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. 2024 Jan 1;9(1):16-24.
doi: 10.1001/jamacardio.2023.4105.

Clonal Hematopoiesis and Cardiovascular Disease in Patients With Multiple Myeloma Undergoing Hematopoietic Cell Transplant

June-Wha Rhee  1 , Raju Pillai  2 , Tianhui He  3 , Alysia Bosworth  3 , Sitong Chen  3 , Liezl Atencio  3 , Artem Oganesyan  3 , Kelly Peng  3 , Tati Guzman  3 , Kara Lukas  3 , Brianna Sigala  3 , Aleksi Iukuridze  3 , Lanie Lindenfeld  3 , Faizi Jamal  1 , Pradeep Natarajan  4   5 , Scott Goldsmith  6 , Amrita Krishnan  6 , Michael Rosenzweig  6 , F Lennie Wong  3 , Stephen J Forman  6 , Saro Armenian  3   7
Affiliations

Clonal Hematopoiesis and Cardiovascular Disease in Patients With Multiple Myeloma Undergoing Hematopoietic Cell Transplant

June-Wha Rhee et al. JAMA Cardiol. .

Abstract

Importance: There is a paucity of information on the association between clonal hematopoiesis of indeterminate potential (CHIP) and cardiovascular disease (CVD) in patients with cancer, including those with multiple myeloma (MM) undergoing hematopoietic cell transplant (HCT), a population at high risk of developing CVD after HCT.

Objective: To examine the association between CHIP and CVD in patients with MM and to describe modifiers of CVD risk among those with CHIP.

Design, setting, and participants: This was a retrospective cohort study of patients with MM who underwent HCT between 2010 and 2016 at City of Hope Comprehensive Cancer Center in Duarte, California, and had pre-HCT mobilized peripheral blood stem cell (PBSC) products cryopreserved and accessible for CHIP analyses. The study team performed targeted panel DNA sequencing to detect the presence of CHIP (variant allele frequency 2% or more).

Main outcomes and measures: The primary end point was the 5-year cumulative incidence and risk for developing de novo CVD (heart failure, coronary artery disease, or stroke) after HCT.

Results: Of 1036 consecutive patients with MM (580 male [56%]; median age, 60.0 years) who underwent a first autologous HCT, 201 patients had at least 1 CHIP variant (19.4%) and 35 patients had 2 or more variants (3.4%). The 5-year incidence of CVD was significantly higher in patients with CHIP (21.1% vs 8.4%; P < .001) compared with those without CHIP; the 5-year incidence among those with 2 or more variants was 25.6%. In the multivariable model, CHIP was associated with increased risk of CVD (hazard ratio [HR], 2.72; 95% CI, 1.70-4.39), as well as of individual outcomes of interest, including heart failure (HR, 4.02; 95% CI, 2.32-6.98), coronary artery disease (HR, 2.22; 95% CI, 1.06-4.63), and stroke (HR, 3.02; 95% CI, 1.07-8.52). Patients who had both CHIP and preexisting hypertension or dyslipidemia were at nearly 7-fold and 4-fold increased risk of CVD, respectively (reference: no CHIP, no hypertension, or dyslipidemia).

Conclusion and relevance: CHIP was significantly and independently associated with risk of CVD in patients with MM undergoing HCT and may serve as a novel biologically plausible biomarker for CVD in this cohort. Patients with MM and both CHIP and cardiovascular risk factors had an exceptionally high risk of CVD. Additional studies are warranted to determine if cardiovascular preventive measures can reduce CHIP-associated CVD risk.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Rhee reported grants from the National Institutes of Health/National Heart, Lung, and Blood Institute and Pfizer outside the submitted work. Dr Atencio reported grants from the V Foundation during the conduct of the study. Dr Natarajan reported grants from Amgen, Allelica, Apple, Boston Scientific, and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnetic Biomedicine, Novartis, Esperion Therapeutics, and TenSixteen Bio, equity from MyOme, Preciseli, and TenSixteen Bio, and spousal employment from Vertex outside the submitted work. Dr Goldsmith reported personal fees from Janssen Pharmaceuticals, Sanofi, and Adaptive Biotechnologies and research funding from Bristol Myers Squibb outside the submitted work. Dr Krishnan reported consultant fees from Bristol Myers Squibb, Sanofi, AbbVie, Roche, Janssen, and GSK outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Characteristics of Clonal Hematopoiesis of Indeterminate Potential (CHIP) Mutations
A, Number of patients harboring CHIP mutations in 1, 2, and 3 or more different genes; B, prevalence of CHIP according to age at transplant; C, spectrum of variant allele frequencies in genes: each dot represents an individual patient; D, number of patients with specific gene mutations; E, percentage of the different mutation subtypes for 4 of the most prevalent CHIP genes; F, spectrum of base-pair changes in the CHIP variants, G, comutation plot showing mutations present in all 204 patients: each column represents a single patient, variant allele frequency (VAF) cutoff used to identify mutations was 0.02.
Figure 2.
Figure 2.. Five-Year Cumulative Incidence of Combined Cardiovascular Conditions
CHIP indicates clonal hematopoiesis of indeterminate potential; HCT, hematopoietic cell transplant.
Figure 3.
Figure 3.. Association Between Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Cardiovascular Disease (CVD) Outcomes
Subdistrubtion hazard ratio (sHR) and 95% CIs for both combined and individual CVD outcomes adjusted for age, race and ethnicity, hematopoietic cell transplant-comorbidity index, hypertension, diabetes, dyslipidemia, and CHIP.
See this image and copyright information in PMC

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