Факторы риска, связанные с карфилзомибными вредными сердечно-сосудистыми явлениями у китайских пациентов с множественной миеломой: ретроспективное когортное исследование в реальном мире.

Introduction

Multiple myeloma (MM) is a malignant hematological disorder characterized by the clonal proliferation of plasma cells in the bone marrow, leading to a spectrum of clinical manifestations, including anemia, bone lesions, renal dysfunction, hypercalcemia, and increased susceptibility to infections. 1 , 2 Globally, MM is the second most common hematological malignancy in high-income countries, with its incidence continuing to rise. 3 In the United States alone, recent estimates indicate that more than 35,000 new cases are diagnosed annually, and the disease accounts for more than 12,000 deaths each year. The chronic, relapsing, and refractory nature of MM imposes a substantial burden on patients’ quality of life and healthcare systems, with direct and indirect costs amounting to several billion dollars worldwide each year. 1 Disease management is further complicated by the heterogeneity of clinical presentations and the frequent development of treatment resistance. 2

Over the past two decades, advances in therapeutic strategies for MM have markedly improved patient outcomes, largely through the introduction of novel agents, including proteasome inhibitors, immunomodulatory drugs (IMiDs), monoclonal antibodies, and autologous stem cell transplantation. 3 , 4 Despite these advances, MM remains incurable for most patients, who eventually experience disease relapse and require multiple lines of therapy. 2 Among the next-generation proteasome inhibitors, carfilzomib provides more potent inhibition of the proteasome's chymotrypsin-like activity than bortezomib. 5 Consequently, it is widely used in patients with newly diagnosed or bortezomib-refractory MM because of its superior clinical efficacy. Based on the phase III trial (CTR20160857), carfilzomib was approved for the treatment of relapsed and refractory MM and has demonstrated significant improvements in overall survival and progression-free survival. 6 , 7 However, its increasing clinical use has been accompanied by growing concerns regarding its safety profile, particularly its potential to induce cardiovascular toxicity. 8 The risk of cardiovascular toxicity appears to be higher with carfilzomib than with other proteasome inhibitors, such as bortezomib and ixazomib, making carfilzomib the proteasome inhibitor with the greatest cardiotoxic potential. 9 The reported incidence of cardiotoxicity varies across studies, with meta-analyses estimating all-grade and high-grade event rates of approximately 8.9% and 4.4%, respectively. Carfilzomib-related cardiovascular adverse events (CVAEs) include hypertension, heart failure, arrhythmias, ischemic heart disease, pulmonary hypertension, and thrombotic microangiopathy. 10 These complications not only increase patient morbidity and reduce quality of life but may also necessitate dose modification or treatment discontinuation, thereby compromising overall therapeutic outcomes.

Although the association between carfilzomib and clinically significant CVAEs is well established, the factors that predispose certain patients to cardiotoxicity remain unclear. A recent retrospective analysis involving racially diverse populations identified hypertension and smoking as significant risk factors for CVAEs during carfilzomib therapy. 11 However, Chinese patients were not included in that study. Carfilzomib was approved for clinical use in China only in 2022, resulting in limited real-world clinical experience. Consequently, evidence regarding the risk factors for carfilzomib-induced CVAEs in the Chinese population remains scarce. Therefore, we conducted a retrospective study to determine the incidence of CVAEs and identify potential risk factors among Chinese patients with MM receiving carfilzomib therapy.

Materials and methods

Study design and population

This real-world, single-center retrospective cohort study was conducted to identify risk factors for CVAEs in patients with MM treated with carfilzomib at Tianjin First Central Hospital, China, between August 2022 and April 2026. Eligible patients met the following inclusion criteria: (a) aged ≥18 years; (b) diagnosed with MM; (c) received at least one dose of carfilzomib; and (d) underwent cardiac function evaluations both before and during carfilzomib therapy. Patients were excluded if they (a) were aged <18 years; (b) lacked cardiac function assessment data; (c) had a diagnosis of light-chain cardiac amyloidosis; (d) had unstable cardiovascular disease (e.g. symptomatic arrhythmia requiring treatment or New York Heart Association Functional Class III or higher heart failure) or developed a new cardiovascular disorder within 3 months before initiating carfilzomib therapy; (e) participated in a clinical trial; or (f) had incomplete or missing clinical data. All eligible patients who received carfilzomib during the study period were consecutively enrolled according to predefined inclusion and exclusion criteria. The final sample size was determined by the number of eligible patients identified during the study period. This study was reviewed and approved by the Ethics Committee of Tianjin First Central Hospital (Approval Number: 20240422-1), which granted a waiver of written informed consent. All study procedures were conducted in accordance with the principles of the Declaration of Helsinki of 1975, as revised in 2024. All patient data were fully deidentified before analysis to protect participant confidentiality. This study is reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. 12

