Ixazomib-Thalidomide-low dose dexamethasone induction followed by maintenance therapy with ixazomib or placebo in newly diagnosed multiple myeloma patients not eligible for autologous stem cell transplantation; results from the randomized phase II HOVON-126/NMSG 21.13 trial.

Introduction A triplet combination including a proteasome inhibitor (PI) and an IMiD has shown significant efficacy in newly diagnosed multiple myeloma (NDMM) patients. A role for maintenance therapy with the PI bortezomib has been suggested in non-head to head comparisons. Therefore, we investigated the efficacy and feasibility of an oral regimen including induction therapy with ixazomib in combination with thalidomide and dexamethasone, followed by a randomization between maintenance therapy with ixazomib or placebo in elderly non-transplant eligible (nte) NDMM. We here report the final analysis of induction therapy and preliminary results of the randomization phase of the study. This trial was registered at www.trialregister. nl as NTR4910. Methods In this prospective multicenter phase II trial nte-NDMM 143 patients were treated with 9 28 day-cycles consisting of ixazomib 4 mg (day 1, 8, 15), thalidomide 100 mg (day 1-28) and dexamethasone 40 mg (day 1, 8, 15, 22) followed by randomization between either ixazomib or placebo (both day 1, 8, 15/28 days) until progression. Primary objectives were comparison of progression free survival (PFS) between maintenance therapy with ixazomib or placebo (hypothesized hazard ratio (HR) 0.39) and to determine the overall response rate (ORR) of induction therapy. Frailty was assessed by a modification of the IMWG frailty index based on age, the Charlson Comorbidity Index and the WHO performance as a proxy for (instrumental) Activities of Daily Living (scoring WHO 0 as 0 points, WHO 1 as 1 point, and WHO 2-3 as 2 points). High risk cytogenetics was defined as del17p, t(4;14) and/or t(14;16). Results The median follow up (FU) from registration is 26.4 months (range 0.9-41.0 months). Patient characteristics are presented in table 1. Following induction treatment ORR (i.e. ≥PR) was 81% (95% confidence interval (CI) 74-87%), ≥ VGPR 47% (95% CI 38-55%) and ≥ CR 9% (95% CI 5-15%). Age ≥76 years, frailty (unfit or frail) or high cytogenetic risk did not affect the rate and quality of response. Median PFS from registration for all patients was 14.3 months (95%-CI 11.8-16.8). Frailty did not affect PFS. The median PFS for high risk and standard risk disease was comparable; 12.4 months (95%-CI 7.3-20.0) versus 14.6 months (95%-CI 11.5-17.4) respectively. The OS from registration at 18 months was 85% (95% CI 77-90). This was 90% (95% CI 72-97), 92% (95% CI 78-97) and 74% (95% CI 61-84) for fit, unfit and frail patients respectively. Seventy-eight patients (55%) were randomized. The reasons for not being randomized were toxicity (17% [24/143]), progressive disease (15% [21/143]), death (3% [5/143]) and other reasons (10% [15/143]). Median FU from randomization is 18.6 months (range 9.0-31.5 months). Baseline characteristics of randomized patients separately are presented in table 1. Upgrade of response occurred in 13% of patients receiving placebo and 10% of patients receiving ixazomib. The median PFS from randomization was 8.4 months (95%-CI 3.0-13.8) in the placebo arm and 10.1 months (95%-CI 5.6-24.1) in the ixazomib arm (p=0.47, figure 1). The OS from randomization at 18 months was 92% (95%-CI 77-97) in the placebo arm and 100% in the ixazomib arm (p=0.85). Toxicity is presented in table 2. The incidence of neuropathy was low; 8% grade 3 (mainly during thalidomide treatment; 5%) and no grade 4. There was no new onset neuropathy during ixazomib maintenance. During induction 24/143 (17%) patients discontinued therapy due to toxicity; 11 thalidomide-related neurotoxicity, 3 infection, 3 skin toxicity, 2 gastro-intestinal (GI) toxicity and 5 other. During maintenance 4/38 (11%) in the placebo (3 neurotoxicity and 1 other) versus 4/39 (10%) in the ixazomib arm (3 neurotoxicity and 1 GI) discontinued therapy due to toxicity. Discontinuation due to toxicity was comparable across age and frailty groups. Conclusion Induction treatment with 9 cycles of ITd in nte NDMM results in a high ORR of 81%, with 47% ≥ VGPR, independent of age, frailty status and cytogenetic risk. Our placebo controlled randomized phase II trial did not show an improvement in response and PFS with ixazomib maintenance therapy until progression. Ixazomib maintenance did not result in additional toxicity as compared to placebo. Zweegman: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schjesvold:Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy; Bayer: Consultancy; Adaptive: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy; Abbvie: Honoraria; Novartis: Honoraria. Levin:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. van de Donk:Janssen Pharmceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Sonneveld:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Abildgaard:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding.