Mechanisms and Potential Treatment Options of Heart Failure in Patients With Multiple Myeloma

Abstract

Multiple myeloma is a pathology of plasma cells, with one of the most common side effects of its treatment is heart failure. In addition, cardiac amyloidosis could cause heart failure by itself. Even though mechanisms of cardiac amyloidosis are known, and they involve lysosomal dysfunction, reactive oxygen species (ROS) accumulation, and infiltrative effect by fibrils, there is no specific agent that could protect from these effects. While the molecular mechanism of doxorubicin cardiotoxicity via topoisomerase II β is established, the only FDA-approved agent for treatment is dexrazoxane. Liposomal doxorubicin can potentially improve response and decrease the development of heart failure due to microscopic liposomes that can accumulate and penetrate only tumor vasculature. Supplements that enhance mitochondrial biogenesis are also shown to improve doxorubicin-induced cardiotoxicity. Other agents, such as JR-311, ICRF-193, and ursolic acid, could potentially become new treatment options. Proteasome inhibitors, novel agents, have significantly improved survival rates among multiple myeloma patients. They act on a proteasome system that is highly active in cardiomyocytes and activates various molecular cascades in malignant cells, as well as in the heart, through nuclear factor kappa B (NF-kB), endoplasmic reticulum (ER), calcineurin-nuclear factor of activated T-cells (NFAT), and adenosine monophosphate-activated protein kinase (AMPKa)/autophagy pathways. Metformin, apremilast, and rutin have shown positive results in animal studies and may become a promising therapy as cardioprotective agents. This article aims to highlight the main molecular mechanisms of heart failure among patients with multiple myeloma and potential treatment options to facilitate the development and research of new preventive strategies. Hence, this will have a positive impact on life expectancy in patients with multiple myeloma.

The Risk of Multiple Myeloma Is Reduced in Metformin Initiators: A Retrospective Cohort Study in Taiwanese Patients with Type 2 Diabetes Mellitus

“…Fourth, two-thirds of patients with MM may have cardiac events [ 56 ], and metformin may exert a prophylactic effect on cardiotoxicity induced by carfilzomib [ 57 ] and may have a positive impact on the life expectancy of patients with MM and heart failure [ 58 ]. In our previous studies, we also demonstrated a reduced risk of hypertension [ 59 ], atrial fibrillation [ 60 ] and heart failure [ 61 ] among metformin users.…”

Molecular insights into the pathophysiology of doxorubicin-induced cardiotoxicity: a graphical representation

“…Upon activation, NF-κβ may stimulate the transcription of anti-apoptotic genes, namely, B-cell lymphoma-2 (BCL-2), cellular inhibitors of apoptosis (cIAP1 and cIAP2) and cFLIP. Conversely, the prolonged activation of NF-κβ, by Dox exposure, leads to chronic inflammation and resultant heart failure (Proskuriakova et al 2021 ; Gordon et al 2011 ). Concisely, Dox impairs NF-κβ activity by overexpressing interleukin 1 beta (IL-1β) and IL-6, as well as by disrupting the IκB-kinase (IKK) complex, which is composed of the kinases IKKα and IKKβ and the adaptor protein NEMO (NF-κB essential modulator) and thus, inhibits the transcription of anti-apoptotic genes in the myocardium (Proskuriakova et al 2021 ; Barczewski et al 2019 ).…”

“…Conversely, the prolonged activation of NF-κβ, by Dox exposure, leads to chronic inflammation and resultant heart failure (Proskuriakova et al 2021 ; Gordon et al 2011 ). Concisely, Dox impairs NF-κβ activity by overexpressing interleukin 1 beta (IL-1β) and IL-6, as well as by disrupting the IκB-kinase (IKK) complex, which is composed of the kinases IKKα and IKKβ and the adaptor protein NEMO (NF-κB essential modulator) and thus, inhibits the transcription of anti-apoptotic genes in the myocardium (Proskuriakova et al 2021 ; Barczewski et al 2019 ). In the context of myocardial infarction and Dox cardiotoxicity, overexpression of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT3) pathway by protagonists driven by the cytokine IL-6, has been shown to offer cardioprotection (Rong et al 2016 ; Fuglesteg et al 2008 ; Fuchs et al 2003 ).…”