Carfilzomib-induced sinus bradycardia: A case report and literature review

Abstract

Carfilzomib is a second-generation irreversible proteasome inhibitors commonly used in the treatment of relapsed or refractory multiple myeloma. However, cardiac toxicity (heart failure, hypertension, coronary heart disease, etc.) has become the main factor leading to its reduction or withdrawal. We report a case of a 55-year-old female patient with multiple myeloma who developed sinus bradycardia following the administration of carfilzomib, along with a review of the relevant literature. The correlation between carfilzomib and cardiotoxicity was assessed by reviewing the medical history, applying the adverse drug reaction correlation evaluation, and using the Naranjo assessment scale. The clinical manifestations included chest tightness, shortness of breath, and abnormal electrocardiogram monitoring. The condition was effectively managed following treatment with a combination of trimetazidine and salbutamol. We conducted a literature review of 27 published cases of proteasome inhibitor-induced cardiac toxicity. In the 27 published cases, 12 cases were caused by carfilzomib (44.4%). To our knowledge, this is the first reported case of carfilzomib-associated sinus bradycardia, expanding the spectrum of proteasome inhibitors-related cardiotoxicity. This provides inspiration for suspected patients to stop using carfilzomib early and symptomatic treatment can effectively reduce mortality and improve prognosis.

Introduction

Multiple myeloma (MM) is a malignant plasma cell disease characterized by abnormal proliferation of bone marrow plasma cells with excessive production of monoclonal immunoglobulin or light chain M protein, which seriously affect the quality of life of patients. ¹ In the current study, the application of proteasome inhibitors (PIs) and immunomodulators can effectively improve the survival outcome of MM patients.^2,3 Carfilzomib, a new type of PI, is composed of a tetrapeptide epoxy ketone structure. ⁴ In 2012, it was approved by the U.S. Food and Drug Administration for patients with relapsed or refractory MM, and then a variety of carfilzomib combination regimens were successively approved.^5,6 In 2021, carfilzomib was approved for sale in China, providing a new treatment for MM patients in China. ⁷ Common causes of dose adjustment or treatment interruption of carfilzomib include neutropenia, hypertension, coronary heart disease, and renal insufficiency.^8–10 We reported the clinical diagnosis and treatment process of a case of bradycardia caused by carfilzomib in a patient with MM, and summarized the relevant literature, aiming to attract the attention of clinicians to strengthen the monitoring of relevant indicators.

Case presentation

This was a case of a 55-year-old female with MM (158 cm, 59.5 kg, body surface area: 1.63 m²). In August 2024, the patient presented with intermittent pain in the right upper arm, which had aggravated for more than half a month, and resulted in a limitation of mobility. The examination conducted at the local hospital showed a lesion in the right humerus. To obtain further diagnosis and treatment, the patient came to our hospital on September 13. The patient self-reported no history of hypertension, heart disease, or familial genetic disorders. Given the limited efficacy of conservative treatment, surgical intervention was considered (high-sensitivity troponin: 0.003 μg/L; B-type natriuretic peptide precursor (proBNP): 48.2 ng/L). On September 18, a partial osteotomy of the right humerus was performed. Intraoperative frozen section diagnosis showed malignant round cell tumors Postoperative pathological and blood bone marrow cell morphological examination results were consistent with plasma cell myeloma (IgA type; Durie-Salmon, stage ⅢA; International Staging System, stage Ⅱ). The patient was subsequently admitted for chemotherapy. The timeline of this case was summarized in Figure 1.

Figure 1.

Treatment and outcome timeline of this case report.

