Review Article
Cardiovascular Complications of Proteasome Inhibitors
Used in Multiple Myeloma
Daniel C. Cole, MD, MHS,* and William H. Frishman, MD†
Abstract: The use of proteasome inhibitors (PI) as targeted chemotherapeu-
tics have significantly improved survival in patients with multiple myeloma
(MM). However, rare and serious cardiovascular complications have occurred
as a result of their use, most commonly congestive heart failure, hypertension,
and arrhythmias. MM occurs in an aged population with many concurrent
cardiovascular risk factors. The primary disease process also contributes to
cardiovascular complications. Furthermore, many MM patients have prior
exposure to cardiotoxic chemotherapy such as anthracyclines. Because of
these occurrences, the identification, prevention, and management of cardio-
vascular complications is made increasingly difficult. Various clinical studies
and case reports have documented cardiotoxicity among all 3 of the currently
approved PIs, bortezomib, carfilzomib, and ixazomib. Carfilzomib has shown
the highest rates of cardiotoxicity, whereas there is conflicting evidence
regarding bortezomib’s role in producing cardiotoxicity. However, various
case reports have documented the existence of adverse cardiac effects. Higher
frequencies of complications have also been seen in “real-life” populations
with cardiovascular co-morbidities who were originally excluded from clini-
cal studies. Ixazomib, the most recently approved PI, has also been proposed
to cause cardiotoxicity, elucidating a possible class effect. PIs are thought
to cause cardiotoxicity through the unfolded protein response, leading to
apoptosis in cardiac myocytes. Apremilast and rutin have been used in an
animal model to reverse this signaling. Standardized guidelines identifying
patients at greatest risk, to prevent and manage complications, have not yet
been developed. Efforts have been made to prioritize patients older than 60
years with anthracycline exposure, cardiovascular risk factors, or amyloido-
sis. Withholding medication, using slower-infusion times, limiting fluids and
providing supportive therapy have been successful. Screening echocardio-
grams have not been proven effective.
Key Words: multiple myeloma, proteasome inhibitors, congestive heart
failure, cardiotoxicity, bortezomib, carfilzomib, ixazomib
(Cardiology in Review 2018;26: 122–129)
O ver the last 10–15 years, there has been an expansion in the
number of targeted multiple myeloma (MM) therapies.1,2 The
current 5-year survival rate has increased from 34.5% in 2000 to
48.5% in 2012 as a result of improved therapy.3 These therapies,
however, are not without cardiovascular risks. The proteasome inhib-
itors (PIs) specifically have shown signs of cardiovascular toxicity in
some patients, most commonly those with congestive heart failure
(CHF), hypertension, and arrhythmias.4,5 In this article, we provide
an update on the currently described cardiovascular complications
From the *Departments of Medicine, Albert Einstein College of Medicine/Monte-
fiore Medical Center, Bronx, NY; and †New York Medical College/Westches-
ter Medical Center, Valhalla, NY.
Disclosure: The authors have no conflicts of interests to report.
Correspondence: William H. Frishman, MD, Department of Medicine, New York
Medical College, 40 Sunshine Cottage Road, Valhalla, NY 10595. E-mail:
­William_Frishman@nymc.edu
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 1061-5377/18/2603-0122
DOI: 10.1097/CRD.0000000000000183
122  |  www.cardiologyinreview.com Cardiology in Review  •  Volume 26, Number 3, May/June 2018
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
of these therapies, as well as a proposed mechanism for these effects
on cardiac myocytes. Much of the evidence, however, comes from
case reports or from clinical studies with small sample sizes as the
incidence of these cardiac complications is relatively rare. Because
most patients diagnosed with MM are between the ages of 65 and
74 years, many already have significant cardiovascular disease risk
factors, the most common being hypertension and coronary artery
disease (CAD).3,6 Furthermore, the natural history of MM can also
lead to cardiovascular events, including CHF and arrhythmias. We
begin by describing the known cardiovascular effects of MM.