Data collection

Patient data were independently extracted from medical records using a standardized data collection form. The following variables were collected:

Demographic characteristics. Sex, age, body weight, and smoking status (current/former smoker or never smoker);

Comorbidities. Diabetes mellitus, hypertension, cardiovascular disease, hyperlipidemia, chronic kidney disease, pulmonary hypertension, and venous thromboembolism (VTE);

MM characteristics. Subtype (immunoglobulin (Ig) G (IgG), IgA, IgD, light chain, and non-secretory) and disease status (newly diagnosed or relapsed/refractory);

Treatment history. History of autologous hematopoietic stem cell transplantation (auto-HSCT) (prior auto-HSCT and auto-HSCT-naïve) and prior exposure to anthracyclines, cyclophosphamide/melphalan (CTX/MEL), IMiDs, daratumumab, dexamethasone, and bortezomib/ixazomib;

Carfilzomib treatment regimen. Carfilzomib plus dexamethasone (Kd); carfilzomib, daratumumab, and dexamethasone (DKd); carfilzomib, daratumumab, lenalidomide/pomalidomide, and dexamethasone (DKRd/DKPd); carfilzomib, lenalidomide/pomalidomide, and dexamethasone (KRd/KPd); carfilzomib, anthracycline, and dexamethasone (KAd); carfilzomib, daratumumab, anthracycline, and dexamethasone (DKAd); carfilzomib, cyclophosphamide, and dexamethasone (KCd); carfilzomib, anthracycline, cyclophosphamide, and dexamethasone (KCAd); and carfilzomib, pomalidomide, cyclophosphamide, and dexamethasone (KPCd);

Treatment characteristics. Maximum carfilzomib dose (20–27 or 56 mg/m 2 ) and duration of carfilzomib therapy;

Baseline laboratory and cardiac assessments. Albumin (ALB), hemoglobin (HBG), lactate dehydrogenase (LDH), serum creatinine (SCr), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and left ventricular ejection fraction (LVEF).

CVAEs

All patients with MM during and after carfilzomib treatment were evaluated using the Naranjo score, 13 which is a method for estimating the probability of adverse drug reactions. The relevance evaluation of the criteria was as follows: definite, ≥9 points; probable, 5–8 points; possible, 1–4 points; doubtful, ≤0 points. In this study, only events with a Naranjo score of 5 or higher were considered carfilzomib-related CVAEs.

CVAEs were defined as the occurrence of one or more of the following conditions after the administration of at least one dose of carfilzomib: severe hypertension, arrhythmia, heart failure, myocardial infarction, VTE, or angina. CVAEs were confirmed using objective clinical evidence, including cardiac biomarkers, electrocardiography, medication records, and documented clinical assessments by healthcare providers. Severe hypertension was defined as a systolic blood pressure of ≥160 mmHg or a diastolic blood pressure of ≥100 mmHg recorded on two consecutive measurements or the initiation of new antihypertensive therapy. This definition corresponds to grade 3 or higher hypertension according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), 14 thereby excluding grade 1 and grade 2 hypertension. Arrhythmia was diagnosed by a clinician based on electrocardiographic findings. Heart failure was diagnosed when at least two of the following were present: symptoms consistent with heart failure, abnormal physical examination findings, and abnormal laboratory results. New-onset VTE was confirmed by a clinician based on imaging findings documented in the medical records. Angina was diagnosed by the treating physician on the basis of newly developed symptoms considered to be related to carfilzomib therapy. All CVAEs were identified and confirmed through comprehensive review of the electronic medical records without independent blinded event adjudication.

