Penn study finds pro­te­a­some inhibitor leads to higher than ex­pec­ted rates of cardiovascular adverse events

Philadelphia, PA (Press Release) – 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 shows the ther­apy comes with the risk of cardiovascular problems in a higher than ex­pec­ted per­cent­age of patients. 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 eight 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. Researchers published their findings today in JAMA Oncology.

Multiple myeloma (MM) is a bone marrow cancer that affects plasma cells. Normal plasma cells work as part of the immune system, but in MM these cells become can­cer­ous and grow out of control, leading to multiple painful bone tumors, as well as anemia, kidney failure, and recurrent in­fec­tions. The American Cancer Society esti­mates there were more than 30,200 new cases of MM in 2017. Standard treat­ments in­clude chemo­ther­apy and radiation. Survival of these patients has im­proved with the use of pro­te­a­some inhibitors.

Carfilzomib is one of three pro­te­a­some inhibitors cur­rently approved for use by the U.S. Food and Drug Admin­istra­tion. [Carfilzomib is marketed in the United States and other countries under the brand name Kyprolis.] Pro­teasomes are essentially garbage workers that break down and elim­i­nate proteins inside a cell. Diseases that require more protein turnover to survive, like MM, 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, an adjunct professor of Hematology Oncology at Penn, is the study’s senior author. Weiss also works in research and devel­op­ment at Janssen Pharma­ceu­ticals, which does not manu­fac­ture or sup­port any of the drugs involved in this analysis.

Researchers gathered data from 24 studies reported from 2007 through 2017, which in­cluded in­­for­ma­tion on 2,594 MM patients. They found 18.1 per­cent of patients who took car­filz­o­mib ex­peri­enced CVAE, with 8.2 per­cent of those cases being grade three or higher, meaning they are categorized as severe. For comparison, a similar review of bor­tez­o­mib, another pro­te­a­some inhibitor [marketed under the brand name Velcade], found just 3.8 per­cent of patients ex­peri­enced CVAE and only 2.3 per­cent were severe.

The most common CVAEs were hyper­tension (12.2 per­cent) and heart failure (4.1 per­cent). Arrhythmias (2.4 per­cent) and ischemic events (1.8) – in which there isn’t enough blood flow to the heart leading to the death of heart muscle – 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 MM and cardiovascular disease, such as older age and obesity. Previous studies have shown nearly two-thirds of MM patients had cardio­vascular disease at base­line, and 70 per­cent ex­peri­enced cardio­vascular events within six 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 said.

Study Funding

The study was sup­ported by the National Institutes of Health (T32-GM075766).

About Penn Medicine

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is con­sis­tently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year.

The University of Pennsylvania Health System's patient care facilities in­clude: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center – which are recog­nized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report – Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital – the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region in­clude Good Shepherd Penn Partners, a part­ner­ship between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of com­munity-based pro­grams and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our com­munity.

Reference

Waman, AJ, et al, "Carfilzomib-Associated Cardiovascular Adverse Events: A Systematic Review and Meta-analysis," JAMA Oncology, Dec 28, 2017 (abstract)

Source: Perelman School of Medicine at the University of Pennsylvania.