Repurposing Leflunomide for Relapsed/Refractory Multiple Myeloma: A Phase 1 Trial

Abstract Introduction: Survival for patients with relapsed/refractory multiple myeloma (RRMM) remains poor; new, well-tolerated and effective treatments are needed. Leflunomide is a commercially available immunosuppressive agent that has been FDA approved since 1998 for the treatment of rheumatoid arthritis. The primary mechanism of action is inhibition of de novo pyrimidine synthesis by targeting dihydroorotate dehydrogenase (DHODH) and thus achieving anti-proliferative effects on B and T lymphocytes. A secondary mechanism of action is inhibition of cytokine and growth factor receptor associated tyrosine kinase activity. Leflunomide has been investigated for its anti-neoplastic potential in a variety of pre-clinical tumor models including multiple myeloma. This study explores the repurposing of leflunomide as a treatment for RRMM. Methods: This phase 1 dose-escalation trial is of single-agent leflunomide in patients with RRMM. Patient enrollment began in December 2015. The study implements a modified rolling six phase 1 dose escalation design. Primary objectives: 1) to determine the maximum tolerated dose and recommended phase 2 dose of leflunomide; 2) to assess the safety and tolerability of leflunomide at each dose level by evaluation of toxicities. Leflunomide is administered using a loading dose of 100 mg daily for the first three days followed by daily dosing in 28-day cycles. The starting dose of daily leflunomide is 20 mg daily, with dose escalation in increments of 20 mg/day, and dose de-escalation in decrements of 10 mg/day. The maximum dose to be tested is 60 mg/day. Results: A total of 10 patients have been enrolled and treated. Median age is 68 (range 48 - 85), median number of prior therapies is 5 (range: 3 - 14), and 9 patients had prior transplant. Double refractory (lenalidomide/bortezomib) disease was noted in 7 patients. One patient discontinued leflunomide for reasons unrelated to toxicity early during cycle 1 and is therefore inevaluable for toxicity or response and was replaced. Nine patients are evaluable for toxicity (see table). Of these patients, the median number of cycles was 3 (range 1- 15). Median follow up is 253 days (range: 28 - 602). High-risk cytogenetics were observed in 5 patients including 2 patients with del17p. One of the nine patients remains on treatment, 7 patients were removed from study due to disease progression, and one was removed because of an adverse event unrelated to study drug that caused delay in treatment. Three patients were treated on DL 1 (20 mg), three on DL3 (40 mg), and 4 patients, thus far, on DL5 (60 mg). The most common toxicities were hematologic. There were 4 patients with grade 1 or 2 neutropenia on the 20 and 40 mg dose levels and 1 patient with grade 4 lymphopenia on the 40 mg dose. All non-hematologic toxicities were ≤ grade 2. There were no DLTs reported at the first three dose levels. Adequate hepatic clearance and tolerance was noted, even in this older population. Response: Eight patients were evaluable for response. While not all patients were treated at the 60 mg dose, a clinical benefit rate of 88% has been seen, with 7/8 achieving stable disease (SD). The median duration of SD among 7 patients thus far is 152 days (range: 0-401). In the four evaluable patients with high risk cytogenetics, all of them achieved a clinical benefit with stable disease. Conclusion: Leflunomide is a safe and well-tolerated option for patients with RRMM. Hematologic responses have not yet occurred at current dosing, but a clinical benefit with single agent dosing has been observed. Additional testing of leflunomide at higher doses and in combination with dexamethasone for RRMM is planned. Moreover, because leflunomide is oral, well tolerated and relatively inexpensive at a cost of approximately $200/month, further investigation as a single agent at earlier stages of disease including high-risk smoldering myeloma is warranted. Download : Download high-res image (181KB) Download : Download full-size image Disclosures Rosenzweig: Celgene: Speakers Bureau. Krishnan: Onyx: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Equity Ownership, Speakers Bureau; Takeda: Speakers Bureau; Sutro: Consultancy.