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Cardiac complications in relapsed and refractory multiple myeloma patients treated with carfilzomib

2015; Springer Nature; Volume: 5; Issue: 1 Linguagem: Inglês

10.1038/bcj.2014.93

2044-5385

Shebli Atrash, Amanda Tullos, Susan Panozzo, Manisha Bhutani, Frits van Rhee, Bart Barlogie, Saad Z. Usmani,

Ubiquitin and proteasome pathways

Carfilzomib is a novel, highly selective, tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, which is the proteolytic core particle within the 26S proteasome, as compared with bortezomib, which reversibly inhibits the 20S proteasome. 1 In vitro, carfilzomib has demonstrated antiproliferative and proapoptotic activities in solid and hematologic tumor cells. 2 In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth in models of multiple myeloma, hematologic and solid tumors. 1 Proteasome inhibition was maintained for ⩾ 48 h following the first dose of carfilzomib in each week of dosing. 1 In addition, carfilzomib administration resulted in the inhibition of the low-molecular mass polypeptide two and multicatalytic endopeptidase complex-like one subunit of the immunoproteasome ranging from 26 to 32% and 41 to 49%, respectively, at a dose of 20 mg/m 2 (ref. 3).5][6][7] In 2012, based on these results, carfilzomib was approved in the United States for single-agent use in the treatment of patients with MM who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of the last therapy. 8arfilzomib has the advantage of a favorable safety profilemost notably a low incidence of peripheral neuropathy, which is a common complication with bortezomib-based regimens.][11] An increasing body of evidence supports the assertion that deficient proteasome activity has a crucial role in the impairment of cardiac function.This effect may be mediated by several mechanisms, the most important of which is putatively the accumulation of unfolded, damaged and undegraded proteins inside myocytes. 11-13However, limited data are currently available on cardiac adverse events associated with carfilzomib treatment.Between 2009 and 2012, which was before regulatory approval of carfilzomib in the United States, we treated 130 patients with relapsed and/or refractory MM, either on a phase 2 compassionate carfilzomib protocol (n = 118) or as single-patient treatment with an investigational new drug (n = 12).We herein report data on those patients who developed a significant cardiovascular adverse event, which was defined as hospitalization owing to a cardiac complication during the first two cycles of therapy with carfilzomib either alone or with dexamethasone.Patients with hospitalization attributed to other causalities, such as infections, or who received concomitant anti-MM drugs were excluded from this analysis.We also describe subsets of patients with baseline echocardiogram findings from before and during carfilzomib treatment and with brain natriuretic peptide (BNP) measurements gathered at baseline and during follow-up.