\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[english]{babel}



\usepackage{float}








\begin{document}

\title{Cardiovascular Complications of Modern Multiple Myeloma Therapy: A
Pharmacovigilance Study}



\author[1]{Zaki Al-yafeai}%
\author[2]{Mohamed Ghoweba}%
\author[3]{Anil Ananthaneni}%
\author[2]{Hamzah Abduljabar}%
\author[2]{David Aziz}%
\affil[1]{LSU Health Shreveport}%
\affil[2]{Affiliation not available}%
\affil[3]{Louisiana State University Health Sciences Center Shreveport}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Background: Multiple myeloma accounts for over 15\% of hematological
malignancies. In attempt to tackle this malady, the FDA approved four
drugs in 2015 which has propagated further development of new
anti-multiple myeloma since. However, the health safety of these new
agents is still ill-defined. The aim of this study is to delineate the
cardiovascular adverse events of these drugs. Methods: We searched the
cardiac adverse events of the newly approved FDA drugs since 2015 using
the U.S. Food and Drug Administration Adverse Events Reporting System
database (FAERS). We calculated the reporting odds ratio (ROR) with 95\%
confidence for four drugs that have the highest incidence of
cardiovascular adverse events. Results: Among the medications that have
approved for MM Between 2015-2020, four novel drugs showed the highest
incidence of cardiotoxicity. ROR (95\% CI) for atrial fibrillation due
to elotuzumab, Ixazomib, daratumumab, and panobinostat compared to other
FAERS drugs was 5.8 (4.4-7.7), 1.9 (1.5-2.3), 4.8 (4.2-5.6), and 5.7
(4.1-8.1), respectively. The ROR (95\% CI) for cardiac failure was 8.2
(6.4-10.5), 4.7 (4.1-5.4), 5.8 (4.9-6.7), and 5.6 (3.8-8.1) and ROR
(95\% CI) for coronary disease was 2.7 (1.9-3.9), 2.7 (2.3-3.2), 2.3
(1.9-2.8), and 4.6 (3.2-6.6) due to elotuzumab, Ixazomib, daratumumab,
and panobinostat versus all other drugs in FAERS. Conclusions: Our
results demonstrated that the newly approved antimyeloma therapy
(elotuzumab, Ixazomib, daratumumab, panobinostat) are significantly
associated previously unknow cardiotoxicity. These results warrant
further studies and highlight the importance of considering the cardiac
history of patients with multiple myeloma when utilizing these novel
agents.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

Multiple myeloma is characterized by neoplastic proliferation of plasma
cells that produce monoclonal immunoglobulins. Proliferation of cells in
the bone marrow often causes osteolytic lesions, osteopenia and/or
pathologic fractures, subsequent hypercalcemia stemming from bone
destruction and anemia mainly due to bone marrow
replacement\textsuperscript{1}. There is also observed renal dysfunction
due to accumulation and precipitation of light chains which form casts
in distal renal tubules \textsuperscript{2}. It is estimated that 35000
new cases are diagnosed annually, accounting for nearly 2\% of all new
cancer diagnoses\textsuperscript{3}. Age-adjusted death rates have not
changed significantly over 2009--2018 and have remained at around 3.1
per 100,000 population\textsuperscript{3}.

While the initial therapy before newer therapeutic advances has
classically consisted of VRd (bortezomib + lenalinomide + dexamethasone)
and/or stem cell transplant with bortezomib/lenalinomide
maintenance\textsuperscript{4}, we have had newer approvals for
treatment of multiple myeloma which have received at least one previous
regimen. Between 2015-2016, the FDA approved 4 new drugs -- elotuzumab
(activates NK cells)\textsuperscript{5}, ixazomib (proteosome
inhibitor)\textsuperscript{6}, daratumumab (targeting
CD38)\textsuperscript{7}, panobinostat(histone deacetylase
inhibitor)\textsuperscript{8} and more recently belantamab and selinexor
in 2020\textsuperscript{9,10}. Clinical Daratumumab is frequently used
in first line regimens along with VRd as D-VRd\textsuperscript{4}.

While the usage of these drugs has increased in the recent years, there
is little published evidence about their cardiovascular adverse effect
profile. One of the largest trials, the CASTOR trial that included 283
and 286 patients in the VRd and D-VRd arms respectively reported few
cardiovascular side effects; two patients with atrial fibrillation in
both arms, one patient with acute coronary syndrome among others in the
D-VRd arm that could not reach statistical significance given low sample
size\textsuperscript{11}. However, a comprehensive study investigating
the cardiovascular profile of the new antimyeloma therapy is lacking.
Therefore, we sought to utilize FAERS database to analyze the reported
cardiovascular adverse events of the newly approved multiple myeloma
therapies since 2015.

