Carfilzomib Combination Significantly Increases PFS in Relapsed Multiple Myeloma

Published: Sunday, Dec 07, 2014

Dr. Keith Stewart

A. Keith Stewart, MBChB

Treatment with the proteasome inhibitor carfilzomib (Kyprolis) in combination with lenalidomide (Revlimid) and dexamethasone increased progression-free survival (PFS) by 8.7 months in patients with relapsed multiple myeloma when compared with lenalidomide and dexamethasone alone, according to interim results from the ASPIRE phase III study presented during the 2014 ASH Annual Meeting.

A. Keith Stewart, MBChB, dean of research at the Mayo Clinic in Scottsdale, AZ, presented results from the open‑label ASPIRE study,1 which was conducted in 90 centers across 20 countries. A total of 792 patients with relapsed multiple myeloma were treated with lenalidomide and dexamethasone, then randomized 1:1 to the addition of either carfilzomib or placebo. The primary endpoint was PFS. Secondary endpoints included overall response rate (ORR) and overall survival (OS).

“This [PFS] was highly positive in favor of the combination therapy arm. The median progression-free survival with Kyprolis with Revlimid and dexamethasone is unprecedented in first-relapse myeloma at over 2 years,” said Stewart.

Median PFS was 26.3 months in the carfilzomib arm versus 17.6 months in the control arm, at a hazard ratio (HR) of 0.69 (CI 95%, 0.57-0.83), P <.0001. The ORR for the carfilzomib arm was 87.1% with a mean time to response (TTR) of 1.6 months; the ORR for the control arm was 66.7% with a mean TTR of 2.3 months (P <.0001). In terms of complete response (CR), 31.8% of patients in the carfilzomib arm had a CR, compared with 9.3% of patients in the control arm, an increase of over 3-fold (P = .0001).

The stringent criteria (P = .005) established for calculating the median OS was not met and could not be estimated at this time. Stewart described OS in the carfilzomib arm as trending favorably, with an HR of 0.79 (0.63-0.99; P = .018), adding that the Kaplan-Meier 24-month OS rates also trended favorably for the carfilzomib arm (73.3%) compared with the control arm (65.0%).

The addition of a third drug to the 2-drug regimen did not increase adverse events (AEs), with almost equal percentages of patients in each arm having experienced any AE. This is notable in that treatment in the carfilzomib arm included not only a third drug, but also lasted 50% longer (ie, 18 months vs 12 months).

The percentage of patients experiencing treatment-emergent AEs (TEAEs) of grade 3 or higher were also similar between the 2 groups. Although serious AEs (SAEs) were somewhat more prevalent in the carfilzomib arm (59.7%) than in the control arm (53.7%), the number of patients discontinuing treatment due to AEs was slightly higher in the control arm (17.7%) than in the carfilzomib arm (15.3%).

The percentage of patients discontinuing due to disease progression was also higher in the control arm than in the carfilzomib arm (50.1% vs 39.8%). The percent of patients who died due to AEs were equivalent between the 2 groups at 6.9%.

According to Stewart, no increase in peripheral neuropathy was evident compared with the control arm, and peripheral neuropathy was not a side effect of carfilzomib. He also said no significant effect in cardiac toxicity was seen, with a slight increase in the carfilzomib arm in all grades as well as in grade 3 toxicity or higher compared with the control arm; the number of cardiac-related AEs was low in both treatment arms. There were more deaths from cardiac failure in the control arm than in the carfilzomib arm, but these numbers were low (3 and 2 deaths, respectively).

“Another secondary objective worth noting is that we measured health-related quality of life for patients who participated in the trial,” Stewart said.  “As can be seen on the curves, as soon as we began to measure, the patients on the 3-drug combination reported better global health status that persisted throughout the 18 months of the study that they were on the drug.”

Inhibition of proteasomes helps to slow or halt the spread of multiple myeloma by targeting cellular mechanisms regulating the levels of proteins that myeloma cells require for continued growth.2 Carfilzomib, which was approved by the FDA in 2012, is an epoxyketone that binds irreversibly to the 20S proteasome, requiring new protein synthesis to replenish cellular levels of the 20S proteasome.3
References
  1. Stewart KA, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone in patients with relapsed multiple myeloma: interim results from ASPIRE, a randomized, open-label, multicenter phase 3 study. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014, San Francisco, CA. Abstract: 79.
  2. Cao B, Mao X. The ubiquitin-proteasomal system is critical for multiple myeloma: implications in drug discovery. Am J Blood Res. 2011;1(1):46-56.
  3. Kuhn DJ, Chen Q, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma.  Blood. 2007; 110(9):3281-3290.
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