Кардиотоксичность, вызванная множественными миэломатерапиями: механистическая конвергенция между протеиновыми ингибиторами, CAR-T и биконкретными антителами.

Introduction

Multiple myeloma (MM) is a hematologic malignancy defined by clonal proliferation of plasma cells in the bone marrow, resulting in overproduction of monoclonal immunoglobulins and progressive organ dysfunction. MM represents about 10% of hematologic malignancies and is generally incurable, though advances in treatment strategies over the past two decades have dramatically improved patient outcomes. Standard-of-care regimens based on alkylators and corticosteroids have been augmented—and in many cases, replaced—by proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies. Cellular immunotherapeutic strategies, most notably chimeric antigen receptor T-cell (CAR-T) therapies and CD3-targeting bispecific antibodies (BsAbs), have more recently shown promise in relapsed/refractory settings, with targeted immune engagement enabling deep responses.

Although such modalities have expanded the therapeutic arsenal against MM, they are also associated with a spectrum of treatment-related toxicities, including cardiovascular adverse events (CVAEs), such as heart failure, arrhythmias, hypertension, and subclinical myocardial dysfunction. Carfilzomib, an irreversible PI, is the most cardiotoxic drug in its class, inducing mitochondrial injury, oxidative stress, unfolded protein response (UPR) activation, and endothelial injury. CAR-T and BsAbs, despite their mechanistic differences, can cause similar cardiac adverse events, often mediated through cytokine release syndrome (CRS) and immune-mediated endothelial stress—pathways that continue to be elucidated. IMiD-associated cardiovascular events are composed primarily of thromboembolic risk rather than direct myocardial injury, and their cardiovascular toxicity profile is milder and mechanistically distinct from that of proteasome inhibitors, CAR-T therapies, and bispecific antibodies. Therefore, IMiDs are not included as a major focus of this review given the mechanistic emphasis on cardiomyocyte stress, mitochondrial dysfunction, ER stress, and immune-mediated endothelial injury.

Patient-related factors influence the risk of cardiotoxicity, including older age, female gender, African American race, and underlying cardiovascular or renal disease. These clinical and demographic variations render universal monitoring protocols difficult and underscore the importance of surveillance strategies that consider individual risk. Several diagnostic modalities, including global longitudinal strain (GLS), ambulatory blood pressure monitoring, and novel omics-based biomarkers, have demonstrated early potential but have not been widely adopted for use in the cardio-oncology care of MM patients.

Despite growing awareness of these complications, there are no specific guidelines for MM therapy. Most current approaches have been extrapolated from previous experience with anthracyclines and immune checkpoint therapies, which may not reflect the unique toxicologic profiles of modern MM therapies. This review aims to synthesize the epidemiology, mechanistic underpinnings, and emerging mitigation strategies for therapy-associated cardiotoxicity in MM. This approach highlights the function of successful cardio-oncology practices that maintain treatment efficacy while reducing cardiovascular damage.

Epidemiology and clinical risk factors of cardiotoxicity in multiple myeloma

Among the newer generation of MM therapies, carfilzomib has been most strongly associated with cardiovascular risk among PIs. In a systematic review and meta-analysis of 24 studies encompassing 2594 patients with MM, all-grade CVAEs occurred in 18.1% of patients and grade 3 or greater events occurred in 8.2% of patients [ 1 ]. These results highlight the significant cardiovascular burden of carfilzomib, particularly in comparison with reversible PIs [ 1 – 4 ]. Several studies reported an approximately 41% higher risk of CVAEs in carfilzomib-treated patients (HR 1.41), and hypertension was seen in 13–20% of patients [ 1 , 5 – 7 ]. In head-to-head comparison trials, 51% of patients treated with carfilzomib had CVAEs versus 17% treated with bortezomib [ 8 – 11 ], and it has been speculated that irreversible PIs like carfilzomib cause more hemodynamic stress and oxidative injury than reversible PIs.

Cardiac adverse effects have also been observed in recipients of CAR-T therapy, including idecabtagene vicleucel (ide-cel), with a 14.1% incidence of CVAEs in one study [ 12 ]. Another study reported a 4% incidence of heart failure specifically among MM patients receiving CAR-T therapy [ 13 ]. A further study identified a correlation between CRS and cardiac toxicity in CAR-T recipients [ 14 ].

Conversely, information regarding BsAbs remains limited. Pharmacovigilance database reporting suggests increased reporting odds ratios (ROR) for fatal cardiovascular events and myocarditis (aROR 1.29 (95% CI 1.12–1.50) and aROR 25.70 (95% CI 9.54–69.23)) following treatment with BsAbs, mainly driven by teclistimab and not blinatumomab [ 15 ]. However, no notable incidence rates have been reported, which could represent either actual safety or underreporting due to limited cardiac monitoring in initial trials. With greater utilization of such therapies, enhanced pharmacovigilance will be required. Overall, the changing cardiotoxicity profiles of therapies for MM highlight the requirement for expectant, risk-based cardiovascular monitoring and additional mechanistic research to facilitate their incorporation into cardio-oncology practice.

