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).