Abstract
This phase 2 study assessed the safety, pharmacokinetics, pharmacodynamics and efficacy of carfilzomib, a selective proteasome inhibitor, in patients with multiple myeloma and varying degrees of renal impairment, including patients on chronic hemodialysis. Patients were grouped by creatinine clearance: >80 ml/min, 50–80 ml/min, 30–49 ml/min, <30 ml/min and chronic hemodialysis. Carfilzomib was administered on days 1, 2, 8, 9, 15 and 16 in 28-day cycles: 15 mg/m2 (Cycle 1), 20 mg/m2 (Cycle 2) and 27 mg/m2 (Cycles 3+). There were no differences in carfilzomib clearance or exposure among patients with normal renal function and any group with renal impairment. Grade 3/4 adverse events (AEs) included anemia (28.0%), thrombocytopenia (20.0%), lymphopenia (18.0%) and fatigue (14.0%). AEs were similar among groups. At 15 mg/m2, proteasome inhibition up to 85% was observed and did not differ among groups. Although nearly 50% of patients were refractory to both bortezomib and lenalidomide, end of study partial response or better (overall response rate) was 25.5% with 7.9 months median duration of response. In conclusion, the pharmacokinetics and safety of carfilzomib were not influenced by the degree of baseline renal impairment, including in patients on dialysis, and carfilzomib was well tolerated and demonstrated promising efficacy.
Highlights
Renal impairment is a frequent and severe complication in patients with multiple myeloma (MM).1,2 The pathology is heterogeneous and includes a variety of factors such as hypercalcemia, cast nephropathy and immunoglobulin light chain damage to tubular cells.3 The incidence of renal insufficiency in patients with newly diagnosed MM varies by the definition; while 50% of 2380 newly diagnosed patients with MM had impaired renal function as determined by elevated creatinine clearance (CrCl) at diagnosis,4,5 only 15–20% had serum creatinine 42.3 mg/dl
Renal impairment has been associated with poor prognosis and shorter survival in patients with MM, because of the advanced state of disease that caused the renal impairment and because of limited treatment options and dose reductions commonly implemented in these patients that lead to diminished efficacy
26.0% of patients had a poor prognosis as assessed by cytogenetic analysis and/or fluorescence in situ hybridization
Summary
Renal impairment is a frequent and severe complication in patients with multiple myeloma (MM). The pathology is heterogeneous and includes a variety of factors such as hypercalcemia, cast nephropathy and immunoglobulin light chain damage (usually irreversible) to tubular cells. The incidence of renal insufficiency in patients with newly diagnosed MM varies by the definition; while 50% of 2380 newly diagnosed patients with MM had impaired renal function as determined by elevated creatinine clearance (CrCl) at diagnosis, only 15–20% had serum creatinine 42.3 mg/dl. The incidence of renal insufficiency in patients with newly diagnosed MM varies by the definition; while 50% of 2380 newly diagnosed patients with MM had impaired renal function as determined by elevated creatinine clearance (CrCl) at diagnosis, only 15–20% had serum creatinine 42.3 mg/dl. While it is true that renal insufficiency may increase the toxicity of various therapies in MM, recent data suggest that novel agents such as thalidomide and bortezomib are safe and effective in patients with MM and renal failure.. Carfilzomib is a selective proteasome inhibitor that, like bortezomib, primarily inhibits the chymotrypsin-like activity of the proteasome.. Carfilzomib showed greater selectivity than bortezomib for the proteasome without inhibiting off-target proteases, and had antiproliferative activity in cells resistant to bortezomib.. In previous phase 2 studies, carfilzomib demonstrated durable responses in heavily pretreated patients with relapsed and/or refractory MM including patients with mild to moderate renal impairment.. Carfilzomib is a selective proteasome inhibitor that, like bortezomib, primarily inhibits the chymotrypsin-like activity of the proteasome. In preclinical studies, carfilzomib showed greater selectivity than bortezomib for the proteasome without inhibiting off-target proteases, and had antiproliferative activity in cells resistant to bortezomib. In previous phase 2 studies, carfilzomib demonstrated durable responses in heavily pretreated patients with relapsed and/or refractory MM including patients with mild to moderate renal impairment. Unlike results shown with intravenous (IV) bortezomib, peripheral neuropathy events during treatment with carfilzomib are mild and occur at a low rate.
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