MULTIPLE MYELOMA: NATURAL DISEASE HISTORY
MM is a plasma-cell malignancy characterized by hypercal-
cemia, renal insufficiency, anemia, and bone lesions. Monoclonal
immunoglobulins are secreted by malignant cells at exceedingly high
rates, leading to renal impairment and deposition in bones. Anemia
results from bone marrow infiltration or renal insufficiency.7 Hyper-
calcemia occurs from monoclonal protein binding of calcium and
upregulation of osteoclastic cytokines.8,9 Coexisting amyloid light-
chain amyloidosis with protein deposition can occur in 12%–30%
of MM patients and can also lead to deposition in myocardium, car-
diomyopathy, and electrical abnormalities.10 Very often, coexisting
amyloid light-chain amyloidosis can go undetected in MM and is a
contributing cause of cardiovascular complications.10,11
Population Risk Factors
To correctly understand the cardiovascular effects of MM
therapies, one must understand the population in which they are
occurring. As stated earlier, many MM patients already have signifi-
cant cardiovascular risk factors as a result of their age. Furthermore,
many have been exposed to known cardiotoxic chemotherapeutic
agents such as the anthracyclines (e.g., doxorubicin). In a recent ret-
rospective observational cohort study of MM patients treated with 3
or more different chemotherapeutics, including bortezomib (a PI),
an immunomodulator such as lenalidomide or thalidomide, and an
anthracycline or alkylating agent, Kistler et al12 looked for differ-
ences in the risk of cardiac events among MM patients and age- and
gender-matched controls without MM. They showed a statistically
significant increased risk for any cardiac event (hazard ratio [HR],
2.2; 95% confidence interval [CI], 1.9–2.5), dysrhythmia (HR, 4.1;
95% CI, 3.5–4.8), CHF (HR, 2.9; 95% CI, 2.2–3.7), cardiomyopathy
(HR, 2.6; 95% CI, 1.8–3.8), and conduction disorders (HR, 1.7; 95%
CI, 1.2–2.5) in the MM population. It has become increasingly com-
plicated to determine what is the exact cause of the cardiovascular
effects, as it may be prior chemotherapy exposure, age-related risk
factors, the primary disease process, new chemotherapeutics, or a
combination of these factors.12
MECHANISMS OF CARDIOTOXICITY
Bortezomib (Velcade; Millenium Pharmaceuticals Inc.,
Cambridge, Ma) is a first-line PI approved by the Food and Drug
Administration (FDA) in 2003 for the treatment of MM and mantle
cell lymphoma. It specifically targets the 26S proteasome and forms
stable, reversible interactions with the chymotrypsin-like site of the
Cardiology in Review  •  Volume 26, Number 3, May/June 2018 Proteasome Inhibitors in Multiple Myeloma
complex, which leads to apoptosis of the affected cells.13 Because
malignant plasma cells have very high rates of proteasome activity,
the agent intends to target their destruction. Myeloid plasma cells,
however, are not the only cells in the body with very high proteasome
activity. Cardiac myocytes are also known to have high rates of prote-
asome activity and protein turnover.14,15 Bortezomib and carfilzomib
(a second-generation PI) have been proposed to cause cardiotoxicity
through apoptosis, specifically through caspase-3/7 signaling, which
is how they exert their oncologic effects as well.14
Nuclear factor kappa light chain enhancer of activated B cells
(NF-κB) is an important growth factor and antiapoptotic signal.16
There have been conflicting reports regarding the effect of PI on
NF-kB signaling, requiring further research to elucidate its role in
PI-mediated cytotoxicity.17,18
Finally, PIs have also been shown to promote apoptosis by
activating the unfolded protein response (UPR) in myeloma cells.19
The UPR is a highly conserved process in which the endoplasmic
reticulum turns on numerous biochemical signaling pathways in
response to the stress resulting from the accumulation of misfolded
or unfolded proteins. This accumulation can become cytotoxic as it
disrupts homeostasis, specifically with regards to calcium regula-
tion and oxidation–reduction balance. The proteasome is central to
overcoming this stress as it digests misfolded or unfolded proteins.20
PIs have been shown to effectively promote apoptosis by allowing
myeloma cells to accumulate unfolded or misfolded immunoglobu-
lins and place a check on the prosurvival activity of the proteasome.19
Fu et al21 demonstrated that PIs can cause cell death in rodent cardiac
myocytes through UPR pathways. In their model, the PIs MG132
and epoxomicin were used; however, the authors felt their results
could be extrapolated to explain how other PIs such as bortezomib
can cause cardiotoxicity through this mechanism.21 The UPR has also
been shown to be activated during ischemia in rodent myocardium.22
BORTEZOMIB
Meta-analyses and other investigations have shown conflicting
findings with regards to the risk of bortezomib-induced cardiotoxic-
ity among cancer patients. In a review of 25 clinical studies of 5718
subjects with a range of different cancers, comparing bortezomib to
control medication, there was no increased risk of all-grade (odds
ratio 1.15, 95% CI, 0.82–1.62; P = 0.41) or high-grade cardiotoxicity
(odds ratio 1.13, 95% CI, 0.58–2.24; P = 0.72).23 Cardiotoxicity was
defined as left ventricular ejection fraction decline or dysfunction,
cardiac failure, cardiomyopathy, cardiac arrest, or cardiac arrhyth-
