Multiple myeloma (MM) 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 phases of cancer treatment include initial therapy with immunomodulators, protease inhibitors, and dexamethasone. Subsequently, if the patient is eligible, autologous stem cell transplant (ASCT) is performed. A maintenance phase follows, and its duration varies according to the identified cytogenetic profile and individual risk factors. Finally, the last phase consists of treating patients with refractoriness or relapse despite established management. In the latter case, triple therapy with immunomodulators, dexamethasone, and proteasome inhibitors (PI) such as carfilzomib is indicated. The function of carfilzomib 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).
One of the most relevant adverse events of carfilzomib is its cardiotoxicity, which covers a broad range of clinical signs and symptoms classified into five categories according to its severity: 1: mild, 2: moderate, 3: severe, 4: life threatening or disabling, and 5: fatal. The last three categories described above correspond to high-grade cardiovascular adverse events (CVAE) (3)(4).
Below, we discuss a case of a MM patient with tumor relapse, who developed severe congestive heart failure after treatment with carfilzomib. Therefore, the medication was discontinued, and neurohormonal blocking therapy was initiated showing subsequent clinical and echocardiographic improvement.
A 60-year-old female with MM diagnosis since 2016, presented to the hospital on December, 2019. 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). Regarding the oncological treatment, on April, 2016, she underwent eight CyBorD cycles (Cyclophosphamide, Bortezomib, Dexamethasone). Later, on March 2018, an ASCT was performed. Then, maintenance therapy with lenalidomide and dexamethasone was started. Nevertheless, due to disease progression, a KRD chemotherapy plan was prescribed (Leflunomide, Carfilzomib, Dexamethasone). A transthoracic echocardiogram prior to the initiation of the therapy evidenced a preserved ventricular systolic function LVEF 58% and GLS of -17%.
After 5 cycles of treatment, the patient experienced a rapid decline in her functional status –NYHA class from I to II – in 2 weeks, paroxysmal nocturnal dyspnea and orthopnea, so she was admitted to the hospital. Based on international recommendations related to monitoring and treatment of CVAE in patients with MM treated with carfilzomib (4), diagnostic studies were indicated. These included serum myocardial injury biomarkers: NT-proBNP of 17570 pg/mL (cut-off point ≥ 900 pg/mL in patients between 50-75 years-old) and troponin I of 0.006 (cut-off point 0-0.017 pg/ml). A transthoracic echocardiogram showed left ventricular concentric hypertrophy, 182 g/m2 of ventricular mass, diffuse hypokinesia, LVEF of 45% and GLS of -11.7%. Based on these findings, congestive severe heart failure secondary to carfilzomib toxicity was considered, classified as a high-grade CVAE. It was decided to discontinue the therapy. 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.
Also, bone marrow studies were performed including flow cytometry, which did not show plasmocytes. Monoclonal component showed protein immunofixation in urine in low quantities, suggesting good partial response to previous treatment. Nevertheless, since the patient had previously shown disease progression with a combination of lenalidomide and dexamethasone, the hematology department decided to add daratumumab (human IgGk monoclonal antibody targeted against CD38) as third line of management.
Forty-five days after discontinuing carfilzomib, during outpatient monitoring at cardiology unit, she reported clinical improvement of dyspnea and orthopnea. A follow-up echocardiogram did not show changes in LVEF but demonstrated significant GLS improvement, –current value of -16.3 and prior value of -11.7 – (Figure 1)