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.