mia. However, when the researchers stratified their results based on
tumor type, there was an increased incidence of cardiotoxicity in
MM patients compared with all other tumor types, both in all-grade
(4.3% vs 2.3%, P < 0.001) and high-grade cardiotoxicity (2.5%
vs 1.8%, P = 0.004).23 This further demonstrates the higher rate of
cardiovascular complications in this population. In a propensity-
matched study of 1790 MM patients treated with bortezomib versus
lenalidomide, there was no increased incidence of hospitalization
for heart failure (HR 1.54, 95% CI, 0.84–2.82).19 The patients were
matched with propensity scores on the basis of age, gender, race,
year of drug initiation, history of CAD, peripheral vascular disease,
diabetes, heart failure, hyperlipidemia, hypertension, myocardial
infarction (MI), arrhythmia, and Charlson/Deyo index. However, the
point estimate for the incidence rate of heart failure hospitalization
was greater in the bortezomib group, despite being nonsignificant,
(3.52/100 person-years vs 2.17/100 person-years).24
Numerous case reports have documented severe cardiotoxic-
ity in patients treated with bortezomib. One such report involved a
66-year-old female with stage IIIB IgG kappa myeloma who was on
her first cycle of cyclophosphamide, bortezomib, and dexametha-
sone.25 Her cardiac history was significant for left bundle branch
© 2017 Wolters Kluwer Health, Inc. All rights reserved. www.cardiologyinreview.com | 123
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
block with a normal ejection fraction (EF). Six hours after her third
weekly dose of 2.5 mg subcutaneous bortezomib, she presented to the
emergency room with progressive dyspnea associated with palpita-
tions. Her electrocardiogram (ECG) showed a normal sinus rhythm
with left bundle branch block. Her troponin increased from 0.323 ng/
ml at presentation to 0.916 ng/ml in 17 hours. An echocardiogram
revealed dilated cardiomyopathy, with a total EF of 15%, lower than
her baseline of 55% documented 2 months prior. Cardiac catheteriza-
tion did not show significant CAD, and her symptoms were deter-
mined not to be due to ischemia. Her Naranjo adverse drug reaction
probability score was 5, indicating a probable relationship between
bortezomib and her acute LV dysfunction. She was treated for acute
heart failure, but her EF only improved to 30%, and her N-terminal
pro-B-type natriuretic peptide (NT-proBNP) level remained elevated
at 11,000 for 3 weeks post presentation. Despite changes in medica-
tion, including removing bortezomib, she developed a line infection,
atrial fibrillation, and ultimately expired 3 months after presentation.25
New-onset arrhythmia has also been documented among
patients receiving bortezomib. Diwadkar et al26 reported on a
66-year-old male with stage IIIA IgA lambda chain MM who
received bortezomib, lenalidomide, and dexamethasone without
any significant cardiovascular history. After 8 cycles of bortezomib
treatment, during a routine pre-stem cell transplant workup, an ECG
demonstrated complete atrioventricular (AV) block with a ventricular
escape rhythm of 55 beats. His troponin I was elevated at 2.49 ng/
ml, the CK-MB was 20.2 ng/ml, and the BNP was 333 pg/ml. An
echocardiogram showed a normal EF with mild hypokinesis of the
mid-inferolateral myocardium. Further cardiac magnetic resonance
imaging (MRI) showed a small subendocardial perfusion defect of
this area with late gadolinium enhancement suggestive of fibrosis
and scar formation (Fig. 1).26 The MRI was not suggestive of cardiac
amyloidosis or any other infiltrative process. His complete AV block
persisted, and he underwent permanent dual chamber pacemaker
placement. Unfortunately, he did not remain a candidate for stem cell
transplant, elected not to receive any more chemotherapy, and died
FIGURE 1.  Cardiac magnetic resonance imaging in a patient
exposed to bortezomib leading to complete heart block
and evidence of myocardial scar. A subendocardial perfu-
sion defect is shown in the inferolateral left ventricle (arrows)
with late gadolinium enhancement suggestive of fibrosis and
scar formation. Reproduced with permission from Case Rep
Cardiol. 2016;2016:3456287.26
Cole and Frishman Cardiology in Review  •  Volume 26, Number 3, May/June 2018

from progression of his disease. The Naranjo adverse drug reaction
score was a 5–6 between bortezomib exposure and new-onset AV
block.26
CARFILZOMIB
Carfilzomib (Kyprolis; Onyx Pharmaceuticals Inc., South San
Francisco, CA) is a novel PI that was approved by the FDA in 2012
for the treatment of patients with MM who have disease progression,
despite being treated with bortezomib and an immunomodulatory
agent such as lenalidomide. Carfilzomib differs from bortezomib by
forming irreversible interactions at the chymotrypsin-like site of the
20S proteasome. These interactions have allowed the drug to possess
greater proteasome inhibition and overcome bortezomib-resistant
myeloma cells lines.27–30 However, cardiac toxicity has also emerged
in proposed mechanisms similar to that of bortezomib. A pooled
analysis of 4 phase II clinical trials of carfilzomib involving 526
patients showed that 7% of patients experienced CHF, and there were
8 cardiac-related deaths, ruled to be possibly related to the treatment.
