The proteasome inhibitor carfilzomib is a promising new agent for the treatment of multiple myeloma (MM). Data presented at the 53rd Annual Meeting of the American Society of Hematology (ASH) highlighted a role for this agent in both the frontline and relapsed and/or refractory settings.
Carfilzomib irreversibly binds to and inhibits the chymotrypsinlike activity of the 20S proteasome.1 This agent differs both structurally and mechanistically from bortezomib, exhibiting sustained and more intense proteasome inhibition.2 Consequently, carfilzomib is proving to be an important new drug in MM, with presentations at ASH helping to elucidate the optimal place of this agent in therapy.
Recent Data on the Safety and Efficacy of Carfilzomib
In addition to evidence suggesting improved clinical outcomes, it appears that carfilzomib is better tolerated than bortezomib. Data from multiple studies indicate low rates of peripheral neuropathy, allowing for the use of this agent over an extended number of cycles without the need for dose reduction.3-6 Overall, the most frequently reported adverse events (AEs) associated with carfilzomib use include fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia.5 The most common grade 3 or higher toxicities are thrombocytopenia, anemia, lymphopenia, pneumonia, and neutropenia.5 Most of these AEs are reversible and usually do not require discontinuation of therapy.
According to updated results from a phase 1b/2 study, singleagent carfilzomib can be used at a dose as high as 56 mg/m2 when administered as a 30-minute infusion in a “stepped-up” regimen, in which patients begin with a lower dose (20 mg/m2) for the first 2 cycles of therapy.4 This strategy resulted in increased pharmacodynamic response and acceptable tolerability in a heavily pretreated population of patients with relapsed and/or refractory disease.4 Ongoing trials are evaluating whether increased proteasome inhibition will result in improved clinical outcomes among patients with MM.
In separate clinical trials, treatment with single-agent carfilzomib also showed promising activity in the relapsed and/or refractory setting in patients who were bortezomib-naive6 or who had unfavorable cytogenetic abnormalities.7 These studies confirm previous phase 1 investigations and establish a dose-response relationship across several relevant end points. The parallel analysis of dose-toxicity relationship is still outstanding in some studies,8 and these results will be important, as the optimal dose and infusion method have not yet been identified.
Findings from trials using multidrug regimens, both in newly diagnosed and relapsed and/or refractory myeloma, were also presented at ASH. These are some of the most exciting results, as they indicate the potential clinical synergy of carfilzomib with other agents, particularly immunomodulators. In the case of patients with newly diagnosed MM who are candidates for high-dose melphalan and autologous stem cell transplant, a regimen of carfilzomib, thalidomide, and dexamethasone appears to show similar outcomes to bortezomib-based therapy.9 In addition, newly diagnosed patients (transplant and nontransplant candidates) who received a combination of carfilzomib, lenalidomide, and dexamethasone tolerated treatment well, and achieved rapid and deep responses.3 As in the single-agent studies, these results paint a promising picture for frontline treatment, both from tolerability and efficacy perspectives, while still leaving unresolved issues such as optimal dose, infusion time, and potential drug combinations.
Taken as a whole, recent data on carfilzomib use offer an exciting perspective on what promises to be an important new player in the treatment of a challenging disease. Although some questions remain unanswered and others have emerged, it is clear that given the level of clinical responses and favorable tolerability, carfilzomib stands poised to assume a prominent role in the treatment of patients with MM.
- Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67:6383-6391.
- Lee SJ, Woo TM, Arastu-Kapur S, et al. Potent inhibition of multiple proteasome subunits by carfilzomib in multiple myeloma and solid tumor patients. Blood (ASH Annual Meeting Abstracts). 2011; 118: Abstract 5068.
- Jakubowiak AJ, Dytfeld D, Jagannath S, et al. Final results of a frontline phase 1/2 study of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in multiple myeloma (MM). Presented at: the 53rd Annual Meeting of the American Society of Hematology (ASH); December 10-13, 2011; San Diego, California. Abstract 631.
- Papadopoulos KP, Lee P, Singhal S, et al. A phase 1b/2 study of prolonged infusion carfilzomib in patients with relapsed and/or refractory (R/R) multiple myeloma: updated efficacy and tolerability from the completed 20/56mg/m2 expansion cohort of PX-171-007. Presented at: the 53rd Annual Meeting of the American Society of Hematology (ASH); December 10-13, 2011; San Diego, California. Abstract 2930.
- Singhal S, Siegel DS, Martin T, et al. Integrated safety from phase 2 studies of monotherapy carfilzomib in patients with relapsed and refractory multiple myeloma (MM): an updated analysis. Presented at: the 53rd Annual Meeting of the American Society of Hematology (ASH); December 10-13, 2011; San Diego, California. Abstract 1876.
- Vij R, Kaufman JL, Jakubowiak AJ, et al. Final results from the bortezomibnaïve group of PX-171-004, a phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory MM. Presented at: the 53rd Annual Meeting of the American Society of Hematology (ASH); December 10-13, 2011; San Diego, California. Abstract 813.
- Jakubowiak AJ, Siegel DS, Singhal S, et al. Unfavorable cytogenetic characteristics do not adversely impact response rates in patients with relapsed and/or refractory multiple myeloma treated with single-agent carfilzomib on the 003 (A1) study. Presented at: the 53rd Annual Meeting of the American Society of Hematology (ASH); December 10-13, 2011; San Diego, California. Abstract 1875.
- Squifflet P, Michiels S, Siegel DS, et al. Multivariate modelling reveals evidence of a dose-response relationship in phase 2 studies of single-agent carfilzomib. Presented at: the 53rd Annual Meeting of the American Society of Hematology (ASH); December 10-13, 2011; San Diego, California. Abstract 1877.
- Sonneveld P, Hacker E, Zweegman S, et al. Carfilzomib combined with thalidomide and dexamethasone (CARTHADEX) as induction treatment prior to high-dose melphalan (HDM) in newly diagnosed patients with multiple myeloma (MM). A trial of the European Myeloma Network (EMN). Presented at: the 53rd Annual Meeting of the American Society of Hematology (ASH); December 10-13, 2011; San Diego, California. Abstract 633.