DOI: https://doi.org/10.21203/rs.3.rs-33846/v1
Proteasome inhibitors such as carfilzomib are indicated in multiple myeloma patients showing relapse and/or refractoriness of clonal activity after initial treatment. However, this therapy has been associated with a significative incidence of cardiotoxicity, especially in patients with known cardiovascular risk factors. Here we report a case of a 60-year-old woman with multiple myeloma, who developed congestive severe heart failure with positive myocardial lesion biomarkers and LVEF and strain reduction, after treatment with carfilzomib. Therefore chemotherapeutic drug was discontinued and neurohormonal blocking and diuretic therapy was started resulting in amelioration of symptoms, without changes in LVEF but with significant GLS improvement. This case illustrates the behavior of carfilzomib induced cardiotoxicity and the expected response to the appropriate pharmacological management. Although high-grade cardiotoxicity is relatively rare in patients with non previous cardiac risk factors, it was a predictable side effect of carfilzomib use. Recognition of this syndrome is critical to instauration of appropriate therapy and prevention of morbimortality.
Multiple myeloma is a clonal plasma cell pathology that represents approximately 10% of the malignant hematological disorders. Average survival is approximately 5 to 7 years, with variations according to individual’s characteristics, tumor stage, cytogenetic alterations, and treatment response (1). The most important phases of the pharmacological management include initial therapy with immunomodulators, protease inhibitors, and dexamethasone. Subsequently, the eligible patients are subjected to autologous transplant. A maintenance phase follows, and its duration varies according to the identified cytogenetic profile and individual specific risk factors. Finally, management of those patients showing relapse and/or refractoriness are found in the last phase. In the latter case, triple therapy with immunomodulators, dexamethasone, and proteasome inhibitors like carfilzomib is indicated. The function of this chemotherapeutic agent is to irreversibly inhibit the protease activity of 20S proteasome, which is responsible for inter-cellular protein degradation through the ubiquitin-proteasome, and to disrupt cellular signaling pathways, leading the cell to apoptosis (2).
Cardiotoxicity is one of the described adverse events of this therapy, which covers a broad range of clinical signs classified in five categories according to its severity: 1: mild, 2: moderate, 3: severe, 4: life threatening or disabling, and 5: fatal. Nevertheless, for practical purposes, many studies classify them according to whether or not they are high-grade, covering the last three toxicity levels described above (3)(4). According to the data published by Shah et al, incidence of carfilzomib induced cardiotoxicity due to all categories and high-grade –including the appearance or exacerbation of heart failure, arrhythmogenic events, or cardiac arrest– is 8,68% and 4.34%, respectively, which represents a larger incidence of cardiotoxicity compared with the use of other PI such as bortezomib, that shows a high-grade cardiotoxicity incidence of 2.3% (2)(3).
Below, we discuss the case of a patient with MM who suffered heart failure due to the use of carfilzomib prescribed for tumor relapse management. This case illustrates different cardiotoxicity clinical and paraclinical signs in a patient who did not have cardiovascular symptoms prior to carfilzomib administration and without any indication of other probable heart failure etiologies. Once there was evidence of a high-grade cardiovascular adverse event, the medication was discontinued, and neurohormonal blocking therapy was initiated showing subsequent clinical and echocardiographic parameter improvement.
The case involves a 60-year-old female with MM diagnosis since 2016. She had a history of primary hypothyroidism treated with levothyroxine, 100 mcg/daily. Resulting from her hematological disease, she had chronic anemia (Hb 8 g/dL), stage 3A- A3 chronic kidney disease (GFR 52 ml/min/1.73 m2), and non-nephrotic proteinuria (1.8 g in urine collection over 24 hours). In relation to the oncological treatment, she received 8 CyBorD therapy cycles in April 2016; later on, in March 2018, she required a hematopoietic precursor autologous transplant. The patient initiated late maintenance therapy with lenalidomide and dexamethasone in May 2019. Nevertheless, the hematology department prescribed a KRD chemotherapy plan due to the disease’s progression since August 2019. Prior to the initiation of such plan, a transthoracic echocardiogram was performed with evidence of preserved ventricular systolic function, LVEF 58% and GLS of -17%.
In December 2019, after 5 cycles of treatment, the patient experienced a rapid decline in her functional status, changing from NYHA functional class I to II in 2 weeks, presenting also paroxysmal nocturnal orthopnea and dyspnea, which was the reason for her hospital admission. Given the symptomatology discussed above and based on international recommendations related to monitoring and treatment of cardiovascular adverse events in patients with MM medicated with carfilzomib (4), extension studies were indicated including serum heart biomarkers: NT-proBNPwith a value of 17,570 pg/mL (cut-off point ≥ 900 pg/mL in patients between 50–75 years old) and troponin I with a value of 0.006 (cut-off point 0-0.017 pg/ml). A transthoracic echocardiogram showed left ventricular concentric hypertrophy, 182 g/m2 ventricular mass, diffuse hypokinesia, LVEF of 45% and SLG of -11.7%, in addition to a lung ultrasound scan with B profile. Based on these findings, high probability of congestive severe heart failure secondary to toxicity by carfilzomib, classified as CVAE grade 3, was considered and the chemotherapeutic drug was discontinued. The following prescription was initiated: enalapril 5 mg twice a day, carvedilol 25 mg twice a day, spironolactone 25 mg/daily, and intravenous furosemide 10 mg four times a day.
In the same manner, bone marrow studies were performed including flow cytometry, which did not show plasmocytes. M component showed protein immunofixation in urine in low quantities, thus suggesting good partial response to previous treatment with carfilzomib. Nevertheless, given that the patient had previously shown progression in the disease with a combination of lenalidomide and dexamethasone, the hematology department added daratumumab (human IgGk monoclonal antibody targeted against CD38) as third line of management.