It should also be noted that patients with New York Heart Association
(NYHA) Class III or IV CHF, recent MI, or unstable angina were
excluded from the studies.4
In the landmark Carfilzomib, Lenalidomide, and Dexametha-
sone versus Lenalidomide and Dexamethasone for the treatment of
Patients with Relapsed Multiple Myeloma (ASPIRE) trial,31 a phase
III confirmatory randomized control trial of carfilzomib, there was
a reported difference in the number of cardiac events. Patients with
a diagnosis of relapsed MM were allocated to receive carfilzomib,
lenalidomide, and dexamethasone or lenalidomide and dexametha-
sone alone. Specifically in the carfilzomib group, the percentage
of grade 3 or higher cardiac failure was 3.8% compared to 1.8%
in the control group (Table 1).32 Grade 3 hypertension (systolic BP
≥160 mm Hg or diastolic BP ≥100 mm Hg, medical intervention
indicated, more than 1 drug or more intensive therapy than previously
used) occurred in 4.3% of the carfilzomib group compared to 1.8%
in the control group (Table 1).32 The authors concluded that there was
no difference in the frequency of deaths because of adverse events
between both groups.31
In the Carfilzomib and Dexamethasone versus Bortezomib
and Dexamethasone for Patients with Relapsed or Refractory Mul-
tiple Myeloma (ENDEAVOR) trial,5 a phase III open-label clini-
cal trial comparing carfilzomib and dexamethasone to bortezomib
and dexamethasone in patients with relapsed or refractory MM, the
investigators found a greater proportion of adverse cardiovascular
events in the carfilzomib population. The proportion of patients with
grade 3 or higher cardiac failure was 4.75% in the carfilzomib group
compared to the 1.75% in the bortezomib group. With regards to
hypertension, 9% of the carfilzomib group and 3% of the bortezo-
mib group populations experienced grade 3 or higher hypertension.
There were 6 deaths because of cardiac events in the carfilzomib
group compared to 5 in the bortezomib group. The results from this
trial suggest that carfilzomib may have a higher rate of cardiotoxicity
compared to bortezomib. The authors also conducted a preplanned
serial echocardiogram study on 151 of the subjects, 75 in the carfil-
zomib group and 76 in the bortezomib group and found 4 patients
in total, 2 from each group, who had a significant reduction in EF at
any time during the study. All except 1 in the carfilzomib group had
a return to their normal EF by the end of the study. Using a mixed
model for repeated measures analysis, they found no significant
effect on EF by treatment or treatment-by-time among the groups (P
values ranged from 0.07 to 0.91).5 Similar rates of grade 3 or higher
heart failure (7%) were seen with carfilzomib, cyclophosphamide,
and dexamethasone given to newly diagnosed MM patients in a dif-
ferent phase II open-label study.33
The above results are from clinical trials where patients did not
have significant cardiac risk factors or a history of cardiotoxic drug
exposure. In a retrospective analysis of 22 patients in Europe exposed
to carfilzomib in a “real-world” setting,34 authors reported 23% of the

TABLE 1.  Common Terminology Criteria for Adverse Events (CTCAE) V4.0: Grade Definitions for Heart Failure
and Hypertension
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
Heart failure* Asymptomatic with Symptoms with mild to Severe with symptoms Life-threatening Death
laboratory (e.g., BNP) moderate activity or at rest or with consequences urgent
or cardiac imaging exertion minimal activity or intervention indicated
abnormalities exertion; intervention (e.g., continuous IV
indicated therapy or mechanical
hemodynamic support)
Hypertension† Pre-HTN (SBP 120– Stage 1 HTN (SBP Stage 2 HTN (SBP Life-threatening Death
139 mm Hg or DBP 140–159 mm Hg or ≥160 mm Hg or consequences (e.g.,
80–89 mm Hg) DBP 90–99 mm Hg): DBP ≥100 mm Hg) malignant HTN,
medical intervention medical intervention transient or permanent
indicated; recurrent indicated; more than neurologic deficit,
or persistent (≥24 h): 1 drug or more hypertensive crisis):
symptomatic diastolic intensive therapy urgent intervention
or to >140–90 mm Hg than previously used indicated
if previously WNL: indicated. Pediatric: same as adult
monotherapy indicated. Pediatric: same as adult
Pediatric: recurrent or
persistent (≥24 h) BP
>ULN: monotherapy
indicated
*Definition: A disorder characterized by the inability of the heart to pump blood at an adequate volume to meet tissue metabolic requirements or the ability to do so only at an
elevation in the filling pressure.
†Definition: A disorder characterized by a pathological increase in BP; a repeated elevation in the BP exceeding 140 over 90 mm Hg.
BNP indicates B-type natriuretic peptide; DBP, diastolic blood pressure; HTN, hypertension; IV, intravenous; SBP, systolic blood pressure; ULN, upper limits of normal; WNL,
within normal limits.
