Common Measures Of Heart And Blood Vessel Health May Predict Risk Of Heart-Related Side Effects During Treatment With Kyprolis

Italian researchers have found that common measures of heart and blood vessel health may predict the risk of heart-related side effects in multiple myeloma patients treated with Kyprolis (carfilzomib).
In particular, the researchers found that myeloma patients who experienced heart-related side effects while being treated with Kyprolis had significantly higher blood pressure, left ventricular mass, and pulse wave velocity before starting Kyprolis treatment than patients who did not experience heart-related side effects.
Blood pressure, left ventricular mass, and pulse wave velocity are well established markers of heart and blood vessel health and can be measured in a physician’s office.
The researchers’ findings are based on data from a prospective single-center study that included 70 multiple myeloma patients, most of whom (90 percent) had relapsed / refractory disease.
In the journal article summarizing their findings, the Italian researchers note that additional studies are needed to confirm their results. If the results are confirmed, the researchers suggest that the markers they identified be included in patient evaluations prior to the start of Kyprolis treatment. This would help identify patients who could benefit from closer monitoring and more aggressive blood pressure treatment during Kyprolis therapy.
Global sales of Kyprolis have been flat for the past 12 months as physicians increasingly turn to alternatives such as Darzalex (daratumumab), Pomalyst (pomalidomide, Imnovid), Empliciti (elotuzumab), and Ninlaro (ixazomib) when choosing treatments for their myeloma patients. Kyprolis sales in the past six months were up just 0.2 percent compared to the previous six months, while the four competing drugs just mentioned experienced double digit growth over the same period.
Safety concerns have been one reason Kyprolis sales have been lagging, particularly concerns about the drug’s impact on the heart. The new Italian study could address some of these concerns by helping physicians identify patients who could benefit from increased heart monitoring and/or preventative use of heart medications to avoid heart-related side effects that might occur during Kyprolis treatment.
At the same time, the study may highlight the risks involved with Kyprolis treatment, given that a third of the patients in the study experienced heart-related side effects.
Background
Kyprolis belongs to the proteasome inhibitor class of drugs, which also includes Velcade (bortezomib) and Ninlaro. Research dating back more than a decade has shown that there is some risk of heart-related side effects during treatment with Velcade, the first and most widely used proteasome inhibitor. Of the three drugs in the proteasome inhibitor class, however, it is Kyprolis that is particularly known for having a risk of heart-related side effects, which can be severe, even fatal.
It is not currently known why Kyprolis has “cardiovascular toxicity,” as the Italian researchers describe it. The researchers note, however, that the way proteasome inhibitors work may interfere with the normal functioning of heart muscle cells, and it also may decrease nitric oxide levels in artery and vein walls, which leads to higher blood pressure.
No predictive factors have been identified yet for the development of heart-related side effects with Kyprolis, according to the study authors. They therefore sought to determine whether parameters commonly used to assess heart damage and heart function might predict the risk of developing heart-related side effects during treatment with Kyprolis.
Study Design
Between April 2017 and April 2018, the researchers enrolled 70 multiple myeloma patients in their prospective study. All patients were seen at the Myeloma Unit of the “Città della Salute e della Scienza” medical campus in Turin, Italy. The mean patient age was 60 years.
The majority of patients in the study (90 percent) had relapsed / refractory multiple myeloma and had received a median of 2.5 prior therapies, including alkylating agents such as melphalan (84 percent of patients), Velcade (80 percent), and immunomodulatory agents such as Revlimid (60 percent).
More than one third of patients (37 percent) had a history of high blood pressure; many patients showed other risk factors for developing heart disease, such as obesity (31 percent), high lipid levels in the blood (11 percent), and diabetes (10 percent).
Patients underwent a comprehensive heart-related evaluation before starting treatment with Kyprolis. The evaluation included office and 24-hour blood pressure measurements, electrocardiograms, transthoracic echocardiograms, and evaluation of carotid-femoral pulse wave velocity. Transthoracic echocardiograms were performed to assess heart damage, and carotid-femoral pulse wave velocity was measured to assess arterial stiffness.
Optimal office blood pressure control was defined as blood pressure below 140/90 mmHg.
The results of the blood pressure monitoring before the start of Kyprolis therapy revealed that half of the patients did not have optimal blood pressure control, and these patients were required to either start blood pressure medication or make adjustments in their current medication.
The median follow-up time was 9.3 months.
Study Results
The Italian researchers found that one third of the patients in their study experienced heart-related side effects a median of 3.6 month after starting treatment with Kyprolis. Most of the heart-related side effects were classified as mild to moderate in nature (78 percent); the remaining 22 percent were severe in nature.
The most common heart-related side effect was excessive blood pressure (91 percent), requiring either an intensification of blood pressure medication (74 percent) or temporary discontinuation of Kyprolis treatment (17 percent).
The two other heart-related side effects observed among the patients in the study were heart attack (myocardial infarction) and abnormal heart rhythm (arrhythmia); there was one instance of each of these side effects (2 patients total, or 3 percent of the total study participants).
The researchers found that patients who experienced heart-related side effects while receiving Kyprolis treatment had significantly higher blood pressure, left ventricular mass, and pulse wave velocity before starting Kyprolis treatment than patients who did not experience these side effects.
The average blood pressure before the start of Kyprolis treatment was 141/82 mmHg for patients who experienced heart-related side effects while receiving Kyprolis treatment compared to 127/74 mmHg for patients who did not experience heart-related side effects.
Similarly, the share of patients who had optimal blood pressure control (below 140/90 mmHg) before Kyprolis treatment was significantly higher among patients who did not experience heart-related side effects than among patients who did (60 percent versus 30 percent).
Left ventricular mass (indexed to body size) was 98 g/m2 for patients who experienced heart-related side effects while receiving Kyprolis treatment compared to 85 g/m2 for patients who did not experience them. The left ventricle is the chamber of the heart responsible for pumping blood out to the rest of the body after it has come from the lungs to the heart. When pumping blood out to the body becomes difficult due, for example, clogging of the arteries and veins, the muscles surrounding the left ventricle grow larger, increasing left ventricular mass.
Pulse wave velocity was 8.5 m/s for patients who experienced heart-related side effects while receiving Kyprolis compared to 7.5 m/s for patients who did not experience them. Pulse wave velocity is a measure of how stiff a person’s arteries are. It is the speed at which a blood pressure pulse travels from the heart through the arteries, and this speed is lower when arteries are flexible and higher when they are stiff.
For more information, please see the study by Bruno, G. et al., “Cardiovascular Organ Damage und Blood Pressure Levels Predict Adverse Events in Multiple Myeloma Patients Undergoing Carfilzomib Therapy,” in Cancers, May 3, 2019 (full text).
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- FDA Approves Once-Weekly Dosing And Revised Safety Information For Kyprolis
- Eyelid-Related Complications Of Velcade Therapy: New Insights And Recommendations
- Nelfinavir-Velcade Combination Very Active In Advanced, Velcade-Resistant Multiple Myeloma
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Thanks for the informative article about Kyprolis, Maike! Although I have heard that side effects may include heart problems for Kyprolis, I did not know the criteria for which that is measured. Given a choice between Kyprolis and another drug with less known side effects, and which may be equally or more effective against myeloma, one can see that another drug might be used. The problem is that many drugs might need to be tried in the course of a patient's battle against this dread disease.