TOURMALINE-MM4 is an international, multicenter, double-blind, placebo-controlled, phase 3 study that examined the efficacy and safety profile of oral ixazomib as maintenance therapy in patients with newly diagnosed multiple myeloma (NDMM) who have not undergone stem-cell transplantation after initial treatment and its impact on progression-free survival (PFS) compared with those taking placebo.
The trial enrolled 706 patients with NDMM who had not undergone stem-cell transplantation and who had a complete response (CR), very good partial response (VGPR), or partial response (PR) to 6 to 12 months of standard-of-care induction therapy. After initial treatment, patients were stratified according to exposure to prior proteasome inhibitor treatment; International Staging System (ISS) disease stage of 1 or 2 versus 3; aged <75 or ≥75 years; and post-induction response of CR, VGPR, or PR. Patients in both the ixazomib group and the placebo comparator group had similar baseline characteristics. Median age was 72 years versus 73 years, respectively; 37.6% of the patients in the ixazomib arm were ≥75 years versus 39.1% in the placebo group, and 34.8% of the ixazomib group had stage 3 disease versus 35.9% in the placebo control group. Both groups had 17% of patients with cytogenetic abnormalities. The trial dosing schedule included a once-daily oral 3-mg capsule of ixazomib or placebo on days 1, 8, and 15 in a 28-day cycle for cycles 1 through 4, and ixazomib or placebo 3 mg or 4 mg on days 1, 8, and 15 in a 28-day cycle for cycles 5 through 26.
TOURMALINE-MM4 study results showed a significant improvement in the primary outcome measure of PFS with ixazomib versus placebo. Median PFS was 17.4 months versus 9.4 months, respectively. A significant reduction in the risk of progression or death (34%) was noted in the ixazomib versus placebo groups. In addition, for patients who had reached CR or VGPR post-induction treatment, the PFS benefit was even greater. Median improvement was 25.6 months in the ixazomib arm versus 12.9 months with placebo. Ixazomib resulted in a median PFS of 10.2 months versus 6.5 months with placebo for patients who had achieved PR post-induction treatment.
The PFS was analyzed for several subgroups. For patients aged <75 years, median PFS was 17.7 months for those treated with ixazomib compared with 9.3 months for those taking placebo. For the subgroup of patients aged ≥75 years, treatment with ixazomib resulted in PFS of 16.7 months versus 10.6 months for those taking placebo. For the subgroup of patients with ISS stage 1 or 2, median PFS was 17.4 months with ixazomib versus 10.6 months with placebo. Patients with stage 3 disease had a median PFS of 16.6 months with ixazomib compared with 7.8 months with placebo. In patients with previous proteasome inhibitor treatment, ixazomib also improved PFS. Median PFS was 16.8 months versus 11.1 months with placebo. A final subgroup analysis showed that proteasome inhibitor–naïve patients had a median PFS of 24.1 months with ixazomib versus 7.7 months with placebo. A secondary outcome measure of time to progression was significantly improved at 17.8 months for the ixazomib arm versus 9.6 months for placebo. Overall survival data are still being collected.
The occurrence of adverse events (AEs) in the ixazomib arm was 91% versus 82% in the placebo arm; the majority were grade 1/2. Grade ≥3 AEs were seen in 37% of those treated with ixazomib and 23% of those given placebo, and the presence of serious AEs was 22% versus 17%, respectively. Patient discontinuation rates due to AEs were 13% and 8% in the ixazomib arm and for placebo, respectively. The most common AEs were nausea at 27% versus 8%, vomiting at 24% versus 4%, and diarrhea at 23% versus 12%, respectively.
The conclusions from the study suggest that ixazomib as maintenance therapy is an efficacious treatment plan with a tolerable safety profile for patients with NDMM who were not treated with stem-cell transplantation.
Abstract and Presentation S200. EHA 2020. June 12, 2020. Ixazomib vs. placebo as post-induction maintenance therapy in newly diagnosed multiple myeloma (NDMM) patients (pts) not undergoing autologous stem cell transplant (ASCT): phase 3 Tourmaline-MM4 trial.