In a planned interim analysis of the phase III ASPIRE trial reported in The New England Journal of Medicine, A. Keith Stewart, MB, ChB, of the Mayo Clinic, Scottsdale, Arizona, and colleagues found that the addition of the proteasome inhibitor carfilzomib (Kyprolis) to lenalidomide (Revlimid)/dexamethasone significantly increased progression-free survival.1 The interim analysis suggested a survival benefit with the three-drug regimen, which was also associated with a significantly higher response rate and improvement in health-related quality of life.
Study Details
In this open-label trial, 792 patients from North America, Europe, and the Middle East with relapsed multiple myeloma and receipt of 1 to 3 prior treatments were randomized to receive carfilzomib plus lenalidomide/dexamethasone (n = 396) or lenalidomide/dexamethasone (n = 396) between July 2010 and March 2012. The primary endpoint was progression-free survival.
Treatment consisted of 28-day cycles, with carfilzomib given via 10-minute infusion on days 1, 2, 8, 9, 15, and 16 (starting dose = 20 mg/m2 on days 1 and 2 of cycle 1 and target dose = 27 mg/m2 for all subsequent treatment) during cycles 1 through 12 and on days 1, 2, 15, and 16 during cycles 13 through 18, after which carfilzomib was discontinued. Lenalidomide (25 mg) was given on days 1 through 21. Dexamethasone (40 mg) was given on days 1, 8, 15, and 22.
Patients previously treated with bortezomib (Velcade) were eligible if they had not progressed during bortezomib treatment. Patients previously treated with lenalidomide and dexamethasone were eligible if they did not discontinue treatment due to adverse effects, did not have disease progression during the first 3 months of treatment, and did not have disease progression at any time during treatment if lenalidomide/dexamethasone was the most recent treatment.
The carfilzomib and control groups were generally balanced for age (median 64 and 65 years, 47% and 53% ≥ 65 years), gender (54% and 59% male), Eastern Cooperative Oncology Group performance status (0 or 1 for 90% and 91%), cytogenetic risk (high in 12% and 13%, standard in 37% and 43%, unknown in 51% and 44%), creatinine clearance (≥ 50 mL/min, required at screening, in 93% and 90%), serum β2 microglobulin (≥ 2.5 mg/L in 81% in both), number of previous regimens (1 in 47% and 40%, 2 or 3 in 53% and 60%), and previous therapies (bortezomib in 66% in both, lenalidomide in 20% in both).
Progression-Free Survival
At the time of the interim analysis, the median progression-free survival was 26.3 months (95% confidence interval [CI] = 23.3–30.5 months) in the carfilzomib group vs 17.6 months (95% CI = 15.0–20.6); the hazard ratio [HR] was 0.69 (95% CI = 0.57–0.83, P = .0001), which crossed the prespecified stopping boundary. The benefit of carfilzomib was observed across all predefined subgroups.
Interim Analysis of Overall Survival
Since the primary study objective was met, an interim analysis of overall survival was also performed, after occurrence of 60% of the 510 events prespecified for final overall survival analysis. The median follow-up was 32.3 months in the carfilzomib group and 31.5 months in the control group.
Survival at 24 months was 73.3% (95% CI = 68.6%–77.5%) in the carfilzomib group vs 65.0% (95% CI = 59.9%–69.5%) in the control group. The median overall survival was not reached in either group, with a trend favoring the carfilzomib group (HR = 0.79, P = .04), but the difference did not cross the prespecified stopping boundary.
Responses and Quality of Life
Overall response rates were 87.1% vs 66.7% (P < .001), including complete response or better in 31.8% vs 9.3% (P < .001) and stringent complete response in 14.1% vs 4.3%. The mean time to response was 1.6 vs 2.3 months, and the median duration of response was 28.6 vs 21.2 months.
Health-related quality of life, assessed by the European Organization for Research and Treatment of Cancer Quality-of-Life Core Module (QLQ-C30) questionnaire, was significantly improved in the carfilzomib group vs the control group during 18 cycles of treatment (P < .001). The minimal clinically important between-group difference on the QLQ-C30 Global Health Status and Quality-of-Life scale is 5.0 points, which was met at cycle 12 (difference = 5.6 points) and approached at cycle 18 (difference = 4.8 points).
Adverse Events
The median duration of treatment was 88.0 weeks in the carfilzomib group and 57.0 weeks in the control group. Adverse events of any grade that were at least 5% more frequent in the carfilzomib group included hypokalemia (28% vs 13%), cough (29% vs 17%), upper respiratory tract infection (29% vs 19%), diarrhea (42% vs 34%), pyrexia (29% vs 21%), hypertension (14% vs 7%), and muscle spasms (27% vs 21%), with rates of treatment discontinuation due to these events being less than 1% in both groups. Peripheral neuropathy occurred in 17% of both groups.
Adverse events of grade 3 or higher occurred in 84% vs 81%, and serious adverse events occurred in 60% vs 54%. Grade 3 or higher adverse events of specific interest included dyspnea (2.8% vs 1.8%), cardiac failure (3.8% vs 1.8%), ischemic heart disease (3.3% vs 2.1%), hypertension (4.3% vs 1.8%), and acute renal failure (3.3% vs 3.1%).
Adverse events led to carfilzomib dose reduction in 11.0% and lenalidomide dose reduction in 43% of the carfilzomib group, lenalidomide dose reduction in 39% of the control group, and discontinuation of treatment in 15.3% and 17.7% of patients. Adverse events led to death in 6.9% of patients in each group, with six deaths in the carfilzomib group and eight deaths in the control group considered related to treatment. The most common causes of toxicity-related death were myocardial infarction (three patients in the carfilzomib group and one in the control group), cardiac failure (one and three patients), and sepsis (three and two patients).
The investigators concluded: “Carfilzomib combined with lenalidomide and dexamethasone led to a significant improvement in progression-free survival, as compared with lenalidomide and dexamethasone alone, in patients with relapsed multiple myeloma. These findings were bolstered by higher response rates, more robust responses, a favorable risk-benefit profile, improved health-related quality of life, and a trend toward improved overall survival with the three-drug regimen.” ■
Disclosure: This study was funded by Onyx Pharmaceuticals. For full disclosures of the study authors, visit www.nejm.org.
Reference
1. Stewart AK, Rajkumar SV, Dimopoulos MA, et al: Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 372:142-152, 2015.
See commentary by Sagar Lonial, MD.
