ixazomib and Heart-Failure

Proteasome inhibitors have become an important drug class in the treatment of multiple myeloma. In addition to its role in myeloma cells, the proteasome plays a critical role in the myocardium, particularly in the context of cardiac stress. The growing awareness of the cardiovascular toxicity of proteasome inhibitors is emerging following the phase 3 trials and the transition into real-world practice. This article reviews the background to this problem and the incidence of the problem in phase 3 trials and subsequent phase 2 trials in new patient cohorts and discusses the strategy to detect and manage this emerging problem.

Topics: Antineoplastic Agents; Boron Compounds; Bortezomib; Clinical Trials as Topic; Drug Approval; Early Diagnosis; Glycine; Heart Failure; Humans; Meta-Analysis as Topic; Multiple Myeloma; Oligopeptides; Proteasome Inhibitors

Proteasome inhibitors (PIs) are standard treatments for multiple myeloma (MM). The risk of cardiac adverse events (CAEs) with PIs has been documented with bortezomib and carfilzomib; however, only a few studies have been reported on ixazomib. Furthermore, the effects of concomitant medications including dexamethasone and lenalidomide remain unclear.. This study aimed to determine the safety signals of adverse events related to CAEs, the effect of concomitant medications, the time to the occurrence of CAEs, and the incidence of fatal clinical outcomes after the occurrence of CAEs for three PIs using the US Pharmacovigilance database.. We examined 1,567,240 cases of 231 drugs registered as anticancer drugs in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database from January 1997 to March 2021. We compared the odds of developing CAEs between patients who received PIs and those who received non-PI anticancer drugs.. Bortezomib treatment resulted in significantly higher reporting odds ratios (RORs) for cardiac failure, cardiac failure congestive, and atrial fibrillation. Carfilzomib treatment resulted in significantly higher RORs for cardiac failure, congestive cardiac failure, atrial fibrillation, and QT prolonged. However, no adverse event CAE signals were observed with ixazomib treatment. A signal was detected for the safety of cardiac failure with bortezomib or carfilzomib, regardless of the presence or absence of concomitant medications. Safety signals for cardiac failure congestive with bortezomib and for cardiac failure congestive, atrial fibrillation, and QT prolonged with carfilzomib were observed only with dexamethasone combination therapy. Co-administration of lenalidomide and its derivatives did not affect the safety of bortezomib and carfilzomib.. We identified CAE safety signals for bortezomib and carfilzomib exposure when compared with 231 other anticancer agents. The safety signal for developing cardiac failure for both the drugs did not differ between patients with and without concomitantly administered medications.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Bortezomib; Dexamethasone; Heart Failure; Humans; Lenalidomide; Multiple Myeloma; Proteasome Inhibitors

Topics: Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Boron Compounds; Cardiotoxicity; Echocardiography; Glycine; Heart Failure; Humans; Magnetic Resonance Imaging; Male; Multiple Myeloma; Protease Inhibitors