We used a composite CVAE endpoint comprising severe hypertension, arrhythmia, heart failure, VTE, myocardial infarction, and angina, consistent with the landmark PROTECT prospective cardio-oncology cohort study. 15 The PROTECT study adopted a similar composite outcome to characterize proteasome inhibitor-associated cardiotoxicity. Although these cardiovascular events differ in their underlying pathophysiology and clinical presentation, they all represent clinically important cardiovascular complications that have been associated with carfilzomib therapy. Owing to the limited sample size and the low expected frequency of individual cardiovascular events in this single-center retrospective cohort, separate analyses of each event subtype would have been underpowered. Therefore, combining these clinically relevant cardiovascular events increased the number of outcome events available for multivariable analysis and improved the statistical stability of the regression models used to identify risk factors for carfilzomib-related CVAEs. Furthermore, the use of a standardized composite endpoint facilitates comparisons with previous cardio-oncology studies.

Statistical analysis

Continuous variables were presented as medians (range), and categorical variables were presented as frequencies and percentages. Categorical variables were compared using the chi-squared test or Fisher's exact test, as appropriate. Continuous variables were compared using the Mann–Whitney U test or the Kruskal–Wallis test, as appropriate. To identify potential predictors of CVAEs associated with carfilzomib therapy, univariable and multivariable logistic regression analyses were performed. The results are reported as odds ratios (ORs) with 95% confidence intervals (CIs). All statistical tests were two-sided, and a P -value <0.05 was considered statistically significant. Variables with a P -value <0.20 in the univariable analysis were included in the multivariable logistic regression model. All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) software, version 23.0.

Results

Patient characteristics

A total of 96 patients with MM who received carfilzomib at Tianjin First Central Hospital between August 2022 and April 2026 were screened for eligibility. After applying the predefined inclusion and exclusion criteria, 74 patients were included in the final analysis, whereas 22 were excluded. The reasons for exclusion were incomplete clinical or cardiac function data (n = 12), unstable baseline cardiovascular disease (n = 5), and concomitant light-chain cardiac amyloidosis (n = 5). The median follow-up duration was 10 months (range, 1–42 months). The baseline demographic and clinical characteristics of the study population are summarized in Table 1 . The median age was 64 years (range, 29–84 years), and the median body mass index (BMI) was 24.2 kg/m 2 (range, 16.6–34.3 kg/m 2 ). Of the 74 patients, 38 (51%) were male. The most common comorbidities were hypertension (50%), cardiovascular disease (30%), chronic kidney disease (24%), pulmonary hypertension (20%), VTE (20%), diabetes mellitus (18%), and hyperlipidemia (14%). Additionally, 18% of patients had a history of smoking, and 15% had previously undergone auto-HSCT. The most common MM subtype was IgG (44%), followed by IgA (27%), light chain (23%), IgD (3%), and non-secretory disease (3%). Previous treatments included anthracyclines (15%), CTX/MEL (45%), IMiDs (64%), daratumumab (55%), dexamethasone (96%), bortezomib (93%), and ixazomib (26%). Most patients (86%) had relapsed or refractory MM. The most frequently administered carfilzomib-based regimen was Kd (22 patients, 30%), followed by DKd (15, 20%), KPd/KRd (13, 18%), DKPd/DKRd (9, 12%), and KCd (8, 11%). Less frequently used regimens included DKCd (3%), KAd (3%), DKAd (1%), KCAd (1%), and KPCd (1%). Overall, 46 of the 74 patients (62%) received a maximum carfilzomib dose of 27 mg/m 2 administered twice weekly. The remaining 28 patients (38%) received a maximum carfilzomib dose of 56 mg/m 2 administered once weekly. As of 1 April 2026, 63 of the 74 patients had discontinued carfilzomib-based therapy for the following reasons: transition to maintenance therapy (n = 18, 28%), disease progression (n = 16, 25%), auto-HSCT (n = 13, 21%), other reasons (n = 8, 13%), and CVAEs (n = 8, 13%). The median duration of carfilzomib therapy was 114 days (range, 2–1303 days). Baseline echocardiography showed that 96% of patients had an LVEF of ≥50%. In addition, elevated baseline NT-proBNP levels were observed in 31 patients (42%) ( Figure 1 ).

