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The proteasome inhibitor carfilzomib has taken on an increasing role in the treatment of multiple myeloma, but new research from the Abramson Cancer Center of the University of Pennsylvania in Philadelphia shows the therapy comes with the risk of cardiovascular problems in a higher than expected percentage of patients.

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An analysis of past studies shows 18 percent of multiple myeloma patients receiving carfilzomib experience cardiovascular adverse events (CVAE) such as hypertension, heart failure, heart attacks, or arrhythmia. More than 8 percent of patients experience high-grade CVAEs that are more severe, which is more than twice as common as with other drugs for treating relapsed myeloma (JAMA Oncol 2017; doi:10.1001/jamaoncol.2017.4519).


Carfilzomib is one of three proteasome inhibitors currently approved for use by the FDA. Proteasomes are essentially garbage workers that break down and eliminate proteins inside a cell. Diseases that require more protein turnover to survive, like multiple myeloma, need more proteasomes. The inhibitor drugs block them from doing their job, causing the cells to fill up with protein and die.


"Like any cancer therapy, the concern with this approach is that it may have an effect on an otherwise healthy part of the body-in this case, the heart," said the study's lead author Adam J. Waxman, MD, a Hematology Oncology fellow in the Perelman School of Medicine at the University of Pennsylvania. Brendan M. Weiss, MD, Adjunct Professor of Hematology Oncology at Penn, is the study's senior author.


Study Details

Researchers gathered data from 24 studies reported from 2007 through 2017, which included information on 2,594 multiple myeloma patients. They found 18.1 percent of patients who took carfilzomib experienced CVAE, with 8.2 percent of those cases being grade 3 or higher. For comparison, a similar review of bortezomib, another proteasome inhibitor, found just 3.8 percent of patients experienced CVAE and only 2.3 percent were severe.


The most common CVAEs were hypertension (12.2%) and heart failure (4.1%). Arrhythmias (2.4%) and ischemic events (1.8%) were observed less commonly.


Researchers also found that higher doses of carfilzomib are associated with higher rates of CVAE, and that carfilzomib was associated with an elevated risk of CVAE compared to control groups who did not receive carfilzomib.


"Taken together, these findings argue that carfilzomib is responsible for an elevated risk, and anyone who is treating patients with this drug needs to be aware that this is a common event," Waxman said.


Researchers say these findings are particularly important since there are already overlapping risk factors for both multiple myeloma and cardiovascular disease, such as older age and obesity. Previous studies have shown nearly two-thirds of multiple myeloma patients had cardiovascular disease at baseline, and 70 percent experienced cardiovascular events within 6 years.


"Clinicians should be paying attention to who may be at highest risk for these events so they can tailor their therapy accordingly," Waxman said.


Researchers also called for further clinical trials to specifically evaluate this connection, arguing that it may be underrepresented by current data.


"If you're not specifically looking for this, you might report it differently," Waxman noted.