Patient-specific modifiers of cardiotoxicity risk in multiple myeloma therapies

CVAEs associated with modern MM therapies— particularly PIs, CAR-T therapy, and BsAbs—do not occur homogeneously across patients. Instead, variability in sex, age, race, and comorbidities like hypertension and renal dysfunction has been associated with the risk of cardiotoxicity. However, these patient-level variables are frequently reported incompletely and rarely integrated into models driven by mechanistic insight. This section synthesizes recent findings on key demographic and clinical modifiers, highlighting mechanistic applicability and implications for personalized cardio-oncology in MM.

Sex-based differences in cardiotoxicity

Sex-specific distinctions in cardiotoxicity following treatment have increasingly arisen, particularly in the setting of immunotherapies. In the CAR-T setting, two reports independently demonstrated significantly higher rates of CVAEs among female patients treated with ide-cel [ 12 , 13 ]. In one study, 72.7% of patients who experienced cardiac events were female, compared to 45.9% in the group without cardiac events ( p = 0.04) [ 16 ]. Although the mechanisms underlying the association between CAR-T and CVAEs remain speculative, several theories have been proposed. Post-menopausal estrogen deficiency may dampen cardioprotective mechanisms, while female patients may experience enhanced immune activation, cytokine release, and endothelial sensitivity, predisposing them to myocardial inflammation and arrhythmias in the context of CRS [ 17 – 19 ]. Despite these findings, sex-stratified analyzes are absent in most MM clinical trials. For example, large-scale trials with carfilzomib and bortezomib report baseline sex distributions without evaluating outcomes by sex [ 7 , 8 , 10 , 20 – 25 ]. Moreover, no trials incorporated hormone levels, immune biomarkers, or vascular metrics in sex-based mechanistic modeling. These exclusions represent a gap in the recognition of sex-specific cardiotoxicity risk.

Comorbidities and organ dysfunction

Baseline patient characteristics heavily influence therapy-related cardiotoxicity risk in MM. Pre-existing cardiovascular disease (CVD) and hypertension are consistently associated with increased cardiotoxic events, especially in those treated with carfilzomib. CVAE rates were 23.5% in patients with CVD versus 7% in those without CVD [ 11 ], while hypertension was associated with greater incidence of both all-grade and high-grade events [ 5 , 11 , 26 – 28 ], potentially through synergistic endothelial dysfunction and oxidative stress.

Renal impairment is also associated with cardiotoxicity with MM therapies. An eGFR below 60 mL/min was independently linked to greater post-treatment cardiac complications in recipients of CAR-T [ 13 , 29 , 30 ]. Blunted cytokine clearance, inflammation, and pharmacokinetic changes are possible contributors, and carfilzomib-mediated renal oscillations may exacerbate cardiovascular stress [ 20 , 31 – 33 ]; therefore, renal-cardiac co-monitoring is indicated. Conversely, diabetes mellitus was not significantly correlated with cardiac events in CAR-T patients upon adjustment [ 13 ], though it may remain a secondary risk modifier in metabolically deranged patients. Notably, cumulative dose and duration of infusion of carfilzomib did not consistently predict cardiotoxicity [ 11 , 21 , 34 , 35 ], and prior exposure to carfilzomib did not influence CAR-T cardiac outcomes [ 8 , 36 , 37 ], suggesting individual vulnerability and therapy-specific mechanisms are more important than dose.

These findings suggest that cardiotoxicity risk in MM is primarily driven by a combination of comorbidities, organ system function, and patient frailty, as opposed to drug dose. They also highlight the importance of incorporating cardiovascular and renal evaluations into pre-treatment planning. Predictive models incorporating machine learning and multi-institutional databases in the future may enable real-time risk stratification and guide personalized cardio-oncology care.

Age, race, and genomic risk factors

Advanced age, particularly over 75 years, has been consistently associated with increased rates of CVAEs in MM patients, including carfilzomib-treated patients [ 5 , 7 , 8 , 11 , 22 , 31 , 38 ]. Aging-related decreases in vascular compliance, endothelial function, and alterations in drug metabolism may heighten vulnerability to hemodynamic insult. Similarly, African American patients—who comprise a disproportionately large proportion of MM diagnoses in the United States—have also demonstrated increased rates of CVAEs following ide-cel treatment [ 12 ]. These disparities may be due to both biologic predisposition (e.g., higher incidence of hypertension and chronic kidney disease) and structural differences, including decreased availability of state-of-the-art cardio-oncology care and underrepresentation in clinical trials.

