ALBERT

Description: Introduction Elderly non-transplant eligible newly diagnosed multiple myeloma (nte-NDMM) patients also benefit from novel therapies, however, overall survival (OS) is inferior in unfit and frail compared to fit patients as defined by the International Myeloma Working Group (IMWG) frailty index. This is caused by a high discontinuation rate due to toxicity. Therefore, a less toxic effective treatment for unfit and frail patients is needed. In view of the favorable safety profile of ixazomib (Ixa) and daratumumab (Dara), we investigated the efficacy and feasibility of treatment with Ixa and Dara plus low dose dexamethasone (Ixa-Dara-dex) in unfit and frail patients. This trial was registered at www.trialregister.nlwww.trialregister.nl as NTR6297. Methods In this prospective multicenter phase II trial, treatment consisted of nine 28 day-induction cycles consisting of Ixa 4 mg (days 1, 8, 15), Dara 16 mg/kg (cycle 1-2: days 1, 8, 15, 22; cycle 3-6: days 1, 15; cycle 7-9: day 1) and dex (in combination with Dara; cycle 1-2: 20 mg; subsequent cycles 10 mg) followed by maintenance therapy with Ixa (days 1, 8, 15, 29, 36, 43) and Dara (day 1) of 8-week cycles, until progression for a maximum of 2 years. A pre-specified efficacy analysis was planned for the first eligible 23 unfit and 23 frail patients separately at the time the data of the first 9 cycles induction therapy was available. Inclusion criteria were unfit or frail NDMM patients according to the IMWG frailty index. Main exclusion criteria were severe cardiac dysfunction, chronic obstructive pulmonary disease with an FEV1

Description: 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. Disclosures 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.

