Background: Treatment of patients with RRMM can be challenging because of debilitating PN caused by the disease itself or by MM treatments. Neuropathy at diagnosis is prevalent (20–54%, depending on evaluation type [Richardson PA, et al. J Clin Oncol. 2009]) and can commonly be exacerbated by MM treatments (eg, bortezomib- or thalidomide-induced PN; BIPN or TIPN). PN reduces quality of life and leads to increased PN-related healthcare expenditures (eg, diagnostic testing and pharmaceutical and non-pharmaceutical interventions [Snowdon JA, et al. Br J Haematol. 2011]). One group has estimated that a single event of treatment-related Grade 3/4 PN costs more than $1,000 (Durie B, et al. J Med Econ. 2013; Epub). Carfilzomib is a selective proteasome inhibitor recently approved in the US for RRMM that, in preclinical models, does not induce neurodegeneration as seen with bortezomib and, in clinical studies, is associated with low rates of PN.
Objectives: An analysis of the PN safety profile for single-agent carfilzomib was performed in a cross-trial safety analysis of 526 patients from 4 phase 2 studies.
Methods: AEs were analyzed from the following studies: PX-171-003-A0, PX-171-003-A1, PX-171-004, and PX-171-005 (NCT00511238, NCT00530816, NCT00721734), in which carfilzomib was dosed at 20−27 mg/m2 in 28-day cycles for all studies except 005 (15−27 mg/m2). Patient assessments included neuropathy history and baseline neuropathy status. An aggregate of PN terms including peripheral neuropathy, neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy were used in the analysis of PN.
Results: The majority of patients in these studies (84.8%) had a history of PN due to previous therapy (42.6% due to bortezomib, 43.3% thalidomide, and 5.9% lenalidomide), with 71.9% of patients having active PN just prior to study entry (all Grade 1 or 2). During treatment with carfilzomib, PN worsened or emerged in only 13.9% overall. Among the 526 patients, 41 (7.8%) experienced Grade 1 PN, 25 (4.8%) Grade 2 PN, and 7 (1.3%) Grade 3 PN. Notably, no ≥Grade 4 PN was reported. In response to a PN-related AE, only 1 patient (0.2%) discontinued treatment and 4 (0.8%) required a dose modification. Of significance, 330/378 (87.3%) of the patients with baseline PN had stable or improved neuropathy during study treatment and did not report any PN-related AEs within 30 days of their last dose of carfilzomib.
Conclusions: In contrast to currently approved MM therapies, carfilzomib is associated with a low rate of treatment-emergent PN, even in patients with a history of PN, and does not exacerbate PN in patients with pre-existing neuropathy. Additionally, there was a low rate of dose reductions or discontinuations due to PN. Future findings from comparative trials will determine whether complications and costs associated with BIPN and TIPN can be minimized with carfilzomib treatment.