Source: National Cancer Institute: NCI, NIH, DHHS May 29, 2009; NIH publication #09-7473 https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_
quickreference_8.5x11.pdf.32

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Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Cardiology in Review  •  Volume 26, Number 3, May/June 2018 Proteasome Inhibitors in Multiple Myeloma
patients developed LV failure requiring hospitalization despite having
a normal EF at a median of 5 months before receiving carfilzomib. Two
patients required treatment in the intensive care unit, and all but one
made a full recovery after cessation of their myeloma therapy (a patient
with a remote history of MI retained an EF of 30%). Also, one patient
experienced pulmonary hypertension (systolic pulmonary artery pres-
sure 49 mm Hg) while on carfilzomib, which required hospitaliza-
tion. Another patient developed symptomatic atrial fibrillation while
on treatment, also requiring hospitalization. Of these 7 patients who
developed cardiac adverse events, 2 of them had significant cardiovas-
cular histories other than hypertension. One had an MI 25 years prior,
and 1 had atrial fibrillation. Eighty-six percent of the study popula-
tion had previous exposure to anthracyclines. Interestingly, the authors
did not find a significant relationship between cumulative doxorubicin
or carfilzomib exposure–related cardiac adverse event risk (P >0.2).
However, they did find that both of the patients requiring intensive
care treatment after developing LV failure were taking carfilzomib and
doxorubicin concomitantly. They postulated that the cardiotoxicity that
developed may be the result of an additive effect.34
To further examine the cardiotoxicity of carfilzomib, Rosen-
thal et al35 performed pretreatment and posttreatment echocardio-
grams in a prospective cohort study of 30 MM patients. All patients
had normal EFs before treatment. Four patients (13%) developed
significant reductions in EF (defined as a decrease of at least 15%)
and one developed a non–ST-elevation MI during the first cycle of
carfilzomib treatment. They concluded that screening echocardio-
grams could not predict which patients would develop significant
cardiovascular events.35
Atrash et al36 also performed a focused analysis on the cardiac
events associated with carfilzomib use. They looked retrospectively
over a period of 4 years and identified 130 MM patients who had
been exposed to carfilzomib. They identified 26 patients who were
hospitalized for cardiac events not attributable to other causes such as
infections nor had received other anti-MM therapies. The significant
cardiac events included CHF, pulmonary edema, cardiopulmonary
arrest, arrhythmias, hypotension, and hypertension. All 130 patients
had baseline echocardiograms and follow-up exams if they became
symptomatic. Among those with 2 imaging studies (93 patients), the
median EF dropped from 55% to 33%. The investigators noted that
halfway through the observed cohort study period, a switch in the
infusion time was made from 2–10 minutes to 30 minutes, arbitrarily
as a strategy to decrease cardiac events. Twenty of the 26 patients
with cardiac events had shorter infusion times, suggesting a possible
relationship. They also noted that all but one of the 26 patients hos-
pitalized with cardiac events had a history of doxorubicin exposure,
further suggesting an additive effect of carfilzomib to cardiotoxicity.36
Dosing effects associated with carfilzomib cardiotoxicity have
also been reported. Land et al37 performed an analysis on a retro-
spective cohort of 110 patients treated with carfilzomib. They found
a statistically significant association (P = 0.003) between the dose
level of >36 mg/m2 and the likelihood of experiencing a cardiac event
(defined as grade 3 or higher hypertension, CHF, CAD, pulmonary
hypertension, MI, stroke, or arrhythmias).31,37 Lendvai et al38 per-
formed a phase II study of carfilzomib dosed at 56 mg/m2 beginning
at days 8 and 9 of cycle 1 and each dose thereafter in a cohort of 44
patients. Twenty percent (9/44) of patients experienced grade 3 or
higher CHF, which the authors reported was a higher proportion than
the 5.7% grade 3 or higher CHF seen in patients exposed to doses of
15 to 27 mg/m of carfilzomib in other studies.2,4,38 As doses as high
as 70 mg/m2 are being administered in specific protocols, clinicians
should especially be on alert for cardiac events.39
Numerous case reports have been described detailing the car-
diotoxicity of carfilzomib. Chari and Hajje40 described the case of a
64-year-old African American female with IgA kappa MM, Stage
IIA, whose chemotherapy history consisted of 5 cycles of bortezomib,
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Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
dexamethasone, and a cumulative dose of 150 mg/m2 liposomal
doxorubicin. She then received salvage high-dose melphalan with
autologous stem cell transplant with bortezomib maintenance and
DCEP (dexamethasone, cyclophosphamide, etoposide and cisplatin).
Her only known cardiovascular risk factor apart from chemotherapy
exposure was hypertension. Her last known EF 2 years before carfil-
zomib treatment was 40%–45%, and she was NYHA class I. After
completing cycle 2 of carfilzomib, she developed worsening dyspnea
and was hospitalized with acute biventricular CHF, with an EF of
14% and BNP of 34,000 pg/ml. Once she was stabilized, carfilzomib
was resumed on cycle 3 with a reduced dose of 20 mg/m2. On day 8
of this cycle, she again developed dyspnea with an EF of 15%–20%.
She completed the cycle, carfilzomib was withdrawn, and she subse-
quently died in hospice 4 months later.40
Grandin et al41 described a series of 6 patients with relapsed
or refractory MM who experienced numerous cardiac events while
on carfilzomib. The most severe case occurred in a 51-year-old white
male without any known cardiovascular disease with IgG lambda
relaxed or refractory MM who had experienced disease progres-
sion despite receiving bortezomib, dexamethasone, and doxorubicin
(total cumulative dose 80 mg/m2). He was started on carfilzomib and
had a normal echocardiogram. After 6 doses, he developed dyspnea,
and an ECG showed anterior ST-segment elevations, a troponin I
level of 2.5 ng/mL, a BNP level of 2026 ng/mL, and NYHA Class
III HF. His cardiac catheterization revealed normal coronary arter-
ies; however, an elevated LV end-diastolic pressure of 32 mm Hg and
anterior and apical akinesis with an EF of less than 20% were noted.
Carfilzomib was stopped and he was sent home. Four days later, he
presented with pulmonary edema and was treated with diuretics, a
beta-blocker, and an angiotensin-converting enzyme inhibitor. A car-
diac MRI 10 days after his initial presentation showed an EF of 38%
without delayed enhancement (Fig. 2).41 After 6 weeks, his symptoms
improved and his laboratory values normalized. A recovery echocar-
diogram showed an EF of 50%. Of note, his ECG had a persistent
QTc prolongation.
IXAZOMIB
The newest PI, ixazomib (Ninlaro; Millenium Pharmaceuti-
cals Inc., Cambridge MA), was approved by the FDA in 2015 for
MM patients who have received at least one prior therapy. It is the
only oral PI available. It was developed to overcome the bortezomib
resistance seen with some patients and to have a better side-effect
profile, especially with regard to peripheral neuropathy.42 Its mecha-
nism of action is similar to that of bortezomib in that it reversibly
inhibits the β5 subunit of the 20S proteasome complex (although
not the 26S proteasome complex bortezomib targets). However, it
inhibits the β1 and β2 subunits as well at higher concentrations. It is
ingested as a prodrug and hydrolyzed to a free boric acid metabolite
that is biologically active.43
Limited data are available on the cardiac effects of ixazo-
mib, as fewer patients have been exposed to the drug. However,
Jouni et al44 reported on the first proposed case of ixazomib-induced
cardiotoxicity. The patient was an 82-year-old male with recurrent
lambda light chain MM who had been treated with lenalidomide/
dexamethasone and cyclophosphamide/ dexamethasone. His cardiac
history included paroxysmal atrial fibrillation but no known CAD.
Because he progressed on his last chemotherapy regimen, he was
started on ixazomib and dexamethasone and had a baseline echocar-
diogram showing an EF of 60%. After 2 months of therapy, he devel-
oped worsening exertional dyspnea and fatigue. No intervention was
performed at that time. After 4 cycles, he went into acutely decom-
pensated heart failure. A regadenoson myocardial perfusion study
showed patchy apical stress-induced ischemia and an EF of 30%–
35%. Cardiac MRI showed a dilated nonischemic cardiomyopathy
Cole and Frishman Cardiology in Review  •  Volume 26, Number 3, May/June 2018

with global hypokinesis and a linear stripe of delayed enhancement
within the interventricular septum (Fig. 3A).44 There was no evidence
of amyloidosis, and his coronary catheterization showed minimal
atherosclerosis. A right ventricular biopsy showed cardiomyocyte
hypertrophy with mild–moderate interstitial fibrosis without evi-
dence of amyloidosis, hemochromatosis, or myocarditis (Fig. 3B).44
His ixazomib therapy was stopped, and his CHF was treated with
beta-blockers and diuretics. Six months after discontinuation, his
FIGURE 2.  Cardiac magnetic resonance imaging in a pa-
tient exposed to carfilzomib with evidence of cardiac injury
(although minimal troponin elevation). The arrow indicates
the left ventricle during gadolinium contrast and no evidence
of hyperenhancement. His ejection fraction was calculated
at 38%. Reproduced with permission from J Card Fail.
2015;21:138–144.41
cardiac function failed to improve on serial echocardiograms. The
authors reported that the timing of the symptoms and the imaging
was very suspicious for ixazomib-induced cardiotoxicity. They pur-
ported a possible class effect of cardiotoxicity among the PIs.44
MANAGEMENT
As cardiotoxicity among PIs continues to emerge, various
strategies have been developed to identify patients at risk and man-
age patients who experience the adverse effects. Unfortunately,
because it is a relatively rare and recently described occurrence,
there are no standard practice guidelines. As stated earlier, screening
echocardiograms have not been successful in identifying patients at
greatest risk. Nevertheless, some institutions have included them in
their management protocols to obtain baseline cardiac functioning
and to monitor for adverse effects over time.40 A careful history, how-
ever, for cardiovascular risk factors and prior chemotherapy expo-
sure, with particular attention to the anthracyclines, has been shown
to be useful.36
Chari and Hajje40 published a set of recommendations in 2014
for both the prevention and management of cardiac events in patients
exposed to carfilzomib (Table 2). Screening echocardiograms are
obtained on all patients older than 60 years, with a history of anthra-
cycline exposure, known or suspected amyloidosis, or other cardio-
vascular risk factors. Repeat echocardiograms are performed every 2
to 3 cycles. When initiating carfilzomib, they recommend that physi-
cians maintain a high suspicion for any cardiopulmonary symptoms
that develop. Specifically, they recommend asking about and paying
close attention to dyspnea at rest or with exertion, orthopnea, parox-
ysmal nocturnal dyspnea, edema, blood pressure, heart rate, oxygen
saturation, daily weight, and a viscosity level for patients with a high
tumor burden. The drug should be administered slowly over 30 min-
utes, instead of 2–10 minutes as indicated in the prescribing instruc-
tions.28,40 If cardiac events emerge, all other cardiopulmonary causes
such as pulmonary embolism, pneumonia, or anemia should be ruled
out first. If carfilzomib toxicity is suspected, it should be withheld
until the complication resolves to below grade 2 (Table 1).31 It then
may be rechallenged with the last used dose or a reduced dose.40 The
prescribing information for carfilzomib recommends that if patients
develop pulmonary hypertension, new or worsening CHF, decreased
LV function, myocardial ischemia, grade 3 or 4 cardiac events, or
pulmonary complications, the dose should be withheld until the
events resolve completely or return to the patient’s baseline. At that

FIGURE 3.  Cardiac magnetic resonance imaging (MRI) and right ventricular biopsy of a patient exposed to ixazomib. A, Short-
axis cardiac MRI view demonstrates the linear stripe of delayed myocardial enhancement within the interventricular septum
(arrow heads). B, Right ventricular biopsy demonstrated cardiomyocyte hypertrophy with mild to moderate interstitial fibrosis
(H&E 200×). Reproduced with permission from Am J Hematol. 2017;92:220–221.44

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Cardiology in Review  •  Volume 26, Number 3, May/June 2018 Proteasome Inhibitors in Multiple Myeloma

TABLE 2.  Recommended Monitoring and Management of Possible Carfilzomib-Associated Cardiac and Vascular-Related
Events
A. Prevention of cardiac and vascular-related events
 Monitor cardiopulmonary symptoms
 Monitor cardiopulmonary signs (vitals, weight, physical exam)
 Administer carfilzomib over 30 minutes
 Check baseline transthoracic echocardiogram, and repeat echocardiogram every 2–3 cycles.*
  Note, if baseline ejection fraction is below normal, consider utilizing prophylactically strategies listed in (B) Monitor BNP*
 Close follow-up by cardiologist or cardiooncologist*
B. Management of treatment emergent possibly cardiac and vascular-related complications
 Rule out alternative causes (e.g., pulmonary embolus, pneumonia, anemia)
 Hold carfilzomib until toxicity resolves to grade <2
 If the decision is made to rechallenge:
  Implement all preventative/monitoring strategies listed in (A)
  Consider dose reduction
  Decrease or eliminate hydration, especially if the patient has completed ≥1 cycle of 27 mg/m2 carfilzomib while retaining stable renal function and without
experiencing tumor lysis
  Minimize corticosteroids and concomitant fluid retention
  Cautious use of diuretics
  Use of antihypertensives as indicated
*Recommended for patients who are at increased cardiac risk (e.g., anthracycline exposure, age >60 years, amyloid, coronary artery disease).
BNP indicates brain natriuretic peptide.
From BMC Cancer. 2014;14:915–924 (Fig. 3).40

point, the last used dose may be resumed or carfilzomib administered
at a reduced dose.28 The investigators also recommend a cardiology
consultation, repeat echocardiogram, and BNP levels upon the reso-
lution of treatment. Specific attention should be paid to the use of
fluids and diuretics. To prevent tumor lysis syndrome and renal toxic-
ity, 250–500 cc of normal saline are recommended to be given with
each infusion.28 However, withholding these fluids may be beneficial
in patients who are fluid overloaded as a result of complications.40
The role of biomarkers such as BNP and NT-proBNP has not
been formalized with respect to monitoring for PI-induced cardio-
toxicity. Diwadkar et al26 suggest that obtaining cardiac biomarkers
such as BNP may be useful in patients at greater risk for cardiovascu-
lar complications to discover subclinical toxic effects. They explain
that earlier detection may lead to earlier treatment and prevention of
further cardiac dysfunction.26 However, BNP and NT-proBNP levels
should be interpreted with caution in MM patients with significant
kidney involvement, as their levels can be increased in the absence of
cardiac dysfunction.45
Although the recommendations above were developed with
respect to carfilzomib, it would be prudent to follow the same guide-
lines on patients beginning bortezomib or ixazomib treatment who
have a significant cardiac history or prior anthracycline exposure.
