Gnanasakthy, Ari

AbstractObjectivesHealth‐related quality of life (HRQoL) is particularly important during maintenance therapy (MT) in newly diagnosed multiple myeloma post‐transplant, when disease symptoms are limited.MethodsWe assessed HRQoL in patients randomised to 26 cycles of MT (ixazomib vs placebo) in TOURMALINE‐MM3 (NCT02181413).ResultsThe characteristics at study entry were well‐balanced between ixazomib (n = 386) and placebo (n = 251) arms. At study entry, EORTC QLQ‐C30 and MY20 scores were high for functional scales and low for symptom scales and were comparable with those of the general population. Changes in subscale scores across intervals, analysed over 30 four‐week intervals using a linear mixed‐effects model, were generally small and similar between arms for the EORTC QLQ‐C30 Global Health Status/QoL, Physical Functioning, and Pain subscales and EORTC QLQ‐MY20 Disease Symptoms subscale and Peripheral Neuropathy item. EORTC QLQ‐C30 Nausea/Vomiting and Diarrhoea subscales were consistently worse for ixazomib than for placebo, in line with the ixazomib toxicity profile. Even when least‐squares mean differences between arms were statistically significant, none reached the established minimal important clinical difference of 10 in multiple myeloma.ConclusionsIn addition to improvement in progression‐free survival with ixazomib, HRQoL was maintained in both arms. Active treatment with ixazomib did not have an adverse impact on HRQoL.

Abstract Background: ENESTop (NCT01698905) is an ongoing, single-arm, phase 2 study evaluating treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) who achieved sustained molecular response 4.5 (MR4.5; BCR-ABL1 ≤ 0.0032% on the International Scale [BCR-ABL1IS]) on second-line nilotinib (NIL). In the primary analysis, 57.9% (95% CI, 48.8%-66.7%) of pts who stopped NIL maintained TFR (no loss of major molecular response [MMR; ie, BCR-ABL1IS > 0.1%], confirmed loss of MR4 [ie, consecutive BCR-ABL1IS > 0.01%], or treatment reinitiation) at 48 weeks. Adverse events (AEs) were reported in 73.8% of pts during the first 48 weeks of TFR vs 77.0% during the year prior to stopping treatment. The incidence of musculoskeletal pain-related AEs was higher during TFR (42.1% vs 14.3%). To assess the potential effect of stopping NIL on quality of life (QOL), pt-reported outcomes were assessed before and during TFR. Methods: ENESTop enrolled adult pts with CML-CP with ≥ 3 years of prior tyrosine kinase inhibitor (TKI) therapy (> 4 weeks of imatinib [IM], then ≥ 2 years of NIL). Pts must have achieved sustained MR4.5 on NIL after switching from IM. Enrolled pts entered a 1-year NIL treatment consolidation phase; those without confirmed loss of MR4.5 (ie, consecutive BCR-ABL1IS > 0.0032%) entered the TFR phase and stopped NIL. Pts with loss of MMR or confirmed loss of MR4 during the TFR phase reinitiated NIL. QOL was assessed via questionnaires completed by pts at specified time points. The MD Anderson Symptom Inventory for CML (MDASI-CML) questionnaire assessed, for a defined set of symptoms, the levels of severity and interference with daily life on a scale of 0 to 10, with 0 being the lowest level. The EQ-5D-5L questionnaire assessed problems experienced by pts (no, slight, moderate, severe, or extreme [ie, interfering with functioning] problems) in 5 dimensions: mobility, self-care, usual activities, anxiety/depression, and pain/discomfort; additionally, overall level of health was assessed on a scale of 0 to 100 using the EQ VAS, with 0 being the lowest level. Results: Of 163 enrolled pts, 126 met the criteria for stopping NIL in the TFR phase; of these 126, 53 had loss of MMR or confirmed loss of MR4, of whom 51 reinitiated NIL. Among pts who completed each questionnaire at week 48 of the consolidation phase, week 12 of the TFR phase, or week 48 of the TFR phase, mean MDASI-CML severity scores were 1.7, 1.5, and 1.2, respectively; mean MDASI-CML interference scores were 1.7, 1.6, and 1.4, respectively; and mean EQ VAS scores were 82.2, 78.8, and 82.3, respectively (Table). Among pts with sustained TFR and scores at both week 48 of the consolidation phase and week 12 or 48 of the TFR phase, minimal changes were observed in MDASI-CML and EQ VAS scores during TFR vs week 48 of the consolidation phase. Among pts who reinitiated NIL, mean MDASI-CML severity and interference scores and mean EQ VAS scores at 24 weeks after the start of retreatment were 1.6, 1.5, and 78.8, respectively; changes in scores between week 24 after treatment reinitiation and week 48 of the consolidation phase were minimal among pts with scores at both time points. Among pts who completed the EQ-5D-5L questionnaire, the proportions who reported problems (any level of severity) in the 5 dimensions were generally similar across time points, although problems with mobility and pain/discomfort were more common during TFR vs week 48 of the consolidation phase, particularly at week 12 of the TFR phase (Table). Conclusion: Changes in QOL after stopping NIL, as assessed using these questionnaires, were minimal. This may be related to pts having a relatively high QOL prior to stopping treatment given that they had tolerated ≥ 3 years of TKI therapy, including ≥ 2 years of NIL, prior to enrollment. Despite the higher incidence of musculoskeletal pain-related AEs observed during TFR (42.1% vs 14.3%), the overall QOL was generally similar between the TFR and consolidation phases. This suggests that these AEs did not have a significant negative impact on QOL. Longer follow-up in ENESTop will be needed to further evaluate trends in QOL after stopping second-line NIL. Disclosures Mahon: NOVARTIS PHARMA: Honoraria, Research Funding; BMS: Honoraria; ARIAD: Honoraria; PFIZER: Honoraria. Boquimpani:BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Takahashi:Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria. Shuvaev:Novartis pharma: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Lipton:Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Turkina:Novartis Pharma: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Moiraghi:NOVARTIS: Speakers Bureau; BMS: Speakers Bureau. Nicolini:Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria. Sacha:Pfizer: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Fellague-Chebra:Novartis: Employment. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Brandt:Novartis: Employment. Gnanasakthy:Novartis: Consultancy, Equity Ownership, Research Funding. Jin:Novartis: Employment, Equity Ownership. Hughes:Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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.