Although still incurable the survival rate of MM

Although still incurable, the survival rate of MM, the second most common hematologic malignancy (Siegel et al., 2014), has improved mainly due to the development of new and highly effective agents, such as immunomodulators and proteasome inhibitors (Kumar et al., 2012). CFZ is an irreversible epoxyketone-based proteasome inhibitor, used in the U.S. as a single or combination agent (along with lenalidomide and dexamethasone) in the treatment of relapsed/refractory MM. The elevated response rate and improved progression-free survival (PFS) observed in patients with relapsed or refractory MM receiving CFZ as a single (Siegel et al., 2013) or combination agent (Stewart et al., 2015; Dimopoulos et al., 2015b), as well as its advantageous benefit-risk profile in comparison to BTZ (Dimopoulos et al., 2015b), another proteasome inhibitor, are associated with significantly higher cardiac and cardiopulmonary adverse events. In the ASPIRE trial, for instance, compared to patients receiving lenalidomide and dexamethasone alone, those given CFZ in addition to lenalidomide and dexamethasone reported higher rates of grade 3 dyspnea (2.8% versus 1.8%), HF (grouped term; 3.8% and 1.8%), ischemic na+/ca2+ exchanger disease (grouped term; 3.3% and 2.1%), and hypertension (preferred term; 4.3% and 1.8%) (Stewart et al., 2015). Likewise, in the ENDEAVOR study, in comparison to the BTZ-dexamethasone group, the patients assigned to the CFZ-dexamethasone developed increased rates of grade 3 hypertension (8.9% vs. 2.6%), dyspnea (5.4% vs. 2.2%), and HF (4.8% vs. 1.8%) (Dimopoulos et al., 2015b). Recent early-phase clinical trials exploring the safety and efficacy of different CFZ doses in patients with newly diagnosed MM also reported cardiac-related dose-limiting toxicity (DLT), likely related to CFZ administration, with a reported maximum tolerated dose (MTD) of 20–36mg/m2 (Bringhen et al., 2014; Mikhael et al., 2015). The overall interpretation of the results from the phase I-III clinical trials indicates an increased risk of cardiac-related events following CFZ treatment, with a reported incidence of grade 3 HF ranging from 4 to 6% (Siegel et al., 2013; Stewart et al., 2015; Dimopoulos et al., 2015a). Besides HF, whose etiology and pathophysiology are poorly understood, other common side effects (potentially related to the vasoactive properties of CFZ) include myocardial ischemia, manifesting as angina and myocardial infarction, as well as systemic and pulmonary hypertension. Previous studies also reported the occurrence of chest pain of unclear etiology during CFZ infusion. In line with this finding, in some of our patients receiving CFZ infused at high-doses (≥36mg/m2), we observed cases of chest pain, sometimes associated with ischemic alterations of the electrocardiogram, without release of cardiac biomarkers in the circulation. This group underwent further cardiac evaluation, which failed to unveil inducible myocardial ischemia and/or significant CAD. The current study stemmed from the attempt to explain this inconsistency, by moving backwards from the bedside to the bench. Our data showed for the first time that CFZ exerts powerful in vitro effects on vascular tone and reactivity. CFZ administered by bolus injection heightened coronary resistance and its spasmogenic action was only partly resolved by NTG and NFP. Of note, the percentage inhibition achieved by NTG on CFZ-induced spasm was significantly higher than NFP (62.2% versus 49.4%). This would suggest a more congruent role for nitrates, rather than calcium channel blockers, in the prevention and treatment of the clinical conditions of exaggerated vascular tone, potentially related to CFZ infusion. Furthermore, CFZ increased the resting vasoconstricting tone of aortic strips, an effect which was further amplified by ablation of the endothelium. Moreover, preincubation with CFZ amplified the spasmogenic effect of different vasopressors and minimized the vasodilatory response to NTG and NFP on the contraction plateau caused by several vasopressors. Once again, NTG proved to be more efficacious than NFP in limiting the combined spasm ensuing from CFZ pretreatment and subsequent incubation with any of the vasopressors used. Finally, after preincubation with CFZ, there was a >50% reduction in the Ach-vasodilating effect. This finding, in conjunction with the stronger antispasmogenic activity consistently exhibited by NTG (as compared to NFP), suggests that CFZ can impair vasodilation via an endothelium dependent mechanism. Since the vasoactive effects of proteasome inhibitors other than CFZ were not investigated, the findings of our study cannot be generalized and assumed to be expression of a drug class effect. This represents a limitation of our study.