\textbf{Methods:}

\textbf{Study Design and Data Collection}

This is a retrospective, pharmacovigilance study of adverse event
analysis of the U.S. Food and Drug Administration's Adverse Event
Reporting System (FEARS) database. FAERS is an online publicly available
post-marketing pharmacovigilance database that records millions of
adverse events, medication error reports, and product quality complaints
submitted by healthcare professionals, manufacturers, and consumers
worldwide for approved drugs and biologic products. Reports are
evaluated by clinical reviewers in the Center for Drug Evaluation and
Research and the Center for Biologics Evaluation and Research. The
database includes data regarding the suspected pharmaceutical agent,
indication for its use, patient characteristics, as well as the reported
adverse event including its date of occurrence, nature, and outcome,
among others. Since the data is anonymized, approval by an ethics
committee (i.e. IRB approval) was not required for this analysis. We
aimed to evaluate the cardiovascular adverse events associated with
newly FDA-approved multiple-myeloma therapeutic agents from the approval
till May 2021. Queries for the specific adverse event terms were
performed according to the Medical Dictionary for Regulatory Activities.
The terms used include ``atrial fibrillation'', ``congestive cardiac
failure, cardiac failure congestive'', ``ventricular dysfunction'',
``systolic dysfunction''; ``diastolic dysfunction'', ``cardiac
disfunction'', ``cardiac failure'', ``cardiomyopathy'', ``myocardial
infarction'', ``angina pectoris'', ``coronary artery disease'',
``coronary artery occlusion'', ``angina unstable'', silent myocardial
infarction, ``acute coronary syndrome'' and were organized in these main
groups.

\textbf{Statistical Analysis}

Statistical testing to measure the association of these drugs with the
specified cardiac events of interest was performed using
disproportionality signal analysis. These were 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. The ROR was considered significant when the lower limit of
the 95\% CI was \textgreater{}1.0.\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
& Drug of interest & All other drugs in FAERS\tabularnewline
\midrule
\endhead
Reports of AE of interest & A & B\tabularnewline
All other AEs & C & D\tabularnewline
\bottomrule
\end{longtable}

ROR: AxD / BxC

\textbf{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
(\textgreater{}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\textless{}0.0001) and 4.6 (95\% CI: 3.8-8.1, P\textless{}0.0001) and
elotuzumab with ROR of 5.8 (95\% CI: 4.4-7.7, P\textless{}0.0001) and
2.7 (95\% CI: 1.9-3.9, P\textless{}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\textless{}0.0001), while ixazomib
exhibited the least association with ROR of 4.7 (95\% CI: 4.1-5.4,
P\textless{}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{]}.

\textbf{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 prolongation\textsuperscript{12,13}. 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 group\textsuperscript{14-16}. Three cases of myocardial
infarction reported with panobinostat compared to placebo
group\textsuperscript{17}. 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
trial\textsuperscript{18}. Interestingly, no major cardiac adverse
events reported associated with daratumumab\textsuperscript{11,19}.

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 events\textsuperscript{20}. 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 events\textsuperscript{21}. 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 amyloidosis\textsuperscript{22}.
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)\textsuperscript{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 fibrillation\textsuperscript{29-33}, while
thalidomide and bortezomib are associated with bradycardia and complete
heart block \textsuperscript{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.

References:

1. Oyajobi, B.O. Multiple myeloma/hypercalcemia. \emph{Arthritis Res
Ther} \textbf{9 Suppl 1} , S4 (2007).

2. Dimopoulos, M.A., Kastritis, E., Rosinol, L., Blade, J. \& Ludwig, H.
Pathogenesis and treatment of renal failure in multiple myeloma.
\emph{Leukemia} \textbf{22} , 1485-93 (2008).

3. Ludwig, H., Novis Durie, S., Meckl, A., Hinke, A. \& Durie, B.
Multiple Myeloma Incidence and Mortality Around the Globe;
Interrelations Between Health Access and Quality, Economic Resources,
and Patient Empowerment. \emph{Oncologist}\textbf{25} , e1406-e1413
(2020).

