Background: Maintenance therapy (MT) in NDMM has been increasingly used to prolong duration of response achieved by ASCT. TOURMALINE-MM3 is a phase 3, double-blind, placebo-controlled study, where ixazomib improved PFS, and is the first study to evaluate the impact of MT on HRQoL post ASCT in NDMM (Dimopoulos et al., Lancet 2019;393:253). HRQoL is an important consideration during MT in NDMM patients with minimal disease burden post ASCT (Anderson et al., Leukemia 2008;22:231).
Aims: To assess HRQoL in patients randomized to ixazomib vs. placebo MT in TOURMALINE-MM3.
Methods: In TOURMALINE-MM3, NDMM patients post ASCT were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo. HRQoL was assessed by EORTC QLQ-C30 (overall/subscale score range, 1-100) at screening, the start of every cycle (1-26), end of treatment, every 4 weeks until start of next line of therapy after progression and twice thereafter. MM-specific symptoms were assessed by EORTC QLQ-MY20 (subscale score range, 1-100) at screening, the start of every 3 cycles between cycles 1-25, end of treatment, every 4 weeks until start of next line of therapy after progression and twice thereafter. For both instruments, higher scores for global and functional domains indicate better HRQoL, while higher scores on symptom scales represent higher levels of symptomatology. Change from study entry in subscale scores, defined in terms of 30 four-week intervals, was analyzed using a linear mixed-effects model among patients who reported HRQoL outcomes at study entry and completed at least one post-study entry assessment.
Results: Characteristics at study entry were well balanced between ixazomib (n = 386) and placebo (n = 251) arms; median age: 58 years; ECOG performance status 0-1: 97%; 79% had at least a very good partial response post ASCT at study entry. At study entry, least squares (LS) mean scores for ixazomib vs. placebo on the EORTC QLQ-C30 were: Global Health Status/QoL, 69.8 vs. 69.1; Physical Functioning, 82.1 vs. 82.0; Pain, 25.3 vs. 25.7; Nausea/Vomiting, 2.3 vs. 2.0; Diarrhea, 5.9 vs. 6.0; and on the EORTC QLQ-MY20 were: Disease Symptoms, 20.3 vs. 19.2; Peripheral Neuropathy, 25.0 vs. 25.6. Compliance with study assessments, averaged across cycles, was high in the treatment phase (≥94%) and similar between treatment groups.
Changes in subscale scores across the 4-week intervals were generally similar between the ixazomib and placebo groups, with treatment differences not reaching the established minimal important difference (MID) of 10 in MM (Kvam et al., Eur J Haematol 2011;87:330). LS mean (95% CI) score changes at interval 24 (week 96) for ixazomib vs. placebo on the EORTC QLQ-C30 included: Global Health Status/QoL, -0.4 (-3.4, 2.7) vs. 1.8 (-1.7, 5.2); Physical Functioning, 0.7 (-1.8, 3.1) vs. 3.0 (0.3, 5.8); Pain, 4.1 (0.5, 7.7) vs. -1.4 (-5.5, 2.7); and on the EORTC QLQ-MY20 were: Disease Symptoms, 5.1 (2.4, 7.9) vs. 0.8 (-2.3, 3.8); Peripheral Neuropathy, -0.7 (-5.1, 3.7) vs. -6.2 (-11.1, -1.3). EORTC QLQ-C30 Nausea/Vomiting and Diarrhea subscales, while consistently worse for ixazomib than placebo (LS mean [95% CI] change at interval 24, 5.0 [3.0, 7.0] vs. 1.0 [-1.3, 3.3] and 4.0 [1.1, 6.8] vs. 0.5 [-2.8, 3.8], respectively), were in line with the ixazomib toxicity profile; treatment differences did not exceed the MID.
Summary/Conclusion: In addition to improvements in PFS with ixazomib, HRQoL was maintained during the protocol-defined treatment period in both arms, and active treatment with ixazomib did not have an adverse impact on HRQoL.