While cytogenetic abnormalities (e.g., t(4;14), t(14;16), and del(17p)) are strong prognostic markers for MM outcomes, their association with cardiotoxicity risk has not been reproducibly shown. However, it is plausible that transcriptomic or epigenomic stress signatures—particularly in the setting of immune-modulatory therapies—can influence cardiovascular vulnerability. A recent report also implicated clonal hematopoiesis of indeterminate potential (CHIP) as an independent cardiovascular event risk factor in MM patients undergoing autologous stem cell transplant (ASCT), with CHIP carriers experiencing significantly higher rates of post-transplant major adverse cardiovascular events (HR: 2.39; 95% CI, 1.08–5.30), even after controlling for conventional CV risk factors [ 39 ]. These results suggest a role for hematopoietic genomic instability in cardiac risk and point to the importance of integrating CHIP screening into cardio-oncology risk stratification models, at least in transplant-eligible MM cohorts.

Implications for precision cardio-oncology

The cumulative evidence suggests that the risk of cardiotoxicity associated with many MM therapies is heavily reliant on factors such as sex, age, race, renal function, and cardiovascular comorbidities, as summarized in Table 1 . These factors are not frequently included in preclinical models, trial stratification, or cardio-oncology surveillance algorithms. The lack of firmly established, individualized risk models—especially those that include multi-omics data, imaging biomarkers such as GLS, and real-time physiological monitoring—hinders our capacity to avert or attenuate cardiovascular complications in susceptible patients.

To approach precision cardio-oncology, future research must aim to create risk-adapted, patient-specific algorithms that integrate demographic, clinical, and molecular factors into pre-treatment planning. Future prospective studies should stratify patients by sex and comorbidities, implement mechanistically rational cardioprotective strategies, and quantify endpoints using standardized cardiac monitoring platforms. This comprehensive approach could allow for the optimized use of newer MM therapies without sacrificing cardiovascular well-being.

Mechanisms of proteasome inhibitor–induced cardiotoxicity in MM

PIs are at the forefront of modern MM therapy, and their use has dramatically improved patient survival outcomes. However, carfilzomib, an irreversible epoxyketone PI, has been consistently associated with heightened CVAEs, including heart failure, arrhythmias, and subclinical myocardial dysfunction—most prominently in the elderly and those with pre-existing cardiac risk. These toxicities typically limit dosing and treatment duration. Mechanistically, PI cardiotoxicity is multi-factorial and increasingly clarified by preclinical models involving murine systems, cardiomyocytes, and omics profiling. Key pathways include endothelial dysfunction, mitochondrial injury, oxidative stress, and protein homeostasis disruption. Secondary effects in the form of dysregulated calcium signaling, UPR, and inflammation also contribute to cardiac damage. This section overviews the mechanistic foundations of PI-induced cardiotoxicity, focusing on carfilzomib, to connect experimental data and clinical significance and guide the implementation of targeted cardioprotective strategies in MM therapy.

Experimental models and approaches

Preclinical investigations of PI–mediated cardiotoxicity in MM are increasingly utilizing models that recapitulate patient physiology. These include aged mice, comorbidity-driven rodent models (e.g., hypertension or metabolic syndrome) [ 33 , 40 – 44 ], and human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (hiPSC-CMs) in 2D and 3D cultures [ 45 – 50 ]. Such models enable functional assessment by echocardiography (e.g., LVEF, GLS), histopathology, and omics-based profiling (transcriptomics, proteomics, metabolomics) [ 33 , 40 , 41 , 46 , 48 , 51 – 53 ]. In various models, carfilzomib has also been found to perturb protein homeostasis, redox balance, and cellular survival pathways—validating clinical findings and supporting its mechanistic association with cardiotoxicity.

Endoplasmic reticulum stress and the unfolded protein response

Carfilzomib cardiotoxicity is intimately associated with endoplasmic reticulum (ER) stress and UPR activation. Via proteasomal inhibition-induced accumulation of misfolded proteins, carfilzomib triggers maladaptive UPR signaling via BiP/GRP78 and CHOP upregulation [ 33 , 40 , 41 , 51 , 54 , 55 ]. Chronic UPR activation promotes apoptosis, as shown in rat cardiomyocytes with CHOP elevation and caspase activation. Notably, metformin attenuates ER stress in aged mouse models, normalizing autophagic flux and preserving cardiac function [ 40 , 41 , 56 – 59 ]. These findings justify the ER stress–UPR axis as a potential target to prevent PI-induced cardiac damage.