Certainly, a class effect of cardiotoxicity among PIs has begun to be
described.44 The role of screening echocardiograms in patients with-
out risk factors has not been well established.35
In terms of targeted strategies to address PI toxicity, the newly
introduced phosphodiesterase-4 inhibitor apremilast, and the biofla-
vonoid rutin have shown promise in reducing the effects of carfilzo-
mib cardiotoxicity in the rodent model.46,47
Apremilast was approved by the FDA in 2014 for the treat-
ment of moderate-to-severe plaque psoriasis and psoriatic arthritis.
As described earlier, the PIs have been known to cause cardiotox-
icity through cellular signaling mechanisms, specifically through
NF-kB pathways and caspase-3/7. Imam et al46 were able to show
decreased levels of cardiac enzymes in rats exposed to carfilzo-
mib and treated with oral apremilast to reverse the adverse car-
diac effects. Furthermore, through gene expression analysis, they
were able to show reduced NF-κB and caspace-3 expression and
increased expression of Iκ-B, the known inhibitor of NF-κB. The
treated mice showed levels of cardiac enzymes and gene expression
similar to carfilzomib naïve controls. However, the authors did not
evaluate whether apremilast had any effect on carfilzomib’s anti-
myeloma cytotoxicity, as the rats were healthy and did not exhibit
any MM disease model.
Imam et al47 also investigated the effects of rutin on revers-
ing carfilzomib-induced cardiotoxicity. Rutin, also known at Vitamin
P, is a bioflavonoid available in many fruits and vegetables that has
been recognized for its anti-inflammatory, anti-oxidant, and car-
dioprotective properties.48,49 In an experimental design similar to
the apremilast study above, the investigators were able to show that
rutin reversed the cardiotoxic effects of carfilzomib when admin-
istered orally.47 Specifically, elevations of cardiac enzymes, lactate
dehydrogenase and CK-MB were reversed to that of controls when
treated with rutin after carfilzomib exposure. Protein content and
expression of NF-κB and expression of p53, the tumor suppressor
gene, were also reversed to levels similar to controls. They were able
to show a reduced expression of beta-myosin heavy chain (MHC)
and an increased expression of alpha-MHC in rats treated with rutin
after carfilzomib.47 A reversed pattern of increased beta-MHC and
decreased alpha-MHC was seen in carfilzomib-only treated animals
and is known to be an expression pattern of hypertrophic cardiac
myocytes in heart failure.50,51 However, the authors also conducted
this study on healthy rats and without a MM disease model and were
not able to evaluate whether rutin increased or decreased carfilzo-
mib’s anti-myeloma cytotoxicity. White blood cell counts, red blood
cell counts, hemoglobin, and hematocrit were measured among the
different treatment groups. Carfilzomib-treated rats had the low-
est values of all the groups. Rutin and carfilzomib-treated rats had
increased counts and at the highest dose of rutin showed complete
blood counts most similar to controls. Further investigation is needed
in a MM disease model in order to evaluate whether rutin counter-
acted carfilzomib’s hematological cytotoxicity.47
CONCLUSION
PIs have improved the survival and management of MM.1
However, cardiovascular effects are continuing to emerge, most
commonly CHF, hypertension, and arrthymias.4,5 Carfilzomib shows
the greatest amount of evidence for adverse cardiovascular events
among the 3 approved PIs for the treatment of MM.5 As these events

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Cole and Frishman Cardiology in Review  •  Volume 26, Number 3, May/June 2018
are relatively rare and “real-life” patients with cardiovascular co-
morbidities are not always included in clinical studies, more targeted
investigations into the cardiovascular effects of these drug class are
needed to truly understand their impact.34 At this time, clinicians
should be on high alert for any cardiopulmonary symptoms that
occur during treatment, especially in those patients with cardiac
histories or risk factors, prior anthracycline exposure, or amyloido-
sis.36,40 The management of events should follow those proposed by
Chari and Hajje40 as above until a standardized consensus emerges.
As with most drug-related adverse events, prevention is key, and
although screening echocardiograms have not shown predictive
value, careful history taking and follow-up is crucial to identify-
ing at-risk patients.35 Apremilast and rutin do show some promise
in reversing cardiotoxicity in animal models; however, further pre-
clinical and clinical studies are needed to evaluate their safety and
efficacy in the target population.46,47 Newer MM therapies are con-
tinuing to be developed, and other classes of medications, including
biologics, are being approved for MM treatment.2 Alternatives to PI
treatment may become valuable and safe approaches to MM patients
with significant cardiovascular history, risk factors, and prior anthra-
cycline exposure.
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