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: Key Points In a multicenter, randomized phase 3 trial, MPR-R was not superior over MPT-T with respect to response rate, PFS, and OS. Grade 3/4 hematologic toxicity requiring growth factor support occurred with MPR-R vs clinically significant neuropathy with MPT-T.

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

Description: BACKGROUND There is a high rate of toxicity-related discontinuation in elderly patients with NDMM, which in general is higher in patients ≥75 years. Therefore, we investigated the feasibility of a dose-adapted MPV scheme in patients ≥75 years and whether the International Myeloma Working Group frailty score (fit, unfit, and frail) predicts feasibility. Moreover, geriatric assessments, including functional assessments, were performed in order to design a model for more precise prediction of feasibility of treatment. METHODS Patients were treated with 9 cycles of MPV: Mel 6 mg/m2, day 1-4; Pred 30 mg/m2, day 1-4; and Bort 1.3 mg/m2 day 1,8,15 and 22 of a 35-day cycle. This first planned analysis on discontinuation rate was restricted to the first 100 eligible consecutive patients out of 240 planned patients. A preliminary analysis of grip strength and walking speed was performed, comparing tertiles. RESULTS Of the 96/100 evaluable patients, none were fit (because of age ≥75 years), 23/96 (24%) were unfit and 64/96 (67%) were frail (9/96 (9%) unknown). 28/64 (44%) frail patients were aged 75-80, and 8/64 (13%) patients were defined frail based on age 〉80 years only. Frail patients were found to have significantly less grip strength and lower walking speed as compared to unfit patients (see table 1), both for men and women. However, 19% (male) and 15% (female) of the patients with low grip strength were not frail, but unfit. For slow walking speed these percentages were 13% and 7% respectively, indicating these tools might be complementary to the IMWG frailty score in predicting outcome. The median follow up was 16 months. The discontinuation rate of MPV in the total population was 49%; 30% in unfit and 55% (including 7% discontinuation of bortezomib only) in frail patients (p=0.055). In patients 〉80 years (by definition frail) discontinuation rate was higher (69% (including 11% bortezomib only)) than in patients aged 75-80 years (37%; p=0.003). Reasons for early discontinuation in unfit versus frail were: progressive disease 1/7 vs 4/31, toxicity 3/7 vs 10/31, death 0/7 vs 4/31, non-compliance 1/7 vs 8/31, other 2/7 vs 5/31. In 72% 6 cycles of MPV were found to be feasible, both in unfit (78%) and frail (73%) patients. Response on protocol was ≥PR 69%, ≥VGPR 29% and ≥CR 7%, not significantly different in unfit versus frail patients. Median progression free survival (PFS) was 17 months: 22 for unfit and 17 months for frail patients (p=0.38). Overall survival (OS) at 18 months was 76%: 88% for unfit and 71% for frail (p=0.26) patients. Conclusions Treatment of elderly NDMM patients ≥75 years with 9 cycles of dose-adjusted MPV results in a high discontinuation rate of 49%: 30% in unfit versus 55% in frail patients, indicating the need for further treatment adjustment and more precise selection of patients. Concerning the first; 6 cycles were found to be feasible in the majority of both unfit and frail patients. Concerning the latter; a preliminary analysis of functional geriatric assessments showed significantly lower performance in frail compared to unfit patients. Moreover, the results of functional geriatric assessments were found to add to the IMWG frailty score, hopefully leading to a better prediction of the feasibility of treatment in elderly NDMM patients. Functional assessments in unfit versus frail patients 1 p=0.18 2 p=0.012 3 p=0.037 4 p=0.014 Additional cognitive and nutritional geriatric assessments and biomarkers (sarcopenia and senescence markers) were performed in all patients. FISH analysis of isolated plasma cells will be available in the majority of patients. This trial was registered at www.trialregister.nl (NTR 4244), EudraCT 2013-000320-33, and supported by the Dutch Cancer Society (project number VU 2013-6411 ) and by an unrestricted grant from Janssen-Cilag. Disclosures Zweegman: Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Ypma:Advisory Board Sanofi (Plerixafor): Membership on an entity's Board of Directors or advisory committees. Minnema:Celgene: Consultancy; BMS: Consultancy; Amgen: Consultancy; Jansen Cilag: Consultancy. van de Donk:BMS: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Amgen: Research Funding. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

Description: Background Melphalan-based regimens, combined with Prednisone and Thalidomide (THAL)(MPT) or Bortezomib (V)(MPV), have been approved as standard therapy of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients. Similar to MPT and MPV also MP-Lenalidomide followed by Lenalidomide (LEN) maintenance (MPR-R) has a superior PFS compared to MP. We compared MPT followed by THAL maintenance (MPT-T) versus MPR-R in non-transplant eligible NDMM patients. Study design Patients were randomised to receive nine 4-weekly cycles of MPT (MEL 0.18 mg/kg days 1-4, PRED 2 mg/kg days 1-4 plus THAL 200 mg days1-28) followed by THAL maintenance 100 mg d1-28 until progression or nine cycles of MPR (MEL 0.18 mg/kg days 1-4, PRED 2 mg/kg days 1-4 plus LEN 10 mg days 1-21) followed by LEN maintenance 10 mg d1-21 until progression. In order to detect an improvement of progression free survival (PFS) with 90% power and a HR of 0.714 for patients receiving MPR-R, 668 patients had to be randomized. The study started in January 2009 and was closed for inclusion in October, 2012. This analysis is restricted to the first 560 eligible randomized patients, i.e. 280 per arm, including the minimum number of events (377) that were required for the primary endpoint. Results Patient characteristics are presented in table 1. The median follow up is 32.6 months. The results of FISH analysis on isolated plasma cells, being performed in 75% and 79% of patients treated with MPT-T and MPR-R respectively, are shown in table 1. Complete response (CR) rates on protocol were 10% (MPT-T) vs. 13% (MPR-R), (p=0.43), ≥ very good partial response (VGPR) rates were 49% vs. 44% (p=0.31), and ≥ partial response (PR) rates were 82% vs. 83% (p=0.91). The median PFS was 20 months (95% CI; 18-23) for MPT-T vs. 22 months (95% CI; 19-27) for MPR-R (HR = 0.86, 95% CI = 0.70-1.05, p-value adjusted for ISS =0.14). The median overall survival (OS) was 49 months (95% CI; 43-54) for MPT-T vs. 50 months (95% CI; 45-54) for MPR-R (HR = 0.79, 95% CI = 0.60-1.05, p-value adjusted for ISS =0.11). Del(17p) was associated with a lower PR rate (OR=0.45, 95% CI 0.22-0.95, p=0.003), worse PFS (HR=1.74, 95% CI 1.20-2.54, p=0.007) and decreased OS (HR=1.98, 95% CI 1.19-3.28, p=0.01). Grade ≥ 3 toxicity during induction and maintenance is presented in table 2. The dose intensity of THAL during induction was median 53% (mean 56%, SD 34%), vs. median 88% (mean 73%, SD 32%) for LEN during induction. There was a significantly higher discontinuation rate due to toxicity associated with THAL (28% within one year, and 58% within two years) vs LEN maintenance (10% within one year, and 16% within two years)(p