Mitochondrial dysfunction and autophagy disruption

Mitochondrial dysfunction is a key mediator of carfilzomib cardiotoxicity. Carfilzomib decreases mitochondrial membrane potential (ΔΨm), lowers ATP synthesis, and increases oxidative stress markers, including reactive oxygen species (ROS) and malondialdehyde (MDA), in rodent and hiPSC-CM models [ 46 – 48 , 60 – 62 ]. These alterations are additive to lowering antioxidant defenses, with decreased superoxide dismutase and catalase activity perturbing redox balance. Empagliflozin, an SGLT2 inhibitor, has demonstrated cardioprotective activity in preclinical investigations through the restoration of mitochondrial function and redox homeostasis, thus identifying mitochondrial stress as a central mechanism and therapeutic target in PI-induced cardiotoxicity [ 33 , 63 , 64 ].

Carfilzomib also impairs autophagy and proteostasis by inhibiting proteasomal breakdown, resulting in an accumulation of misfolded proteins and damaged organelles. This overwhelms the autophagy-lysosome pathway, as evidenced by LC3B accumulation and impaired autophagic flux in in vivo and in vitro models [ 33 , 40 , 65 , 66 ], resulting in apoptosis. Proteomic data reveal dysregulation of nuclear and sarcomeric proteins and upregulation of chaperone proteins, including HSP90AA1, HSPA4, and BAG3—markers of proteotoxic stress. BAG3, in particular, plays an essential role in the degradation of cytoskeletal proteins, and its loss is associated with myofibrillar disorganization and enhanced vulnerability to PI-mediated injury in iPSC-CMs [ 48 , 49 , 67 , 68 ]. These findings validate BAG3 as a cardio-oncology biomarker and therapeutic target.

Comparative toxicity and protective interventions

Carfilzomib displays a higher level of cardiotoxicity than other PIs, as it irreversibly inhibits the β5 and β2 subunits of the proteasome, while bortezomib and ixazomib preferentially inhibit the β5 and β1 subunits [ 3 , 69 – 72 ]. This dual inhibition results in a higher proteotoxic load and greater activation of stress response pathways, which is associated with more cardiac dysfunction in preclinical studies [ 40 ]. Omics profiling reveals overlap in oxidative stress and apoptosis pathways between carfilzomib and the cardiotoxic anthracycline doxorubicin [ 52 , 73 , 74 ]. This mechanistic convergence suggests that carfilzomib may exert anthracycline-like cardiac effects, highlighting the need for vigilant monitoring and shared protective strategies. Several pharmacologic agents have shown cardioprotective effects in preclinical models of carfilzomib-induced toxicity. Metformin improves cardiac results through AMPK signaling recovery, ROS inhibition, and autophagy induction [ 40 , 41 , 43 , 75 , 76 ]. Empagliflozin, an SGLT2 inhibitor that is now a pillar of standardized heart failure therapy, also reduces oxidative damage and preserves mitochondrial and cardiac function independent of glucose control [ 33 , 77 – 79 ]. All-trans-retinoic acid (ATRA) reduces inflammation and fibrosis in carfilzomib-treated models through RAAS pathway modulation [ 70 , 80 ]. These interventions suggest the possibility of cardioprotection during PI treatment and warrant further study.

Clinical implications

Despite robust preclinical evidence regarding carfilzomib’s cardiotoxicity, translational gaps are significant. Most findings stem from in vitro testing or animal models, with insufficient validation in human tissues, clinical imaging, or biomarker-focused studies. This disconnect hinders the development of accurate monitoring and targeted therapeutic approaches in the clinic. The recent European Society of Cardiology Cardio-Oncology guidelines recommend monitoring with natriuretic peptides and echocardiograms [ 81 ]. This is based on data suggesting that patients with elevated natriuretic peptides had a 10.8-fold increased relative risk of CVAEs, including heart failure, compared to patients without elevated natriuretic peptides [ 8 , 71 , 82 , 83 ]. To more adequately address gaps in knowledge regarding PIs and cardiotoxicity in MM, approaches need to be established to move mechanistic data into predictive biomarkers, real-time monitoring strategies, and evidence-based cardioprotection. Bridging these gaps will be essential to the long-term efficacy and safety of new MM therapies.

Distinct mitochondrial and apoptotic pathways across PIs

While mitochondrial dysfunction is a central feature of carfilzomib-induced cardiotoxicity, emerging comparative data highlight key mechanistic differences between PIs. By contrast, bortezomib affects mitochondrial function primarily in endothelial cells without significant direct cardiomyocyte toxicity [ 84 – 89 ], suggesting a cardiac-selective vulnerability to carfilzomib. In preclinical cardiomyocyte models, carfilzomib—rather than bortezomib—activates caspase-3/−7, consistent with intrinsic (mitochondrial) apoptosis; upstream events likely involve Bax/Bak–mediated outer-membrane permeabilization and cytochrome-c release, although the initiating triggers remain under study [ 33 , 46 , 52 ].

