Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies

Abstract

Carfilzomib, a selective proteasome inhibitor, was approved in 2012 for the treatment of relapsed and refractory multiple myeloma. Safety data for single-agent carfilzomib have been analyzed for 526 patients with advanced multiple myeloma who took part in one of 4 phase II studies (PX-171-003-A0, PX-171-003-A1, PX-171-004, and PX-171-005). Overall analyses of adverse events and treatment modifications are presented, as well as specific analyses of adverse events by organ system. Overall, the most common adverse events of any grade included fatigue (55.5%), anemia (46.8%), and nausea (44.9%). In the grouped analyses, any grade adverse events were reported in 22.1% for any cardiac (7.2% cardiac failure), 69.0% for any respiratory (42.2% dyspnea), and 33.1% for any grouped renal impairment adverse event (24.1% increased serum creatinine). The most common non-hematologic adverse events were generally Grade 1 or 2 in severity, while Grade 3/4 adverse events were primarily hematologic and mostly reversible. There was no evidence of cumulative bone marrow suppression, either neutropenia or thrombocytopenia, and febrile neutropenia occurred infrequently (1.1%). Notably, the incidence of peripheral neuropathy was low overall (13.9%), including patients with baseline peripheral neuropathy (12.7%). Additionally, the incidence of discontinuations or dose reductions attributable to adverse events was low. These data demonstrate that single-agent carfilzomib has an acceptable safety profile in heavily pre-treated patients with relapsed/refractory multiple myeloma. The tolerable safety profile allows for administration of full-dose carfilzomib, both for extended periods and in a wide spectrum of patients with advanced multiple myeloma, including those with pre-existing comorbidities. ABSTRACTpression including thrombocytopenia, and dose-limiting peripheral neuropathy (PN) (up to 30% Grade 1/2 and 7-15% Grade 3/4). The PN often leads to discontinuation, and can be debilitating and occasionally irreversible. [19][20][21] Thalidomide is even more strongly implicated in PN, 22 and a recent analysis of patients with newly diagnosed MM revealed that although thalidomide improved efficacy when added to melphalan-prednisone, it negatively impacted safety. 23 Maintenance therapy, as well as consolidation strategies, with many of these drugs are being investigated as important ways to improve and prolong responses in patients with MM, 24 and these extended treatment periods may draw increased attention to tolerability and cumulative toxicities when considering longterm treatment options.Carfilzomib was initially evaluated in 2 phase I studies 25 and PX-171-002 26) investigating two different dosing schedules: 5 consecutive days of a 14-day cycle and 2 consecutive days/week for 3 weeks of a 28-day cycle). Consecutive day dosing demonstrated promising antitumor activity. However, single-agent carfilzomib administered using the 2 consecutive day dosing schedule (PX-171-002) was better tolerated and was chosen for further exploration in ph...

Replacement of bortezomib with carfilzomib for multiple myeloma patients progressing from bortezomib combination therapy

“…22 In our study, lymphopenia, thrombocytopenia, anemia and neutropenia were the most common Xgrade 3 hematologic AEs, which is similar to those observed with singleagent carfilzomib. 22 Fever and hypokalemia were the most common Xgrade 3 nonhematologic AEs in our study, whereas pneumonia, fatigue and dyspnea were the most common Xgrade 3 nonhematologic AEs with single-agent carfilzomib. 22 One patient (2.7%) had CHF, which compares favorably with the four phase II studies that investigated single-agent carfilzomib, in which 30 patients (5.7%) had Xgrade 3 CHF.…”

“…22 Fever and hypokalemia were the most common Xgrade 3 nonhematologic AEs in our study, whereas pneumonia, fatigue and dyspnea were the most common Xgrade 3 nonhematologic AEs with single-agent carfilzomib. 22 One patient (2.7%) had CHF, which compares favorably with the four phase II studies that investigated single-agent carfilzomib, in which 30 patients (5.7%) had Xgrade 3 CHF. Dyspnea was not observed in our study.…”

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

“…Carfilzomib has been used in combination with lenalidomide and dexamethasone and as a single agent in patients with relapsed and/or refractory MM and varying degrees of renal function (Badros et al , 2013; Niesvizky et al , 2013; Siegel et al , 2013). Whole blood and PBMC samples from patients receiving 15 or 20 mg/m 2 of carfilzomib with 40 mg of dexamethasone and 10, 15 or 25 mg of lenalidomide (study PX‐171‐006) were taken 1 h after the first dose of carfilzomib and analysed for active site activity and occupancy.…”

Analysis of carfilzomib cardiovascular safety profile across relapsed and/or refractory multiple myeloma clinical trials

“…11,28 Carfilzomib-based regimens have been generally well tolerated, but concerns for CV toxicity have been raised. 10,[13][14][15]29 Here, we assessed carfilzomib-associated CV AEs in phase 1-3 clinical trials. Across all RRMM phase 3 trials, treatment with carfilzomib was associated with a numeric increase in cardiac AE incidence.…”

“…12 In pivotal phase 2 and 3 studies, there has been a reported increase in CV AEs. 10,[13][14][15] In the phase 3 ASPIRE and ENDEAVOR studies, the grade $3 cardiac failure incidence was 3.8% (KRd) vs 1.8% (Rd) and 4.8% (Kd) vs 1.8% (Vd). 10,15 Post hoc analyses of ASPIRE and ENDEAVOR data according to age showed increased cardiac failure risk in elderly patients.…”