The patient was treated with VLD regimen (bortezomib (2 mg i.h. d1, d4), doxorubicin liposome (20 mg i.v. d2, d3) and dexamethasone (20 mg i.v. d1)) since September 20. After the end of the second cycle, the patient developed significant enlargement of the local mass along with tenderness (normal electrocardiogram (ECG); proBNP: 67 ng/L). Subsequently, the chemotherapy regimen was changed to KT-DECP (carfilzomib 30 mg i.v. d1, d2, 43 mg i.v. d8, d9, d15, d16; thalidomide 100 mg p.o. qn; dexamethasone, 20 mg i.v. d1, d2, d3, d4; etoposide, 60 mg i.v. d3, d4, d5, d6; cyclophosphamide, 600 mg i.v. d3, d4, d5, d6; cisplatin, 16 mg i.v. d3, d4, d5, d6). Subsequently, the patient was discharged after the symptoms of the right upper arm swelling and tenderness were relieved. On January 10, 2025, the patient was admitted to further treatment, and the admission examination showed a slow heart rate. As no additional adverse reactions were observed, KT-DECP treatment was continued. On January 14, the patient developed palpitation, breathlessness and chest tightness after chemotherapy (heart rate: 38–45 bpm; high-sensitivity troponin: 0.003 μg/L; proBNP: 762 ng/L, RR interval: 1.91 s). The RR interval refers to the time interval between two consecutive R waves on ECG, which reflects the duration of one cardiac cycle corresponding to ventricular electrical depolarization and repolarization. Both the ECG report and the long RR interval suggested that the patient suffered sinus bradycardia with arrhythmia (Figure 2). The 24H dynamic ECG results revealed that the lowest heart rate was 33 bpm, while the highest was 112 bpm, both of which were consistent with sinus rhythm. Occasional atrial premature beats and ventricular premature beats were observed. Additionally, a downward displacement of the ST segment was noted, but no conduction abnormalities were detected. Fortunately, the results of echocardiography were normal, and the biplane ejection fraction was more than 50%, indicating that the cardiac structure was unaffected.

Figure 2.

Twelve-lead electrocardiogram before (a) and after (b) chemotherapy with carfilzomib; 12-lead electrocardiogram after discontinuation of carfilzomib and symptomatic treatment (c).

After evaluation by clinical pharmacists and doctors, sinus bradycardia caused by carfilzomib was considered. Other causes such as hypothyroidism, electrolyte imbalance, and conduction system disease were considered but ruled out based on the results of the examination. Consequently, carfilzomib was discontinued, and trimetazidine hydrochloride tablets (20 mg p.o. tid) and salbutamol sulfate sustained-release capsules (8 mg p.o. bid) were given for symptomatic treatment. And then the indicators returned to normal levels (normal ECG; proBNP: <20 ng/L) and the patient was discharged. On February 10, the patient was re-admitted to the hospital, and the regimen was changed to DaraV (Daratumumab, bortezomib)-DECP. There was no cardiac discomfort that occurred again. Therefore, the diagnosis of sinus bradycardia induced by carfilzomib was established. Up to October 2025, ECG results of the patient demonstrated normal findings. Follow up at 1- and 3-months post-discontinuation showed sustained normal heart rate and no recurrence of bradycardia.

Discussion and review of literature

In this article, we introduce a case of sinus bradycardia that occurred in a patient during carfilzomib therapy for MM. Cardiac toxicity is a common adverse reaction in the treatment of carfilzomib, and among the PIs used in clinical practice, carfilzomib has the strongest correlation with cardiac toxicity. In a 55-year-old female patient, several potential causes of sinus bradycardia were considered. First, the patient had no history of cardiovascular disease, and echocardiography revealed no abnormalities, suggesting that the bradycardia was not secondary to cardiac insufficiency. Second, thyroid function was assessed after the patient presented with symptoms such as chest tightness. The measured thyroid-stimulating hormone level was 0.64 mIU/L, which excluded hypothyroidism as a cause of the sinus bradycardia. Third, hyperkalemia was also considered as a potential etiology. Repeated serum potassium measurements during treatment consistently showed values below 5.5 mmol/L, ruling out hyperkalemia as a contributing factor.

Additionally, the potential relationship between the carfilzomib and adverse reactions was evaluated using multiple assessment methods. According to the evaluation method for the association of adverse drug reactions by the National Adverse Drug Reaction Monitoring Center: (1) The patient in this case had no history of bradycardia or other related symptoms but developed sinus bradycardia with arrhythmia following the application of carfilzomib. Therefore, there is a reasonable time relationship between the use of carfilzomib and the occurrence of cardiac toxicity (+); (2) According to the clinical application guidelines for the treatment of MM with carfilzomib, ¹¹ cardiac toxicity meets the known adverse reaction types of carfilzomib (+); (3) After discontinuing the carfilzomib, the results of ECG returned to normal (+); (4) After the first use of carfilzomib, ECG monitoring prompts heart rate to slow down. The patient experienced palpitations and chest tightness when administered again. The ECG report showed sinus bradycardia with arrhythmia, meeting the same adverse reaction event occurred (+); (5) Thalidomide, discontinued at the same time, may also cause cardiac toxicity. Although there are few reports on this, it cannot be entirely ruled out (±). However, the temporal relationship with carfilzomib administration and resolution upon its discontinuation strongly supports carfilzomib as the primary cause. The clinical pharmacist evaluated the association between carfilzomib and sinus bradycardia as “highly probable.” In addition, we also evaluated the relationship between carfilzomib and sinus bradycardia by the Naranjo adverse drug reaction probability scale. The results showed that the relationship between carfilzomib and bradycardia was “most likely” (score of 7). ¹² The details were shown in Table 1.