Carfilzomib-related CVAEs

Among the 74 patients who received carfilzomib-based therapy, 36 (48.6%) developed CVAEs. Severe hypertension was the most common cardiovascular complication, occurring in 50% of patients with CVAEs, followed by arrhythmia (47%). Other CVAEs included heart failure (22%), VTE (14%), myocardial infarction (3%), and angina (3%). The median time from treatment initiation to the first CVAE was 56 days (range, 4–559 days), with 67% (24/36) occurring within the first 3 months of therapy. Heart failure had the earliest median onset, occurring 24 days after treatment initiation (range, 4–241 days). The median onset times for severe hypertension, arrhythmia, VTE, myocardial infarction, and angina were 83, 87, 83, 493, and 45 days, respectively. The clinical characteristics of patients with carfilzomib-related CVAEs are summarized in Table 2 .

Potential factors associated with carfilzomib-related CVAEs

Four variables with univariable P <0.20 were included in the multivariable logistic regression model: elevated baseline NT-proBNP levels, diabetes mellitus, daratumumab-containing regimens, and cytotoxic agent-containing regimens. Univariable analysis showed that elevated baseline NT-proBNP levels ( P = 0.002) and daratumumab-containing regimens ( P = 0.021) were significantly associated with carfilzomib-related CVAEs, whereas cytotoxic agent-containing regimens showed a borderline association ( P = 0.065). Although diabetes mellitus was not significantly associated with CVAEs in the univariable analysis ( P = 0.164), it was retained in the multivariable model because of its established role as a cardiovascular risk factor. As shown in Table 3 , multivariable logistic regression identified elevated baseline NT-proBNP levels as an independent predictor of CVAEs ( P = 0.002). In addition, Kaplan–Meier analysis was performed to compare CVAE-free survival according to baseline NT-proBNP status, and differences in time to the first CVAE were evaluated using the log-rank test. The median CVAE-free survival was significantly shorter in patients with elevated NT-proBNP levels than in those with normal NT-proBNP levels (1.80 months, 95% CI: 0.78–2.82 months vs 14.30 months, 95% CI: 3.55–25.06 months). The log-rank test demonstrated a significant difference in CVAE-free survival between the two groups ( P = 0.001). The corresponding Kaplan–Meier curves are shown in Figure 2 .

Discussion

In this real-world retrospective cohort study, CVAEs occurred in 48.6% (36/74) of patients who received carfilzomib-based therapy for MM. This incidence was substantially higher than the 8.9% and 18.1% reported in two meta-analyses of randomized controlled trials (RCTs). 10 , 17 However, our findings were consistent with those of the prospective PROTECT observational study, 15 in which CVAEs occurred in 51% of 65 patients treated with carfilzomib. The PROTECT cohort included 55 White and 10 Black participants. Similar rates of cardiovascular complications have also been reported in pharmacovigilance studies. The higher incidence observed in our study compared with RCTs may reflect differences in study populations and clinical practice. Real-world patients often have a greater burden of comorbidities, more advanced disease, and greater clinical heterogeneity than participants enrolled in clinical trials, all of which may contribute to an increased risk of CVAEs. 18 , 19 Three factors may explain the higher incidence of CVAEs observed in our real-world cohort compared with that reported in RCTs: differences in patient selection, cardiovascular event surveillance, and routine clinical practice. First, RCTs typically employ stringent eligibility criteria, often excluding patients with pre-existing cardiac dysfunction, multiple cardiovascular comorbidities, elevated baseline cardiac biomarkers, or unstable cardiovascular disease. These patients are generally considered to be at higher risk of treatment-related cardiotoxicity. In contrast, our consecutively enrolled real-world cohort and the PROTECT study included a broader spectrum of patients, thereby reflecting routine clinical practice more closely. This difference in patient selection may have contributed to the higher incidence of CVAEs observed in our study. Second, cardiovascular safety monitoring differs between clinical trials and routine practice. RCTs generally follow predefined cardiac monitoring schedules, which may not capture transient or mild cardiovascular events occurring between scheduled assessments. In contrast, we identified CVAEs through comprehensive review of electronic medical records covering the entire treatment period. This approach may have facilitated the identification of mild-to-moderate cardiovascular events that might not have been captured during scheduled trial assessments. Third, treatment practices differ between clinical trials and routine care. Clinical trials generally employ standardized treatment protocols, fluid management strategies, and supportive care, whereas real-world practice often involves individualized treatment combinations and dose adjustments based on patients’ clinical conditions. Six categories of CVAEs were identified in our cohort: severe hypertension, arrhythmia, heart failure, VTE, myocardial infarction, and angina. Severe hypertension was the most common cardiovascular adverse event, accounting for 50% of all CVAEs, which is consistent with previous reports. 8 , 20 The median time to onset of severe hypertension was 83 days (range, 7–428 days) after treatment initiation, indicating that hypertension may develop during either the early or later stages of carfilzomib therapy. Early-onset hypertension has been proposed to result from acute vascular effects of carfilzomib, including endothelial dysfunction and increased peripheral vascular resistance, whereas late-onset hypertension may reflect cumulative cardiovascular stress and vascular remodeling associated with sustained blood pressure elevation. Hypertension is a well-recognized CVAE associated with carfilzomib therapy. 18 , 21 Accordingly, blood pressure should be monitored throughout treatment to facilitate early detection and appropriate management of hypertension. Previous studies have suggested that proteasome inhibition may induce oxidative stress and endothelial injury, thereby promoting vasoconstriction and arterial stiffening. 22 Early initiation of antihypertensive therapy, when clinically indicated, has also been recommended to reduce the risk of subsequent cardiovascular complications. 23 , 24