Clinically, low tauroursodeoxycholic acid (T-UDCA) levels have been linked with heightened risk of cardiotoxicity with carfilzomib, suggesting it as a potential biomarker [ 85 ]. These observations further refine the mechanistic distinctions among PIs and underscore the need for PI-specific risk stratification.

Proteostasis disruption and endothelial injury

Beyond cardiomyocyte-intrinsic pathways, protein homeostasis disruption and endothelial dysfunction differentiate the cardiotoxic profiles of PIs. Proteomic profiling in hiPSC-CMs demonstrates sarcomeric and mitochondrial protein turnover disruption, injuring both structure and metabolism [ 48 , 86 – 88 ].

Vascular and endothelial damage is a central mediator of PI–induced cardiotoxicity. Clinically, carfilzomib decreases endothelial function as measured by flow-mediated dilation (FMD), placing vascular dysfunction as both a driver and biomarker of toxicity [ 89 – 91 ]. Preclinical models demonstrate that carfilzomib increases vascular ROS, impairs aortic contractility, and disrupts endothelial autophagy—effects that can be mitigated by metformin [ 33 , 91 , 92 ]. Transcriptomic profiling further shows more severe pro-inflammatory and oxidative responses in endothelial tissues exposed to carfilzomib than bortezomib, reinforcing the contribution of vascular injury to the clinical phenotype [ 93 – 95 ].

Comparative toxicity across carfilzomib, bortezomib, and ixazomib

Structural and functional differences across PIs translate into distinct mechanistic and clinical toxicity profiles. As a β5/β2 irreversible inhibitor, carfilzomib induces more severe mitochondrial dysfunction, proteostasis disruption, and vascular injury than reversibly β5/β1-inhibiting bortezomib [ 3 , 96 – 99 ]. While bortezomib can cause cardiotoxicity at higher doses—mainly vascular and autonomic—its impact is generally mild and reversible. Ixazomib, which has little β2 activity, is the least cardiotoxic and is sometimes used as an experimental negative control [ 96 , 100 , 101 ].

These mechanistic differences argue for agent-specific risk assessment and highlight the potential utility of selecting lower-toxicity PIs or applying cardioprotective co-therapies in higher-risk populations.

Interventional strategies and translational gaps

Preclinical data support several pharmacologic agents—most notably metformin and empagliflozin—as promising cardioprotective therapies against PI–mediated cardiotoxicity. These agents normalize AMPK signaling, reduce ER stress and oxidative damage, improve mitochondrial function, and preserve endothelial function [ 33 , 40 , 41 , 92 , 102 ]. ATRA also showed promise through modulation of the renin-angiotensin system and reducing carfilzomib-induced cellular stress [ 70 ].

Despite strong preclinical data, clinical studies of these agents with MM therapies are lacking. Future studies should evaluate these drugs in stratified patient populations based on cardiovascular risk and treatment exposure. Furthermore, bridging gaps in preclinical studies, including mapping upstream UPR signaling and translating findings to the clinic, will be instrumental in improving therapeutic efficacy in MM while reducing cardiotoxicity.

Mechanisms of CAR-T–associated cardiotoxicity in multiple myeloma

CAR-T therapy targeting BCMA has transformed the treatment of relapsed/refractory MM but is associated with a distinct set of cardiovascular toxicities. Unlike the direct cardiac toxicities of PIs, CAR-T–associated cardiotoxicity is largely immune-mediated—led by systemic inflammation and endothelial dysfunction. CRS is the primary instigator, which sets off inflammatory cascades culminating in endothelial injury, myocardial stress, and arrhythmias. Although supportive care for CRS has improved, the mechanistic understanding of how immune activation causes cardiac damage remains limited. Importantly, recipients of BCMA-directed CAR-T cells and CD3-engaging BsAbs almost uniformly have relapsed/refractory MM and have undergone multiple prior lines of therapy, including PIs, IMiDs, alkylators, and often ASCT [ 12 , 16 ]. This cumulative treatment burden may predispose to endothelial dysfunction, myocardial stress, and immune dysregulation, thereby increasing susceptibility to treatment-related cardiovascular events compared with newly diagnosed patients [ 12 , 13 , 27 ]. This section synthesizes data on CAR-T–related cardiotoxicity in MM, focusing on cytokine signaling, endothelial dysfunction, and myocardial vulnerability.

Cytokine-mediated inflammation, endothelial dysfunction, and cardiac impairment in CAR-T therapy

CRS is the main cause of cardiotoxicity following CAR-T therapy for relapsed/refractory MM. IL-6, IFN-γ, and TNF-α elevations are strongly associated with cardiac events. In a large multicenter cohort of CAR-T recipients with hematologic malignancies, 26% experienced cardiac disorders [ 13 , 103 , 104 ]. In that cohort, troponin and NT-proBNP rose in parallel with cytokine peaks, linking inflammation to myocardial stress [ 19 , 27 , 105 , 106 ]. Early administration of tocilizumab (anti–IL-6), as recommended by NCCN guidelines, has emerged as the primary intervention for mitigating severe CRS-related cardiac complications, with corticosteroids as adjunctive therapy when inflammation escalates [ 13 , 19 , 107 – 110 ].

