Subgroup analysis of ASPIRE and ENDEAVOR trials: carfilzomib in RRMM

Carfilzomib has been approved for the treatment of Relapsed or Refractory Multiple Myeloma (RRMM) patients, that have received one to three prior lines of therapy. Data from both the ASPIRE and ENDEAVOR trials showed that patients receiving carfilzomib displayed a significant increase in both progression‐free survival (PFS) and overall survival (OS) compared to patients in the control groups who were treated with standard of care. However, a question that needs to be addressed is when treatment should be given in RRMM patients for maximum efficacy. Maria-Victoria Mateos, from the University Hospital Salamanca, Spain and colleagues, conducted post hoc analyses of data from both the ASPIRE and ENDEAVOR trials, in order to establish the difference in efficacy of carfilzomib in patients with either early or late relapse following their most recent therapy. The findings were published in Hematological Oncology in January 2018.

Study design:

• Patients (pts) in the ASPIRE and ENDEAVOR trials were assigned to subgroups of:
  • Early relapsers (relapse ≤1 year from starting the most recent prior line of therapy)
  • Late relapsers (relapse >1 year from starting the most recent prior line of therapy)
• Relapse was determined by investigator assessment:
  • In ASPIRE, pts were required to have symptomatic disease
  • In ENDEAVOR, pts were assessed for serological relapse/progression without needing to show symptoms of the disease
• An independent review committee assessed responses and disease progression in a blinded manner for ASPIRE and

  ENDEAVOR:

  • PFS summarized using the Kaplan‐Meier method
  • HRs for PFS were estimated using an unstratified Cox proportional‐hazards model
• Pts who received ≥1 dose of study treatment were included in safety analyses

Demographics:

• No of pts with early relapse:
  • ASPIRE = 113/396 (KRd arm) vs 104/396 (Rd arm)
  • ENDEAVOR = 123/464 (Kd arm) vs 116/465 (Vd arm)
• No of pts with late relapse:
  • ASPIRE = 263/396 (KRd arm) vs 267/396 (Rd arm)
  • ENDEAVOR = 335/464 (Kd arm) vs 340/465 (Vd arm)
• High-risk cytogenetics (early relapsers vs late relapsers):
  • ASPIRE = 12.4% and 11.4% (KRd arm) vs 4% and 11.6% (Rd arm)
  • ENDEAVOR = 28.5% and 18.5% (Kd arm) vs 5% and 21.2% (Vd arm)
• Higher proportions of early relapsers than late relapsers with 3 prior lines of therapy and receiving prior treatment with bortezomib or lenalidomide in both trials

Key Findings:

• Median PFS for early relapsers:
  • ASPIRE (KRd arm vs Rd arm) = 21.4 vs 7 months (HR = 0.714; 95% CI, 0.508–1.004; P = 0.0257)
  • ENDEAVOR (Kd arm vs Vd arm) = 13.9 vs 7 months (HR = 0.598; 95% CI, 0.423–0.846; P = 0.0017)
• Median PFS for late relapsers:
  • ASPIRE (KRd arm vs Rd arm) = 29.7 vs 2 months (HR = 0.675; 95% CI, 0.533–0.854; P = 0.0005)
  • ENDEAVOR (Kd arm vs Vd arm) = 22.2 vs 2 months (HR = 0.486; 95% CI, 0.382–0.620; P < 0.0001)
• Better responses to therapy observed in pts in the carfilzomib arms of ENDEAVOR and ASPIRE than in the control arm
• Overall Response Rate (ORR) for early relapsers:
  • ASPIRE (KRd arm vs Rd arm) = 83.2% vs 8%
  • ENDEAVOR (Kd arm vs Vd arm) = 63.4% vs 1%
• Overall Response Rate (ORR) for late relapsers:
  • ASPIRE (KRd arm vs Rd arm) = 89.0% vs 7%
  • ENDEAVOR (Kd arm vs Vd arm) = 81.8% vs 8%
• Safety results comparable to those previously reported for the ASPIRE and ENDEAVOR trials at the time of the PFS analysis
• Rates of grade ≥ 3 adverse events (AEs):
  • Early relapsers: ASPIRE (KRd arm vs Rd arm) = 82.1% vs 0%; ENDEAVOR (Kd arm vs Vd arm) = 68.9% vs 74.6%
  • Late relapsers: ASPIRE (KRd arm vs Rd arm) = 85.0% vs 3%; ENDEAVOR (Kd arm vs Vd arm) = 74.6% vs 64.6%
• Comparable rates of discontinuation of any study drug due to AEs between treatment arms for both early and late relapsers in both trials

This study showed an improved PFS and ORR in patients who received carfilzomib as part of their treatment, regardless of either early or late relapse status. The results also suggested that patients with a late relapse, following the most recent prior line of therapy, had better clinical outcomes in comparison to patients with early relapse.