Prospective Study of Cardiac Events During Proteasome Inhibitor Therapy for Relapsed Multiple Myeloma

J Clin Oncol. 2019 Aug 1;37(22):1946-1955. doi: 10.1200/JCO.19.00231. Epub 2019 Jun 12.


Purpose: Cardiovascular adverse events (CVAEs) can occur during proteasome inhibitor (PI) therapy. We conducted a prospective, observational, multi-institutional study to define risk factors and outcomes in patients with multiple myeloma (MM) receiving PIs.

Patients and methods: Patients with relapsed MM initiating carfilzomib- or bortezomib-based therapy underwent baseline assessments and repeated assessments at regular intervals over 6 months, including cardiac biomarkers (troponin I or T, brain natriuretic peptide [BNP], and N-terminal proBNP), ECG, and echocardiography. Monitoring occurred over 18 months for development of CVAEs.

Results: Of 95 patients enrolled, 65 received carfilzomib and 30 received bortezomib, with median 25 months of follow-up. Sixty-four CVAEs occurred, with 55% grade 3 or greater in severity. CVAEs occurred in 51% of patients treated with carfilzomib and 17% of those treated with bortezomib (P = .002). Median time to first CVAE from treatment start was 31 days, and 86% occurred within the first 3 months. Patients receiving carfilzomib-based therapy with a baseline elevated BNP level higher than 100 pg/mL or N-terminal proBNP level higher than 125 pg/mL had increased risk for CVAE (odds ratio, 10.8; P < .001). Elevated natriuretic peptides occurring mid-first cycle of treatment with carfilzomib were associated with a substantially higher risk of CVAEs (odds ratio, 36.0; P < .001). Patients who experienced a CVAE had inferior progression-free survival (log-rank P = .01) and overall survival (log-rank P < .001). PI therapy was safely resumed in 89% of patients, although 41% required chemotherapy modifications.

Conclusion: CVAEs are common during PI therapy for relapsed MM, especially with carfilzomib, particularly within the first 3 months of therapy. CVAEs were associated with worse overall outcomes, but usually, discontinuation of therapy was not required. Natriuretic peptides were highly predictive of CVAEs; however, validation of this finding is necessary before uniform incorporation into the routine management of patients receiving carfilzomib.

Trial registration: NCT02178579.

Publication types

  • Multicenter Study
  • Observational Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Bortezomib / administration & dosage
  • Cardiovascular Diseases / chemically induced
  • Cardiovascular Diseases / complications
  • Disease-Free Survival
  • Electrocardiography
  • Female
  • Heart Diseases / chemically induced*
  • Heart Diseases / complications
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Molecular Targeted Therapy
  • Multiple Myeloma / complications*
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / mortality
  • Natriuretic Peptide, Brain / analysis
  • Neoplasm Recurrence, Local / complications
  • Neoplasm Recurrence, Local / drug therapy
  • Oligopeptides / administration & dosage
  • Prospective Studies
  • Proteasome Inhibitors / adverse effects*
  • Proteasome Inhibitors / therapeutic use
  • Risk Factors
  • Time-to-Treatment
  • Treatment Outcome
  • Troponin I / analysis
  • Troponin T / analysis


  • Oligopeptides
  • Proteasome Inhibitors
  • Troponin I
  • Troponin T
  • Natriuretic Peptide, Brain
  • Bortezomib
  • carfilzomib

Associated data