Results:
The total number of adverse events (AEs) from all drugs in the FAERS database was over 20 million. Of those, the total number of AEs caused by the newly-approved therapeutic agents for multiple myeloma (including in combination with other medications) evaluated in this study was 30,797. Ixazomib had the highest number of total reported AEs with 13,701, followed by daratumumab with 10,235, while belantamab mafodotin had the lowest with 351 AEs. Out of the 30,797 AEs reported, 1131 were cardiac AEs. These included heart failure, atrial fibrillation, and coronary artery disease. Heart failure was reported the most with 470 AEs, while atrial fibrillation came next with 346, and coronary heart disease with 315. Ixazomib had the highest reported heart failure and coronary heart disease AEs with 189 and 145 AEs respectively. Daratumumab had the highest atrial fibrillation AEs at 164 [Table 1].
Next, we analyzed the characteristics of the cardiac related AEs associated with elotuzumab, ixazomib, daratumumab, panobinostat, selinexor, and belantamab mafodotin. Since very few cardiac AEs reported for selinexor, and belantamab mafodotin, further analysis was not conducted for these medications [supplemental tables 5-6]. The majority of cardiac AE was among patients belonged to 65-85 age group (>55-59%), except, panobinostat which affected 40% of that age group. Overall, almost all of these cardiac AEs reported were serious (98%-100%). Consistently, the death rate was 25%-35% among cardiac adverse events on patients received elotuzumab, ixazomib, daratumumab. However, panobinostat reported the least mortality (3.5%) consistent with its relatively lower cardiac AEs on the older patients. However, more than one third of panobinostat-related reported cardiac AEs are not age specified [table 2 and supplemental tables 1-6]. Finally, gender biased-cardiac AEs are relatively higher among males, however, the results are not clear considering multiple reports were labeled as non-specific [table3].
The data was presented as reporting odds ratios (RORs) of reported cardiac adverse events concomitant with the use of a newly approved multiple myeloma agent compared to the same reported adverse events within the entire database of pharmaceuticals within FAERS. Atrial fibrillation and coronary heart disease were mostly associated with the use of panobinostat with ROR of 5.7 (95% CI: 4.1-8.1, P<0.0001) and 4.6 (95% CI: 3.8-8.1, P<0.0001) and elotuzumab with ROR of 5.8 (95% CI: 4.4-7.7, P<0.0001) and 2.7 (95% CI: 1.9-3.9, P<0.0001) respectively. Coronary artery disease had the lowest ROR with all agents with odds ratio between 2.3-4.6. Heart failure was reported the most with the use of elotuzumab with ROR of 8.2 (95% CI: 6.4-10.5, P<0.0001), while ixazomib exhibited the least association with ROR of 4.7 (95% CI: 4.1-5.4, P<0.0001). Of note, panobinostat’s and daratumumab’s ROR values were closely related compared to other agents [Figure 1 A-C and Table 4].
Discussion :
The results of this study demonstrated an association between the use of the newest novel multiple myeloma agents and cardiotoxicity. Among all of the adverse events reported for these new agents on FAERS, cardiac complications represented little less than 10%. Of all of the newly FDA approved multiple myeloma agents, elotuzumab, Ixazomib, daratumumab, panobinostat showed significant cardiac adverse events. Interestingly, cardiac failure, atrial fibrillation and coronary artery diseases were profoundly the highest of all reported cardiotoxicity. Interestingly, Isatuximab and belantamab mafodotin showed safer cardiac profile compared to elotuzumab, Ixazomib, daratumumab, panobinostat.
The fascinating ELOQUENT trials showed that elotuzumab significantly reduced multiple myeloma progression. Unspecified cardiac adverse events were reported among 7 patients with one death from heart failure with no concerning effects on QT prolongation12,13. The TOURMALINE trials that demonstrated the efficacy of Ixazomib on multiple myeloma reported similar adverse cardiac events (heart failure, myocardial infarction and arrhythmia) between the Ixazomib and the placebo group14-16. Three cases of myocardial infarction reported with panobinostat compared to placebo group17. Additionally,17.6% of patient who received panobinostat and bortezomib and dexamethasone reported cardiac complications (most frequently atrial fibrillation, tachycardia, palpitation, and sinus tachycardia) on phase 3 PANORAMA-1 trial18. Interestingly, no major cardiac adverse events reported associated with daratumumab11,19.
While the study demonstrated undefined cardiovascular complications for new antimyeloma therapy, future studies are needed to investigate the underlying biological mechanisms driving this association. Moreover, prior cardiovascular functioning and other cardiac disorders were not considered while performing this study. Additionally, it is also important to state that FAERS-based studies typically examine association and not causality. Utilizing passive surveillance systems such as FAERS poses several limitations that pertain to this study including reporting bias, inaccuracy, and incompleteness of adverse events reports. The wholistic profile of patients (co-morbidities, risk factors, family history, etc.) are unknown. Moreover, it is important to note that pre-existing cardiovascular comorbidities including cardiac dysfunction and arrhythmias are specifically common within age groups with the most reported adverse events20. Furthermore, multiple myeloma can worsen age-related cardiac dysfunction. In general, multiple myeloma is the third most common type of malignancy associated with cardiovascular disease, hence, the disease may have contributed to the reported adverse events21. For example, cardiac amyloidosis is frequently seen in multiple myeloma patients which can lead to cardiac dysfunction. Arrhythmias such as atrial fibrillation, paroxysmal ventricular tachycardias, and atrial flutter are well-reported in patients with multiple myeloma which are believed to be secondary to multi-factorial arrhythmogenesis secondary to age, electrolyte disturbances, and cardiac amyloidosis22. Due to these limitations, our results should be taken in consideration after further prospective, longitudinal studies have been performed.
Older therapeutic agents used in the treatment of multiple myeloma have been implicated in a plethora of cardiovascular adverse events. For example, doxorubicin is associated with a dose-related and usually irreversible Type I cardiac dysfunction that is thought to be related to excess generation of reactive oxygen species (ROS)23. The use of other major proteasome inhibitors including bortezomib and carfilzomib is associated with congestive heart failure and reversible cardiac dysfunction secondary to structural mitochondrial abnormalities and decreased nitric oxide levels with endothelial dysfunction, respectively Cardiac arrythmias associated with commonly used therapeutic agents have been well established in literature. For example, melphalan, doxorubicin, and cyclophosphamide are mainly associated with atrial fibrillation29-33, while thalidomide and bortezomib are associated with bradycardia and complete heart block 22,34.
The significance of our data stems from the increasing use of new agents for multiple myeloma. As addressed above, multiple clinical trials showed sporadic cardiac adversaries of the novel multiple myeloma agents, however, a more thorough investigation of the cardiovascular profile of these medications is lacking. Our study strongly agrees with the aforementioned studies and showed enhanced cardiotoxicity especially atrial fibrillation, coronary artery disease and heart failure. Based on our results, we recommend physicians to discuss the cardiovascular risk with patients upon starting these medications. Electrocardiography and echocardiogram maybe help establish baseline cardiac function prior initiating these regimens.
In conclusions, novel multiple myeloma agents are associated with enhance atrial fibrillation, coronary artery disease and heart failure. Patient risk stratification and baseline cardiac functioning testing (electrocardiography and echocardiogram) should be considered upon initiating these agents.
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Funding: The authors declare that this work was not supported by any funds or grants.
Acknowledgment: None.
Conflict of Interests: The authors have no relevant financial or non-financial interests to disclose.
Data Availability: The datasets from the current study are available from the corresponding author upon request.