Severe Heart Failure after Using Bortezomib in a Patient with Multiple Myeloma and Cardiac Amyloidosis of Normal Wall Thickness

Abbreviations

AL, Immunoglobulin light chain

MM, Multiple myeloma

INTRODUCTION

Immunoglobulin light chain (AL) amyloidosis is a progressive and potentially fatal disease. As plasma cell dyscrasia is frequently the causative factor, proteasome inhibitors now are the mainstay of the treatment; its associated cardiotoxicity,¹ however, is a looming concern, particularly in individuals with amyloid-infiltrated myocardium. Hence, the baseline cardiovascular assessment is crucial for risk stratification before initiating proteasome inhibitor therapy. In this report, we present the case of a woman who developed cardiogenic shock following the administration of bortezomib for multiple myeloma (MM) and AL amyloidosis.

CASE

A 62-year-old previously-well female visited National Taiwan University Cancer Center because of an unintentional weight loss of 10 kilograms in past 2 years. Concurrently, she reported anorexia, asthenia, and gastrointestinal upset. Laboratory data showed normocytic anemia (hemoglobin 9.5 g/dL, mean corpuscular volume 89.4 fL), renal insufficiency (creatinine 2.0 mg/dL), and a reversed albumin/globulin ratio (albumin 3.9 g/dL; total protein 8.0 g/dL). Serum immunofixation showed immunoglobulin A (2302.85 mg/dL)/kappa light chain (516.00 mg/dL) monoclonal gammopathy, and electrophoresis showed a β2 paraprotein peak of 24.5%. The proportion of Bence Jones protein was 14% in 24-hour urine analysis. In addition, a bone marrow biopsy revealed hypercellularity, eosinophilic amorphous material deposits in vascular walls with positive apple green birefringence in Congo red staining. Immunohistochemical analysis demonstrated increased CD138+ plasma cells with aberrant CD56 expression, positive for kappa and negative for lambda light chains. MM complicated with immunoglobulin deposition disease was diagnosed.

The patient was referred to emergency department of National Taiwan University Cancer Center for dyspnea and dizziness. At triage, she was afebrile and normotensive. Her breath sounds were clear while irregularly slow heart beats with grade II pansystolic murmurs were auscultated. She did not have buffalo shoulder or ecchymosis, and the rest of physical examination was unremarkable. Electrocardiography showed sinus bradycardia with first-degree atrioventricular block (Figure 1A), and a chest radiograph revealed increased bilateral infiltrates but no cardiomegaly (Figure 1B). Blood gas analysis revealed metabolic acidosis, and a trans-thoracic echocardiogram showed normal sizes of cardiac chambers with preserved contractility (Figure 1C). Systemic workup to investigate potential organ involvement of amyloidosis was performed. Duplex imaging confirmed neither compromised flow nor structural anomalies of bilateral carotid arteries. To investigate possible neurological involvement, a random abdominal skin biopsy was performed yet only mild lymphoid cell infiltration in the papillary dermis was present. Biopsies of the stomach and duodenum, nevertheless, showed positive Congo red stain with positive apple green light focal birefringence. MM with AL amyloidosis was therein diagnosed.

Figure 1.

(A) 12-lead electrocardiogram. (B) Chest X ray. (C) Baseline trans-thoracic echocardiogram. (D) Coronary angiography. (E) Clinical trajectory. BiPAP, bi-level positive airway pressure; GI, gastrointestinal; VCd, bortezomib, cyclophosphamide, dexamethasone; Vd, bortezomib, dexamethasone; VT, ventricular tachycardia.

Bortezomib (1.2 mg/m²) and dexamethasone (8 mg) were administered for three times as the anti-myeloma induction therapy. Two days after second dose of bortezomib and immediately after sedation for biopsy, the patient developed the worsening bradycardia with frequent long electrocardiographic pauses. Electrocardiogram exhibited first degree atrioventricular block with occasional ventricular premature complexes. Dopamine was initiated for hemodynamic support, along with diuretics and thoracentesis to manage congestion. She was then transferred to National Taiwan University Hospital. Follow-up echocardiography revealed a dramatic reduction in left ventricular ejection fraction from 65% to 30%. Additional cyclophosphamide (100 mg) was introduced with the third dose of bortezomib AL amyloidosis was evident through the pathology of gastrointestinal tract biopsy. However, transient asystole with syncope occurred, necessitating intensive inotropes and mechanical ventilation. Pulmonary artery catheter documented plummeting cardiac output at 1.39 L/min/m², elevated pulmonary capillary wedge pressure at 21 mmHg, and high systemic vascular resistance at 2933 dynes/sec/cm⁵, indicating cardiogenic shock. Emergent coronary angiography exhibited unobstructed circulation (Figure 1D). A temporary pacemaker was placed, and an endomyocardial biopsy was conducted, in hypertrophic myocardium and arteriolosclerosis with fatty deposits, along with interstitial fibrosis and positive Congo red stain (Figure 2). AL amyloidosis with cardiac involvement was confirmed. Approximately 22 hours after biopsy, pulseless ventricular tachycardia ensued. Because of the patient’s do-not-resuscitate order, she was discharged home against medical advice in a critical condition 10 days after the institution of bortezomib and dexamethasone. The overall admission course is summarized (Figure 1E).

Figure 2.

Stains of endomyocardial biopsy. (A) Hematoxylin and eosin showed hypertrophy and arteriolosclerosis with fatty deposit. (B) Masson trichrome revealed interstitial fibrosis. (C) Apple green light birefringence by Congo red. (D) Equivocal transthyretin. (E) Equivocal kappa chain. (F) Negative lambda chain.

DISCUSSIONS

MM accompanied with AL amyloidosis is a challenging clinical scenario, and cardiac involvement is usually of the most dismal prognosis. Although proteosome inhibitors are currently the major player in therapy, its cardiovascular toxicity might be overlooked and remains a major clinical concern. In this report, this patient with MM and AL amyloidosis developed cardiogenic shock after receiving bortezomib-based therapy (namely, VCD). Below, we review the literature regarding cardiac amyloidosis and the clinical use of bortezomib.

AL amyloidosis arises from accumulation of excessively produced immunoglobulins by malignant plasma cells in various tissues. Among the organs involved, myocardial amyloid infiltration contributes largely to morbidity and mortality, manifesting as arrhythmias, conduction abnormalities, and heart failure.² A positive monoclonal protein screening and tissue-proof are gold standard for diagnosis.³ A hallmark feature of echocardiogram characterizes elevated left ventricular wall thickness, which emerged as a prominent red flag sign. However, normal wall thickness is still possible especially in AL subtype.⁴

In a retrospective study, left ventricular wall thickness less than 12 mm was found in 38% of the subjects with AL amyloidosis.⁵ Another study reported similar incidence, and patients with normal chamber wall thickness were still all classified as AL subtype.⁶ In our case, an endomyocardial biopsy confirmed amyloid deposition, albeit an absence of thickened wall. These findings highlighted the limitation of increased wall thickness in diagnosing AL cardiac amyloidosis.

The integration of proteasome inhibitors into the induction therapy has significantly improved the treatment of MM. Bortezomib, as a first-in-class medication, has become the clinically preferred drug for its limited marrow toxicity, and its dosage needs not be adjusted for renal function.¹ Yet, bortezomib-related cardiotoxicity should be a clinical concern. In an in vitro study, cardiotoxicity was confirmed by a widened endoplasmic reticulum and the presence of lysosomes/autophagosomes in rat heart cells exposed to bortezomib.⁷ Intriguingly, whether the pathophysiology of bortezomib-related cardiotoxicity translates to the development of clinical complications remains debatable. In the landmark SWOG S0777 trial,⁸ neither general cardiac adverse events nor arrhythmias were increased by adding bortezomib to the therapy. Likewise, a previous meta-analysis reported comparable rates of all-grade or high-grade cardiotoxicity when compared with placebo.⁹ In our case, the sudden occurrence of decompensated heart failure after bortezomib suggested a drug-related cause rather than the typical disease course of cardiac amyloidosis. In such complicated scenarios, multi-disciplinary assessments are recommended by guidelines to facilitate integrated care.¹⁰

In conclusion, individuals diagnosed with both MM and cardiac amyloidosis should be carefully evaluated before initiating proteasome inhibitors. Even normal left ventricular wall thickness does not exclude AL cardiac amyloidosis, and a thorough initial assessment by a cardio-oncology panel is essential to optimize the therapeutic regimen.

LEARNING POINTS

MM complicated with AL cardiac amyloidosis is a devastating clinical condition. Even a normal cardiac chamber wall thickness does not exclude AL amyloid involvement. Patient outcomes have been markedly improved since the introduction of proteasome inhibitors, of which bortezomib has been established as the first choice in anti-myeloma treatment. Notably, the potential bortezomib-related cardiac adverse events should be of concern.

DECLARATION OF CONFLICT OF INTEREST

The authors declared no potential conflict of interest.

FUNDING/SUPPORTING INSTITUTION

None.