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

Abstract

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: ClinicalTrials.gov NCT02178579.

Conflict of interest statement

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

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Robert F. Cornell

Honoraria: Takeda Pharmaceuticals, Karyopharm Therapeutics

Consulting or Advisory Role: Takeda Pharmaceuticals, Karyopharm Therapeutics

Research Funding: Takeda Pharmaceuticals

Bonnie Ky

Honoraria: UpToDate

Consulting or Advisory Role: Roche, Bristol-Myers Squibb, Mateon Therapeutics, Gilead Sciences, Bioinvent, American College of Cardiology

Speakers’ Bureau: Bristol-Myers Squibb

Research Funding: Pfizer, Roche, Singulex

Patents, Royalties, Other Intellectual Property: Patent on use of neuregulin-1b as biomarker in heart failure; pending patent application on use of immunoglobulin E as biomarker of cardiotoxicity

Brendan M. Weiss

Employment: Janssen Research & Development

Stock and Other Ownership Interests: Johnson & Johnson

Honoraria: Novartis

Research Funding: Janssen Research & Development (Inst), GlaxoSmithKline (Inst), Prothena (Inst)

Deepak K. Gupta

Research Funding: Astellas Pharma

Patents, Royalties, Other Intellectual Property: Patent pending for new heart failure biomarkers

Joseph R. Carver

Consulting or Advisory Role: Boehringer Ingelheim

Adam D. Cohen

Consulting or Advisory Role: Celgene, GlaxoSmithKline, Bristol-Myers Squibb, Seattle Genetics, Janssen Oncology, Oncopeptides, Kite Pharma, Takeda Pharmaceuticals, Seattle Genetics

Research Funding: Bristol-Myers Squibb, Novartis (Inst)

Patents, Royalties, Other Intellectual Property: Patents related to CAR T cells and biomarkers of cytokine release syndrome

Expert Testimony: Janssen Oncology

Travel, Accommodations, Expenses: Celgene, Bristol-Myers Squibb, GlaxoSmithKline, Takeda Pharmaceuticals

Alfred L. Garfall

Consulting or Advisory Role: Kite Pharma, Surface Oncology

Research Funding: Amgen (Inst), Novartis (Inst), Tmunity Therapeutics (Inst)

Madan Jagasia

Honoraria: Incyte, Mallinckrodt, Genentech

Consulting or Advisory Role: Incyte, Kadmon

Research Funding: Mallinckrodt, Janssen Oncology

Travel, Accommodations, Expenses: Incyte, Mallinckrodt, Kadmon

Javid Moslehi

Consulting or Advisory Role: Pfizer, Novartis, Bristol-Myers Squibb, Myokardia, Deciphera, Audentes Therapeutics, AstraZeneca

Research Funding: Pfizer, Bristol-Myers Squibb

Rupal O’Quinn

Consulting or Advisory Role: Bracco Diagnostics, Guidepoint Global

Travel, Accommodations, Expenses: Bracco Diagnostics

Michael R. Savona

Stock and Other Ownership Interests: Karyopharm Therapeutics

Consulting or Advisory Role: Karyopharm Therapeutics, Celgene, TG Therapeutics, Merck

Research Funding: Sunesis Pharmaceuticals (Inst), TG Therapeutics (Inst), Astex Pharmaceuticals (Inst), Incyte (Inst), Takeda Pharmaceuticals (Inst)

Patents, Royalties, Other Intellectual Property: Product license Boehringer Ingelheim (minority owner)

Edward A. Stadtmauer

Consulting or Advisory Role: Celgene, Takeda Pharmaceuticals, Novartis, TEVA Pharmaceuticals Industries, Janssen, Amgen, Sanofi

Dan T. Vogl

Consulting or Advisory Role: Celgene, Amgen, Karyopharm Therapeutics, TEVA Pharmaceuticals Industries, Janssen, Active Biotech, Takeda Pharmaceuticals, Karyopharm Therapeutics

Daniel Lenihan

Consulting or Advisory Role: Roche/Genentech, Bristol-Myers Squibb, Prothena, ION Pharma, Takeda Pharmaceuticals, Pfizer

No other potential conflicts of interest were reported.

Figures

FIG 1.

Cumulative incidence curves for time to first cardiac event (all grades) estimated using Fine and Gray method for competing risk survival analysis. CHF, congestive heart failure.

FIG 2.

Kaplan-Meier curves of (A) overall survival (OS) and (B) progression-free survival (PFS) according to occurrence of cardiovascular adverse event (CVAE) versus no CVAE.