Endothelial injury is a central aspect of CAR-T–associated cardiotoxicity. TNF-α and IL-1β augment adhesion molecule upregulation (VCAM-1, ICAM-1), cause angiopoietin-2 release, and disrupt barrier integrity, leading to capillary leak and myocardial vulnerability [ 111 – 114 ]. Cytokine-releasing CAR-T–activated immune cells create a feedback loop between inflammation and endothelial stress. Pharmacologic inhibition of TNF-α, IL-1β, or focal adhesion kinase (FAK) decreases endothelial activation in preclinical models, therefore providing additional rationale for vascular protection strategies in CAR-T cardio-oncology practice [ 115 ]. Arrhythmias, such as atrial fibrillation and sinus tachycardia, occur frequently during high-grade CRS, commonly with cardiac biomarker elevation [ 13 , 27 , 116 – 120 ]. Reversible systolic dysfunction has also been described and usually improves with CRS resolution, with a presentation that is akin to stress cardiomyopathy/Takostubo’s cardiomyopathy often observed during sepsis or severe stress [ 14 ]. Mechanistic data on cytokine-induced arrhythmogenesis remain limited. Ion channel modulation, autonomic imbalance, or myocardial edema are suspects, but additional work is needed to guide risk stratification and monitoring.

TNF-α as a therapeutic target: integrated mechanistic insights and future directions

TNF-α is arguably the most significant cytokine in CAR-T–induced cardiotoxicity. However, this conclusion is based on very limited evidence, primarily small case series, and therefore, TNF-α–associated cardiac effects should be considered preliminary and hypothesis-generating rather than definitive mechanistic drivers. In a small series of MM patients who received CAR-T, etanercept—a TNF-α inhibitor—ameliorated symptoms of CRS without compromising CAR-T function, though cardiac endpoints were not directly assessed [ 121 ]. Future clinical studies should incorporate cardiovascular endpoints and biomarker-stratified enrollment to formally test TNF-α–directed strategies as part of cardioprotective regimens with CAR-T therapy. However, caution is warranted, as TNF-α inhibition—particularly with agents like infliximab—has been associated with worse outcomes in patients with moderate-to-severe heart failure, as demonstrated in the ATTACH trial, which led to a black box warning for this population [ 122 ]. Systems biology approaches, such as single-cell sequencing and cytokine profiling, have started to elucidate the immunologic foundations of CAR-T therapy-related cardiotoxicity. An investigation of BCMA-targeted CAR-T therapy revealed IL-6, IFN-γ, and TNF-α as key mediators in the inflammatory cascade of CRS [ 123 ], thereby implicating them in endothelial activation and myocardial distress. These observations substantiate the use of real-time cytokine monitoring and risk stratification models for cardiovascular event prediction. Mitigation strategies have focused on IL-6 blockade with tocilizumab, particularly if administered early in CRS, which reduces cardiovascular complications in MM patients [ 107 , 124 , 125 ]. Corticosteroids and TNF-α inhibitors (e.g., etanercept) may be of further value, but cardiac-specific evidence is needed [ 121 ]. Inhibition of the FAK has also shown activity in preclinical models for reducing endothelial injury [ 111 , 126 ]. Despite these developments, direct mechanistic links between cytokine surges and myocardial injury remain understudied. Most data to date are associative, with limited interrogation of immune cell infiltrate, calcium metabolism, or ion channel modulation. Future studies should include cardiac imaging, biomarker definition, and prospective trials to define the full range of CAR-T–induced cardiotoxicity. Risk stratification based on CRS grade, baseline cardiovascular condition, and cytokine profiles will be necessary to personalize prevention. In parallel, the 2022 European Society of Cardiology (ESC) Cardio-Oncology Guidelines endorsed a comprehensive baseline cardiovascular evaluation in all cancer patients slated to receive potentially cardiotoxic therapies—especially those with pre-existing CVD. Key components of this assessment include a 12-lead electrocardiogram (ECG), transthoracic echocardiography with GLS, and serum biomarkers like high-sensitivity troponins (hs-TnI or hs-TnT) and natriuretic peptides (BNP or NT-proBNP). Elevated baseline NT-proBNP (>125 ng/L) and abnormal GLS (>15% relative reduction from baseline) are predictive of subsequent cardiotoxic events and subclinical dysfunction. Patients are stratified into groups based on risk, guiding the frequency of surveillance and need for cardiology co-management [ 81 ]. This ESC-endorsed, risk-adapted framework aligns with evolving mitigation strategies in MM cardio-oncology and reinforces the importance of personalized care that prioritizes both cardiac safety and therapeutic efficacy.