Cardiac arrhythmias accounted for 47% of all CVAEs in this study. The median time to onset was 87 days (range, 15–581 days) after treatment initiation, indicating that arrhythmias may occur throughout the course of carfilzomib therapy. Previous studies have suggested that carfilzomib may contribute to arrhythmogenesis through direct cardiomyocyte injury, disrupted calcium homeostasis, and mitochondrial dysfunction. 25 Our results support the importance of baseline cardiovascular assessment and ongoing cardiac monitoring during carfilzomib therapy, particularly in patients considered to be at increased cardiovascular risk. Heart failure accounted for 22% of all CVAEs in our cohort and had the earliest median onset (24 days; range, 4–241 days), suggesting that cardiac dysfunction may develop soon after treatment initiation. Experimental studies have shown that carfilzomib can induce cardiomyocyte injury through mechanisms including mitochondrial dysfunction, impaired adenosine triphosphate (ATP) production, and reduced myocardial contractility, findings that have been demonstrated in human induced pluripotent stem cell-derived cardiomyocyte models. 26 Prompt recognition and appropriate management of heart failure symptoms remain important to reduce morbidity and optimize clinical outcomes. 21 , 27

VTE accounted for 14% of all CVAEs in this cohort. The median time to onset was 83 days (range, 27–559 days), similar to that observed for severe hypertension. Myocardial infarction and angina were uncommon, with one case of each event (3% of all CVAEs). The myocardial infarction occurred 493 days after treatment initiation, whereas angina developed on day 45. Although VTE and myocardial ischemic events were infrequent, they are clinically important because of their potential severity. Overall, the distribution of cardiovascular event subtypes varied considerably. Severe hypertension and arrhythmia were the most common CVAEs and occurred throughout the treatment course, whereas heart failure tended to develop earlier after treatment initiation. Although VTE and myocardial ischemic events occurred less frequently, they remain clinically significant and require continued vigilance during routine cardiovascular monitoring.

