ASH 2017 | Final analysis of the phase III ASPIRE clinical trial

On Monday 11 December 2017, an oral abstract session was held entitled: Session: 653. Myeloma: Therapy, excluding Transplantation I. A. Keith Stewart from the Center for Individualized Medicine, Mayo Clinic, Scottsdale, Arizona presented the final analysis of the phase III ASPIRE clinical trial. The presented abstract was entitled: Abstract 743: Overall Survival (OS) of Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Treated with Carfilzomib, Lenalidomide, and Dexamethasone (KRd) Versus Lenalidomide and Dexamethasone (Rd): Final Analysis from the Randomized Phase 3 Aspire Trial. To see details of the trial set-up, see previously published MM Hub article.

Key Findings:

• Median follow up: KRd = 48.8 months, Rd = 48.0 months 
• Median OS follow up of ≈ 67 months 
• Median duration of treatment: KRd = 88 weeks; Rd = 57 weeks 
• Carfilzomib discontinued after 18 cycles 
• KRd showed a 9.5 months median improvement in PFS vs Rd: 26.1% vs 16.6%; HR = 0.66; 95% Cl,0.55-0.78; P < 0.0001
• The pre-planned final analysis for OS was performed after 510 deaths, providing 85% power to detect with a 1-sided significance level of 0.025 and a 23.5% reduction in the risk of death for KRd vs Rd 
• Median OS increase of 7.9 months for KRd: 48.3 vs 40.4 months for KRd vs Rd, HR = 0.79; 95% CI, 0.67–0.95, P = 0.0045
• At first relapse, KRd showed an 11.4 months median improvement in OS: 47.3 vs 35.9 months for KRd vs Rd 
• High risk population defined as t(4;14), t(14;16), or deletion 17p in ≥ 60% of plasma cells: High-risk patients KRd = 48 pts; Rd = 52 pts
•  Higher ORR in high-risk KRd group vs Rd (79.2% vs 59.6% pts) 
• 9 month improvement in median PFS in high-risk KRd vs Rd, HR = 0.70
•  OS via subgroup analysis:
  • Median OS in patients receiving 1 prior line of therapy: 47.3 vs 35.9 months for KRd vs Rd
    • Treatment prior to first relapse
      • Bortezomib: Median OS for KRd vs Rd: 45.9 vs 33.9 months; (HR = 0.82; 95% CI, 0.56–1.19])
      •  Transplant: Median OS for KRd and Rd: 57.2 vs 38.6 months
• OS by response category in the KRd group: CR or better = 67.0 months, VGPR = 47.2 months, PR = 31.6 months, < PR = 14.6 months
•  Adverse Effects (AEs) for KRd vs Rd:
  • Leading to treatment discontinuation: 33.4% vs 30.1%
  • Serious AEs: 65.6% vs 56.8%
• Higher percentage of non-hematologic treatment-emergent adverse event (TEAEs) in KRd vs Rd
  • Diarrhea: 44.4% vs 37.3%; Cough: 29.6% vs 18.0; Pyrexia: 29.8% vs 21.6%; URTI: 30.1% vs 20.8; Hypokalemia: 29.6% vs 14.9%; Muscle spasms: 27.0% vs 21.1%

 Overall conclusion:

• ASPIRE is the second phase III trial in RRMM to demonstrate a statistically significant prolonged OS with a carfilzomib-based regimen
• KRd displayed a statistically significant and clinically meaningful reduction in the risk of death vs Rd, with an improved median OS of 7.9 months (48.3 vs 40.4 months; HR = 0.79, P = 0.0045)
• At first relapse, KRd displayed an 11-month improvement in median OS vs Rd (47.3 vs 35.9 months; HR = 0.81)
• In patients with 1 prior line of therapy, median OS was improved by 12 months in patients that had previously received bortezomib (45.9 vs 33.9 months)
• There was a 7.9-month improvement in median OS in the no prior bortezomib group with KRd vs Rd (48.3 vs 40.4 months) HR = 0.80; (95% CI, 0.55–1.17])
• The addition of carfilzomib led to:
  • Higher ORR
  • A tripling of CRR
  • A significantly prolonged PFS and OS
• Safety is consistent with previous findings and new safety signals were not observed for KRd after extended follow-up
• KRd is an excellent treatment option proven to extend survival in RRMM, particularly at first relapse

To listen to Dr. David Siegal discussing the final analysis of this trial, click here.