Repurposing leflunomide for relapsed/refractory multiple myeloma: a phase 1 study

References

• Kastritis E, Zervas K, Symeonidis A, et al. Improved survival of patients with multiple myeloma after the introduction of novel agents and the applicability of the International Staging System (ISS): an analysis of the Greek Myeloma Study Group (GMSG). Leukemia. 2009;23(6):1152–1157.
   PubMed Web of Science ®Google Scholar
• Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516–2520.
   PubMed Web of Science ®Google Scholar
• Howlader N, Noone A, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2016. Bethesda, MD: National Cancer Institute, based on November 2018 SEER data submission, posted to the SEER web site, April 2019. Available from: https://seer.cancer.gov/csr/1975_2016/.
   Google Scholar
• Pulte D, Redaniel MT, Brenner H, et al. Recent improvement in survival of patients with multiple myeloma: variation by ethnicity. Leuk Lymphoma. 2014;55(5):1083–1089.
   PubMed Web of Science ®Google Scholar
• Anderson KC, Kyle RA, Rajkumar SV, et al. Clinically relevant end points and new drug approvals for myeloma. Leukemia. 2008;22(2):231–239.
   PubMed Web of Science ®Google Scholar
• Kumar SK, Dimopoulos MA, Kastritis E, et al. Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia. 2017;31(11):2443–2448.
   PubMed Web of Science ®Google Scholar
• Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33(9):2266–2275.
   PubMed Web of Science ®Google Scholar
• Breedveld FC, Dayer JM. Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2000;59(11):841–849.
   PubMed Web of Science ®Google Scholar
• Mattar T, Kochhar K, Bartlett R, et al. Inhibition of the epidermal growth factor receptor tyrosine kinase activity by leflunomide. FEBS Lett. 1993;334(2):161–164.
   PubMed Web of Science ®Google Scholar
• Buettner R, Morales C, Caserta E, et al. Leflunomide regulates c-Myc expression in myeloma cells through PIM targeting. Blood Adv. 2019;3(7):1027–1032.
   PubMed Web of Science ®Google Scholar
• Xu X, Shen J, Mall JW, et al. In vitro and in vivo antitumor activity of a novel immunomodulatory drug, leflunomide: mechanisms of action. Biochem Pharmacol. 1999;58(9):1405–1413.
   PubMed Web of Science ®Google Scholar
• Ringshausen I, Oelsner M, Bogner C, et al. The immunomodulatory drug Leflunomide inhibits cell cycle progression of B-CLL cells. Leukemia. 2008;22(3):635–638.
   PubMed Web of Science ®Google Scholar
• Dietrich S, Kramer OH, Hahn E, et al. Leflunomide induces apoptosis in fludarabine-resistant and clinically refractory CLL cells. Clin Cancer Res. 2012;18(2):417–431.
   PubMed Web of Science ®Google Scholar
• White RM, Cech J, Ratanasirintrawoot S, et al. DHODH modulates transcriptional elongation in the neural crest and melanoma. Nature. 2011;471(7339):518–522.
   PubMed Web of Science ®Google Scholar
• Hail N, Jr., Chen P, Bushman LR. Teriflunomide (leflunomide) promotes cytostatic, antioxidant, and apoptotic effects in transformed prostate epithelial cells: evidence supporting a role for teriflunomide in prostate cancer chemoprevention. Neoplasia. 2010;12(6):464–475.
   PubMed Web of Science ®Google Scholar
• Baumann P, Mandl-Weber S, Volkl A, et al. Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells. Mol Cancer Ther. 2009;8(2):366–375.
   PubMed Web of Science ®Google Scholar
• Metzler C, Fink C, Lamprecht P, et al. Maintenance of remission with leflunomide in Wegener’s granulomatosis. Rheumatology.2003;43(3):315–320.
   Web of Science ®Google Scholar
• Metzler C, Miehle N, Manger K, et al. Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener’s granulomatosis. Rheumatology (Oxford). 2007;46(7):1087–1091.
   PubMed Web of Science ®Google Scholar
• Josephson MA, Gillen D, Javaid B, et al. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation. 2006;81(5):704–710.
