Meletios A. Dimopoulos, MD
As reported by Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens, Alexandra Hospital, and colleagues in The Lancet Oncology, a prespecified interim analysis of the phase III ENDEAVOR trial has shown a significant overall survival benefit for carfilzomib (Kyprolis) vs bortezomib (Velcade) in patients with relapsed or refractory multiple myeloma. Carfilzomib was previously approved in this setting on the basis of an interim analysis showing median progression-free survival, the primary study endpoint, of 18.7 vs 9.4 months (hazard ratio = 0.53, P = .0001).
In the open-label trial, 929 patients from 198 sites in 27 countries in Europe, North America, South America, and the Asia-Pacific region were randomized between June 2012 and June 2014 to receive carfilzomib (n = 464) or bortezomib (n = 465). Patients had relapsed or refractory disease and had received between one and three previous lines of therapy. Randomization was stratified by International Staging System (ISS) stage, previous lines of treatment, previous proteasome inhibitor therapy, and planned route of bortezomib delivery.
Treatment consisted of carfilzomib at 20 mg/m2 on days 1 and 2 of cycle 1 and 56 mg/m2 thereafter via 30-minute intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles; bortezomib at 1.3 mg/m2 via IV bolus or subcutaneous injection on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone at 20 mg orally or via IV infusion was given on days 1, 2, 8, 9, 15, 16, 22, and 23 in the carfilzomib group and on days 1, 2, 4, 5, 8, 9, 11, and 12 in the bortezomib group. Overall, 77% of the bortezomib group received subcutaneous bortezomib throughout study treatment, with the remainder receiving IV drug at some point during treatment. The overall survival analysis was performed in the intent-to-treat population, with a cutoff in January 2017.
For the carfilzomib vs bortezomib groups: median age was 55 vs 55 years (52% vs 55% ≥ 65 years); 21% vs 24% were at cytogenetic high risk; 44% in both and 56% in both had ISS stage I and II disease; 50% vs 51% had received two or three prior treatments; and 54% vs 54% had received prior bortezomib and 70% vs 75% received an immunomodulatory agent.
For the overall survival analysis, median follow-up was 37.5 months in the carfilzomib group vs 36.9 months in the bortezomib group. Median overall survival was 47.6 months (95% confidence interval [CI] = 42.5 months to not estimable) in the carfilzomib group vs 40.0 months (95% CI = 32.6–42.3 months) in the bortezomib group (hazard ratio [HR] = 0.791, P = .010). In a subgroup analysis, hazard ratios consistently favored carfilzomib treatment, including among patients with one vs two to three previous treatments, patients with or without prior bortezomib, and patients with or without prior immunomodulatory therapy.
Following study drug discontinuation due to disease progression, toxicity, or other reason, 67% of carfilzomib patients and 70% of bortezomib patients received subsequent therapy. Additional treatments were generally similar between groups except for the use of immunomodulatory drugs (lenalidomide [Revlimid] in 32% vs 37%, pomalidomide [Pomalyst] in 16% vs 24%, and thalidomide [Thalomid] in 9% vs 13%) and proteasome inhibitors (carfilzomib in 1% vs 8%, bortezomib in 25% vs 12%). In the intention-to-treat population, the median time to next treatment from randomization was 26.3 months vs 14.4 months. A post-hoc landmark analysis of overall survival from time of disease progression in patients whose disease progressed showed median survival of 21.5 months vs 21.5 months (HR = 1.032, P = .61).
Grade ≥ 3 adverse events occurred in 81% of the carfilzomib group and 71% of the bortezomib group; the most common adverse events were anemia (16% vs 10%), hypertension (15% vs 3%), pneumonia (9% vs 9%), thrombocytopenia (9% vs 9%), fatigue (7% vs 8%), dyspnea (6% vs 2%), decreased lymphocyte count (6% vs 2%), diarrhea (4% vs 9%), and peripheral neuropathy (1% vs 6%). Grade ≥ 3 cardiac failure occurred in 6% vs 2%, and grade ≥ 3 acute renal failure occurred in 6% vs 3%. Grade ≥ 2 peripheral neuropathy, a secondary endpoint of the study, occurred in 7% vs 35% of patients.
Serious adverse events occurred in 59% vs 40% of patients, with the most common being pneumonia (8% vs 9%), pyrexia (4% vs 1%), and dyspnea (4% vs 1%). The most common reasons for treatment discontinuation were cardiac failure (2%) in the carfilzomib group and peripheral neuropathy (5%) in the bortezomib group. Treatment-related death occurred in five carfilzomib patients (1%), due to pneumonia in two, interstitial lung disease in one, septic shock in one, and an unknown cause in one; treatment-related death occurred in two bortezomib patients (< 1%), due to cardiac arrest and pneumonia.
The investigators concluded: “Carfilzomib provided a significant and clinically meaningful reduction in the risk of death compared with bortezomib. To our knowledge, carfilzomib is the first and only multiple myeloma treatment that extends overall survival in the relapsed setting over the current standard of care. This study is informative for deciding which proteasome inhibitor to use for treating this disease.” ■