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High Risk of CV Events With PIs for Myeloma

Patients with relapsed multiple myeloma had a 40% incidence of cardiovascular adverse events (CVAEs) during treatment with proteasome inhibitors (PIs), particularly early in the course of treatment, a prospective multicenter study showed.

Overall, 38 of 95 patients had at least one CVAE during a median follow-up of 25 months. More than half of the 64 total events were grade ≥3 in severity, and 86% of CVAEs occurred within the first 90 days of treatment. CVAEs were associated with worse progression-free survival (PFS) and overall survival (OS).

CVAEs occurred more often in patients treated with carfilzomib (Kyprolis) than with bortezomib (Velcade), but carfilzomib was the treatment of choice for most patients, as reported online in the Journal of Clinical Oncology.

“[Carfilzomib] is an important and effective treatment option for patients with myeloma,” lead author Robert Frank Cornell, MD, of Vanderbilt University Medical Center in Nashville, Tennessee, said in a statement. “Importantly, we recommend patients have routine monitoring with BNP (brain natriuretic peptide) or NT (N-terminal) proBNP during treatment, as elevations of these were highly predictive of cardiac events.”

By virtue of older age and a high prevalence of CV risk factors and disease, patients with multiple myeloma have a high risk of CV events. PIs have contributed substantially to the dramatic improvement in myeloma treatment and are associated with improved PFS and OS. As a result of patients’ improved longevity, CV complications of treated myeloma have become more apparent, Cornell and co-authors noted in their introduction to their findings.

Prior studies documented associations of both carfilzomib and bortezomib with CVAEs, although early data suggested increased cardiotoxicity with carfilzomib. Detailed data on the frequency, type, and clinical time frame of PI-associated CVAEs have been lacking, the authors continued. Additionally, no validated protocols have existed to identify patients at highest risk for CV toxicity or to guide management of patients who have CVAEs.

Investigators conducted a prospective observational study to clarify the association between PI therapy and CVAEs in patients with relapsed multiple myeloma. The primary objective was to quantify the incidence of and determine risk factors for CV events in patients treated with bortezomib or carfilzomib. PFS and OS were secondary objectives.

The 95 patients were enrolled from September 2015 to March 2018. They had a median age of 66 and an age range of 40-86. At enrollment, 65 patients were being treated with carfilzomib and 30 with bortezomib. Median time from diagnosis to enrollment was 37.4 months in the carfilzomib group and 18.6 months in the bortezomib group. The carfilzomib group had a median treatment history of two prior lines of therapy for myeloma as compared with one for the bortezomib group.

About half the patients had a family history of CV disease, 13% had diabetes, 40% had hypertension, and 30% had dyslipidemia. The carfilzomib group included significantly more tobacco users than the bortezomib group (43% vs 13%, respectively, P=0.004). About 60% of the patients had class I heart function. Additionally, 37% of the patients had elevated baseline BNP (>100 pg/mL) or NTproBNP (>125 pg/mL).

The data analysis showed that 33 (50.7%) of the carfilzomib-treated patients had one or more CVAEs as compared with five (16.7%) patients treated with bortezomib (P=0.005). The authors reported that 56 (87.5%) of the 65 CVAEs occurred in patients treated with carfilzomib. Heart failure was the most common CVAE (n=23), followed by grade 3/4 hypertension (13), and cardiac chest pain (nine).

Baseline elevation of BNP or NTproBNP significantly increased the odds of CVAE in patients treated with carfilzomib (OR 10.8, 95% CI 3.1-37.9). Additionally, BNP elevation during the first 3 weeks of carfilzomib treatment significantly increased the odds of CVAE (OR 36.0, 95% CI 4.4-296.0). Fourteen carfilzomib-treated patients with elevated BNP had 21 CVAEs, associated with a median BNP increase of 165 pg/mL from baseline. Additionally, 10 patients with NTproBNP elevation during carfilzomib treatment 18 had CVAEs associated with a mean increase in NTproBNP of 5,925 pg/mL from baseline.

Natriuretic peptide levels returned to near-baseline levels after a median of 24.5 days. The peptides were predictive for all categories of CVAEs.

Patients who had a CVAE had significantly worse PFS and OS. Median PFS was 10.4 months for patients with a CVAE versus 28.4 months for those without events. Median OS was 18.1 months with a CVAE and not yet reached among patients who were CVAE free.

Overall, 34 patients died during the study, with myeloma the cause in most (88%) cases. One sudden cardiac death occurred within 24 hours after carfilzomib infusion. One patient each died of progressive heart failure, graft-versus-host disease, and respiratory failure.

The study provided some much-needed prospective data on the association between PI therapy and CVAEs, according to Tomas G. Neilan, MD, director of cardio-oncology at Massachusetts General Hospital in Boston. The trial also identified a potential strategy for identifying high-risk patients, he said.

“Most of the events were heart failure events, most were within 3 months, and their NTproBNP was elevated, so surveillance is entirely plausible and practical by measuring a widely available biomarker,” Neilan, who was not involved with the research, told MedPage Today in an email.

“Most of the patients who had a heart failure event had an elevated NTproBNP at baseline, so would cardiac optimization prior to therapy have helped?” he added.

Cornell disclosed relationships with Takeda and Karyopharm.


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