Maintenance therapy with ixazomib after induction, high-dose therapy, and autologous stem cell transplantation (ASCT) prolonged progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (MM), study results published in The Lancethave shown.
Despite the improved PFS and OS achieved with ASCT in patients with newly diagnosed MM, most patients eventually relapse. Maintenance therapy is thought to prolong PFS and improve overall survival (OS) for these patients. Lenalidomide is approved for use in this setting; however, it has a high discontinuation rate due to treatment-emergent adverse events and has not demonstrated consistent benefit in high-risk patients.
An alternative to lenalidomide would be a proteasome inhibitor because of its different mode of action. Data from prior trials suggest that use of bortezomib as maintenance therapy could prolong PFS; however, the agent is not well suited for long-term use. Ixazomib has a convenient once-weekly oral dosing, tolerability, and favorable toxicity profile. Therefore, the TOURMALINE-MM3 study (ClinicalTrials.gov Identifier: NCT02181413) sought to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT for newly diagnosed MM.
The TOURMALINE-MM3 study is a phase 3, double-blind, placebo-controlled study conducted in 167 clinical or hospital sites in 30 countries. Eligible participants were adults (age, 52 to 64 years) with symptomatic multiple myeloma (confirmed according to International Myeloma Working Group criteria) who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by melphalan 200 mg/m2 conditioning and single ASCT within 12 months of diagnosis.
Patients were randomly assigned in a 3:2 ratio to oral ixazomib 3 mg or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following standard-of-care regimen. The initial dose was increased to 4 mg from cycle 5 if tolerated during cycles 1 to 4. Randomization was stratified by induction regimen, preinduction disease stage, and response posttransplantation. The primary end point was progression-free survival by intention-to-treat analysis. Safety was assessed in all patients who received at least 1 dose of ixazomib or placebo, according to treatment actually received.
A total of 656 patients were enrolled between July 31, 2014, and March 14, 2016, and randomly assigned to ixazomib maintenance therapy (395 patients) or placebo (261 patients). After median 31 months of follow-up, ixazomib maintenance therapy reduced the risk of disease progression or death by 28% vs placebo (median PFS 26.5 months [95% CI 23.7-33.8] vs 21.3 months; hazard ratio 0.72; 95% CI 0.58-0.89; P = .0023).
No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (8 [3%] patients) at the time of analysis. Serious adverse events were reported in 108 of 394 (27%) patients in the ixazomib group and 51 of 259 (20%) patients in the placebo group. During the treatment period, one patient in the ixazomib group died during the treatment period, and none died in the placebo group.
In addition, overall health-related quality of life was assessed using patient self-reported instruments including the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and MY-20 instruments. Patients completed self-assessments at screening; at the start of every cycle (C30) or at the start of cycles 1, 4, 7, 10, 13, 16, 19, 22, and 25 (MY-20); and at end of treatment. Continued follow-up included self-assessments every 4 weeks until disease progression and every 12 weeks following disease progression.
Mean global health status scores were unchanged from study entry in both the treatment and placebo groups. Consistency and similarity in scores throughout the study and between the 2 groups, respectively, indicate that ixazomib maintenance did not have a negative impact on overall quality of life. The only negative factors were related to nausea or vomiting and diarrhea, which is consistent with the reported safety profile of ixazomib maintenance.
This study was funded by Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.
Dimopoulos MA, Gay F, Schjesvold F, et al; TOURMALINE-MM3 study group. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet.2019;393(10168):353-264.