Once Weekly Versus Twice Weekly Carfilzomib Dosing in Patients with Relapsed and Refractory Multiple Myeloma (A.R.R.O.W.): Efficacy and Safety Analyzed By Age Group
Authors: Dimopoulos Meletios A , Niesvizky Ruben , Moreau Philippe , Siegel David S , Hajek Roman , Mateos Maria-Victoria , Cavo Michele , Huang Mei , Zahlten-Kumeli Anita , Weisel Katja 
Published: October 2019

Abstract

Introduction: The primary analysis of the phase 3 A.R.R.O.W. study indicated that patients (pts) with relapsed and refractory multiple myeloma (RRMM) who received once weekly carfilzomib (70 mg/m2) plus dexamethasone (Kd; once weekly group) had significantly prolonged progression-free survival (PFS) compared with those who received twice weekly (27 mg/m2) Kd (twice weekly group) (11.2 vs 7.6 months [mos]; hazard ratio [HR], 0.69, 95% confidence interval [CI], 0.54-0.88; P=0.0029), with comparable safety profiles (Moreau P, et al. Lancet Oncol. 2018;19:953-964). Herein, we present a subgroup analysis of the A.R.R.O.W. study to investigate the impact of age on the efficacy and safety of the once weekly vs twice weekly carfilzomib dosing in RRMM.
Methods: Adult pts with RRMM and 2-3 prior regimens received carfilzomib once weekly (20 mg/m2 C1D1,70 mg/m2 thereafter) or twice weekly (20 mg/m2 C1D1,2;27 mg/m2 thereafter) plus weekly dexamethasone (40 mg) in 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was PFS; secondary endpoints included overall response rate (ORR) per International Myeloma Working Group-Uniform Response Criteria, overall survival, and safety. Endpoints were analyzed according to age group (<65 vs ≥65 y, <75 vs ≥75 y) in this analysis. The comparisons were not adjusted for multiplicity.
Results: Of the 478 pts enrolled in A.R.R.O.W., 208 pts were <65 y (once weekly, n=104; twice weekly, n=104), 270 were ≥65 y (once weekly, n=136; twice weekly, n=134), 400 were <75 y (once weekly, n=194; twice weekly, n=206) and 78 were ≥75 y (once weekly, n=46; twice weekly, n=32). Carfilzomib treatment duration was longer in the once weekly group vs the twice weekly group in all evaluated age groups (Table 1). Median PFS was prolonged with once vs twice weekly treatment for pts <65 y (12.2 vs 5.6 mos; HR, 0.596; 95% CI, 0.415-0.857; P=0.0024) and longer for pts ≥65 y (11.2 vs 8.7 mos; HR, 0.836; 95% CI, 0.609-1.148; P=0.1344) (Table 1, Figure 1A,B); Median PFS was also longer in the once weekly group for pts <75 (11.1 vs 7.4 mos; HR, 0.707; 95 % CI, 0.545-0.917; P=0.0043) and ≥75 y (12.2 vs 9.5 mos; HR, 0.798; 95% CI, 0.430-1.483; P=0.2385) (Table 1, Figure 1C,D). ORR was improved with once vs twice weekly treatment for pts <65 y (64.4% vs 34.6%; odds ratio [OR], 3.420; 95% CI, 1.935-6.045; P<0.0001) and for pts ≥65 y (61.8% vs 45.5%; OR, 1.933; 95% CI, 1.190-3.140; P=0.0051); ORR outcomes were also improved with the once-weekly treatment for pts <75 y and ≥75 y. In the once and twice weekly treatment groups, 38.4% and 11.5%, respectively, had a very good partial response or better (≥VGPR), and 8.7% and 3.8% had a complete response or better (≥CR) among pts <65 y; 30.9% and 14.9% had a ≥VGPR, and 5.9% and 0% had a ≥CR among pts ≥65 y. Rates for stringent complete response, CR and VGPR for each age subgroup are shown in Table 1. Overall, 119 (57.8%) pts <65 y, 187 (70.0%) pts ≥65 y, 245 (61.7%) pts <75 y, and 61 (80.2%) pts ≥75 y experienced ≥1 treatment-emergent grade ≥3 AE (Table 2). Key safety data are presented in Table 2. The incidence of grade ≥3 cardiovascular events was numerically similar or lower with once weekly Kd vs the twice weekly regimen across age subgroups. Treatment-emergent grade 5 AEs occurred in 19 (9.2%) pts <65 y, 21 (7.9%) pts ≥65 y, 34 (8.6%) pts <75 y, and 6 (7.9%) pts ≥75 y (Table 2).
Conclusion: Once weekly Kd at 70 mg/m2 improved PFS and ORR for all age groups compared with twice weekly administration. Pts <65 y experienced maximum PFS benefit with once weekly Kd. The benefit of Kd was also apparent in elderly pts ≥75, which is consistent with findings from the phase 3 ENDEAVOR study. Furthermore, the safety profile associated with once weekly Kd was comparable to that of twice weekly Kd across age groups, suggesting that once weekly carfilzomib dosing at 70 mg/m2 is an effective and convenient regimen for pts with RRMM irrespective of age.

Disclosures
Dimopoulos: Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria. Niesvizky:BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Amgen Inc.: Consultancy, Research Funding. Moreau:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siegel:Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau. Hajek:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Mateos:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, 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; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavo:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Huang:Amgen: Employment, Equity Ownership. Zahlten-Kumeli:Amgen: Employment, Equity Ownership. Weisel:Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria.