Final ASPIRE Results Confirm Survival Benefit With Carfilzomib Plus Lenalidomide and Dexamethasone in Relapsed/Refractory Myeloma

According to final results from the phase III ASPIRE study assessing patients with relapsed/refractory multiple myeloma (MM), adding the proteasome inhibitor carfilzomib to a lenalidomide and dexamethasone regimen improves response rates and overall survival (OS), without increasing the risk of adverse events (AEs).

“The addition of carfilzomib resulted in a higher objective response rate, a tripling of the complete response rate, and significant and clinically relevant prolongation of both progression-free survival (PFS) and OS,” reported lead author Keith Stewart, MBChB, MBA, of the Division of Hematology/Oncology at the Mayo Clinic in Scottsdale, Arizona, at the 2017 ASH Annual Meeting.

In earlier results, researchers found that the three-drug regimen significantly improved PFS, compared with lenalidomide and dexamethasone alone in patients with relapsed/refractory MM; the latest results include a final OS analysis.

Adult patients with relapsed/refractory MM who had received one to three prior lines of therapy were included. Participants were randomized 1:1 to receive carfilzomib, lenalidomide, and dexamethasone (n=396) or the standard treatment of lenalidomide and dexamethasone (n=396) in 28-day cycles:

  • lenalidomide 25 mg on days 1-21 of each cycle
  • dexamethasone 40 mg on days 1, 8, 15, and 22 of each cycle
  • carfilzomib administered as a 10-minute infusion at a starting dose of 20 mg/m2 on days 1 and 2 of cycle 1; a target dose of 27 mg/m2 on days 1, 2, 8, 9, 15, and 16 during cycles 1-12; and 27 mg/m2 on days 1, 2, 15, and 16 during cycles 13-18

Patients were treated until withdrawal of consent, disease progression, or unacceptable toxicity. After 18 treatment cycles, patients in the carfilzomib arm received treatment with lenalidomide and dexamethasone alone.

As of April 28, 2017 (data cutoff), patients had been followed for a median of 67 months in each arm (ranges not provided).

Compared with patients treated with lenalidomide-dexamethasone alone, those who also received carfilzomib had a longer median OS: 48.3 months (range = 42.4-52.8 months) versus 40.4 months (range = 33.6-44.4 months), for a 21 percent reduction in the risk of death (hazard ratio [HR] = 0.79; 95% CI 0.67-0.95; p=0.004).

The authors also identified factors associated with longer OS among carfilzomib-treated patients, including a lower number of prior lines of therapy and disease stage (per Revised International Staging System [R-ISS] score).

For patients who received only one prior line of therapy, median OS was 11.4 months longer in the three- than two-drug group (47.3 vs. 35.9 months [HR=0.81; 95% CI 0.62-1.06; p value not provided]). For patients who received two or more prior lines of therapy, median OS was 6.5 months longer (48.8 vs. 42.3 months [HR=0.79; 95% CI 0.62-0.99; p value not provided]).

The survival benefit with carfilzomib also persisted regardless of prior exposure to bortezomib: Median OS was improved by 12 months in patients with prior bortezomib exposure (45.9 vs. 33.9 months [HR=0.82; 95% CI 0.56-1.19]) and 7.9 months in those without (48.3 vs. 40.4 months [HR=0.80; 95% CI 0.55-1.17]).

Median OS also was longer among patients who received carfilzomib despite R-ISS:

  • R-ISS stage I: not reached for carfilzomib-treated patients vs. 58.0 months for lenalidomide and dexamethasone (HR=0.49; 95% CI 0.26-0.92; p value not provided)
  • R-ISS stage II: 45.4 months vs. 41.2 months (HR=0.86; 95% CI 0.68-1.10; p value not provided)
  • R-ISS stage III: 23.3 months vs. 18.8 months (HR=1.05; 95% CI 0.66-1.68; p value not provided)

As seen in the TABLE, safety profiles were similar between both treatment arms. Fatal AEs were reported in 11.5 percent of carfilzomib-treated patients and 10.5 percent of those who received lenalidomide and dexamethasone alone.

“The safety is consistent with previous findings, and no new safety signals were observed for carfilzomib, lenalidomide, and dexamethasone after extended follow-up,” Dr. Stewart said. “This combination should be considered a standard of care in relapsed/refractory MM.”

The study is limited by its open-label design, which may have introduced bias.

The authors report financial relationships with Celgene and Amgen.


Reference

Stewart AK, Siegel D, Ludwig H, et al. 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. Abstract 743. Presented at the 2017 American Society of Hematology Annual Meeting, December 11, 2017; Atlanta, GA.

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