Immune-mediated cardiac toxicity of BCMA×CD3 and CD3-engaging bispecific antibodies in multiple myeloma

BsAbs targeting BCMA and CD3 are an emerging immunotherapy for relapsed/refractory MM, and there is growing evidence regarding their role in immune-mediated CVAEs. CRS is usually implicated in their pathogenesis, though direct immune-mediated myocardial injury has also been proposed. Regulator warnings, including black box warnings, highlight the need for better mechanistic understanding and vigilance for these toxicities. Available clinical data and postulated mechanisms of BsAb-mediated cardiotoxicity are reviewed here, contrasting with CAR-T and highlighting the need for harmonized cardiovascular monitoring as BsAbs are increasingly used.

Early clinical pharmacovigilance data suggest emerging mechanistic distinctions between BCMA-targeting and GPRC5D-targeting CD3 bispecific antibodies. BCMA×CD3 agents such as teclistamab demonstrate higher reporting signals for myocarditis (aROR 25.7) and cardiogenic shock (aROR 3.6), consistent with potentially greater on-target immune activation and endothelial stress [ 144 ]. In contrast, GPRC5D×CD3 agents such as talquetamab exhibit attenuated cardiovascular signals but higher dermatologic and taste-related toxicities. These divergent toxicity patterns may reflect differences in antigen distribution, T-cell activation kinetics, or tissue-specific immune engagement, though mechanistic studies remain limited.

Clinical observations and incidence patterns

Of 3668 BsAb-related reports that underwent a pharmacovigilance analysis, 20.4% included CVAEs, with the BCMAxCD3 BsAB teclistamab having elevated ROR for myocarditis (25.7) and cardiogenic shock (3.6) [ 15 ]. Of note, 83.3% of CVAEs were without reported CRS, pointing to other immune-mediated mechanisms [ 15 ]. Teclistamab, elranatamab, and alnuctamab clinical trials have described the incidence of tachyarrhythmias, troponin elevation, decreased ejection fraction, and isolated incidents of cardiogenic shock [ 127 – 130 ]. Clinical manifestations are usually coincident with systemic inflammation, but the mechanisms of pathogenesis are uncertain—confounded by the absence of systematic cardiac monitoring in early trials.

Comparative context: CAR-T and CD3 T-cell engagers

Due to their shared T-cell activation and cytokine release processes, understanding toxicities associated with CAR-T therapy offers context for BsAb–related cardiotoxicity. Incidences of cardiovascular events reaching 25.6% were described in a meta-analysis of over 2000 CAR-T recipients, including arrhythmias, heart failure, and troponin rise—frequently in combination with CRS and peak cytokines [ 131 ]. While BsAbs induce more titratable and temporary immune responses compared to the extended cytokine burst of CAR-T cells, both therapies have superimposable toxicity profiles that encompass endothelial activation and myocardial stress [ 132 ]. Whether these represent convergent downstream effects or shared mechanisms is unclear. Side-by-side comparisons of CAR-T and BsAbs can reveal agent-specific dangers and guide targeted cardioprotective measures throughout T-cell–based treatments.

Proposed mechanisms of cardiac injury

Mechanistic insight into BCMA×CD3 BsAb-associated cardiotoxicity is mainly derived from literature of CAR-T therapies. A well-supported mechanism involves IL-6–mediated myocardial depression, acting via gp130/JAK-STAT3 signaling and iNOS induction, resulting in contractile dysfunction and hypotension [ 131 , 133 – 137 ]. TNF-α also operates through NF-κB–mediated oxidative stress and apoptosis, while IFN-γ induces inflammatory macrophage polarization, which may cause myocarditis and arrhythmias [ 134 , 138 – 142 ]. Additional cytokines, including IL-1β and GM-CSF can potentiate endothelial damage and systemic inflammation, worsening microvascular dysfunction and myocardial stress. Yet, direct evidence that cytokine surges cause cardiac events in BsAb-treated patients is lacking. Most results are associative, with limited data to establish causality [ 15 , 127 , 129 , 131 ].

Immune cell activation and endothelial injury

Direct immune cell activation may also contribute to BCMA×CD3 BsAb cardiotoxicity. CD3 stimulation augments T-cell activation with cytokine release, which may damage the endothelial layer. Preclinical studies have shown that activated T cells and monocytes can infiltrate the myocardium and cause inflammation, fibrosis, and conduction abnormalities [ 130 , 134 , 143 – 146 ]. Endothelial cells treated with IL-1β, TNF-α, and IFN-γ upregulate adhesion molecules and lose barrier function, which may enhance myocardial vulnerability. No direct imaging or histopathologic confirmation of immune cell infiltration is available in BsAb-treated patients, calling for cardiac MRI, PET, or biopsy studies to confirm this hypothetical mechanism.

