Ixazomib cardiotoxicity: A possible class effect of proteasome inhibitors
Authors: Hayan Jouni, Mary C. Aubry, Martha Q. Lacy, S. Vincent Rajkumar, Shaji K. Kumar, Robert L. Frye, Joerg Herrmann
Journal: American Journal of Hematology (2016)

The introduction of bortezomib has revolutionized the treatment of multiple myeloma (MM) and significantly improved outcomes in MM patients.1, 2 Similar to many other chemotherapeutic agents, there are numerous reports of bortezomib-induced cardiotoxicity.3 Furthermore, the FDA announced "several deaths due to cardiac events that occurred within hours or a few days after administration of carfilzomib" and cases of heart failure have been described.4, 5 Ixazomib (MLN9708) is a novel oral proteasome inhibitor that is showing great promise in the treatment of AL-amyloidosis and MM.6, 7 We herein present the first case of ixazomib-induced cardiotoxicity in the literature. An 82-year-old-male with history of paroxysmal atrial fibrillation and no known coronary artery disease was diagnosed with lambda light chain MM in 2007. He was treated with lenalidomide/dexamethasone with subsequent remission until 2011 when he had recurrence. His MM progressed through repeat lenalidomide/dexamethasone in 2013-2014, and his treatment regimen was switched to cyclophosphamide/prednisone in April 2014 through July 2014 with continued progression of his MM. A transthoracic echocardiogram performed in April 2014, continued demonstrated normal left ventricular size and function with an ejection fraction of 60%. Given his MM progression, he enrolled in a phase-II clinical trial that utilized ixazomib (MLN9708) and dexamethasone obtaining a very good partial response to therapy. Two months after initiation of therapy, he developed gradually worsening exertional dyspnea and fatigue. By the end of four cycles of ixazomib/dexamethasone, he experienced acutely decompensated heart failure with marked lower extremity edema, orthopnea, and paroxysmal nocturnal dyspnea which prompted referral to cardiology for further evaluation. Work-up included a regadenoson myocardial perfusion study, which demonstrated patchy apical stress-induced ischemia with an ejection fraction of 30-35%. He was in sinus rhythm throughout the evaluation and never demonstrated persistent tachycardia. Subsequent cardiac magnetic resonance imaging (CMR) was negative for cardiac amyloidosis and showed findings compatible with dilated non-ischemic cardiomyopathy with global hypokinesis including a peculiar linear stripe of delayed enhancement within the interventricular septum (Figure 1, Panel A). He had minimal coronary atherosclerosis on coronary angiography. Right ventricular biopsy showed cardiomyocyte hypertrophy with mild–moderate interstitial fibrosis (Figure 1, Panel B). There was no evidence for amyloidosis, hemochromatosis, or myocarditis on biopsy. The timeline of symptom onset, previously normal echocardiogram and findings on CMR were suspicious for ixazomib-induced cardiotoxicity. Ixazomib therapy was discontinued and he was started on carvedilol, spironolactone, and furosemide. He could not tolerate angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers due to hypotension, and furosemide was discontinued when he demonstrated evidence for volume depletion. No improvement of cardiac function was seen on serial echocardiograms up to 6 months following discontinuation of ixazomib. However, he did not have any further episodes of decompensated systolic heart failure. Unfortunately, he experienced recurrent, gradual increase in lambda light chain levels and is now being considered for alternative therapies that do not include proteasome inhibitors. Cardiac magnetic resonance imaging and right ventricular biopsy. Panel (A) Short-axis cardiac magnetic resonance imaging view demonstrates the liner stripe of delayed myocardial enhancement within the interventricular septum (arrow heads). Panel (B) Right ventricular biopsy demonstrated cardiomyocyte hypertrophy with mild to moderate interstitial fibrosis (H&E 200×). [Color figure can be viewed at wileyonlinelibrary.com] We report the first case of ixazomib-induced cardiotoxicity, extending concerns about a possible class-adverse effect. However, most MM patients receive multiple chemotherapeutic regimens with varying degrees of cardiotoxicity, which makes it very difficult to ascertain the stand-alone cardiotoxic effects of any particular drug in clinical practice. In animal models that have never been exposed to other agents, proteasome inhibitor treatment was found to cause significant cardiac dysfunction.8, 9 In pigs, prolonged and high-level proteasome inhibition for 3 months poses a particular risk and even more so in the presence of cardiovascular risk factors such as hyperlipidemia, which generates a greater burden of substrates for the ubiquitin-proteasome system.9 Profound impairment of systolic function, however, can be noted even in otherwise normal animals exposed to bortezomib for only 3 weeks at doses that are comparable to human chemotherapy regimens.8 Histologic evaluations of the hearts of the animals in these studies outlined cardiomyocyte hypertrophy as well as profound fibrosis similar to what was seen on the right ventricular biopsy of our patient.8, 9 A liner interventricular stripe of myocardial delayed enhancement on CMR, as noted here, has been reported in a bortezomib-induced cardiotoxicity case previously.10 However, this remains a nonspecific finding for dilated non-ischemic cardiomyopathy and is not universally seen in all cases of heart failure during proteasome inhibitor therapy.4 In summary, Ixazomib can result in cardiotoxicity in a manner similar to that observed with other proteasome inhibitors suggesting a potential adverse class effect. Furthermore, there is evidence for structural damage consistent with type I chemotherapy-induced cardiotoxicity. Patients should be carefully monitored during therapy with proteasome inhibitors and development of any cardiopulmonary symptoms should be carefully evaluated. HJ and JH wrote the manuscript. MCA, MQC, SVR, SKK, and RLF assisted in the medical management of the patient and critically reviewed this manuscript.