Table 1.

The Naranjo score results for carfilzomib-induced bradycardia.

Relativity problem	Yes	No	Not known or not done	Score
1. Are there previous conclusive reports on this reaction?	√			1
2. Did an adverse event appear after the suspected drug was given?	√			2
3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given?	√			1
4. Did the adverse reaction appear when the drug was readministered?	√			2
5. Are there alternative causes that could have caused the reaction?			√	0
6. Did the reaction reappear when a placebo was given?			√	0
7. Was the drug detected in any body fluid in toxic concentrations?			√	0
8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased			√	0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?		√		0
10. Was the adverse event confirmed by any objective evidence?	√			1

After reviewing literatures and guidelines, clinical pharmacists further confirmed that the adverse reaction is closely related to carfilzomib. The reasons are as follows: the 2022 ESC (European Society of Cardiology) Oncology Cardiology Guidelines ¹³ states that when patients apply PIs, the risk of serious cardiovascular adverse events increases. Therefore, strict cardiovascular risk assessment, early prevention, and proper monitoring and management are necessary before using carfilzomib treatment. We recommend continuous ECG monitoring during the first few cycles of carfilzomib therapy, especially in patients with pre-existing cardiac risk factors. In addition, the global phase III clinical trial ENDEAVOUR study also reported efficacy and safety data of carfilzomib. ¹⁴ The results showed that compared with the bortezomib + dexamethasone regimen, the incidence of heart failure was significantly increased with the carfilzomib + dexamethasone regimen (4.8% vs 1.1%).

PIs, including bortezomib, carfilzomib, and ixazomib, are the main therapeutic drugs for MM. In recent years, a variety of cardiac adverse reactions during treatment induced by PIs have been of concern. We investigated previously reported cases of cardiotoxicity associated with PIs, with a total of 23 publications compassing 26 cases (Table 2).^15–37 The patients we studied are predominantly over 50 years old, with a significant proportion having a history of cardiovascular diseases such as hypertension. We hypothesize that elderly individuals with underlying diseases have weakened cardiac function, thereby increasing the likelihood of experiencing adverse cardiac reactions following the administration of PIs. And in 26 patients, there were 15 cases of heart failure, 4 cases of ventricular dysfunction, and one case each of myocarditis, pericardial effusion, angina, myocardial scar, hypertension, myocardial infarction, and Brugada syndrome. The majority of patients developed symptoms after four to five cycles of treatment. The time to symptom onset ranged from as early as 1 day to as long as nine cycles among the enrolled patients. At present, there is no case of sinus bradycardia with arrhythmia caused by carfilzomib similar to that reported in this paper. Studies have shown that carfilzomib cardiotoxicity may involve direct myocardial injury, autonomic dysfunction, or ischemic effects. The mechanism of bradycardia remains unclear but may relate to impaired conduction or autonomic modulation. ³⁸ In addition, only four patients chose to continue the original PIs treatment after symptom relief. It is also worth noting that three patients died because of the rapid progression of the cancer after drug withdrawal. In the early detection of abnormal heart rate, electrocardiography, echocardiography, cardiac magnetic resonance imaging, and monitoring of certain biochemical markers (such as troponin, myocardial enzymes, and proBNP) remain the primary tools utilized by most researchers. These methods hold significant value for guiding the management of subsequent clinicians. Long-term follow-up and monitoring are necessary, since abnormal ECG caused by chemotherapy drugs can increase the risk of cardiovascular disease in patients. ³⁹ These cases remind us to strengthen the monitoring of PIs administration, which is critical for ensuring patient medication safety and should be highly prioritized by clinical physicians.

