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Weekly Carfilzomib Safe and Effective

February 2015 Vol 8, Special Issue: Payers' Perspectives in Oncology - Multiple Myeloma
Kate Smith

San Francisco, CA—The weekly administration of carfilzomib may be equivalent to the current practice of twice-weekly injections, according to an abstract presented at ASH 2014 by Antonio Palumbo, MD, of the University of Turin, Italy, and colleagues.

“With weekly injections, treatment becomes more feasible, and we can keep patients on treatment longer. That translates into efficacy,” Dr Palumbo said in an interview.

The phase 1/2 study evaluated the safety and efficacy of weekly carfilzomib in elderly patients newly diagnosed with myeloma (median age, 74 years) and determined the maximum tolerated dose for weekly administration of the drug. The rationale for studying weekly carfilzomib came from the observation that the weekly administration of bortezomib has proved safe and efficacious.

“We have previously seen that with once-weekly administration of bortezomib, the risk of adverse events, especially peripheral neuropathy, was diminished significantly,” Dr Palumbo said.

To evaluate once-weekly carfilzomib, Dr Palumbo and colleagues enrolled 12 patients in a dose-finding phase of the trial and then added 18 patients for phase 2 of the study. The escalating doses started at 45 mg/m2; the maximal planned dose was 70 mg/m2. Carfilzomib was given on days 1, 8, and 15, along with oral cyclophosphamide and oral dexamethasone. Of the 30 patients in the trial, 21 received the maximum tolerated dose (70 mg/m2) ­of carfilzomib.

After the completion of 9 cycles, patients received 28-day maintenance cycles with carfilzomib at the maximum tolerated dose until disease progression or intolerance.

The median relative dose intensity was 100% for carfilzomib, 100% for cyclophosphamide, and 96% for dexamethasone. At the time of the analysis, 77% of patients had received at least 4 cycles.

No Increase in Toxicity, High Response Rates
Dr Palumbo reported that the “grade 3/4 adverse events were very rare and very low” with once-weekly higher-dose carfilzomib, and they were not increased over what has been observed with twice-weekly dosing. Dose reductions also appeared to be required less frequently (10%) with once-weekly dosing than with twice-weekly dosing (21%).

Grade 3/4 hematologic events were observed in 23% of patients in this study compared with 27% in studies of twice-weekly dosing; grade 3/4 nonhematologic events were seen in 30% and 29% of patients, respectively.

With once-weekly dosing, grade 3/4 adverse events were primarily grade 3 neutropenia (10%), anemia (10%), and cardiac toxicity (7%), and grade 4 cardiac toxicity (7%) and pulmonary embolism (3%). Grade ≥3 thrombocytopenia, fatigue/fever, gastrointestinal toxicity, infection, and venous thromboembolism occurred in fewer than 5% of patients each.

Showing data from a study of twice-weekly carfilzomib (36 mg/m2), he noted that toxicity numbers were “superimposed with ours,” a finding that Dr Palumbo called “reassuring.”

Deep Responses Achieved
The preliminary response data showed an overall response rate of 86%, with 64% of patients having at least a very good partial response, 41% achieving at least a near-complete response (CR), and 25% achieving a CR, stringent CR, or near-CR.

By cycle 9, a very good partial response or better was achieved by 91% of patients receiving weekly carfilzomib compared with 77% of patients receiving the drug twice weekly at 36 mg/m2 in previous studies. A near-CR was reached by cycle 9 in 41% of patients with once-weekly dosing and by 47% of patients on the twice-weekly schedule.

The median time to first response (at least a partial response) was 1 month, and the median duration of response was not reached in the study.

Dr Palumbo indicated that the response rates will improve over time. “We need at least 6 cycles to maximize response,” he pointed out. “We start seeing stringent CRs at 8 cycles. Some patients improved their response beyond induction, into maintenance. With prolonged treatment, we will increase the percentage of patients with more profound CRs.”

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Last modified: July 6, 2021
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