In a review recently published in Frontiers in Oncology, the authors focused on the second-generation proteasome inhibitor carfilzomib, discussing its biochemical properties, mechanism of action, toxicity profile, and pivotal clinical trials evaluating its efficacy in relapsed or refractory (R/R) multiple myeloma (MM).
Proteasomes are protein complexes that degrade unneeded or damaged intracellular proteins and have important roles in cell survival and cell cycle progression by controlling the levels of key regulatory proteins in both normal and cancer cells. Cancer cells rely more heavily than normal cells on proteasome-mediated proteolysis due to the accumulation of proteins from uncontrolled gene transcription. This makes the proteasome a promising therapeutic target in a number of cancers, including R/R MM.
Bortezomib, a first-generation proteasome inhibitor, was the first to received US Food and Drug Administration (FDA) approval in R/R MM in 2003, followed by carfilzomib in 2012 and ixazomib in 2015. Carfilzomib is a second-generation proteasome inhibitor that binds irreversibly with the proteasome. It has a short half-life of approximately 20 minutes, and unlike many other drugs, is not metabolized in the liver and instead is metabolized into inactive peptides or diol compounds in the plasma.
Carfilzomib has been shown to overcome the major toxicities associated with bortezomib, such as peripheral neuropathy, and has demonstrated improved efficacy relative to bortezomib in the treatment of MM in both preclinical and clinical settings. To date, at least 10 pivotal clinical trials evaluating carfilzomib regimens against R/R MM have been completed or are in progress. These included a variety of comparisons of other regimens (such as bortezomib and dexamethasone) with carfilzomib monotherapy and carfilzomib in combination therapy (carfilzomib and dexamethasone [Kd]; carfilzomib, lenalidomide and dexamethasone [KRd]; daratumumab, carfilzomib and dexamethasone [DKd]; and isatuximab, carfilzomib and dexamethasone [IKd]). Most recently, findings from the CANDOR and IKEMA trials led to the FDA approval of DKd treatment regimen (in 2020) and the IKd treatment regimen (in 2021), respectively, for adult patients with R/R MM who have received 1 to 3 lines of prior therapy.
The most common any-grade adverse events (AEs) reported in the integrated safety profile for single agent carfilzomib in patients with advanced MM (4 phase 2 studies: PX-171-003-A0, PX-171-003-A1, PX-171-004 and PX-171-005; N=526) included fatigue (55.5%), anemia (46.8%), nausea (44.9%), thrombocytopenia (36.3%), and dyspnea (34.6%). Although carfilzomib has a different toxicity profile than other proteasome inhibitors, it has been associated with a higher occurrence of cardiovascular AEs.
A systematic literature review of the use of carfilzomib across 29 eligible clinical trials found that the occurrence of all-grade and high-grade cardiotoxicity was 8.68% and 4.92%, respectively. In contrast, when considering clinical trials of bortezomib, the rates of all-grade and high-grade cardiotoxicity were 3.8% and 2.3%, respectively. Thus, patients’ cardiovascular risk factors should be assessed prior to initiating carfilzomib therapy and treatment-emergent cardiovascular AEs should be monitored closely during therapy. Carfilzomib treatment has also been associated with renal toxicity.
“These side-effects continue to challenge the treatment of MM with carfilzomib and optimization of carfilzomib treatment regimens to attenuate such effects is a timely need,” the authors wrote in their review.
Jayaweera SPE, Wanigasinghe Kanakanamge SP, Rajalingam D, Silva GN. Carfilzomib: a promising proteasome inhibitor for the treatment of relapsed and refractory multiple myeloma. Front Oncol. 2021;11:740796. doi:10.3389/fonc.2021.740796