   PubMed Web of Science ®Google Scholar
• Parekh JM, Vaghela RN, Sutariya DK, et al. Chromatographic separation and sensitive determination of teriflunomide, an active metabolite of leflunomide in human plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2010;878(24):2217–2225.
   PubMed Web of Science ®Google Scholar
• Skolnik JM, Barrett JS, Jayaraman B, et al. Shortening the timeline of pediatric phase I trials: the rolling six design. J Clin Oncol . 2008;26(2):190–195.
   PubMed Web of Science ®Google Scholar
• Pawlik A, Herczynska M, Kurzawski M, et al. The effect of exon (19C > A) dihydroorotate dehydrogenase gene polymorphism on rheumatoid arthritis treatment with leflunomide. Pharmacogenomics. 2009;10(2):303–309.
   PubMed Web of Science ®Google Scholar
• O’Doherty C, Schnabl M, Spargo L, et al. Association of DHODH haplotype variants and response to leflunomide treatment in rheumatoid arthritis. Pharmacogenomics. 2012;13:1427–1434.
   PubMed Web of Science ®Google Scholar
• Bohanec Grabar P, Rozman B, Tomsic M, et al. Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients. Eur J Clin Pharmacol. 2008;64(9):871–876.
   PubMed Web of Science ®Google Scholar
• Zonder JA, Mohrbacher AF, Singhal S, et al. A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood. 2012;120(3):552–559.
   PubMed Web of Science ®Google Scholar
• Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med . 2015;373(7):621–631.
   PubMed Web of Science ®Google Scholar
• Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006;108(10):3458–3464.
   PubMed Web of Science ®Google Scholar
• Richardson PG, Xie WL, Jagannath S, et al. A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood. 2014;123(10):1461–1469.
   PubMed Web of Science ®Google Scholar
• Chan V, Charles BG, Tett SE. Population pharmacokinetics and association between A77 1726 plasma concentrations and disease activity measures following administration of leflunomide to people with rheumatoid arthritis. Br J Clin Pharmacol. 2005;60(3):257–264.
   PubMed Web of Science ®Google Scholar
• Rozman B. Clinical pharmacokinetics of leflunomide. Clin Pharmacokinet. 2002;41(6):421–430.
   PubMed Web of Science ®Google Scholar
• Yao X, Wu Y, Jiang J, et al. A population pharmacokinetic study to accelerate early phase clinical development for a novel drug, teriflunomide sodium, to treat systemic lupus erythematosus. Eur J Pharm Sci. 2019;136:104942.
   PubMed Web of Science ®Google Scholar
• Dispenzieri A, Kyle RA, Katzmann JA, et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood. 2008;111(2):785–789.
   PubMed Web of Science ®Google Scholar
• Mateos MV, Hernandez MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013;369(5):438–447.
   PubMed Web of Science ®Google Scholar
• Rajkumar SV, Landgren O, Mateos MV. Smoldering multiple myeloma. Blood. 2015;125(20):3069–3075.
   PubMed Web of Science ®Google Scholar
• Lakshman A, Rajkumar SV, Buadi FK, et al. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J. 2018;8(6):59.
   PubMedGoogle Scholar
• Lonial S, Jacobus S, Fonseca R, et al. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019. DOI:10.1200/JCO.19.01740
   PubMed Web of Science ®Google Scholar
• Landgren O, Cavo M, Chari A, et al. Updated results from the phase 2 Centaurus Study of Daratumumab (DARA) monotherapy in patients with intermediate-risk or high-risk smoldering multiple myeloma (SMM). Blood. 2018;132(Supplement 1):1994–1994.
   PubMedGoogle Scholar
• Bustoros M, Liu CJ, Reyes K, et al. Phase II trial of the combination of ixazomib, lenalidomide, and dexamethasone in high-risk smoldering multiple myeloma. Blood. 2018;132(Supplement 1):804–804.
   PubMedGoogle Scholar
• Liu CJ, Ghobrial IM, Bustoros M, et al. Phase II trial of combination of elotuzumab, lenalidomide, and dexamethasone in high-risk smoldering multiple myeloma. Blood. 2018;132(Supplement 1):154–154.
   Google Scholar