Four phase 3 studies of the oral proteasome inhibitor (PI) ixazomib for multiple myeloma in the newly-diagnosed, relapsed/refractory, and maintenance settings: TOURMALINE-MM1, -MM2, -MM3, and -MM4

Abstract

e174 PO-162 Four phase 3 studies of the oral proteasome inhibitor (PI) ixazomib for multiple myeloma in the newly-diagnosed, relapsed/refractory, and maintenance settings: TOURMALINE-MM1, -MM2, -MM3, and -MM4 J. San Miguel, P. Moreau, V. Rajkumar, A. Palumbo, T. Facon, G. Morgan, R. Orlowski, M. Cavo, H. Einsele, F. Neumann, R. Labotka, S. Lonial, P. Richardson Clinica Universidad de Navarra, Centro Investigacion Medica Aplicada (CIMA) Pamplona, Spain; University Hospital Hotel Dieu, Nantes, France; Division of Hematology, Mayo Clinic, Rochester, MN, USA; Azienda Ospedaliero-Universitaria (AOU), University of Torino, Torino, Italy; Hopital Claude-Huriez, Lille, France; University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA; MD Anderson Cancer Center, Houston, TX, USA; Seragnoli Institute of Haematology, University School of Medicine, Bologna, Italy; Medizinische Klinik und Poliklinik II, Julius Maximilians Universitat Wurzburg, Wurzburg, Germany; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; Winship Cancer Institute of Emory University, Atlanta, GA, USA; Dana-Farber Cancer Institute, Boston, MA, USA Background: Triplet regimens combining a PI with an immunomodulatory drug (IMiD) plus dexamethasone (dex) have been shown to be highly effective for the treatment of multiple myeloma (MM), resulting in improved long-term outcomes. These improved outcomes have increased the focus on extended treatment, including maintenance therapy; however, the feasibility of long-term treatment with current regimens is limited due to toxicities or the need for regular clinic visits. Ixazomib is the first oral PI to be studied in the clinic, with encouraging early-phase data. A phase 1 study showed weekly administration of single-agent ixazomib to be TOURMALINE-MM1 TOURMALINE-MM Setting Relapsed/refractory MM Newly diagnosed MM Regimen Ixazomib plus Iendex vs Iendex Ixazomib plus Iendex vs Dosing Ixazomib 4 mg or placebo on days 1 ,8, and 15 Ixazomib 4 mg or plac on days 1, 8, and 1 Len 25 mg on days 1e21 Dex. 40 mg on days 1, 3, 15, and 22 Len 25 mg on days 1 Dex. 40 mg on day 1, 8,15, and 22 28-day cycles 28-day cycles Enrollment 722 patients Estimated 701 Primary end point PFS PFS Main secondary end points OS, OS in del17p, response rate, DOR, TTP, safety, PFS and OS in patients with high-risk cytogenetics OS, response rate, DOR, TTP, safety, PFS and O patients with high-ris cytogenetics Abbreviations: ASCT, autologous stem cell transplantation; dex, dexamethasone; DOR, duration of r survival; TTP, time to progression: TTR, time to response. 15th International Myeloma Workshop, September 23-26, 2015 generally well tolerated in patients with relapsed/refractory MM, with a low incidence of peripheral neuropathy (PN) (20% overall, only 1 case of grade 3 PN), and encouraging preliminary efficacy (Kumar et al Blood 2014). The feasibility of the all-oral combination of ixazomib plus lenalidomide (len) and dex has also been demonstrated, with a 90% overall response rate (including 62% VGPR) and a manageable safety profile with limited PN (6% grade 3) reported in patients with newly diagnosed MM (Kumar et al Lancet Oncol 2014). These studies, together with population pharmacokinetic results, identified the recommended ixazomib phase 3 dose as 4 mg weekly for patients with relapsed/refractory or newly diagnosed MM (Gupta et al Br J Clin Pharmacol 2015). The recommended phase 3 dose for ixazomib maintenance therapy was identified as 3 mg, increasing to 4 mg after 4 cycles if tolerated, using an exposure-safety-efficacy analysis approach (Gupta et al EHA 2014). On the basis of these preliminary data, 4 phase 3 trials of ixazomib are ongoing in the following settings: relapsed and/or refractory MM (TOURMALINE-MM1, NCT01564537), newly diagnosed MM (NDMM) (TOURMALINE-MM2, NCT01850524), MM maintenance therapy following autologous stem cell transplantation (ASCT) (TOURMALINE-MM3, NCT02181413), MM maintenance therapy after initial therapy without ASCT (TOURMALINE-MM4, NCT02312258). Methods: The four trials are shown in the Table. All are randomized, placebo-controlled, double-blind, multicenter studies. Patients in the TOURMALINE-MM1 and -MM2 studies will receive the all-oral combination of ixazomib plus len-dex, while those in the TOURMALINE-MM3 and -MM4 maintenance trials will receive single-agent ixazomib. Progression-free survival is the primary endpoint for all four trials. Recruitment for TOURMALINEMM2, -MM3, and -MM4 is ongoing The authors would like to thank Jane Saunders of FireKite, an Ashfield company, part of UDG Healthcare plc, for writing support during the development of this abstract, which was funded by Millennium Pharmaceuticals, Inc. 2 TOURMALINE-MM3 TOURMALINE-MM4 MM maintenance post-ASCT MM maintenance without ASCT Iendex Ixazomib maintenance vs placebo Ixazomib maintenance vs placebo ebo 5 Ixazomib 3 mg or placebo on days 1, 8, and 15 for cycles 1e4 Ixazomib 3 mg or placebo on days 1, 8, and 15 for cycles 1e4 -21 s Ixazomib 4 mg or placebo on days 1, 8, and 15 for cycles 5e26 Ixazomib 3 or 4 mg, or placebo on days 1 , 8, and 15 for cycles 5e26 28-day cycles 28-day cycles Estimated 652 Estimated 761