Cardiac dysfunction is frequently subclinical in patients with MM, and many patients remain asymptomatic until the disease has progressed. Accordingly, the early identification of patients at increased risk of cardiotoxicity is important for optimizing treatment strategies and improving clinical outcomes. 20 , 28 In the present study, multivariable logistic regression analysis identified elevated baseline NT-proBNP levels as an independent predictor of CVAEs. This finding is consistent with the PROTECT study, 15 which likewise reported an association between elevated baseline natriuretic peptide levels and subsequent CVAEs. NT-proBNP is an inactive cleavage product of the precursor of BNP that is released predominantly by ventricular cardiomyocytes in response to increased myocardial wall stress and pressure overload. Its circulating concentration reflects myocardial stress and cardiac pressure burden, making it a sensitive biomarker of cardiac dysfunction. NT-proBNP is widely used in clinical practice for the diagnosis, risk stratification, and prognostic assessment of heart failure, coronary artery disease, and other cardiovascular disorders. 29 – 31 In patients with MM, elevated baseline NT-proBNP levels may reflect underlying structural or functional cardiac abnormalities that are not yet clinically apparent. Increased NT-proBNP concentrations have been associated with subclinical myocardial abnormalities, including myocardial fibrosis, diastolic dysfunction, and impaired myocardial strain. Such pre-existing cardiac changes may reduce cardiovascular reserve and increase susceptibility to cardiotoxicity during treatment with potentially cardiotoxic agents such as carfilzomib. Elevated NT-proBNP levels are also associated with increased ventricular wall stress, reduced ventricular compliance, and elevated filling pressures, findings that are consistent with diastolic dysfunction or early myocardial injury. Although these mechanisms were not directly evaluated in the present study, they provide biological plausibility for the observed association between elevated baseline NT-proBNP levels and CVAEs. Our findings support the potential value of baseline NT-proBNP as a biomarker for identifying patients at increased risk of carfilzomib-related cardiovascular toxicity. 31 – 33 Our findings support the assessment of NT-proBNP before initiating carfilzomib therapy as part of baseline cardiovascular risk evaluation. Patients with elevated baseline NT-proBNP levels may be at increased risk of CVAEs and may therefore benefit from closer cardiovascular monitoring during treatment. Blood pressure should be assessed at baseline and every follow-up visit. Home blood pressure monitoring is encouraged, with a target blood pressure below 130/80 mmHg. NT-proBNP should be tested at baseline and repeated in every cycle for the first six treatment cycles to detect subclinical myocardial injury. Clinicians should consider urgent NT-proBNP testing for patients with new-onset dyspnea, peripheral edema, palpitations, or unexplained fatigue. Baseline echocardiography screens for pre-existing arrhythmias and evaluates LVEF, with repeated echocardiograms required at all follow-ups. Routine echocardiographic surveillance is scheduled every three cycles during carfilzomib therapy. Urgent echocardiography is necessary when NT-proBNP continues to increase or new cardiac symptoms emerge. This monitoring protocol allows timely and flexible clinical interventions, including reduced intravenous fluid infusion, diuretic use, prolonged carfilzomib infusion time, and initiation or dose adjustment of cardiovascular medications, particularly antihypertensives. Patients presenting with multiple cardiovascular risk factors, particularly those with a history of CVAEs or elevated baseline NT-proBNP levels, may benefit from a comprehensive cardiovascular assessment before initiating carfilzomib therapy. Because these patients may be at increased risk of treatment-related cardiovascular complications, individualized cardiovascular management and closer monitoring may facilitate the safe continuation of anticancer therapyand reducing the risk or severity of CVAEs. 15

Furthermore, Doran et al. evaluated a racially diverse cohort comprising 86 Black and 75 White patients and reported that multiple baseline cardiovascular risk factors were associated with an increased risk of carfilzomib-related CVAEs. 11 Specifically, diabetes mellitus, hypertension, hyperlipidemia, smoking, and obesity were associated with a higher incidence and greater severity of CVAEs. We used the same definition of multiple cardiovascular risk factors but did not observe a significant association in our cohort. Notably, after adjustment for potential confounding factors in Doran et al.'s study, the association between multiple baseline cardiovascular risk factors and carfilzomib-related CVAEs was no longer statistically significant. Taken together, these findings suggest that the cumulative burden of cardiovascular risk factors may not independently predict carfilzomib-related cardiovascular toxicity, although further validation in larger cohorts is warranted. In addition, a small prospective cohort study suggested that daratumumab may exert cardioprotective effects when administered in combination with carfilzomib. The authors proposed that the two agents might exert opposing effects on cardiomyocyte oxidative stress and calcium homeostasis. 34 However, our single-center retrospective study was not designed or adequately powered to evaluate this potential drug interaction, and no definitive conclusions can therefore be drawn. Larger multicenter prospective studies are needed to clarify the cardiovascular effects of combined daratumumab and carfilzomib therapy and to determine whether daratumumab confers cardioprotective benefits in this setting.

