Subgroup analysis of the ENDEAVOR trial: carfilzomib versus bortezomib for patients with multiple myeloma and renal impairment

In the open-label, multi-center phase III ENDEAVOR trial (NCT01568866) carfilzomib and dexamethasone (Kd56) showed superior progression-free survival (PFS) compared with bortezomib and dexamethasone (Vd) in patients with relapsed/refractory multiple myeloma (RRMM). It is important to evaluate the efficacy and safety of proteasome inhibitors in MM patients with renal impairment as renal failure is a common complication and can lead to dismal outcomes in this patient population. Our steering committee member, Professor Meletios Dimopoulos and colleagues conducted a subgroup analysis of ENDEAVOR to assess the safety and efficacy of Kd56 versus Vd in RRMM patients with varying degrees of renal impairment at randomization. The paper was published in Blood on 10 January 2019.

Data shown as Kd56 versus Vd cohorts

Patients and methods

• N = 929 patients with RRMM from 27 countries
• Patients were randomly assigned 1:1 to receive Kd56 or Vd
• Previous treatment lines: one vs two vs three
• ISS stage: 1 vs 2-3
• Patients were divided into six groups according to creatinine clearance (CrCL)
  • CrCL ≥ 15 to < 50 mL/min: n = 85 (median age = 72 years) and n = 99 (median age = 72 years)
  • CrCL 50 to < 80 mL/min: n = 186 (median age = 68 years) and n = 177 (median age = 68 years)
  • CrCL ≥ 60 mL/min: n = 193 (median age = 60 years) and n = 189 (median age = 61 years)

Key findings

Efficacy

• Median PFS
  • CrCL ≥ 15 to < 50 mL/min: 14.9 vs 6.5 months, HR = 0.49 (95% CI, 0.320–0.757)
  • CrCL 50 to < 80 mL/min: 18.6 vs 9.4 months, HR = 0.48 (95% CI, 0.351–0.652)
  • CrCL ≥ 60 mL/min: not reached (NR) vs 12.2 months, HR = 0.60 (95% CI, 0.434–0.827)
• Median overall survival (OS)
  • CrCL ≥ 15 to < 50 mL/min: 42.1 vs 23.7 months, HR = 0.66 (95% CI, 0.443–0.989)
  • CrCL 50 to < 80 mL/min: 42.5 vs 32.8 months, HR = 0.83 (95% CI, 0.626–1.104)
  • CrCL ≥ 60 mL/min: NR vs 42.3 months, HR = 0.75 (95% CI, 0.554–1.009)
• Complete renal response (CrCL improvement to ≥ 60 mL/min in any 2 consecutive visits if baseline CrCL < 50 mL/min) rates in patients with CrCL ≥ 15 to < 50 mL/min in the two treatment arms: 15.3% (95% CI, 8.4–24.7) vs 14.1% (95% CI, 8.0–22.6)
• Median PFS and OS in complete renal responders
  • PFS: 14.1 vs 9.4 months, HR = 0.805 (95% CI, 0.438–1.481)
  • OS: 35.3 vs 29.7 months, HR = 0.91 (95% CI, 0.524–1.577)

Safety

Grade ≥ 3 adverse events

• CrCL ≥ 15 to < 50 mL/min: 87.1% vs 79.4%
• CrCL 50 to < 80 mL/min: 84.4% vs 71.8%
• CrCL ≥ 60 mL/min: 77.1% vs 65.9%

Taken together, Kd56 improved PFS and OS in comparison with Vd in RRMM patients regardless of their baseline renal function. Furthermore, Kd56 showed a favourable safety profile that supports the use of Kd56 as standard of care for RRMM patients with renal impairment.