Carfilzomib is approved on a twice-weekly dosing schedule for the treatment of relapsed or refractory multiple myeloma (MM), but in the phase III ARROW trial, patients experienced better responses with a once-weekly dosing.
A more convenient schedule “can improve access to this efficacious therapy for patients unable to make twice-weekly visits to the clinic,” lead author María-Victoria Mateos, MD, PhD, from the University Hospital of Salamanca in Spain, noted during her presentation at the 2018 ASCO Annual Meeting, adding that treatment with the less-frequent, higher-dose carfilzomib was not associated with increased toxicity.
The phase III ARROW trial was designed to confirm earlier findings reported from the phase I CHAMPION-1 trial, which established 70 mg/m2 as the maximum tolerated dose of carfilzomib. “More than 100 patients received once-weekly 70 mg/m2 on days 1, 8, and 15 – rather than the approved schedule of [carfilzomib] on two consecutive days on three consecutive weeks,” study co-author James R. Berenson, MD, from the Institute for Myeloma and Bone Cancer Research in West Hollywood, California, told ASH Clinical News. “We were encouraged enough by the results to give [carfilzomib] once a week in our clinic, even though it’s off-label.”
Between August 2015 and November 2016, investigators enrolled 478 patients with relapsed and refractory MM who had received at least two prior lines of therapy (including a proteasome inhibitor and an immunomodulatory drug). Patients were randomized 1:1 to receive dexamethasone plus carfilzomib in one of two dosing schedules:
- once-weekly: carfilzomib 20 mg/ m2 on day 1 of cycle 1, followed by carfilzomib 70 mg/m2 on days 1, 8, and 15 for the subsequent treatment cycles (n=240)
- twice-weekly carfilzomib: carfilzomib 20 mg/m2 on day 1 of cycle 1, followed by 27 mg/m2 on days 8, 9, 15, and 16 of subsequent cycles (n=238)
Participants were treated for a median of 38 weeks in the once-weekly group and 29.1 weeks in the twice-weekly group (ranges not reported).
After a median follow up of 12 months (range not reported), 126 patients in the once-weekly group (53%) and 148 in the twice-weekly group (62%) experienced disease progression or death, for a median progression-free survival (PFS; primary endpoint) of 11.2 months and 7.6 months, respectively. This translated to a hazard ratio for PFS of 0.69 for once- versus twice-weekly carfilzomib (95% CI 0.544-0.883; p=0.003).
The superiority in PFS was seen across different patient subgroups, including those defined by age (<65 or ≥65 years), baseline Eastern Cooperative Oncology Group status, and International Staging System score, or refractoriness to bortezomib at baseline.
The overall response rate (secondary endpoint) also was higher in the once-weekly group: 63 percent versus 40.8 percent (odds ratio [OR] = 2.49; 95% CI 1.72-3.60; p<0.0001). This included a complete response rate of 5 percent and 2 percent, respectively.
Dr. Berenson called the results “astonishing,” because preclinical data suggested that carfilzomib two days in a row was better than once-weekly. The mechanisms behind the improved results with less-frequent dosing are still unclear, he added. “[Perhaps] getting the maximum concentration higher with that one push, rather than over two consecutive days – where the maximum concentration doesn’t get as high – will be more important in determining the drug’s effectiveness,” he proposed. “At the same time, we thought it would be associated with more toxicity. What’s perplexing is that we saw the increased efficacy, but not increased toxicity.”
In both the once- and twice-weekly treatment groups, 95 percent and 97 percent of patients, respectively, experienced any-grade adverse event (AE), and 68 percent and 72 percent experienced a grade ≥3 AE. Rates of carfilzomib discontinuation due to AEs (13% and 12%) and treatment-related deaths (9 and 8) also were similar.
The higher carfilzomib dose was not associated with increased hematologic toxicity or higher rates of “adverse events of interest,” the authors observed. This included grade ≥3 peripheral neuropathy (n=0 for once-weekly and n=1 for twice-weekly), acute renal failure (4 and 6), cardiac failure (3 and 4), ischemic heart disease (1 for each), and pulmonary hypertension (0 and 1).
Though Dr. Berenson called these results “great news for patients,” the study is limited by the lack of data on overall survival, which will require longer-term follow-up. He added that these data will be submitted to the U.S. Food and Drug Administration to support approval of once-weekly carfilzomib dosing.
The authors report financial relationships with Amgen, which also provided funding for this study and editorial support for the presentation.
Mateos MV, Moreau P, Berenson JR, et al. Once-weekly vs twice-weekly carfilzomib (K) dosing plus dexamethasone (d) in patients with relapsed and refractory multiple myeloma (RRMM): Results of the randomized phase 3 study A.R.R.O.W. Abstract #8000. Presented at the 2018 ASCO Annual Meeting, June 1, 2018; Chicago, IL.