Dual therapy with carfilzomib improves PFS in MM patients with cytogenetic abnormalities
Combination therapy with carfilzomib and dexamethasone (Kd) affords better progression-free survival (PFS) compared with bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (MM), regardless of baseline cytogenetic risk status, according to a preplanned subgroup analysis of the phase III ENDEAVOR study.
Selected cytogenetic abnormalities, such as t(4;14) and del(17p) are not rare in MM, occurring in approximately 11 and 14 percent of patients, respectively. Such abnormalities are associated with poor outcomes and have been shown to affect treatment response and survival. [Haematologica 2015;100:1327–1333; J Clin Oncol 2013;31:2806–2809; Leukemia 2014;28:269–277]
In ENDEAVOR, 785 of the 929 patients (84.5 percent) from North America, Europe and the Asia Pacific region randomized to receive either carfilzomib or bortezomib with dexamethasone had known cytogenetic risk status. Cytogenetic abnormalities were categorized as high risk in 210 patients (Kd, n=97; Vd, n=113) and as standard risk in 575 (Kd, n=284; Vd, n=291). [Leukemia 2017;31:1368–1374]
The subgroup analysis by cytogenetic risk showed that Kd was consistently superior to Vd, with the primary endpoint of PFS improving significantly in patients receiving carfilzomib. Specifically, median PFS in the high-risk group was 8.8 months with Kd vs 6.0 months with Vd (hazard ratio [HR], 0.65; 95 percent CI, 0.45 to 0.92; p=0.0075). In the standard-risk group on the other hand, median PFS was not estimable for Kd vs 10.2 months with Vd (HR, 0.44; 0.33 to 0.58; p<0.0001).
Overall response rates in both the high- and standard-risk groups were higher with Kd (72.2 and 79.2 percent, respectively) than with Vd (58.4 and 66.0 percent, respectively). Moreover, the proportion of patients achieving complete response or better was higher in the Kd vs Vd arm in both the high-risk group (15.5 vs 4.4 percent) and the standard-risk group (13.0 vs 7.9 percent).
Safety and tolerability profiles with Kd and Vd in the settings of high- and standard-risk cytogenetics were consistent with previously published data for the overall population. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred at a slightly higher rate among patients receiving carfilzomib (70 to 75 percent) than among those receiving bortezomib (63 to 68 percent). [Lancet Oncol 2016;17:27–38]
Of note, TEAE-related treatment discontinuations were numerically lower with Kd (19 to 22 percent across cytogenetic risk groups with both Kd and Vd) given that median treatment durations across groups were longer for Kd vs Vd (30.3 to 40.9 weeks vs 22 to 28 weeks).
Despite the existence of several limitations including the open-label study design and use of genetic subtypes to risk-classify patients, the present analysis suggests that Kd should be considered in patients with relapsed or refractory MM across cytogenetic risk subgroups, the authors said.
“As patients with high-risk cytogenetics still have poor outcomes after frontline treatment, including therapies incorporating novel agents, the benefit-risk profile of carfilzomib-based regimens by cytogenetic risk status merits further evaluation in the upfront setting,” they added. [Blood 2016;127:2955–2962]