and survival (overall [OS] and progression-free [PFS]). Leflunomide is administered orally with a loading dose of 100 mg daily for the first 3 days followed by 20 mg daily thereafter. Cycles are 28 days. Pomalidomide is administered at a starting dose of 4 mg PO on days 1-21, and dexamethasone is given at a dose of 40 mg PO (20 mg for participants over 75) on days 1, 8, 15, and 22. Pts are followed monthly for toxicity and response and continue treatment until disease progression or failure to tolerate the regimen.
Results: A total of 11 pts have been enrolled to date, with 9 pts evaluable for response. The median age of the cohort is 53; 6 pts are male and 3 are female. The median number of prior lines of therapy is 2 (range 1-4). Of the evaluable pts, 4 had clasic high-risk cytogentics, and a total of 5 pts had gain of 1q by FISH. Three pts were refractory to lenalidomide, 3 to bortezomib and 1 to anti-CD38 monoclonal antibody. All 9 evaluable pts were pomalidomide naïve. The ORR was 44% with a median DoR of 7.5 months. The median time to progression has not been reached. At 1 year, 51% of patients have not progressed. The most common adverse events (AEs) were hematologic. One pt had grade 4 thrombocytopenia, which was a dose limiting toxicity. Grade 3 AEs included lymphopenia (1 pt) and neutropenia (3 pts). One additonal pt had grade 2 neutropenia. Grade 3 non-hematologic AEs included hypophosphatemia (1 pt) and diarrhea (1 pt). Grade 2 non-hematologic AEs included peripheral neuropathy (1 pt), squamous cell carcinoma (1 pt), and fever (1 pt).
Conclusions: Leflunomide, pomalidomide, and dexamethasone represent an all-oral treatment that appears safe and well tolerated in all 9 patients we treated thus far. Early ORR and DoR data are encouraging and compare favorably to an earlier phase 3b study of pomalidomide and dexamethasone, which demonstrated an ORR of 32.6%, median DoR of 7.4 months, and median PFS of 4.6 months. Our study has now met criteria to proceed to the second stage, and enrollment will continue.