ASPIRE clinical trial to assess carfilzomib, lenalidomide and dexamethasone in relapsed MM

In January 2015 Stewart K et al. from The Mayo Clinic, published the results of the ASPIRE phase 3 study in The New England Journal of Medicine. This study assessed the efficacy of a triple-drug regimen: carfilzomib (a proteasome inhibitor) plus lenalidomide and dexamethasone, for the treatment of relapsed Multiple Myeloma (MM). A total of 792 patients with relapsed Multiple Myeloma, MM were recruited between July 2010 and March 2012, and randomly assigned into two treatment groups: carfilzomib or placebo, against a background of a combined lenalidomide and dexamethasone regime. The primary end-point was progression free survival (PFS) in the intention to treat (ITT) population.

Treatment:

• Treatment was administered in 28-day cycles until withdrawal of consent, disease progression or unacceptable AE’s
• Carfilzomib was administered as a 10-minute infusion:
  • Days 1, 2, 8, 9, 15 and 16 during cycles 1-12
  • Days 1, 2, 15 and 16 during cycles 13-18
• Dosing of carfilzomib was started at 20 mg/m² on days 1 and 2 of cycle 1, with a target dose of 27 mg/m² thereafter
• Carfilzomib was discontinued after cycle 18 and both groups continued with lenalidomide plus dexamethasone
• Lenalidomide (25 mg) was given on days 1 to 21 of each cycle
• Dexamethasone (40 mg) was administered on days 1, 8 15 and 22 of each cycle

Key Findings:

• A total of 118 patients (29.8%) in the carfilzomib group and 86 patients (21.7%) in the placebo group were still receiving treatment at the time of cut-off for the interim analysis (June 2014)
• Median PFS:
  • carfilzomib = 26.3 months (95% CI, 23.3-30.5)
  • placebo = 17.6 months (95% CI 15.0-20.6)
  • HR = 0.69; 95% CI, 0.57-0.83; P=0.0001
• The benefit of PFS was observed across all sub-groups
• Median follow-up:
  • carfilzomib = 32.3 months
  • placebo = 31.5 months
• Kaplan-Meier 24-month Overall Survival (OS):
  • carfilzomib = 73.3% (95% CI, 68.6-77.5)
  • placebo = 65.0% (95% CI, 59.9-69.5)
• Median OS was not reached in either group, but there was a trend in favour of the carfilzomib group: HR for death = 0.79 (95% CI, 0.63-0.99; P=0.04)
• Overall Response Rates (ORR) (P<0.001):
  • carfilzomib = 87.1% (95% CI, 83.4-90.3)
  • placebo = 66.7% (95% CI, 61.8-71.3)
• Complete Response (CR) (P<0.001):
  • carfilzomib = 31.8%; placebo = 9.3%
• Mean time to response:
  • carfilzomib = 1.6 months; placebo = 2.3 months
• Median duration of response:
  • carfilzomib = 28.6 months; placebo = 21.2 months
• Health related quality of life improved in the carfilzomib group vs placebo across 18 cycles of treatment (P<0.001)
• The minimal clinically important difference for between group differences was met at cycle 12.
• Median duration of treatment:
  • carfilzomab = 88 weeks (range, 1.0-185.0)
  • placebo = 57.0 weeks (range, 1.0-201.0)
• Adverse Effects (AE’s):
  • AE’s leading to dose reductions: carfilzomib group: 11.0% reduction in carfilzomib; lenalidomide was reduced in 43.4% of the carfilzomib group and in 39.1% of the placebo group
  • AE’s ≥ grade 3: carfilzomib = 83.7%; placebo = 80.7%
  • Serious AE’s: carfilzomib = 59.7%; placebo = 53.7%
  • Death due to AE’s: 6.9% of patients
• Overall 14 treatment-related deaths: carfilzomib = 6 patients; placebo = 8 patients
• Death during treatment or within 30 days of the last dose of therapy: carfilzomib = 7.7%; placebo = 8.5%

In conclusion, the addition of carfilzomib to the combination treatment of lenalidomide plus dexamethasone, resulted in a significant improvement in PFS in patients with relapsed MM. Specifically there was a 31% decreased risk of disease progression and an 8.7-month increase in median PFS. This promising outcome therefore continues the trend towards a triple drug regimen for patients with relapsed MM. Indeed, data from this trial was pivotal in driving approval of the described regimen for MM patients by both the EMA and US FDA in 2015.