Description: Introduction There is a high rate of treatment discontinuation (TD) in elderly patients with nte-NDMM, that negatively impacts overall survival (OS). In order to prevent TD identification of unfit and frail patients is a prerequisite, either to withhold or adapt treatment. Although the IMWG frailty score (IMWG-FS) identifies frail patients with higher TD and inferior OS there is a need for refinement. Therefore, we prospectively evaluated the feasibility of a dose-adjusted Melphalan-Prednisone-Bortezomib (MPV) regimen in nte-NDMM patients ≥75 years of age. In addition, we investigated the prognostic value of a geriatric assessment (GA) and muscle mass and function for TD and OS. This is a preliminary analysis of 220/240 included patients. A final update, including multivariable prediction models, of 240 patients will be available at the ASH meeting. Methods Patients were treated with 9 cycles of MPV: M 6 mg/m2, day 1-4; P 30 mg/m2, day 1-4; and V 1.3 mg/m2 day 1,8,15 and 22 of a 35-day cycle. Functional, cognitive, mental health, nutritional status and comorbidities were assessed at baseline (Table 1). Muscle mass and function were determined by CT scan and hand grip strength (HGS) and gait speed (GS), respectively. Presarcopenia was defined as low skeletal muscle mass (Skeletal Muscle Index (SMI) cm/m2) only, sarcopenia when additionally low muscle function (HGS or GS) was present, and severe sarcopenia when all 3 parameters were abnormal. Cut offs for muscle mass parameters were defined by sex-specific p5 and p10 values reported in the literature and a Bayesian statistical change point model. Associations between TD or OS and aforementioned factors were assessed via univariable regression models. Multivariable prediction models will be developed using variable selection procedures. Results 218/220 patients were eligible for frailty analysis; 61% frail, 28% unfit and 3% fit patients (7% unknown), according to IMWG-FS. Median follow-up was 22 months (inter quartile range (IQR) 15-32). TD within 9 cycles of MPV was 44%, being significantly higher in frail as compared to unfit patients (51% vs 29%, hazard ratio (HR) 2.52, 95% confidence interval (CI) 1.32-4.80, p=0.005, Fig. 1A). Overall response rate and median progression free survival were 74% and 17 months (IQR 12-22 months), both unaffected by frailty. Median OS was 45 months. Frail patients had a significant inferior OS as compared to unfit patients (median 31 versus 45 months, HR 2.13, 95% CI 1.21-3.76, p=0.009) (Fig. 1b). Frail patients were older, had significantly more comorbidities, lower physical function (both self-reported [EORTC QoL questionnaire and (i)ADL] and by physical examination [GS and HGS]), worse cognitive function, and more depression and malnutrition as compared to unfit patients (Table 1). Low muscle mass was detected in 13-22% of frail (depending on cut off) versus 5% of unfit patients. Sarcopenia was detected in 13-18% of frail (depending on cut off) and 5% of unfit patients. These data indicate that there are biological differences between unfit and frail patients. Subsequently, we investigated which GA and sarcopenia characteristics were associated with TD and OS. For TD, all IMWG-FS parameters but ADL, WHO ISS 3, muscle mass, depression and risk for malnutrition were associated (table 2). For OS all IMWG-FS parameters, WHO ISS 3, cytogenetic risk, muscle mass, depression, (risk of) malnutrition and cognitive function were associated (table 2). Interestingly, although there was a strong association between muscle mass as determined by CT-scan and both TD and OS, muscle function tests (HGS and GS) were not. Neither were sarcopenia definitions incorporating muscle function. Remarkably, self-reported physical functioning revealed from the QLQ-C30 was associated with TD and OS. Conclusion We here confirm the predictive value of the IMWG-FS for TD and OS. Importantly, we provided a biological background of frailty by showing more geriatric impairments and loss of muscle mass in frail versus unfit patients. In addition to known predictive factors for OS; IMWG-FS, ISS and cytogenetics, we found that GA and low muscle mass, but not muscle function, were associated with clinical outcome. We are currently developing a novel predictive scoring system for TD and OS incorporating these novel parameters, with the aim to refine currently available prediction models for identification of elderly patients who will benefit from therapy. Disclosures 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. Minnema:Servier: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy, Research Funding; Janssen: Consultancy. 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:Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Zweegman:Takeda: 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; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Introduction Data from clinical trials indicate that elderly non-transplant eligible newly diagnosed multiple myeloma (nte-NDMM) patients also benefit from novel therapies. However, overall survival is inferior in unfit and frail compared to fit patients as defined by the International Myeloma Working Group (IMWG) frailty index, caused by a high discontinuation rate due to toxicity. Therefore, there is a need for less toxic treatment for unfit and frail patients. In view of the favorable safety profile of ixazomib and daratumumab, we investigated the efficacy and feasibility of treatment with ixazomib, daratumumab and low dose dexamethasone (IDd) in unfit and frail patients. This trial was registered at www.trialregister.nl as NTR6297. Methods In this prospective multicenter phase II trial treatment consisted of 9 28 day-induction cycles consisting of ixazomib (I) 4 mg (days 1, 8, 15), daratumumab (D) 16 mg/kg (cycle 1-2: days 1, 8, 15, 22; cycle 3-6: days 1, 15; cycle 7-9: day 1) and dexamethasone (in combination with daratumumab (d); cycle 1-2: 20 mg; subsequent cycles 10 mg) followed by maintenance therapy with I (days 1, 8, 15, 29, 36, 43) and D (day 1) of 8-week cycles, until progression for a maximum of 2 years. The primary objective is to determine the overall response rate (ORR) on induction therapy. Aiming for an ORR of at least 65% and considering 50% as a too low ORR, with an optimal Simon 2-Stage design, α = 0.10 and β = 0.20, 60 unfit and 60 frail patients should be included, increased to 66 for both populations to account for ineligibility. A pre-specified safety analysis was planned when for the first 10 unfit and 10 frail patients separately the data of the first 4 cycles of induction therapy are available. Inclusion criteria were NDMM, either being unfit or frail according to the IMWG frailty index. Main exclusion criteria were severe cardiac dysfunction, chronic obstructive pulmonary disease with an FEV1