4. Kumar, S.K. \emph{et al.} Multiple myeloma. \emph{Nat Rev Dis
Primers} \textbf{3} , 17046 (2017).

5. Magen, H. \& Muchtar, E. Elotuzumab: the first approved monoclonal
antibody for multiple myeloma treatment. \emph{Ther Adv Hematol}
\textbf{7} , 187-95 (2016).

6. Raedler, L.A. Ninlaro (Ixazomib): First Oral Proteasome Inhibitor
Approved for the Treatment of Patients with Relapsed or Refractory
Multiple Myeloma. \emph{Am Health Drug Benefits} \textbf{9} , 102-5
(2016).

7. Sanchez, L., Wang, Y., Siegel, D.S. \& Wang, M.L. Daratumumab: a
first-in-class CD38 monoclonal antibody for the treatment of multiple
myeloma. \emph{J Hematol Oncol} \textbf{9} , 51 (2016).

8. Laubach, J.P., Moreau, P., San-Miguel, J.F. \& Richardson, P.G.
Panobinostat for the Treatment of Multiple Myeloma. \emph{Clin Cancer
Res} \textbf{21} , 4767-73 (2015).

9. Offidani, M., Corvatta, L., More, S. \& Olivieri, A. Belantamab
Mafodotin for the Treatment of Multiple Myeloma: An Overview of the
Clinical Efficacy and Safety. \emph{Drug Des Devel Ther} \textbf{15} ,
2401-2415 (2021).

10. Joseph, N.S., Tai, Y.T., Anderson, K.C. \& Lonial, S. Novel
Approaches to Treating Relapsed and Refractory Multiple Myeloma with a
Focus on Recent Approvals of Belantamab Mafodotin and Selinexor.
\emph{Clin Pharmacol} \textbf{13} , 169-180 (2021).

11. Palumbo, A. \emph{et al.}Daratumumab, Bortezomib, and Dexamethasone
for Multiple Myeloma. \emph{N Engl J Med} \textbf{375} , 754-66 (2016).

12. Dimopoulos, M.A. \emph{et al.}Elotuzumab plus Pomalidomide and
Dexamethasone for Multiple Myeloma.\emph{N Engl J Med} \textbf{379} ,
1811-1822 (2018).

13. Passey, C., Darbenzio, R., Jou, Y.M., Lynch, M. \& Gupta, M. Effects
of elotuzumab on QT interval and cardiac safety in patients with
multiple myeloma. \emph{Cancer Chemother Pharmacol} \textbf{78} ,
1237-1244 (2016).

14. Facon, T. \emph{et al.} Oral ixazomib, lenalidomide, and
dexamethasone for transplant-ineligible patients with newly diagnosed
multiple myeloma. \textbf{137} , 3616-3628 (2021).

15. Dimopoulos, M.A. \emph{et al.}Ixazomib as Postinduction Maintenance
for Patients With Newly Diagnosed Multiple Myeloma Not Undergoing
Autologous Stem Cell Transplantation: The Phase III TOURMALINE-MM4
Trial. \emph{J Clin Oncol} \textbf{38} , 4030-4041 (2020).

16. Moreau, P. \emph{et al.} Oral Ixazomib, Lenalidomide, and
Dexamethasone for Multiple Myeloma. \emph{N Engl J Med} \textbf{374} ,
1621-34 (2016).

17. San-Miguel, J.F. \emph{et al.}Panobinostat plus bortezomib and
dexamethasone versus placebo plus bortezomib and dexamethasone in
patients with relapsed or relapsed and refractory multiple myeloma: a
multicentre, randomised, double-blind phase 3 trial. \emph{Lancet Oncol}
\textbf{15} , 1195-206 (2014).

18. Plummer, C., Driessen, C., Szabo, Z. \& Mateos, M.V. Management of
cardiovascular risk in patients with multiple myeloma. \emph{Blood
Cancer J} \textbf{9} , 26 (2019).

19. Dimopoulos, M.A. \emph{et al.}Daratumumab plus pomalidomide and
dexamethasone versus pomalidomide and dexamethasone alone in previously
treated multiple myeloma (APOLLO): an open-label, randomised, phase 3
trial. \emph{Lancet Oncol} \textbf{22} , 801-812 (2021).

20. Virani, S.S. \emph{et al.} Heart Disease and Stroke Statistics-2020
Update: A Report From the American Heart Association. \emph{Circulation}
\textbf{141} , e139-e596 (2020).

