Bortezomib-Induced Congestive Cardiac Failure in a Patientwith Multiple Myeloma

Ajay Gupta • Anvita Pandey • Sumit Sethi

Published online: 28 September 2011

� Springer Science+Business Media, LLC 2011

Abstract Bortezomib therapy is known to be associated

with neurological side effects and thrombocytopenia. Its

cardiac side effects are however not well known. The

patient, a 70-year-old woman, with a previous history of

myocardial infarction and subsequent coronary stenting,

was detected to have multiple myeloma stage IIIa. She was

started on Inj. Bortezomib (1.3 mg/m2) and Tab. Dexa-

methasone 40 mg on a weekly basis. She showed good

response to therapy. Three days after administration of the

22nd dose of bortezomib, she presented to the hospital with

congestive cardiac failure. Echocardiography revealed a

drop in the left ventricular ejection fraction from pre-

treatment levels of 45–50 to 25%. Patient was treated

medically for left ventricular failure secondary to a sus-

pected ischemic etiology. Coronary angiography revealed

non-critical coronary artery disease with patent right cor-

onary artery and left circumflex stents. The N-terminal pro-

brain natriuretic peptide (NT-proBNP) levels that were

initially raised 4,030 pg/ml (\125 pg/ml) declined to

2,280 pg/ml a week later and subsequently normalized

over the next 2 weeks. The patient responded well to

treatment and was then discharged. The left ventricular

ejection normalized over the next 3 months. Cardiac side

effects of bortezomib are not well reported. Elderly

patients and those with preexisting cardiac conditions

could be at increased cardiovascular risk. Since this risk

increases once a cumulative dose of 20 mg/m2 has been

administered, patients need to be monitored more inten-

sively once this threshold has been attained. Increased

awareness of these cardiac side effects is necessary for

patients’ safety.

Keywords Multiple myeloma � Bortezomib �Cardiac failure � Reversible

Introduction

Bortezomib is an important new drug used in the therapy of

multiple myeloma [1, 2]. Bortezomib therapy is known to

be associated with neurological side effects and thrombo-

cytopenia [3, 4]. Its cardiac side effects are however not

well known [5–12].

We describe precisely the report of such a case who

developed congestive cardiac failure while on therapy and

which resolved upon discontinuation of bortezomib.

Case Report

The patient, a 70-year-old lady, and also a known diabetic

and hypertensive on therapy, presented with severe back

pain of 4-month duration.

In 2001, the patient had inferior wall myocardial

ischemia with left ventricular dysfunction after which she

underwent percutaneous transluminal coronary angioplasty

All authors have contributed equally to the manuscript.

A. Gupta (&)

Max Cancer Center, Saket, P-41, South Extension-2, New Delhi,

India

e-mail: ajayajaygupta2002@rediffmail.com

A. Pandey

Department of Medical Oncology, Max Cancer Center, Saket,

New Delhi, India

S. Sethi

Department of Cardiology, Max Heart and Vascular Center,

Saket, New Delhi, India

123

Cardiovasc Toxicol (2012) 12:184–187

DOI 10.1007/s12012-011-9146-7

with stent placement to the left circumflex (90% lesion)

and the right coronary artery (95% lesion).

She remained asymptomatic till the date of present

complaints. She was admitted to a private hospital with

complains of severe backache. She was found to be ane-

mic. Her hemogram was the following: hemoglobin (Hb)—

6.7 g/dl (12–15 g/dl), total leukocyte count—8.6 9 109/l

(4,000–10,000 109/l), platelets—160 9 109/l (150–450 9

109/l). Peripheral smear was unremarkable except for

rouleaux formation.

She was given 2 units of blood transfusion. Kidney

function tests were normal with serum urea—23/mg dl

(15–38 mg/dl), serum creatinine—0.5 mg/dl (0.6–1.3 mg/

dl), and liver function tests were also normal. In view of

persistent back pain and anemia, she was evaluated for

multiple myeloma. Serum protein electrophoresis was per-

formed. M spike was present—4.94 g/dl. Serum immuno-

electrophoresis revealed the following: immunoglobulin A

(IgA)—49 mg/dl, immunoglobulin G (IgG)—4,912 mg/dl,

immunoglobulin M (IgM)—\25 mg/dl. Beta-2 microglob-

ulin levels were also raised—6.178 mg/l (0.7–3.4 mg/l).