Table 2.

Summary of previous studies reporting cardiotoxicity caused by PIs.

Study	Gender/age	PIs	Latent period	Type of cardiotoxicity	Past history of cardiovascular disease	Sympotoms	Treatment and prognosis	The effect on PIs
Bockorny et al. 15	Female/56	Bortezomib	4 times, 12 weeks	Pericardial effusion and mitral regurgitation	Hypertension	Exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea	Angiotensin II receptor antagonist and β-blockers; symptomatic improvement	Discontinued
Médrrez-Toro and colleagues 16	Female/60	Carfilzomib	30 times, 140 days	Congestive severe heart failure	Chronic anemia	Paroxysmal nocturnal dyspnea and orthopnea	Enalapril 5 mg twice a day, carvedilol 25 mg twice a day, spironolactone 25 mg daily, and intravenous furosemide 10 mg four times a day; symptomatic improvement	Discontinued
Takamatsu et al. 17	Female/79	Bortezomib	5 days	Acute myocardial infarction	None	Left chest pain and an ECG showed an ST elevation in aVR and ST depression in I, II, aVF and V3–V6	Nitroglycerin, heparin, oxygen, metal stents, aspirin (100 mg/day) and clopidogrel (75 mg/day); symptomatic improvement	Discontinued
Gupta and colleagues 18	Female/70	Bortezomib	22 times, 157 days	Congestive cardiac failure	Myocardial infarction, hypertensive, inferior wall myocardial ischemia, left ventricular dysfunction	Severe backache	Diuretics, nitroglycerine drip, low molecular weight heparin; symptomatic improvement	Discontinued
Subedi and colleagues 19	Male/86	Bortezomib	22 days	Acute congestive heart failure	Myocardial infarction	Acute shortness of breath	Oxygen, diuretics, β-blocker, and angiotensin-converting enzyme inhibitor; symptomatic improvement	Discontinued
Serra et al. 20	Male/65	Carfilzomib	4 times, 50 days	Heart failure	Hypertension, dyslipidemia	Worsening dyspneaatrial, fibrillation with a high ventricular rate, left ventricular systolic dysfunction, right ventricular hypokinesia	Diuretic, β-blocker, angiotensin converting enzyme inhibitor, mineralocorticoid-receptor antagonist therapy; symptomatic improvement	Discontinued
Meseeha and colleagues 21	Female/66	Bortezomib	3 times	Acute left ventricular dysfunction	Hypertensive, left bundle branch block	Acute shortness of breath, palpitations	Symptomatic improvement	Discontinued
Feng et al. 22	Female/52	Bortezomib	14 days	Heart failure	None	Palpitation, dyspnea	Oxygen therapy, strong heart, diuresis, anti-infection, anti acid, hemostasis; symptomatic improvement	Discontinued
Feng et al. 22	Male/58	Bortezomib	6 days	Acute left heart failure, arrhythmia	None	Palpitation, dyspnea	Correct hypoxia, sedation, asthma, cardiac, diuretic; symptomatic improvement	Discontinued
Honton et al. 23	Male/58	Bortezomib	4 months	Asymptomatic heart failure	None	\	Symptomatic improvement	Reused
Takakuwa et al. 24	Female/74	Carfilzomib	2 days	Acute heart failure	None	Peripheral oxygen saturation reduced to 88%, ejection fraction reduced from 59% to 28%, radiography revealed pulmonary congestion with pleural effusions	Norepinephrine, dobutamine, furosemide, and human atrial natriuretic peptide; death	Discontinued
Diwadkar and colleagues 25	Male/66	Bortezomib	8 cycles	Complete heart block and evidence of myocardial scar	Hyperlipidemia	Myocardial thinning, small subendocardial perfusion defect in the midinferolateral segment with focal late gadolinium enhancement	Implanted a permanent dualchamber pacemaker.	Discontinued
Jakubowiak and colleagues 26	Female/68	Carfilzomib	30 days	Acute congestive cardiac failure with fluid overload	Hypertension	Orthopnea, demonstrated hypoxemia	Lasix, enalapril, carvedilol; symptomatic improvement	Discontinued
Jakubowiak and colleagues 26	Male/70	Carfilzomib	12 days	Hypertension	Hypertension	Nausea, vomiting, dizziness	Injection of normal saline and furosemide; symptomatic improvement	Reused