21. Al-Kindi, S.G. \& Oliveira, G.H. Prevalence of Preexisting
Cardiovascular Disease in Patients With Different Types of Cancer: The
Unmet Need for Onco-Cardiology.\emph{Mayo Clin Proc} \textbf{91} , 81-3
(2016).

22. Shah, N., Rochlani, Y., Pothineni, N.V. \& Paydak, H. Burden of
arrhythmias in patients with multiple myeloma. \emph{Int J Cardiol}
\textbf{203} , 305-6 (2016).

23. Ewer, M.S. \& Lippman, S.M. Type II chemotherapy-related cardiac
dysfunction: time to recognize a new entity. \emph{J Clin Oncol}
\textbf{23} , 2900-2 (2005).

24. Gupta, A., Pandey, A. \& Sethi, S. Bortezomib-induced congestive
cardiac failure in a patient with multiple myeloma. \emph{Cardiovasc
Toxicol} \textbf{12} , 184-7 (2012).

25. Bockorny, M., Chakravarty, S., Schulman, P., Bockorny, B. \& Bona,
R. Severe heart failure after bortezomib treatment in a patient with
multiple myeloma: a case report and review of the literature. \emph{Acta
Haematol} \textbf{128} , 244-7 (2012).

26. Hacihanefioglu, A., Tarkun, P. \& Gonullu, E. Acute severe cardiac
failure in a myeloma patient due to proteasome inhibitor bortezomib.
\emph{Int J Hematol} \textbf{88} , 219-222 (2008).

27. Herrmann, J. \emph{et al.}Chronic proteasome inhibition contributes
to coronary atherosclerosis.\emph{Circ Res} \textbf{101} , 865-74
(2007).

28. Herrmann, J. \emph{et al.}Primary proteasome inhibition results in
cardiac dysfunction. \emph{Eur J Heart Fail} \textbf{15} , 614-23
(2013).

29. Feliz, V. \emph{et al.}Melphalan-induced supraventricular
tachycardia: incidence and risk factors. \emph{Clin Cardiol} \textbf{34}
, 356-9 (2011).

30. Olivieri, A. \emph{et al.}Paroxysmal atrial fibrillation after
high-dose melphalan in five patients autotransplanted with blood
progenitor cells. \emph{Bone Marrow Transplant} \textbf{21} , 1049-53
(1998).

31. Kaakeh, Y., Overholser, B.R., Lopshire, J.C. \& Tisdale, J.E.
Drug-induced atrial fibrillation.\emph{Drugs} \textbf{72} , 1617-30
(2012).

32. Mathur, P., Paydak, H., Thanendrarajan, S. \& van Rhee, F. Atrial
Fibrillation in Hematologic Malignancies, Especially After Autologous
Hematopoietic Stem Cell Transplantation: Review of Risk Factors, Current
Management, and Future Directions. \emph{Clin Lymphoma Myeloma Leuk}
\textbf{16} , 70-5 (2016).

33. Chatap, G., Giraud, K. \& Vincent, J.P. Atrial fibrillation in the
elderly: facts and management.\emph{Drugs Aging} \textbf{19} , 819-46
(2002).

34. Fahdi, I.E. \emph{et al.}Bradycardia during therapy for multiple
myeloma with thalidomide.\emph{Am J Cardiol} \textbf{93} , 1052-5
(2004).

\textbf{Funding:} The authors declare that this work was not supported
by any funds or grants.

\textbf{Acknowledgment:} None.

\textbf{Conflict of Interests:} The authors have no relevant financial
or non-financial interests to disclose.

\textbf{Data Availability:} The datasets from the current study are
available from the corresponding author upon request.

\textbf{Author Contributions}

All the authors contributed to the study design, writing and analysis.
Data collection and analysis {[}Zaki Al-Yafeai, Anil Ananthaneni,
Mohamed Ghoweba{]}, design {[} Zaki Al-Yafeai, Hamzah Abduljabar, David
Aziz{]}. The first draft was written by {[}Zaki Al-Yafeai{]} with edits
and revision from all the authors. All authors read and approved the
manuscript.

\textbf{Hosted file}

\verb`Primary data.pptx`  available at \url{https://authorea.com/users/472173/articles/570929-cardiovascular-complications-of-modern-multiple-myeloma-therapy-a-pharmacovigilance-study}

\selectlanguage{english}
\FloatBarrier
\end{document}

