Higher-dose carflizomib (Kyprolis) “provided a high overall response rate with a remarkable duration of response in patients with relapsed or refractory multiple myeloma” in a phase II study, Nikoletta Lendvai, MD, PhD, and colleagues from Memorial Sloan Kettering Center, New York, wrote in Blood. Of 42 patients evaluable for response, 23 (55%) achieved at least a partial response, with 4 requiring dexamethasone, the researchers reported.
Median duration of response was 11.7 months (range, 6.7–14.7). At a median follow-up of 18.4 months (range, 6.5–25.2), median progression-free survival was 4.1 months (range, 2.5–11.8), and overall survival was 20.3 months. The investigators concluded that the reported data “support future studies of carfilzomib 56 mg/m2 either alone or in combination with dexamethasone to validate its potential use as a standard option in clinical practice.”
Single-agent carfilzomib, a selective inhibitor, has been shown to be safe and effective in a series of phase II studies in advanced multiple myeloma, generally administered as a 2-to 10-minute intravenous infusion twice weekly for 3 weeks of a 4-week cycle at 20 mg/m2 for cycle 1 and then at 27 mg/m2 (20/27 mg/m2). “Based on these studies, carfilzomib is currently indicated in the United States for patients with relapsed and refractory [multiple myeloma] using the 20/27 mg/m2 dose,” the investigators stated.
As carfilzomib continues to be developed, its use at higher doses is being investigated, and preliminary reports suggest improved activity with manageable adverse events at higher doses, the investigators commented. In the current single-center, open-label study, carfilzomib was administered at 20 mg/m2 on days 1 to 2 of cycle 1, and at 56 mg/m2 thereafter (30-minute infusion), with the option of adding dexamethasone at 20 mg for suboptimal response/progression.
Eligibility requirements included measurable symptomatic multiple myeloma that had relapsed or was refractory to at least two prior treatment regimens (median, 5). Prior treatment with bortezomib (Velcade) and immunomodulatory drugs was required, with 77% refractory to bortezomib and 64% to both bortezomib and lenalidomide (Revlimid). The median age of patients was 63, and 43% were male.
The 23 patients who achieved at least a partial response as their best response included 1 with a complete response and 9 with a very good partial response. They further noted that 19 patients achieved at least a partial response with single-agent carfilzomib, and 4 of 11 patients who received dexamethasone because of a suboptimal initial response eventually achieved at least a partial response and continued treatment for an additional 4.5 cycles on average.
Six patients who achieved at least a partial response with single-agent carfilzomib had disease progression, and then had dexamethasone added to their regimen. Of these, four achieved at least stable disease and continued treatment for an additional 5.5 cycles on average, the researchers reported. “Treatment was active in bortezomib-refractory subgroups, but these patients tended to have poorer outcomes compared with nonrefractory patients.”
The most frequent grade 3/4 adverse events “possibly related to carfilzomib included lymphopenia (43%), thrombocytopenia (32%), hypertension (25%), pneumonia (18%), and heart failure (11%),” the investigators noted. “It is possible that the increased rates of cardiovascular events reported here, particularly worsening of previously controlled hypertension, are a dose-dependent phenomenon associated with carfilzomib, but we also cannot rule out the potential impact of established cardiovascular risk factors in our study population,” the investigators noted. In addition to hypertension, these included cardiomyopathy and prior exposure to cardiotoxic therapies.
Adding dexamethasone did not have a clinically meaningful impact on the types or rates of adverse events. Grade 3/4 adverse events attributed to dexamethasone included fatigue, gastric ulcer, and hyperglycemia, each affecting one patient. Seven patients (16%) discontinued treatment due to adverse events, and 17 required dose reductions. Two patients died for reasons other than disease progression but considered unrelated to study treatment.
“Moving forward, more efficacy and safety data are needed to better characterize the benefit-to-risk profile of carfilzomib 56 mg/m2 ± dexamethasone in relation to standard doses of single-agent carfilzomib across [multiple myeloma] populations with respect to response, survival outcomes, and safety,” the investigators stated. Two studies are looking at higher-dose carfilzomib in patients with multiple myeloma and another at the drug’s effect on cardiac function.
“Until data from these studies become available, it would appear practical to ensure adequate blood pressure control before initiating carfilzomib 56 mg/m2 and to closely monitor patients with a history of hypertension or other cardiovascular risk factors,” the authors cautioned. “In addition, avoidance of overhydration, especially in patients with cardiac risk factors, and obtaining a baseline echocardiogram prior to initiating therapy may be indicated.” ■
Lendvai N, et al: Blood. June 24, 2014 (early release online).