Urine electrophoresis was negative. Thereafter, she was

referred to our hospital.

Bone marrow aspiration and biopsy performed for the

evaluation of multiple myeloma revealed 35% plasma

cells. Myeloid to erythroid ratio was 4:1. Skeletal survey

revealed compression collapse of D4-D6, D11, L1 and L5

vertebrae. Old fractures were seen in the right inferior

ischiopubic ramus and anterior pillar of the right acetabu-

lum. Lytic lesions were also seen in the right ala of the

sacrum and multiple ribs. Patient was thus diagnosed to be

a case of multiple myeloma, stage III A.

2-D echo (two dimensional echocardiography) before

starting treatment showed left ventricular ejection fraction

(LVEF)—45–50%, with trace tricuspid regurgitation (TR)

and posterior and inferior wall akinesia.

She was started on Inj. Bortezomib (1.3 mg/m2) ? Tab.

Dexamethasone 40 mg on a weekly basis.

At the end of four months of weekly bortezomib (viz

16 doses of bortezomib), evaluation was performed. The

patient showed marked clinical improvement. She was

able to walk and perform activities of daily living on her

own without any assistance. Serum IgG levels had

reduced to 3,513 mg/dl. She then continued on the same

regimen.

However, 3 days after the 22nd dose (cumulative dose

of bortezomib 28.6 mg/m2), patient was presented to the

hospital emergency department with complaints of uneas-

iness and restlessness. Physical examination revealed a

pulse rate—106/min, blood pressure—180/100 mmHg,

raised jugular venous pressure (JVP) and bilateral crepi-

tations on chest examination. Electrocardiogram (ECG)

performed was suggestive of sinus tachycardia.

Cardiac enzymes measurements at presentation revealed

creatinine phosphokinase (CPK)—52.0 IU/l (normal range:

26–140 u/ml), creatinine kinase—MB (CK–MB)—21.0U/l

normal range (0–24.0 u/l), troponin I (Trop-I)—0.04 ng/ml

(normal range:\0.04 ng/ml). N-terminal pro-brain natriuretic

peptide (NT-proBNP)—4,030 pg/ml was increased (normal

range:\ 125 pg/ml). Serial measurements of cardiac

enzymes taken over the next 2 days were non-contributory

and were as follows: CPK—47 IU and 39 IU, CPK–MB—17

and 14 IU and troponin I (0.05 and 0.04 ng/ml), respectively.

2-D echocardiography revealed global hypokinesia with

a left ventricular ejection fraction (LVEF) of 25% with

akinesia of the posterior and inferior wall. Patient was

treated medically with diuretics, nitroglycerine drip, and

low molecular weight heparin for left ventricular failure

secondary to a suspected ischemic etiology. She underwent

coronary angiography that however revealed non-critical

coronary artery disease with patent right coronary artery

and left circumflex stents. 2-D echocardiography per-

formed after 96 h of admission revealed a LVEF of

30–35%. It was repeated after 3 weeks when the LVEF

was 40%. Evaluation after 3 months revealed that the

LVEF had returned to pretreatment levels of 45–50% with

persistent akinesia of the posterior and inferior wall.

The N-terminal pro-brain netriuretic peptide (NT-

proBNP) levels that were initially raised 4,030 pg/ml

(\125 pg/ml) declined to 2,280 pg/ml a week later and

subsequently normalized over the next 2 weeks.

The patient responded well to the treatment and was

then discharged.

Bortezomib was discontinued, and she was started on

oral melphalan and prednisolone which she continues to

take till date.