The present study has several limitations. First, this was a single-center retrospective study conducted at a tertiary hospital in northern China, which may limit the generalizability of the findings. Variations in cardiovascular screening protocols, carfilzomib dosing strategies, patient comorbidity profiles, and referral patterns across institutions may have introduced selection and measurement bias that could not be fully addressed through statistical adjustment. Moreover, the study included only 74 patients, of whom 36 experienced CVAEs. The relatively small sample size and limited number of outcome events may have reduced the statistical power to detect modest associations and affected the stability of the multivariable logistic regression model. According to the commonly cited events-per-variable (EPV) guideline for logistic regression, approximately 10 outcome events per predictor variable are generally recommended. Because the final multivariable model included 4 candidate variables and 36 outcome events, the EPV was approximately 9, indicating a small risk of model overfitting. Although substantial overfitting is unlikely, some degree of model instability cannot be excluded. Second, cardiac troponin was not routinely measured at baseline or during follow-up in our real-world clinical practice. Consequently, troponin data were unavailable for all participants and could not be incorporated into the risk stratification analyses. Previous cardio-oncology studies have shown that combining baseline troponin and NT-proBNP measurements may improve the prediction of chemotherapy-related cardiotoxicity. Therefore, the absence of troponin data precluded the development of a dual-biomarker risk model incorporating both cardiac biomarkers. The lack of troponin measurements may have limited the accuracy of cardiovascular risk stratification in our cohort and reduced the predictive performance of the proposed risk model. In addition, the retrospective design resulted in incomplete longitudinal cardiac follow-up data, precluding analyses of long-term clinical outcomes associated with CVAEs, including overall survival and other time-to-event outcomes. To address these limitations and further evaluate the predictive value of elevated baseline NT-proBNP for CVAEs, future studies should consider establishing standardized multicenter prospective registries across China. Such registries could incorporate uniform diagnostic criteria for CVAEs, standardized baseline assessment of both cardiac troponin and NT-proBNP, and geographically diverse patient populations with adequate numbers of outcome events. Larger, multicenter datasets would facilitate more robust subgroup analyses, improve the stability of multivariable prediction models, reduce the influence of inter-institutional heterogeneity, and enhance the generalizability of the findings. Ultimately, these efforts may provide stronger evidence to support evidence-based cardiovascular surveillance strategies for Chinese patients with MM receiving carfilzomib therapy.

Conclusion

In this real-world clinical cohort, the incidence of carfilzomib-related CVAEs was higher than that reported in RCTs. Different CVAE subtypes exhibited distinct incidence rates and temporal patterns. Although many CVAEs occurred within the first 3 months of treatment, delayed events were also observed, highlighting the importance of continued cardiovascular surveillance throughout carfilzomib therapy. Elevated baseline NT-proBNP levels were independently associated with an increased risk of subsequent carfilzomib-related CVAEs in Chinese patients with MM. These findings suggest that baseline NT-proBNP may be a useful biomarker for cardiovascular risk stratification before treatment initiation. Patients with elevated baseline NT-proBNP levels may benefit from closer cardiovascular monitoring during carfilzomib therapy, although prospective multicenter studies are needed to validate these findings and establish optimal monitoring strategies.

Acknowledgments

None.

Footnotes

ORCID iD: Xiao-Chen Wei https://orcid.org/0000-0002-4536-2510

Ethics approval and consent to participate: The study was reviewed and approved by the Ethics Committee of Tianjin First Central Hospital (Approval No. 20240422-1).

Author contributions statement: Xiao-Chen Wei conceived, designed, and supervised the study. Hai-Rong Lyu and Xiao-Chen Wei performed data analysis and drafted the manuscript. Ying Xiao and Fan Chen collected the data. All authors reviewed and approved the final manuscript.

Funding: This study was supported by the Bethune Charitable Foundation (Grant No. Z04JKM2023E040).

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement: The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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