Adding Carfilzomib to Lenalidomide and Dexamethasone Extends Overall Survival in Multiple Myeloma

Compared with standard therapy of lenalidomide and dexamethasone, the addition of carfilzomib improved survival, without increasing the risk of adverse events (AEs) in patients with relapsed or refractory multiple myeloma (MM), according to final results from the phase III ASPIRE trial.1

“At interim analysis … the addition of carfilzomib significantly improved progression-free survival (PFS) compared with [lenalidomide and dexamethasone],” the study investigators, led by David S. Siegel, MD, PhD, of John Theurer Cancer Center at Hackensack University Medical Center in New Jersey, wrote in the Journal of Clinical Oncology.2 “Despite prolonged treatment exposure in the [carfilzomib] group, rates of discontinuation because of AEs were lower … and the frequency of AE-related deaths was identical in the two groups,” they noted.

In the final overall survival (OS) analysis, researchers evaluated long-term survival and safety data from 792 patients enrolled in the trial. All participants had MM and had previously received one to three lines of therapy. Patients were randomized 1:1 to receive lenalidomide and dexamethasone with or without the proteasome inhibitor carfilzomib in the following 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 8, 9, 15, and 16 of cycle 1 and days 1, 2, 8, 9, 15, and 16 during cycles 2-12; and 27 mg/m2 on days 1, 2, 15, and 16 during cycles 13-18

Treatment continued until disease progression, study withdrawal, or unacceptable toxicity. After 18 cycles, patients in the carfilzomib group received lenalidomide and dexamethasone alone, due to limited long-term safety data with carfilzomib when the trial was initiated.

After a median follow-up of 48 months (range not provided), patients treated with carfilzomib had longer median PFS (primary endpoint) than those receiving standard-of-care alone: 26.1 months (range = 23.2-30.3 months) vs. 16.6 months (range = 14.5-19.4 months). This translated to a hazard ratio (HR) of death or disease progression of 0.66 (95% CI 0.55-0.78; p<0.001).

OS, a secondary endpoint, was extended in the carfilzomib group, after a median followup of 67 months (range not reported): 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 (HR=0.79; 95% CI 0.67- 0.95; p=0.004). “Notably, the OS benefit was not a result of poor outcomes in the lenalidomidedexamethasone group,” the authors wrote. “The reported median OS of 40.4 months in the lenalidomidedexamethasone group is similar to that observed in other phase III studies of relapsed/refractory MM.”

Investigators also conducted separate analyses to identify factors associated with longer median OS among carfilzomibtreated patients, finding that fewer prior lines of therapy and less-severe cytogenetic risk predicted extended survival (p values not reported):

  • 1 prior line of therapy: 47.3 months vs. 35.9 months (HR=0.81; 95% CI 0.62-1.06)
  • ≥2 previous therapies: 48.8 months vs. 42.3 months (HR=0.79; 95% CI 0.62-0.99)
  • standard cytogenetic risk: 49.0 months vs. 41.4 months (HR=0.74; 95% CI 0.56-0.97)

However, in patients with high-risk cytogenetics, the median OS was similar in both groups (36 months vs. 36 months; HR=1.08; 95% CI 0.67-1.74).

Additionally, there was an observed improvement in the median OS by 18.6 months among patients with prior transplantation at first relapse in the carfilzomib group versus the lenalidomide and dexamethasone group (57.2 months vs. 38.6 months, respectively; HR=0.71; 95% CI 0.48-1.05).

Discontinuation of treatment was high in both groups (85.9% for carfilzomib and 90.4% for standard-of-care), mostly due to disease progression (47.5% and 56.6%, respectively). However, “despite prolonged treatment exposure in the carfilzomib versus lenalidomidedexamethasone group, rates of treatment discontinuation because of AEs were similar in the two groups (19.9% and 21.5%, respectively),” the investigators noted.

Safety profiles also were similar in both treatment arms and consistent with previous reports from these agents. The most common AEs of any grade in both groups included anemia, neutropenia, diarrhea, fatigue, cough, and respiratory tract infections. Rates of serious AEs were not significantly different between the carfilzomib and standard-of-care groups, as well (65.3% vs. 56.8%; p value not reported).

“Early treatment with an effective regimen is important to maximize OS, because shorter response durations and increased treatment resistance are associated with each subsequent line of therapy,” the investigators concluded. “Carfilzomib plus lenalidomide and dexamethasone is a highly effective therapy for patients at first relapse, which should be reflected in future treatment algorithms.”

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

The authors report financial relationships with Celgene and Amgen, which sponsored the trial.

References

  1. Siegel DS, Dimopoulos MA, Ludwig H, et al. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018;36:728-34.
  2. Dimopoulos MA, Stewart AK, Masszi T, et al. Carfilzomib, lenalidomide, and dexamethasone in patients with relapsed multiple myeloma categorised by age: secondary analysis from the phase 3 ASPIRE study. Br J Haematol. 2017;177:404-13.

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