Monitoring and mitigation strategies

Cardiovascular risk management with BsAb therapy has been adopted from CRS management. Inflammation is typically controlled by tocilizumab, but its cardioprotective role in BsAb-induced toxicity is not established, while corticosteroids are reserved for high-grade CRS or myocarditis [ 129 , 131 ]. Monitoring comprises serial troponin and NT-proBNP levels, ECG, and echocardiography for detection of early cardiac damage [ 127 , 130 ]. However, optimal thresholds and monitoring durations have yet to be established. Expert consensus recommends baseline cardiovascular risk assessment and multidisciplinary review for T-cell–redirecting therapies, but no BsAb-specific guidelines exist (Table 2 ). With expanding clinical use, future trials with standardized cardiac assessments are necessary to inform evidence-based cardio-oncology care.

Key gaps and research needs

Amid growing awareness of CVAEs with BsAbs, their mechanism remains unclear. To date, no preclinical model has evaluated cardiac histopathology, cytokine kinetics, or immune infiltration under the context of BsAb exposure. Likewise, clinical trials have yet to investigate cardioprotective agents such as tocilizumab or anakinra with cardiac-specific endpoints.

Notably, up to one-third of CVAEs are independent of CRS, suggesting that delayed immune effects, endothelial damage, or subclinical inflammation may be responsible for cardiac injury [ 15 , 128 , 130 , 131 , 134 ]. However, in the absence of biomarker monitoring and imaging studies, these mechanisms are inferential, and there are no standardized monitoring strategies for BsAb-treated patients with cardiovascular risk. While BsAbs constitute a breakthrough in relapsed/refractory MM treatment, their cardiac risks remain under-investigated. Going forward, the field must focus on BsAb-specific preclinical modeling, systematic cardiac monitoring, and prospective testing of cardioprotective measures. Mechanistically informed approaches will be important to balance efficacy with cardiovascular safety with BsAbs.

Converging mechanistic pathways across therapeutic classes

Notwithstanding their unique immunologic and pharmacologic characteristics, PIs, CAR-T therapies, and CD3-BsAbs exhibit some common pathways of cardiac damage, summarized in Table 3 [ 15 , 33 , 40 , 105 , 147 ]. Mitochondrial damage, ER stress, proteostasis disruption, oxidative damage, and endothelial activation frequently arise as primary contributors to cardiotoxicity across these modalities. Interestingly, all three classes of therapies have been linked to disrupted autophagic flux, defective AMPK signaling, and elevated levels of stress-responsive chaperones, including BAG3, that detrimentally affect protein homeostasis and cytoskeletal structure [ 40 , 41 , 48 , 49 , 67 ]. Such cellular derangements may have synergistic interactions with each other in patients undergoing combination or sequential therapies and thereby exacerbate cardiovascular damage. Though these MM therapies have different structures and mechanisms of action, there are strikingly consistent mechanisms in the downstream molecular pathways marked by mitochondrial injury, inflammation, and endothelial dysfunction leading to cardiotoxicity. Recognition of this commonality enables a cohesive approach to risk stratification and underpins the evaluation of global cardioprotective therapies—such as metformin, empagliflozin, and TNF-α blockade—across treatment regimens [ 33 , 41 , 102 , 121 ].

Conclusions

Cardiotoxicity has emerged as a progressively appreciated constraint in the management of MM as new therapeutic classes—PIs, CAR-T therapies, and CD3-engaging BsAbs—continue to revolutionize clinical outcomes. Future research must prioritize the development of BSAb-specific and CAR-T–relevant preclinical models, prospective evaluation of cardioprotective pharmacotherapies, and standardized cardio-oncology surveillance protocols. Multidisciplinary collaboration will be required to achieve mechanistic validation and clinical translation, while precision cardio-oncology approaches—supported by individualized risk profiling, mechanistic understanding, and biomarker-guided intervention—will be critical to optimizing the use of existing MM therapies.

Author contributions

ARC wrote and revised the manuscript, KP reviewed and revised the manuscript, and NS and NLP conceptualized, wrote, revised, and reviewed the manuscript.

Competing interests

NS is an inventor on patent applications through The University of Texas MD Anderson Cancer Center and reports research funding from Panbela Therapeutics. KP reports consulting from AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Johnson & Johnson, Kite, Legend Biotech, Merck, Pfizer, Novartis, Sanofi, and Regeneron; has served on advisory boards for Sanofi and Novartis; and reports research support from Bristol Myers Squibb, Celgene, Kite, Oricel, and Indapta. NP reports research support from CPRIT RP200670, NIH/NCI 1P01CA261669-01, and Kiniksa Pharmaceuticals. All other authors declare no competing interests.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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