Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma

Abstract

BACKGROUNDIxazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma. METHODSIn this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receive ixazomib plus lenalidomide-dexamethasone (ixazomib group) or placebo plus lenalidomidedexamethasone (placebo group). The primary end point was progression-free survival. RESULTSProgression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P = 0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of response were 78% in the ixazomib group and 72% in the placebo group, and the corresponding rates of complete response plus very good partial response were 48% and 39%. The median time to response was 1.1 months in the ixazomib group and 1.9 months in the placebo group, and the corresponding median duration of response was 20.5 months and 15.0 months. At a median follow-up of approximately 23 months, the median overall survival has not been reached in either study group, and follow-up is ongoing. The rates of serious adverse events were similar in the two study groups (47% in the ixazomib group and 49% in the placebo group), as were the rates of death during the study period (4% and 6%, respectively); adverse events of at least grade 3 severity occurred in 74% and 69% of the patients, respectively. Thrombocytopenia of grade 3 and grade 4 severity occurred more frequently in the ixazomib group (12% and 7% of the patients, respectively) than in the placebo group (5% and 4% of the patients, respectively). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group). Patient-reported quality of life was similar in the two study groups. CONCLUSIONSThe addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. (Funded by Millennium Pharmaceuticals; TOURMALINE-MM1 ClinicalTrials.gov number, NCT01564537.)

Continuous treatment with lenalidomide and low‐dose dexamethasone in transplant‐ineligible patients with newly diagnosed multiple myeloma in Asia: subanalysis of the FIRST trial

“…In relapsed/refractory multiple myeloma, Rd has been the basis for new regimens in combination with the proteasome inhibitors carfilzomib (Stewart et al , 2015) and ixazomib (Moreau et al , 2016) and the monoclonal antibodies elotuzumab (Lonial et al , 2015) and daratumumab (Dimopoulos et al , 2016). In patients with NDMM, the addition of bortezomib to Rd (VRd) has improved clinical outcome in comparison with Rd alone (Durie et al , 2015).…”

The next generation of novel therapies for the management of relapsed multiple myeloma

“…However, its approval for clinical use was based on the Phase III, randomized, double-blinded, placebo-controlled study -TOURMALINE-MM1 [20]. In this study, 722 patients with relapsed MM after one to three lines of prior therapy but not refractory to prior lenalidomide or PI-based therapy were enrolled to compare ixazomib in addition to lenalidomide and dexamethasone (IRd) compared with lenalidomide and dexamethasone (Rd) [20]. The median PFS and ORR were 20.6 months and 78.3% with IRd compared with 14.7 months and 71.5% with Rd (p = 0.012) [20].…”

“…In this study, 722 patients with relapsed MM after one to three lines of prior therapy but not refractory to prior lenalidomide or PI-based therapy were enrolled to compare ixazomib in addition to lenalidomide and dexamethasone (IRd) compared with lenalidomide and dexamethasone (Rd) [20]. The median PFS and ORR were 20.6 months and 78.3% with IRd compared with 14.7 months and 71.5% with Rd (p = 0.012) [20]. Importantly, ixazomib appeared to provide equal therapeutic benefit to patients with relapsed MM who had high-risk cytogenetic features such as deletion 17p, t(4;14) and t(14;16) as they had a similar PFS as the remainder of the standard risk patients [20].…”

Barriers and Facilitators of Using Sensored Medication Adherence Devices in a Diverse Sample of Patients With Multiple Myeloma: Qualitative Study (Preprint)

“…Concern is warranted for several reasons. Many recently approved medications are oral and taken on complex irregular schedules (Thalidomide [7], Lenalidomide [8], Pomalidomide [9], Ixazomib [10] and Panobinostat [11]). Furthermore, oral steroids such as dexamethasone continue to be a mainstay of therapy which increases the pill burden.…”