Severe Right-Sided Heart Failure and Pulmonary Hypertension with Carfilzomib Treatment in Multiple Myeloma.

Carfilzomib, a second-generation irreversible proteasome inhibitor, is currently considered the preferred therapy for relapsed and refractory multiple myeloma. There are several cardiovascular adverse effects described with carfilzomib chemotherapy most commonly being hypertension, dyspnea and decreased cardiac ejection fraction. We report a case of newonset pulmonary hypertension with right ventricular (RV) heart failure in a patient receiving carfilzomib. Awareness of this rare side effect of this drug is essential for prompt diagnosis and management. We also propose close monitoring of RV and pulmonary artery pressures along with left ventricular function in echocardiographic assessment in patients with carfilzomib chemotherapy. Copyright:

INTRODUCTION

Carfilzomib, a second-generation irreversible proteasome inhibitor (PI), is currently considered the preferred therapy for relapsed and refractory multiple myeloma (MM). Several cardiovascular adverse events (CVAEs) have been described. We describe a case of pulmonary artery hypertension with acute severe right-sided heart failure.

CASE PRESENTATION

We present a case of a 47-year-old female with high-risk immunoglobulins A kappa MM diagnosed initially in April 2018 when routine urine examination showed proteinuria and subsequent kidney biopsy showed kappa light chain proximal tubulopathy. Bone marrow examination revealed an increased number of plasma cells and diagnosis of MM was confirmed.

An echocardiogram done at the time showed a left ventricular ejection fraction (LVEF) of 60% as part of the routine prechemotherapy work up. She received induction chemotherapy and subsequently autologous stem cell transplantation. The patient attained complete remission and started maintenance regimen with carfilzomib, thalidomide, and dexamethasone. After three monthly cycles of this regimen, dose of carfilzomib was increased to 56 mg/sq m, when she developed progressive shortness of breath, weakness, and fatigue. She experienced no chest pain, cough, or fever. Her shortness of breath had become progressively worse until it became disabling and she presented to the emergency department for evaluation.

On initial examination, she was found to be having acute hypoxic respiratory failure and hypotension. The initial laboratory workup showed white blood cell 9 K/μL, Hb 12.5 g/dl, platelets 26 K/μL. Na 139 mmol/L, K 4.2 mmol/L, Cl 106 mmol/L, bicarb 13 mmol/L, anion gap 20, serum creatinine 1.5 mg/dl (baseline 0.6 mg/dl), lactate 7.3 mmol/l, troponin 0.76 ng/ml (normal <0.04 ng/ml). Although her chest computed tomography scan was negative for pulmonary embolism, it showed dilatation of her right ventricular (RV), inferior vena cava and hepatic veins, as shown in Figure 1.

Figure 1

Computed tomography chest and abdomen showing dilated right ventricular, dilated inferior vena cava, hepatic veins, liver mottled appearance suggestive of congestion

The patient was admitted to the medical intensive care unit was started on broad-spectrum antibiotics cefepime, vancomycin, diuretics, and bilevel positive airway pressure therapy. Cardiology team was consulted and dobutamine drip was started. An echocardiogram showed preserved left ventricular (LV) systolic function, dilated RV with evidence of severe pulmonary hypertension and tricuspid regurgitation [Figure 2].

Figure 2

Echocardiogram showing right ventricular dilation, tricuspid regurgitation

Right heart catheterization confirmed elevation in pulmonary artery pressures (54/19 mmHg with a mean value of 32 mm Hg) with a normal wedge pressure of 7 mmHg. The right atrial and RV pressure were 8 mm and 53 mm Hg, respectively. The transpulmonary gradient was 25 mmHg, pulmonary vascular resistance was 3.7 Woods units and cardiac output was 6.7 L/min. Based on these hemodynamic findings, a diagnosis of severe isolated right-sided heart failure with severe tricuspid regurgitation and RV pressure overload was confirmed.

Carfilzomib was discontinued on admission. She gradually improved during the rest of the hospital admission and was subsequently discharged home. She continued thalidomide 100 mg daily after the discharge. Follow-up echocardiogram after 6 months showed LVEF of 60%, but most importantly RV function significantly improved with no evidence of pulmonary hypertension. At present, her MM remains in remission with chemotherapy regimen of daratumumab, thalidomide, and dexamethasone.

