Can low-dose Rd treatment be safe for patients with multiple myeloma and Brugada syndrome? How can this treatment affect a patient’s survival and quality of life?
What is Multiple Myeloma?
Multiple myeloma (MM) is a type of cancer that can infect plasma cells, the cells which help you fight infections by creating antibodies. When a person has multiple myeloma, cancerous plasma cells tend to overpopulate healthy blood cells in the bone marrow. This results in the abnormal production of antibodies which creates complications in your body.
MM is considered the second most frequent hematologic malignancy which accounts for 15% of all blood cancers. Clinical manifestations of cancer include hypercalcemia, osteolytic bone lesions, anemia, and renal failure.
Treatment includes the introduction of novel agents such as: immunomodulatory agents or IMiDs (thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), and monoclonal antibodies (daratumumab, elotuzumab). All of these have improved patients’ survival and life expectancy.
Treatment is done through triplet induction therapy with the help of steroids, proteasome inhibitors, and IMiDs, followed by autologous stem-cell transplantation and maintenance therapy. However, these drugs are often associated with adverse cardiovascular events especially in patients with pre-existing CV comorbidities.
Patients with multiple myeloma along with an active disease require prompt treatment in order to stop the progression of the disease that causes organ damage. Many patients are susceptible to developing CV events such as heart failure or hypertension which are caused by risk factors and treatment-related cardiotoxicities. In fact, according to a US study by Kistler, in 22,000 MM patients, almost 70% experienced a CV event during treatment. This emphasizes the importance of knowing the cardiac status before treatment and prognosis.
What is Brugada Syndrome?
Brugada syndrome is a rare disorder that is characterized by irregular heart rhythms in the lower chambers of the heart. If left untreated, the syndrome can cause fainting, seizures, difficulty breathing, and sudden death. Signs and symptoms usually happen during adulthood, but can develop at any age.
First reported in 1992, Brugada is classified currently as one of the rarest hereditary diseases. It is linked to premature sudden death in patients with normal-shaped hearts. The disease mechanism is caused by right ventricular conduction delay and ST elevation in the right precordial leads. People with this syndrome on average life to about 40 years. But if treated appropriately, they can have a normal life span.
Mutation occurs usually in the SCN5A gene which results in the loss of function of the cardiac sodium channel which leads to heterogeneity of repolarization and reentrant arrhythmias. Lethal arrhythmias occur during resting or sleeping which often leads to sudden cardiac death. Accurate identification and treatment are thus vital to avoid such cardiac events.
Brugada syndrome is a greater risk for people of Asian descent, mostly Japanese and Southeast Asian heritage. According to research, it also occurs 8 to 10 times more often in men than women. This could be linked to male testosterone.
Case Report: Brugada Syndrome and MM
In December 2011, a 37year old man was rushed to the hospital seeking care for a pathologic fracture involving the D3 vertebra. His medical records and history show b-thalassemia trait, benign prostatic hyperplasia, arterial hypertension, and spontaneous Brugada electrocardiogram (ECG) pattern, which was diagnosed in 2010 as a result of presyncope episodes and did not require treatment.
The patient’s ECG showed a coved ST-segment elevation which was followed by a negative T-wave, a result consistent with h a type 1 BrS ECG pattern. He was given a flecainide test and tested positive. In line with the 2013 expert consensus statement, he was diagnosed with BrS.
Laboratory tests showed normal levels of hemoglobin, calcium, and creatinine. Serum electrophoretic proteinogram showed 2 monoclonal spikes in the gamma region which were then confirmed by serum immunofixation. The patient had negative results for urine electrophoresis and immunofixation. He was given bone marrow aspiration after acquiring consent. Analysis of the bone marrow showed 10% cell infiltration which then lead to the diagnosis of MM.
Due to the CVD risk, the patient refused the systemic antimyeloma treatment. He was then successfully treated with radiotherapy at the site of his vertebral lesion. It was followed by 4 cycles of high-dose dexamethasone. He was then followed up with sera and radiologic examinations until October 2015 during the time he was admitted to the hematology division for disease progression.
The patient then underwent a follow-up magnetic resonance imaging which revealed multiple lytic lesions within his spine, femora, and pelvic bones. Laboratory workup revealed anemia (hemoglobin 8.2 g/dL), increased levels of protein (3.91 g/dL), and a mild increase of b2-microglobulin (2.91 mg/L), with normal levels of serum calcium and creatinine. Serum immunofixation revealed IgGk M protein, and the serum k/l light chain ratio was 82. The bone marrow smears presented plasma cells comprising 30% of total cellularity.
All these findings were suggestive of active disease requiring prompt treatment. However, we could find no literature reports regarding the safety of antimyeloma agents in patients with BrS. After discussing different second-line treatment options and their side effects with the patient, doctors initiated therapy with low-dose lenalidomide, an IMiD associated with moderate thromboembolic risk, and relatively safe from a cardiac standpoint. Considering the expanding list of drugs that can be fatal to BrS patients, the rationale for our choice was to use the less cardiotoxic drug.
Lenalidomide was administered at a dosage of 10 mg daily on days 1-21 of 28-day cycles, and it was combined with dexamethasone at a dose of 40 mg per week. Acetylsalicylate was administered as venous thromboembolism prophylaxis in accordance with standard clinical practice. The echocardiography, performed before starting treatment, showed a structurally normal heart with a good systolic and diastolic function of both ventricles (left ventricular ejection fraction 60%); no valvular disease or arrhythmias were reported.
During disease reevaluation a year after treatment, the hospital used skeletal magnetic resonance imaging. It revealed an almost complete resolution of bony lesions. As a result, the patient has completed 41 cycles of therapy without any adverse events while he continues to experience VGPR (M protein 0.18 g/dL), and the patient has a good quality of life (Eastern Cooperative Oncology Group performance status 0; New York Heart Association functional class I).
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