Carfilzomib Bests Bortezomib Across Multiple Myeloma Subgroups

Meletios A. Dimopoulos, MD

Treatment with carfilzomib (Kyprolis) reduced the risk of progression or death by 47% compared with bortezomib (Velcade) for patients with relapsed multiple myeloma, according to findings from the phase III ENDEAVOR trial that were published in Lancet Oncology in conjunction with the 2015 ASH Annual Meeting.¹

In the study, the median progression-free survival (PFS) with carfilzomib was 18.7 versus 9.4 months with bortezomib (HR, 0.53, 95% CI, 0.44-0.65; P <.0001). Median overall survival was 24.3 months in the bortezomib arm but had not yet been reached in the carfilzomib group (HR, 0.79; P = .066).

“The randomized, open-label phase III ENDEAVOR study demonstrated that carfilzomib in combination with dexamethasone led to a significant reduction in the risk of progression or death when compared with bortezomib and dexamethasone in patients with relapsed multiple myeloma,” lead author Meletios A. Dimopoulos, MD, professor of Clinical Therapeutics at the National and Kapodistrian University of Athens, School of Medicine, said during a presentation of the study. “Higher response rates, a greater depth of response, and longer duration of response were also observed with carfilzomib versus bortezomib across cytogenetic subgroups.”

In the phase III study, 929 patients were randomized to receive carfilzomib as a 30-minute infusion along with dexamethasone (n = 464) or bortezomib and dexamethasone (n = 465). The median age of patients enrolled in the trial was 65 years. All but 7% of patients had ECOG PS of 0 or 1 (about 50% ECOG 0), and about 20% of the patients had high-risk cytogenetic by fluorescence in situ hybridization.

Carfilzomib was administered at a starting dose of 20 mg/m² on days 1 and 2 of the first cycle. If tolerated, the dose was escalated to 56 mg/m² on day 8 of the first cycle. After this point, the 56-mg/m² dose was maintained on days 9, 15, and 16 then throughout subsequent cycles. In the control arm, patients received bortezomib at 1.3 mg/m². The majority of patients received bortezomib subcutaneously (75%).

In a subgroup analysis,² those with high-risk cytogenetics had a median PFS of 8.8 months with carfilzomib (n = 97) versus 6.0 months with bortezomib (n = 113; HR, 0.646). In patients with standard risk cytogenetics, the median PFS was not evaluable for carfilzomib (n = 284) versus 10.2 months for bortezomib (n = 291; HR, 0.439).

Those with high-risk cytogenetics who received 1 prior therapy had a median PFS of 11.1 versus 7.4 months, for carfilzomib and bortezomib, respectively (HR, 0.59). With more than 2 prior lines of therapy, median PFS was 7.6 months with carfilzomib versus 5.6 months for bortezomib (HR, 0.66).

The largest margin of benefit for carfilzomib was seen for patients at standard risk who received just 1 prior therapy. In this group, the median PFS with carfilzomib was not yet reached compared with 12.1 months with bortezomib (HR, 0.38; CI, 0.25-0.58).

“Carfilzomib had a favorable benefit—risk profile in patients with high-risk relapsed multiple myeloma, and was superior to bortezomib, regardless of baseline cytogenetic risk status,” explained Dimopoulos.

Across the full population of the study, the objective response rate was 76.9% with carfilzomib versus 62.6% with bortezomib. The complete response rate with carfilzomib was 12.5% versus 6.2% with bortezomib. The rate of very good partial response or better with carfilzomib was 54.3% compared with 28.6% with bortezomib.

In a second subgroup analysis presented at the ASH meeting,³ those treated with 1 prior therapy across the full study had a median PFS of 22.2 months with carfilzomib (n = 232) versus 10.1 months for bortezomib (n = 233; HR, 0.447). In patients treated with ≥2 prior therapies, the median PFS was 14.9 months for carfilzomib (n = 232) versus 8.4 months for bortezomib (n = 232; HR, 0.604).

“In this head-to-head comparison, carfilzomib plus dexamethasone resulted in a two-fold decrease in the risk of progression or death, compared with bortezomib plus dexamethasone, a result that was consistent regardless of age or prior bortezomib exposure,” Dimopoulos, said in a statement. “For patients with multiple myeloma, these results are clinically meaningful and translate to more than nine months without disease progression.”

Grade 3 adverse events (AEs) occurred more frequently in the carfilzomib arm compared with bortezomib (73% vs 67%). Additionally, serious AEs were more common with carfilzomib (48% vs 36%). However, dose reductions associated with AEs were more frequent with bortezomib versus carfilzomib (48% vs 23%). Treatment discontinuation due to AEs and on-study deaths were comparable between the two arms.

Grade ≥3 hematologic AEs occurred in a similar proportion of patients in both groups, including anemia, thrombocytopenia, neutropenia, upper respiratory infection, and pneumonia. However, there was an increase in the incidence of hypertension and dyspnea with carfilzomib versus bortezomib. The most frequent non-hematologic grade ≥3 AEs were diarrhea, fatigue, dyspnea, pyrexia, constipation, and insomnia.

Peripheral neuropathy occurred in 5% of patients treated with bortezomib and 1.3% of those in the carfilzomib arm. The proportion of patients with grade ≥2 peripheral neuropathy was significantly higher with bortezomib (32% versus 6%; P <.0001).

Carfilzomib is approved as a treatment for patients with relapsed multiple myeloma following one to three prior lines of therapy, based on results from the phase III ASPIRE trial. This study demonstrated a 31% reduction in the risk of disease progression with the triplet compared with lenalidomide and low-dose dexamethasone alone.

A supplemental new drug application was submitted to the FDA for carfilzomib plus dexamethasone in patients with relapsed myeloma, based on an earlier assessment of the ENDEAVOR trial. The FDA is scheduled to make a decision regarding the application by January 22, 2016.

“Coupled with results previously seen in the ASPIRE pivotal trial, data from the ENDEAVOR study support the use of Kyprolis as a backbone therapy for the management of relapsed multiple myeloma, a difficult-to-treat blood cancer,” Sean E. Harper, MD, executive vice president of Research and Development at Amgen, the company developing carfilzomib, said in a statement.

References:

1. Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study [published online December 5, 2015]. Lancet Oncol. DOI: 10.1016/S1470-2045(15)00464-7.
2. Moreau P, Joshua D, Chng W-J, et al. Impact of Prior Treatment on Patients with Relapsed Multiple Myeloma Treated with Carfilzomib and Dexamethasone Vs Bortezomib and Dexamethasone in a Subgroup Analysis of the Phase 3 Endeavor Study (NCT01568866). Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 729.
3. Chng W-J, Goldschmidt H, Dimopoulos MA, et al. Efficacy and Safety of Carfilzomib and Dexamethasone vs. Bortezomib and Dexamethasone with Relapsed Multiple Myeloma Based on Cytogenetic Risk Status: Subgroup Analysis from the Phase 3 Study ENDEAVOR (NCT01568866). Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 30.

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