Chakraborty and colleagues 27	Female/58	Bortezomib	112 days	Left ventricular dysfunction	Hypertension	Generalized weakness, nausea and vomiting	Lisinopril, carvedilol, isosorbide dinitrate; symptomatic improvement	Discontinued
McGregor and colleagues 28	Male/71	Carfilzomib	2 months	Right ventricular dysfunction	Hypertension	Acute dyspnea	Symptomatic improvement	Discontinued
Pandey et al. 29	Male/49	Bortezomib	5 times, 137 days	Heart failure with reduced ejection fraction	None	ECG showed severely decreased left ventricular systolic function	Symptomatic improvement	Discontinued
Azad et al. 30	Female/63	Carfilzomib	4 days	Biventricular heart failure	None	Tachypneic	Bilevel-positive air pressure, furosemide 20 mg intravenous injections; symptomatic improvement	Discontinued
Alali and Baljevic 31	Female/40	Bortezomib	5 times, 22 days	Perimyocarditis	None	Ventricular tachycardia, syncope	Spironolactone, captopril, intravenous furosemide, sotalol; symptomatic improvement	Discontinued
Ghisoni et al. 32	Female/65	Carfilzomib	20 days	Brugada syndrome	Hypertension	ST-segment elevation in V1–V2 and a QTc interval of 498 ms	symptomatic improvement	Reused
Voortman and Giaccone 33	Male/53	Bortezomib	84 days	Heart failure	None	Fatigue, orthopnea, dyspnea	symptomatic improvement	Discontinued
Ikoma et al. 34	Male/76	Carfilzomib	3 months	Congestive heart failure	Hypertension	Dyspnea, orthopnea	Diuretics; symptomatic improvement	Discontinued
Ikoma et al. 34	Female/75	Carfilzomib	5 months	Heart failure	None	Dyspnea on exertion, exacerbated lower limb edema, coarse crackles in the bilateral chest	Diuretics; the cardiac function was not restored	Discontinued
Toro and colleagues 35	Female/60	Carfilzomib	105 days	Congestive heart failure	Chronic anemia	Paroxysmal nocturnal dyspnea, orthopnea	Enalapril 5 mg bid, carvedilol 25 mg bid, spironolactone 25 mg, intravenous furosemide 10 mg qid; symptomatic improvement	Discontinued
Uruno et al. 36	Female/59	Carfilzomib	1 month	Cardiac dysfunction	None	Palpitations, fatigue, exertional dyspnea, facial edema	Phosphodiesterase-5 inhibitor, endothelin receptor antagonist, prostaglandin derivatives; symptomatic improvement	Discontinued
Yasui et al. 37	Male/70	Bortezomib	90 days	Coronary spastic angina	None	Chest pain	Benidipine (4 mg, bid); symptomatic improvement	Reused

PIs: proteasome inhibitor; ECG: electrocardiogram; ST: plateau phase of the ventricular myocyte action potential; aVR: augmented Vector Right; aVF: augmented Vector Foot; QTc: corrected QT interval.

Conclusion

This article focuses on the pharmacovigilance of cardiac toxicity in patients with MM who are treated with carfilzomib. Clinical pharmacists play an essential role in evaluating heart rate and ECG findings, enabling timely discontinuation of carfilzomib to prevent severe consequences such as heart failure. Pharmacists are deeply involved in both treatment and monitoring, summarizing effective strategies for patient care, including: (1) Comprehensive assessments of the cardiac health status of the patient, particularly left ventricular function and electrophysiological parameters, should be conducted prior to initiating treatment to facilitate personalized treatment planning. (2) Closely monitoring cardiac function indicators (ECG, echocardiography, blood pressure, heart rate, troponin I, high-sensitivity troponin I, B-type natriuretic peptide, proBNP) during treatment to detect early changes in cardiac function, adjust medication regimens promptly, and minimize harm caused by cardiotoxic reactions. (3) Managing severe respiratory distress, hypertension, or heart failure appropriately, reducing or discontinuing medication as required, and continuing cardiovascular risk assessment for 12 months post-treatment with carfilzomib.