Cain, Lauren E.

Background Maintenance therapy improves PFS in NDMM pts. Additional active, well-tolerated treatment options that are suitable for long-term administration are required. The international, multicenter, double-blind, placebo-controlled, phase 3 TOURMALINE-MM4 trial (NCT02312258) of the oral PI ixazomib as maintenance therapy post-induction in non-transplant NDMM pts met its primary endpoint of PFS. Ixazomib demonstrated a significant and clinically meaningful benefit vs placebo, with a manageable and well-tolerated toxicity profile. Feasible, tolerable options for long-term therapy are particularly important in this setting, as pts are often elderly and/or frail. We report herein a subgroup analysis of TOURMALINE-MM4 according to age and frailty status. Methods Pts who achieved ≥partial response (PR) after 6-12 months of standard-of-care induction therapy were randomized 3:2 to ixazomib or placebo maintenance for up to 24 months. The sum of 4 components - age (<75 vs 75-80 vs >80 years; score 0 vs 1 vs 2), the Katz Index of Independence in Activities of Daily Living (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) - was used to classify pts as fit (total score: 0), unfit (score: 1), or frail (score: ≥2). Analyses of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and MY20 modules were conducted to evaluate the effects of treatment on QoL within subgroups defined by frailty status and age. Results In the ixazomib (n=425) vs placebo (n=281) arms, there were similar proportions of pts aged <65, 65-74, and ≥75 years and of pts classified as fit, unfit, and frail (Table 1). Baseline disease and treatment characteristics were generally balanced in ixazomib vs placebo pts across the different age and frailty groups, with some numerical differences observed. In pts aged <65 years, higher rates of International Staging System (ISS) stage III disease and fit pts and a lower rate of complete (CR) or very good partial (VGPR) response post-induction were seen (Table 1). Across frailty groups, a higher rate of CR or VGPR was seen in fit pts, a lower rate of ISS stage III disease was seen in unfit pts, and a higher rate of ISS stage III disease and a lower rate of CR or VGPR were seen in frail pts (Table 1). PFS benefit with ixazomib vs placebo 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 aged <65 years, 0.615 (95% CI 0.467-0.810, p<0.001, median 17.9 vs 9.3 months) in pts aged 65-74, and 0.740 (95% CI 0.537-1.019, p=0.064, median 16.7 vs 10.2 months) in pts aged ≥75 years. HRs for time to progression (TTP) were similar to those for PFS. PFS benefit with ixazomib vs placebo was also seen across frailty groups (Figure), with similar HRs for TTP. Rates of grade ≥3 treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuation due to TEAEs were higher or similar with ixazomib vs placebo across age and frailty subgroups (Table 2). Rates were generally somewhat higher in older age groups and in unfit/frail pts in both arms; nevertheless, rates of discontinuation due to TEAEs across groups were <20%, even in pts aged ≥75 years and frail pts (Table 2). With ixazomib, rates of common gastrointestinal TEAEs were similar across age groups; rash and liver impairment appeared less common and peripheral neuropathy more common in older pts (Table 2). Covariate-adjusted changes in QoL subscales from baseline were estimated at each cycle using repeated measures linear mixed models stratified by frailty status. In all frailty groups, the mean changes in each treatment arm were small over time (<10 points on a 0-100 scale) and similar between arms, indicating that continued treatment with ixazomib vs placebo maintenance did not adversely affect pts' QoL. Analyses by age were generally consistent with the results by frailty. Conclusions Ixazomib as post-induction maintenance therapy in non-transplant NDMM pts results in PFS benefits vs placebo regardless of age or frailty status. Ixazomib appeared generally well tolerated across groups, with TEAE rates in both arms generally elevated in elderly/frail vs younger/fit pts. Ixazomib is a feasible and effective maintenance option for prolonging PFS across this heterogeneous pt population. Disclosures Bringhen: Takeda: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Vorog:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Labotka:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Wang:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Cherepanov:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Cain:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Manne:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Dimopoulos:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Beigene: Honoraria; Amgen: Honoraria. OffLabel Disclosure: Use of the oral proteasome inhibitor ixazomib as maintenance therapy in patients with newly diagnosed multiple myeloma not undergoing stem cell transplantation

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.

