Cardiovascular adverse events (CVAEs) commonly occur during proteasome inhibitor (PI) therapy for relapsed/refractory multiple myeloma (MM), particularly in patients with elevated natriuretic peptides or who were receiving carfilzomib, according to results from the Prospective Observation of Cardiac Safety With Proteasome Inhibitor (PROTECT) study. The analysis, published in the Journal of Clinical Oncology, also determined that patients who experienced CVAEs had shorter progression-free survival (PFS) and overall survival (OS) than patients who did not.
In the PROTECT study, Robert F. Cornell, MD, of Vanderbilt University Medical Center in Nashville, examined the incidence of and risk factors for CVAEs in 95 patients with relapsed/refractory MM receiving bortezomib or carfilzomib over 18 months after enrollment.
All enrolled participants had received at least one prior line of chemotherapy. Patients with symptomatic cardiac arrhythmia or New York Heart Association class 3 or 4 symptomatic heart failure (HF) within three months of enrollment were excluded. In addition, patients with light chain amyloidosis, albuminuria, troponin elevation, or certain cases of end-organ biopsy were excluded.
Treatment was initiated with physician choice of either:
- carfilzomib-based therapy (n=65)
- bortezomib-based therapy (n=30)
Compared with the patients receiving bortezomib, patients in the carfilzomib cohort were more likely to be male (74% vs. 50%), to have used tobacco (43% vs. 13%), and to have enrolled later after diagnosis (median time to enrollment = 37.4 vs. 18.6 months). Sixty percent of patients in the carfilzomib group had received one or two prior lines of therapy, compared with 73% of bortezomib-treated patients who had received one prior line. Median ages were similar between each group: 66 years (range = 42-85 years) in the carfilzomib group and 66.5 years (range = 40-86 years) in the bortezomib group.
Patients were treated with carfilzomib-based therapy for a median of 99 days (range = 81-147 days), and carfilzomib was most often administered in combination with pomalidomide and dexamethasone. The median duration of treatment in the bortezomib-based therapy cohort was 126 days (range = 84-206 days). Bortezomib in combination with cyclophosphamide and dexamethasone was the most common bortezomib regimen.
Enrolled patients underwent cardiovascular assessments at baseline and at the start of each chemotherapy cycle for the first six cycles of PI therapy. Cardiac biomarkers (troponin I or T, brain natriuretic peptide [BNP], or N-terminal proBNP [NTproBNP]) were tested twice per cycle, on day 1 and day 8 or 15. Electrocardiogram (ECG) and cardiologist assessments were performed on day 1 of each cycle, and transthoracic echocardiogram (TTE) was tested on the first day of cycles 2, 4, and 6. For an additional 12 months, patients were clinically observed for CVAEs, and cardiovascular assessments were performed at the time of any suspected CVAE. No changes to chemotherapy were made based on laboratory abnormalities alone.
A total of 64 CVAEs occurred during the study, 56 (87.5%) of which were related to carfilzomib-based treatment. The authors also found that significantly more patients receiving carfilzomib experienced CVAEs, compared with those receiving bortezomib-based therapy (50.7% vs. 16.7%; p=0.005).
The most common CVAE across treatment groups was HF (n=13), followed by grade 3 or 4 hypertension (n=13), and cardiac chest pain (n=9). Atrial fibrillation occurred twice and acute coronary syndrome occurred three times, with one sudden cardiac death after a myocardial infarction within 24 hours of carfilzomib treatment during the second week.
When assessing risk factors predictive of CVAEs, the authors found that elevated natriuretic peptide levels at baseline (BNP >100pg/mL or NTpro-BNP >125 pg/mL) increased the risk for CVAEs more than 10-fold (odds ratio [OR] = 10.8; 95% CI 3.1-37.9; p<0.001). Patients who developed elevated levels during the first three weeks of therapy also were at higher risk of CVAEs than those who did not (OR=36.0; 95% CI 4.4-296; p<0.001).
Twenty-one CVAEs occurred in 14 carfilzomib-treated patients with BNP elevations, with a median increase of 165 pg/mL (range = 107-320 pg/mL) from baseline at time of event. In 10 patients with elevated NTproBNP, 18 CVAEs occurred, with a median NTproBNP increase of 5,925 pg/mL (range = 673-10,454 pg/mL) from baseline. The investigators noted that these values returned to near-baseline levels at a median of 24.5 days (range = 19-34.5 days) after the event.
Other cardiovascular tests, including troponin I or T, ECG, and TTE, were not predictive of CVAEs.
PFS and OS for patients who experienced a CVAE were lower than for those who did not, though p values were not reported:
- median PFS: 10.4 months (range = 3.3-14.5 months) vs. 28.4 months (range = 10.6 months to not reached), respectively
- median OS: 18.1 months (range = 11.6 months to not reached) vs. not reached, respectively
Thirty-four patients died during the study, with 88% of deaths resulting from MM disease progression. One death was due to progressive HF, one as a result of graft-versus-host disease, and one due to respiratory failure. One sudden cardiac death occurred within 24 hours of a carfilzomib infusion.
The researchers concluded that, while CVAEs were common in patients with MM undergoing PI therapy and were associated with inferior PFS and OS, in most cases, the CVAEs did not require discontinuation of therapy. In approximately half of the reported CVAEs (48%; n=31), patients could continue PI-based therapy without chemotherapy modification, while 41% (n=26) required a dose reduction and/or delay before the patient could resume PIs. PI-based therapy was discontinued due to cardiovascular toxicity in only 11% of instances (n=7).
Because 86% of CVAEs occurred in the first three months of therapy, measuring and monitoring natriuretic peptides levels using BNP or NTproBNP may help identify which patients are at the highest risk for CVAEs. "Natriuretic peptide testing and detailed cardiovascular medical history are highly predictive of carfilzomib-based CVAEs and should be considered as part of management for this treatment," the authors wrote.
Limitations of this analysis include a lack of standardized treatment and dosing. In addition, the study did not reach its enrollment goal of 65 bortezomib-treated patients because it "is no longer a first-line choice for relapsed MM," the authors explained. "However, because of the high CVAE rate with carfilzomib, the study remained adequately powered to evaluate for differences in outcome between cohorts."
The authors reported no conflicts of interest.
Cornell RF, Ky B, Weiss BM, et al. Prospective study of cardiac events during proteasome inhibitor therapy for relapsed multiple myeloma. J Clin Oncol. 2019;37:1946-55.