Forty-five days after discontinuing carfilzomib, the patient attended ambulatory follow-up through the cardiology department and reported clinical improvement of dyspnea and orthopnea. A control echocardiogram was performed without changes in LVEF but with significant GLS improvement, with current value of -16.3 and prior value of -11.7. (Fig. 1)
Patients with multiple myeloma have a greater probability of developing cardiovascular events than general population. Pertinent risk factors include those related to the patient (age and other cardiovascular risk factors), factors related specifically to the disease (chronic anemia, kidney failure, hyperviscosity, amyloidosis), or those secondary to chemotherapeutic agent toxicity (5).
Survival rates of MM patients with relapse or refractoriness at ≥ 1 first line treatment has improved in a significant manner with the development of proteasome inhibitors, including carfilzomib. Nevertheless, this medication has been associated with an increase in cardiovascular events incidence, which is dosage dependent. (2) Recently, a meta-analysis (6) reported that from 2594 patients with MM treated with carfilzomib, 18% suffered cardiovascular events and 8.2% of those were high risk events (≥ 3 grade). Heart failure (4.1%) and high blood pressure (12.2%) were the most common cardiovascular events while arrhythmia (2.4%) and ischemic events (1.8%) occurred less frequently.
Herein, we report the case of a 60-year-old MM patient with chronic anemia, kidney failure, and proteinuria, who, after 5 cycles of KRD therapy, suffered 13% deterioration of the left ventricular function (LVEF current 45%, previous 58%), high NT-pro BNP levels, GLS deterioration (current − 11% previous − 17%) and signs and symptoms of severe congestive heart failure.
Underlying mechanisms related to cardiovascular complication associated with carfilzomib have not been completely established. Mouse models have shown that administration of sub-micromolar concentrations of carfilzomib generates inhibition of proteasome activity similar to chymotrypsin, with subsequent damage of cardiac myocytes and apoptosis induction (2) (7). High doses of proteasome inhibitors have also been reported to negatively regulate nitric oxide synthase function, resulting in endothelial vascular dysfunction and cardiovascular risk (8).
Prevention and management of cardiotoxicity induced by carfilzomib, as well as other IP, is based on the reduction of the administered dose or on medication interruption in cases where high level toxicity has been evidenced. Additionally, the therapy combined with ACE inhibitors or ARBs and beta blockers has shown to be effective in limiting the development of interstitial fibrosis, intracellular oxidative stress reduction, and intracellular calcium cycle metabolism enhancement (4).
Even though cardiotoxicity with the use of bortezomib has been reported, it is less frequent in comparison to carfilzomib possibly because the latter is more potent and joins the β unit of proteasome 20S irreversibly (9). These findings have been correlated to the reported case since the patient, in spite of having received prior treatment with bortezomib, had heart failure subsequent to the use of carfilzomib, which was substantiated with echocardiogram prior to treatment without systolic dysfunction.
Currently, there is clinical evidence related to the potential reversibility of myocardial dysfunction in MM patients treated with carfilzomib. A retrospective cohort study showed that 16.3% MM patients treated with carfilzomib decreased their LVEF during treatment; nevertheless, after interruption of carfilzomib and initiation of the beta-blocker, angiotensin converting enzyme inhibitors and diuretics, all patients improved their systolic function in two months average (10). In our case, after the interruption of carfilzomib and initiation of the neurohormonal blocking therapy mentioned above, the patient showed improvement of dyspnea, as well as GLS, with preserved LVEF. These data suggest that optimization of heart failure management and interruption of medication in high level adverse event cases are important for the patients’ clinical improvement and echocardiographic parameters.
This case illustrates the behavior of carfilzomib induced cardiotoxicity and the expected response to the appropriate pharmacological management. The use of carfilzomib as a chemotherapeutic agent in the management of refractory multiple myeloma has, as an adverse effect, its potential cardiotoxicity. High level toxicity can take forms such as emergence or deterioration of heart failure, as it happened in the reported case, which is founded on heart function detriment by cardiomyocyte apoptosis induction through cellular proteasome inhibition. Its diagnosis is based on clinical and paraclinical parameters where diagnostic images, such as an echocardiogram, play a crucial role for its follow-up and prognosis, as do the myocardial damage serum markers and neurohumoral axis activation markers. Lacking appropriate management, cardiotoxicity, particularly high-level cardiotoxicity, can increase morbidity and mortality in patients and costs to the health system. For this reason, when cardiotoxicity is documented, it is necessary to take measures such as the reduction or interruption of medication as well as the initiation of neurohumoral blocking in order to limit interstitial fibrosis and cardiomyocyte oxidative stress.
Ethical Approval and Consent to participate/ Consent for publication
The autors declare that informed consent was obtained for the publication of this case report. The patient provided consent and gave permission to have her case, including diagnostic images.
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The authors confirm that there have been no financial or nonfinancial involvements in either authors that might raise the question of bias in the work reported or in the conclusions, implications, or opinions.
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All authors contributed significantly to the manuscript. All authors provided critique and feedback on the manuscript. All authors read and approved the final version of the manuscript.
We thank Oscar Reyes MD, hematologist and oncologist at the Hospital Universitario Nacional de Colombia, for his support in the oncological treatment of the patient during hospitalization and the ambulatory follow-up.
Author informations
Arnold Méndez-Toro MD, Cardiology Unit, Hospital Universitario Nacional de Colombia
E-mail: [email protected]