BACKGROUND: Proteasome inhibitors (PIs) combined with an Rd backbone constitute commonly used regimens in RRMM in the US. Lack of data from head-to-head clinical trials comparing the efficacy of these PI-Rd triplets and the extent to which efficacy translates to benefit in routine care highlight the need for real-world evidence. We conducted a comparative effectiveness analysis of time to next therapy (TTNT) of these PI-Rd triplet combinations in a real-world representative cohort of RRMM patients. METHODS: In this retrospective cohort study, RRMM patients who initiated an index regimen with IRd, KRd, or VRd in ≥2nd line of therapy (LOT 2+) were followed between 1/2014-9/2018 in Optum's deidentified national electronic health records database. This database captures information on all patients treated by >140,000 providers across 50 states in the US. It is representative of the US general population. Baseline data included: a modified frailty score utilizing age and Charlson Comorbidity Index1, ECOG performance status, CRAB symptoms, ISS stage, cytogenetic risk (high: del[17p], t[4;14], or t[14;16]), history of: cardiovascular disease, peripheral neuropathy, stem-cell transplant, and uncontrolled hypertension, prior PI and/or IMID exposure and refractory status, time from diagnosis to start of index LOT, time from start of frontline therapy to start of LOT 2, and treatment-free interval prior to index LOT. Duration of therapy (DOT) and TTNT were estimated using Kaplan-Meier methods and compared using stratified (by LOT) ± baseline-adjusted Cox proportional hazard models with a repeated measures analysis of pt-LOTs with robust sandwich estimators to account for inclusion of patients in multiple LOTs. The main analysis was repeated in subgroups a priori defined by frailty score, cytogenetic risk, prior PI and/or IMID exposure and LOT. Observations were censored at time of loss to follow up/end of study period (9/30/2018). RESULTS: Overall, 650 patients with 733 pt-LOTs (IRd, n=168; KRd, n=208; VRd, n=357) were included; 20% of the RRMM patients in this cohort were treated at academic centers. In the I-/K-/V-Rd groups, respectively, median age was 71/65/71 years and 42/22/38% patients were ≥75 years old; 39/55/46% and 28/14/29% patients had a modified frailty score of intermediate and frail, respectively; 71/88/80% had a symptomatic relapse with at least 1 CRAB symptom; 20/28/13% patients had high cytogenetic risk; 69/72/90% patients were treated in 2-3 LOT, and 63/70/32% patients had prior exposure to a PI+IMID (P<0.05 for all). The median follow-up was 14.4 months. Unadjusted median DOT of index LOT was 12.3/7.2/10.0 months, with a lower risk of discontinuation of the oral PI component for I in comparison to both K and V (HR[I vs K] of 0.66 and HR[I vs V] of 0.68) and R component in the IRd vs KRd and VRd groups (HR[I vs K] of 0.64 and HR[I vs V] of 0.75) (P<0.05 for all). Unadjusted median TTNT was 12.7/8.6/14.2 months for I-/K-/V-Rd in LOT ≥2; with HR for TTNT of 0.76 (IRd vs KRd; P<0.05); 1.01 (IRd vs VRd; P=0.96); 1.33 (KRd vs VRd; P<0.05). The adjusted HRs for TTNT I-/K-/V-Rd in LOT ≥2 were 0.82 (IRd vs KRd); 0.93 (IRd vs VRd); 1.13 (KRd vs VRd; P>0.05 for all), and were comparable between all 3 groups. A significant TTNT benefit for IRd vs KRd was observed among patients with high cytogenetic risk (HR: 0.47) and with intermediate frailtymodified score (HR: 0.60; P<0.05 for all). CONCLUSIONS: In this real-world representative RRMM cohort, in unadjusted analyses, the IRd group had a longer DOT of the PI and R components and a longer TTNT in comparison with KRd. After adjusting for baseline confounders to separate the treatment effect, the I/K/V-Rd triplet combinations were comparable in TTNT, but IRd was significantly better than KRd in patients with high-risk cytogenetics and with an intermediate frailty score. Residual confounding is always a potential limitation of any non-randomized study. Conversely, the results of randomized, clinical trials are limited in generalizability as 40-60% of patients are excluded due to inability to meet eligibility criteria. This is especially pertinent in an elderly RRMM population as demonstrated in the real-world effectiveness results in this study. Ref: 1. Palumbo, et al. Blood. 2015;125:2068-2074 Figure Disclosures Chari: Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Oncoceutics: Research Funding; Novartis Pharmaceuticals: Research Funding; GlaxoSmithKline: Research Funding; Array Biopharma: Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Romanus:Takeda: Employment. Raju:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Other: Xcenda received funding from Takeda to complete this analyses., Research Funding; Xcenda, LLC: Employment. Cain:Takeda: Employment. Blazer:Xcenda: Employment; Takeda: Other: Xcenda received funding from Takeda for completion of this analysis, Research Funding. Farrelly:Xcenda: Employment; Takeda: Other: Xcenda received funding from Takeda for completion of this analysis, Research Funding. Stull:Takeda: Employment. Ailawadhi:Pharmacyclics: Research Funding; Cellectar: Research Funding; Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding.