Ixazomib Maintenance Therapy in NDMM Patients Not Treated with Stem-Cell Transplantation

The TOURMALINE-MM4 trial is an international, multicenter, double-blind, placebo-controlled, phase 3 study examining the efficacy and safety profile of oral ixazomib as maintenance therapy following initial treatment and its impact on progression-free survival (PFS) compared with placebo in patients with newly diagnosed multiple myeloma (NDMM) who have not undergone stem-cell transplantation (SCT). The trial enrolled 706 patients with NDMM who had not undergone SCT and who had 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. Following initial treatment, patients were stratified according to prior proteasome inhibitor treatment exposure; International Staging System disease stage of 1 or 2 versus 3; aged <75 years or ≥75 years; and post-induction response of CR, VGPR, or PR. The 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; 34.8% of the ixazomib group had stage 3 disease versus 35.9% in the placebo control group; and both groups had 17% of patients with cytogenetic abnormalities. The dosing schedule for the trial 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 or 4 mg on days 1, 8, and 15 in a 28-day cycle for cycles 5 through 26.

The results of TOURMALINE-MM4 showed a significant improvement in the primary outcome measure of PFS with ixazomib versus placebo, with a median PFS of 17.4 months versus 9.4 months, respectively. There was a significant reduction in risk of progression or death (34%) 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 with a median improvement of 25.6 months in the ixazomib arm versus 12.9 months for placebo. For patients who had achieved PR post-induction treatment, ixazomib resulted in a median PFS of 10.2 months versus 6.5 months with placebo.

The PFS was analyzed for several subgroups. For patients <75 years of age, 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 ≥75 years, treatment with ixazomib resulted in PFS of 16.7 months versus 10.6 months with 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. Ixazomib also improved PFS in patients with previous proteasome inhibitor treatment with a median PFS of 16.8 months versus 11.1 months with placebo. A final subgroup analysis revealed proteasome inhibitor–naive 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 because of AEs was 13% in the ixazomib arm and 8% for placebo. 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 ixazomib as maintenance therapy for NDMM in patients not treated with SCT is an efficacious treatment plan with a tolerable safety profile.


Reference

  • 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.

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