Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study

Abstract

Renal impairment is associated with poor prognosis in multiple myeloma (MM). This subgroup analysis of the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib vs high-dose dexamethasone assessed efficacy and safety in patients with relapsed MM with varying degrees of renal impairment (creatinine clearance (CrCl) o30, 30-50, 51-80 and 480 ml min À1). Time to progression (TTP), overall survival (OS) and safety were compared between subgroups with CrCl p50 ml min À1 (severe-to-moderate) and 450 ml min À1 (no/mild impairment). Response rates with bortezomib were similar (36-47%) and time to response rapid (0.7-1.6 months) across subgroups. Although the trend was toward shorter TTP/OS in bortezomib patients with severeto-moderate vs no/mild impairment, differences were not significant. OS was significantly shorter in dexamethasone patients with CrCl p50 vs 450 ml min À1 (P ¼ 0.003), indicating that bortezomib is more effective than dexamethasone in overcoming the detrimental effect of renal impairment. Safety profile of bortezomib was comparable between subgroups. With dexamethasone, grade 3/4 adverse events (AEs), serious AEs and discontinuations for AEs were significantly elevated in patients with CrCl p50 vs 450 ml min À1. These results indicate that bortezomib is active and well tolerated in patients with relapsed MM with varying degrees of renal insufficiency. Efficacy/safety were not substantially affected by severe-tomoderate vs no/mild impairment.

Salvage treatment with upfront melphalan 100 mg/m2 and consolidation with novel drugs for fulminant progression of multiple myeloma

“…The combination of cyclophosphamide, bortezomib, and dexamethasone induced ORR in up to 75% of refractory or relapsed MM patients [15]. Thalidomide and bortezomib maintained their high efficacy and acceptable toxicity profile in patients with renal impairment [19,20].…”

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

“…Clinical trials have demonstrated that carfilzomib and bortezomib are clinically active regardless of the degree of renal insufficiency in patients (Jagannath et al , 2005; San‐Miguel et al , 2008; Badros et al , 2013). Consistent with this, we found that carfilzomib induces consistent and potent inhibition of multiple proteasomal active sites in MM patients, regardless of patient renal function.…”

Pathogenesis and treatment of renal failure in multiple myeloma

“…[60][61][62] In the SUMMIT and CREST trials, bortezomib treatment was found to lead to an overall response rate of 25 and 30% in patients with moderate and severe renal impairment, respectively, 65 whereas the toxicity was comparable to that of patients without renal impairment. In a subanalysis of the APEX trial, bortezomib was effective in patients with renal impairment, including those with severe renal impairment, 66 with response rates and time to response similar across all subgroups of patients with varying degrees of renal function. Time to progression and overall survival were not substantially affected in patients with severe to moderate renal impairment compared to those with no or mild renal impairment or to the overall APEX population.…”