Sara Bringhen, MD University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino speaks about ASH 2020 abstract – 1381 Progression-Free Survival (PFS) Benefit Demonstrated and Quality of Life (QoL) Maintained across Age and Frailty Subgroups with the Oral Proteasome Inhibitor (PI) Ixazomib Vs Placebo As Post-Induction Maintenance Therapy in Non-Transplant Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts): Analysis of the TOURMALINE-MM4 Phase 3 Trial.
Context
In NDMM pts, maintenance care increases PFS. There is a need for additional active, well-tolerated treatment options that are acceptable for long-term administration. The primary endpoint of PFS was achieved by the international, multicenter, double-blind, placebo-controlled, phase 3 TOURMALINE-MM4 (NCT02312258) trial of oral PI ixazomib as post-induction maintenance therapy in non-transplant NDMM pts. With a manageable and well-tolerated toxicity profile, Ixazomib showed a significant and clinically important benefit compared to placebo. In this setting, viable, tolerable long-term therapy options are especially relevant as pts are often elderly and/or weak. A subgroup review of TOURMALINE-MM4 by age and fragility status is stated herein.
Methodology
After 6-12 months of standard-of-care induction therapy, Pts that obtained partial response (PR) were randomized to ixazomib or placebo maintenance 3:2 for up to 24 months. The number of 4 components was used to identify pts as fit (total score: 0), unfit (score: 1), or fragile (score: ⇠2): age (<75 vs 75-80 vs >80 years; score 0 vs 1 vs 2), the Katz Index of Independence in Daily Living Activities (ADL; >4 vs ⇠4, score 0 vs 1), the Lawton Instrumental ADL Scale (>5 vs ⇠5, score 0 vs 1), and the Charlson Comorbidity Index ( ⇠1 vs ⇠2, score 0 vs 1). Analyses of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire The core modules 30 and MY20 were performed to determine the effects of treatment on QoL within frailty-status and age-defined subgroups.
Outcomes
There were equal proportions of pts aged <65, 65-74, and ⇠75 years and pts listed as fit, unfit, and weak in the ixazomib (n=425) vs placebo (n=281) weapons (Table 1). Baseline disease and treatment features were generally balanced across the various age and frailty classes in ixazomib vs. placebo pts, with some numerical variations observed. Higher rates of stage III disease and fit pts of the International Staging System (ISS) and a lower rate of complete (CR) or very good partial (VGPR) response post-induction were seen in pts aged <65 years (Table 1). A higher rate of CR or VGPR was seen in fit pts across frailty groups, a lower rate of ISS stage III disease was seen in unfit pts, and a higher rate of ISS stage III disease was seen in fragile pts, and a lower rate of CR or VGPR was seen.
Ixazomib vs placebo PFS gain was seen across age groups, with hazard ratios (HRs) of 0.576 (95% confidence interval [CI] 0.299-1.108, p=0.095, median 11.0 vs 9.3 months) in pts <65 years of age, 0.615 (95% CI 0.467-0.810, p<0.001, median 17.9 vs 9.3 months) in pts 65-74 years of age, and 0.740 (95% CI 0.537-1.019, p=0.064, median 16.7 vs 10.2 months) in pts x75 years of age. HRs were similar to those for PFS for time to progression (TTP). The advantage of PFS with ixazomib vs. placebo was also seen in fragile classes, with similar TTP Hours.
Grade 3 treatment rates-emergent adverse events (TEAE), moderate TEAEs, and discontinuation due to TEAEs were higher or comparable across age and frailty subgroups with ixazomib vs placebo (Table 2). In older age groups and in unfit/frail pts in both weapons, rates were generally slightly higher; however, rates of discontinuation due to TEAEs across groups were < 20 percent, including in pts aged 75 years and frail pts (Table 2). The rates of common gastrointestinal TEAEs were comparable across age groups with ixazomib; rash and liver impairment were less common, and peripheral neuropathy in older pts was more common.
In each period, covariate-adjusted changes in baseline QoL subscales were calculated using repeated measurements of linear mixed models stratified by fragility status. Mean changes in each treatment arm were minimal over time 10 points on a scale of 0-100) and comparable between arms in all frailty classes, suggesting that continuation of ixazomib vs placebo maintenance did not adversely affect pts ‘QoL. Analysis by age was largely consistent with the fragility findings.
Findings
Ixazomib results in PFS benefits vs. placebo, regardless of age or frailty status, as post-induction maintenance therapy in non-transplant NDMM pts. In general, Ixazomib was well tolerated across classes, with TEAE rates typically elevated in elderly/frail vs younger/fit pts in both weapons. Ixazomib is a feasible and efficient alternative for maintenance to expand PFS through this heterogeneous population of pt.