Among patients with relapsed or refractory multiple myeloma, adding carfilzomib to lenalidomide and dexamethasone (KRd) improves overall survival (OS) compared with lenalidomide and dexamethasone (Rd) alone, especially after first relapse, according to final findings from the randomized phase III ASPIRE trial (abstract 743) presented at the 59th American Society of Hematology (ASH) Annual Meeting and Exposition last month in Atlanta.
The findings bolster earlier evidence that carfilzomib improves OS, from the phase III ENDEAVOR trial.
“ASPIRE is the second phase III trial in relapsed and refractory multiple myeloma to demonstrate a statistically significant prolongation of OS with a carfilzomib-based regimen,” said A. Keith Stewart, MBChB, MBA, of the Center for Individualized Medicine at the Mayo Clinic in Scottsdale, Arizona. “The KRd efficacy advantage is most pronounced at first relapse, with an 11-month improvement in OS (47.3 months vs 35.9 months; hazard ratio [HR], 0.81).”
The ASPIRE study enrolled 792 patients with symptomatic multiple myeloma and measurable relapsed or progressive disease after 1–3 prior treatment regimens, after partial or complete response to at least one prior regimen. Patients who had suffered progressive disease on bortezomib, or who had lenalidomide or dexamethasone intolerance, were not eligible for the study.
Patients were stratified by prior bortezomib, prior lenalidomide, and β-microglobulin. Patients were randomly assigned to be administered 28-day cycles of KRd (n = 396) or Rd (n = 396). The study arms were well balanced with two exceptions: 46.7% of KRd-treated patients compared with 40.7% of Rd-treated patients had stage III disease at diagnosis, and 46.5% vs 39.6% had only one prior treatment regimen. After cycle 18, carfilzomib was discontinued in the KRd arm.
The updated final investigator-assessed progression-free survival for the intent-to-treat population of 792 patients demonstrated a 9.5-month improvement with KRd over Rd (median progression-free survival of 26.1 vs 16.6 months; HR, 0.66; 95% CI, 0.55–0.78; P < .0001).
A preplanned final OS analysis was conducted after 510 patient deaths. Data cutoff was April 28, 2017, at a median follow-up of 67 months.
KRd was associated with an improved OS compared to Rd (48.3 months vs 40.4 months; HR, 0.79; P = .0045). Subgroup analyses revealed a trend toward better OS for KRd over Rd for patient age, stage at diagnosis, risk group, R-ISS stage, and prior regimens. Median OS was 11.4 months longer for patients in the KRd group than the Rd group at first relapse (47.3 vs 35.9 months), and 12 months longer among patients who were administered bortezomib before first relapse (45.9 vs 33.9 months).
“Median OS was 18.6 months longer for patients receiving transplant prior to first relapse (57.2 vs 38.6 months),” Dr. Stewart said.
Patients were on KRd therapy longer than Rd therapy, Dr. Stewart said: median 88 vs 57 weeks.
No new safety signals were detected for KRd after extended follow-up and treatment did not impact post-relapse OS. Grade ≥ 3 adverse events included cardiac failure (4.3% KRd vs 2.1 Rd), ischemic heart disease (3.8% vs 2.3%), hypertension (6.4% vs 2.3%), and venous thrombotic events (4.8% vs 3.3%).