Once-weekly (70 mg/m2 ) vs twice-weekly (56 mg/m2 ) dosing of carfilzomib in patients with relapsed or refractory multiple myeloma: A post hoc analysis of the ENDEAVOR, A.R.R.O.W., and CHAMPION-1 trials

Philippe Moreau, Keith A Stewart, Meletios Dimopoulos, David Siegel, Thierry Facon, James Berenson, Noopur Raje, Jesus G Berdeja, Robert Z Orlowski, Hui Yang, Haijun Ma, Zandra Klippel, Anita Zahlten-Kumeli, Khalid Mezzi, Karim Iskander, Maria-Victoria Mateos, Philippe Moreau, Keith A Stewart, Meletios Dimopoulos, David Siegel, Thierry Facon, James Berenson, Noopur Raje, Jesus G Berdeja, Robert Z Orlowski, Hui Yang, Haijun Ma, Zandra Klippel, Anita Zahlten-Kumeli, Khalid Mezzi, Karim Iskander, Maria-Victoria Mateos

Abstract

Combination of carfilzomib with dexamethasone (Kd) is approved for use in relapsed and/or refractory multiple myeloma (RRMM), with carfilzomib administered twice weekly at 56 mg/m2 (Kd56 BIW) or once weekly at 70 mg/m2 (Kd70 QW). Post hoc cross-trial comparisons were performed to compare efficacy and safety profiles of Kd70 QW vs Kd56 BIW dosing schedules using data from three trials of patients with RRMM: A.R.R.O.W., CHAMPION-1, and ENDEAVOR. To select for comparable patient populations, side-by-side efficacy and safety comparisons were performed in subgroups of patients with 2-3 prior lines of therapy who were not refractory to bortezomib. The overall response rate (ORR) was 69.9% (95% confidence interval [CI], 61.7-77.2) for Kd70 QW and 72.4% (95% CI, 65.9-78.2) for Kd56 BIW. Median progression-free survival (PFS) was 12.1 months (95% CI, 8.4-14.3) for Kd70 QW and 14.5 months (95% CI, 10.2-not evaluable) for Kd56 BIW. Frequency of grade ≥ 3 adverse events (AEs) was 67.6% for Kd70 QW and 85.3% for Kd56 BIW. Regression analyses (adjusting for prognostic factors) of all patients in the trials who received Kd70 QW vs Kd56 BIW estimated a PFS hazard ratio of 0.91 (95% CI, 0.69-1.19; P = .47) and an ORR odds ratio of 1.12 (95% CI, 0.74-1.69; P = .61). These results suggest that Kd70 QW has a comparable efficacy profile compared with Kd56 BIW and represents a convenient and well-tolerated treatment for patients with RRMM.

Keywords: carfilzomib; dosing schedule; once-weekly; relapsed and/or refractory multiple myeloma.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
PFS of Kd70 QW and Kd56 BIW subgroups (patients with 2‐3 prior lines of therapy and not refractory to prior bortezomib). CI, confidence interval; HR, hazard ratio; Kd56 BIW, twice‐weekly carfilzomib dosed at 56 mg/m2 in combination with a standard dexamethasone dose; Kd70 QW, once‐weekly carfilzomib dosed at 70 mg/m2 in combination with a standard dexamethasone dose; NE, not evaluable; PFS, progression‐free survival
FIGURE 2
FIGURE 2
Regression analysis results of PFS of Kd70 QW vs Kd56 BIWa. aAll 808 patients with observed data receiving Kd70 QW in the A.R.R.O.W. (n = 240) and CHAMPION‐1 (n = 104) trials and Kd56 BIW in the ENDEAVOR (n = 464) trial. Includes treatment group, age, ISS stage, bortezomib‐refractory status, lenalidomide‐refractory status, and number of prior lines of therapy as covariates. bReference group (hazard ratio = 1.0). Covariate effect refers to the effect of the corresponding category vs reference category of the variable. CI, confidence interval; ISS, International Staging System; Kd56 BIW, twice‐weekly carfilzomib dosed at 56 mg/m2 in combination with a standard dexamethasone dose; Kd70 QW, once‐weekly carfilzomib dosed at 70 mg/m2 in combination with a standard dexamethasone dose; PFS, progression‐free survival
FIGURE 3
FIGURE 3
Multiple Cox regression analysis results of PFS of Kd70 QW and Kd56 BIWa. aAll 808 patients with observed data receiving Kd70 QW in the A.R.R.O.W. (n = 240) and CHAMPION‐1 (n = 104) trials and Kd56 BIW in the ENDEAVOR (n = 464) trial. Direct‐adjusted survival curves derived from the Cox regression model with treatment group, age, ISS stage, bortezomib‐refractory status, lenalidomide‐refractory status, and number of prior lines of therapy as covariates. CI, confidence interval; HR, hazard ratio; Kd56 BIW, twice‐weekly carfilzomib dosed at 56 mg/m2 in combination with a standard dexamethasone dose; Kd70 QW, once‐weekly carfilzomib dosed at 70 mg/m2 in combination with a standard dexamethasone dose; PFS, progression‐free survival
FIGURE 4
FIGURE 4
Regression analysis results of ORR of Kd70 QW vs Kd56 BIWa. aAll 808 patients with observed data receiving Kd70 QW in the A.R.R.O.W. (n = 240) and CHAMPION‐1 (n = 104) trials and Kd56 BIW in the ENDEAVOR (n = 464) trial. Includes treatment group, age, ISS stage, bortezomib‐refractory status, lenalidomide‐refractory status, and number of prior lines of therapy as covariates. bReference group (odds ratio = 1.0). Covariate effect refers to the effect of the corresponding category vs reference category of the variable. CI, confidence interval; ISS, International Staging System; Kd56 BIW, twice‐weekly carfilzomib dosed at 56 mg/m2 in combination with a standard dexamethasone dose; Kd70 QW, once‐weekly carfilzomib dosed at 70 mg/m2 in combination with a standard dexamethasone dose; ORR, overall response rate

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