DISCUSSION

Carfilzomib is a proven first-line chemotherapeutic drug that extends overall survival in relapsed MM.[1] Our case highlights the importance that in addition to monitoring LV function, assessment of pulmonary pressures and RV function needs to be taken into account when treating MM patients with carfilzomib. Carfilzomib has emerged as a frontline agent for the treatment of relapsed refractory MM after promising results in ENDEAVOR and ASPIRE trials.[23] The first-generation PI, Bortezomib is usually well tolerated. It is administered in the outpatient. The most common side effects are peripheral neuropathy and thrombocytopenia.[4]

Carfilzomib is a second-generation irreversible PI. ASPIRE (CArfilzomib, Lenalidomide, and DexamethSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma) Trial and ENDEAVOR (RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma) clinical trials showed that dyspnea, heart failure, hypertension was more common in the carfilzomib arm versus the control group.[23] Waxman et al.[5] found an incidence of 8.2% of high-grade CVAEs and overall incidence of 18.1% CVAEs with higher doses of carfilzomib and close monitoring of cardiovascular function was suggested for these patients.[5] Carfilzomib targets the 20 S constitutive proteasome in the heart and leads to a strong inhibition of the cardiac proteasome enzymes [Figure 3]. Several molecular mechanisms have been proposed for the CVAEs with carfilzomib including oxidative stress and myocyte apoptosis in animal models, endothelial dysfunction, perivascular fibrosis, increased coronary vascular tone, and decreased coronary relaxation.[567]

Figure 3

Pathophysiology of the adverse effects of proteasomal inhibitors

Apart from clinical trials, data from the “real world” experience as reported by Danhof et al.[8] showed that 23% of MM patients treated with carfilzomib developed LV failure despite having normal ejection fraction before treatment. In our institution during a 4-year study period from 2009 to 12, out of 130 patients treated 26 (20%) patients developed cardiac adverse events including congestive heart failure, hypertension, and arrhythmias.[9] Both these real-world studies contain patients who were heavily pretreated and most of them were exposed to other cardiovascular risk factors including doxorubicin.[89]

However, right-sided heart failure and pulmonary artery hypertension have been rarely described with carfilzomib, though mentioned as a potential adverse effect in the drug insert provided by the drug maker.[1] Management of pulmonary hypertension involves diagnosis confirmation with echocardiography and right heart catheterization. The role of cardiac biomarkers (cardiac troponin, brain natriuretic peptide [BNP] and N-terminal proBNP) which are invariably elevated, though useful in diagnosis, but levels do not correlate with clinical symptoms or hospitalizations.[89]

Carfilzomib chemotherapy for MM patients requires close monitoring for CVAEs. There are some general recommendations which start with detailed history including history of prior doxorubicin exposure, radiation therapy and physical examination. Monitoring cardiac function with cardiac biomarkers and echocardiography is recommended[10] [Table 1]. Administration over 30 min with reduced prehydration has been also suggested to decrease cardiac adverse events.[89]

Table 1

Suggested guidelines for the management of cardiovascular adverse events with carfilzomib

Comprehensive history for the potential risk factors and physical examination of the patient

Baseline transthoracic echocardiogram, and cardiac biomarkers BNP, troponins, NT-proBNP levels, serial measurements in high risk cases

Administer carfilzomib over 30 min with decreased dose/reduced prehydration

Higher dose carfilzomib >36 mg/m2 needs to monitored more closely with cardiac biomarkers and 3-6 monthly echocardiograms

Close monitoring of the co-administration of known cardiotoxic agents such as doxorubicin, cyclophosphamide etc. and dose reduction if possible

BNP: Brain natriuretic peptide

CONCLUSION

Overall, right-sided heart failure and pulmonary hypertension are novel side effects of carfilzomib and its awareness is of vital importance to both the oncologist and cardiologist.

Additionally, cardiovascular adverse effects of carfilzomib are dose related and more close periodic monitoring of cardiovascular function is required. Overall, there is a need for guidelines for the risk stratification and appropriate management of CVAE associated with chemotherapeutic agents and both the oncologist and cardiologists needs to be aware of these rare side-effects for optimal medical management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.