Discussion

Bortezomib is an antitumor compound which inhibits

proteasome activity. It impairs the activation of nuclear

factor (NF)—kB, blocking the inhibitory kB that is

required for IF—kB translocation into the nucleus. Acti-

vation of NF—kB is important for cell survival. IF is

involved in regulation of apoptosis (BCL2, LCL2L1), cell

cycle progression, inflammation and angiogenesis [1, 2].

Bortezomib therapy is known to be associated with neu-

rological side effects and thrombocytopenia [3, 4]. Its cardiac

side effects are however not well known. Indeed, only a few

case reports have discussed this phenomenon [5–9]. These

reports provide alarming signals that treatment with Bort-

ezomib might be associated with significant cardiac events.

In the largest study reported so far, serious unexpected

cardiac side effects requiring hospitalization were observed

in 8 of the 69 patients receiving bortezomib (6 of multiple

Cardiovasc Toxicol (2012) 12:184–187 185

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myeloma, 2 of non–Hodgkin’s lymphoma) [5]. 3 of these

patients were women. 6 of the patients had previously been

treated with anthracyclines.

Four patients had developed symptomatic congestive

cardiac failure with LVEF ranging from 20 to 35%. Bra-

dycardia with atrioventricular block requiring pacemaker

implantation developed in another 4 patients.

Age[60 years and administration of at least 4 cycles of

bortezomib were the major risk factors associated with

development of cardiovascular side effects in this study.

Cardiac symptoms were recorded only after a cumulative

dose of 20 mg/m2 of bortezomib had been given [5]. In our

case, the dysfunction occurred after a cumulative dose of

28.6 mg/m2.

Various mechanisms have been proposed to explain this

toxicity. Bortezomib is known to worsen ischemic heart

disease [10, 11]. The presence of reduced proteasome

activity is associated with an increased rate of apoptosis in

smooth muscle cells, resulting in atherosclerotic plaque

instability due to weakening of the fibrous cap and

enlargement of the necrotic core [10, 11]. This causes

increased propensity of the atherosclerotic plaque to rup-

ture resulting in ischemic complications.

Cell culture experiments have demonstrated that bort-

ezomib causes significant structural abnormalities within

the mitochondria of the cardiomyocytes resulting in

decreased adenosine triphosphate (ATP) synthesis and

reduced cardiac contractility [12]. Thus bortezomib treat-

ment can result in significant left ventricular contractile

dysfunction. The reversibility of cardiac failure on stopping

bortezomib and negative findings on angiography lend

further credence to this theory [8, 12].

In our case, because of the past history of coronary

artery disease, the mechanism behind cardiac failure can-

not be precisely delineated. It could have been because of

depression of myocardial contractility, worsening of cor-

onary artery disease or both. Echocardiography revealed

global hypokinesia. The findings of akinesia in the pos-

terior and inferior walls were also present before the start

of treatment. Cardiac enzymes were not elevated. Angi-

ography showed patent stents to the right coronary artery

and left circumflex artery.

An interesting finding was the elevation of NT-proBNP

detected in our case. A similar elevation of NT-proBNP has

been described in a patient with lung cancer on bortezomib

which was detected when he developed cardiac failure with

LVEF of 10–15%. Upon discontinuation of bortezomib,

LVEF improved to 45%. His NT-proBNP had risen to

2,569 ng/l, post 2 cycles, and to 5,177 ng/l when admitted

for cardiac failure. Reversibility of cardiac failure on

stopping bortezomib and the negative angiographic find-

ings suggested that cardiac failure was drug induced. His

NT-proBNP levels normalized as the ejection fraction

improved [6].

It would be interesting to investigate whether NT-

proBNP levels could serve as a surrogate marker for left

ventricular dysfunction in patients on bortezomib.

Conclusion

Cardiac side effects of bortezomib are not well reported.

Elderly patients those with preexisting cardiac conditions

or exposure to anthracyclines could be at increased car-

diovascular risk. Since this risk increases once a cumula-

tive dose of 20 mg/m2 has been administered, patients need

to be monitored more intensively once this threshold has

been attained. Increased awareness of the cardiac side

effects of bortezomib is necessary for patients’ safety.

Conflict of interest None.

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