Carfilzomib-induced tumor lysis syndrome in relapsed multiple myeloma: a report of two cases
Abstract
Background: Tumor lysis syndrome (TLS) is a potentially fatal complication of cancer therapy characterized by severe electrolyte and metabolic abnormalities such as hyperphosphatemia, hyperkalemia, and hypocalcaemia. TLS usually occurs in aggressive hematologic malignancies such as Burkitt lymphoma and acute leukemia. TLS has rarely been observed in multiple myeloma (MM).Case report: We present 2 patients with relapsed MM who developed TLS after the first cycle of carfilzomib treatment. Conclusion: Carfilzomib is a next-generation proteasome inhibitor with proven efficacy in relapsed/refractory MM. Recently, increasing frequency of TLS has been reported in MM, especially after treatment with proteasome inhibitors. The potential complications of TLS should be considered especially during the first cycle of carfilzomib treatment.
Introduction
Tumor lysis syndrome (TLS) is a life-threatening compli- cation of cancer treatments that results from the rapid destruction of malignant cells and release of intracellular components into the systemic circulation. TLS often occurs in hematologic neoplasms with high proliferation rates and tumor burden such as acute leukemia and Burkitt lymphoma.1 TLS is uncommon in patients with multiple myeloma (MM) because of the relatively low proliferation rate and is, therefore, classified as a low-risk disease for TLS.2,3 In recent years, increasing frequency of TLS has been reported in MM, especially after treatment with pro- teasome inhibitors. Here we report 2 patients with relapsed MM who developed TLS after initiation of carfilzomib.A 55-year-old man was diagnosed with immunoglobulin G (IgG)–kappa MM, ISS stage III (International Staging System) in 2009. He was treated with 4 cycles of bortezomib,cyclophosphamide, and dexamethasone (VCD); then he underwent treatment with high-dose melphalan and autolo- gous hematopoietic stem cell transplantation (ASCT) in 2010. He attained complete remission. He relapsed in 2013 and was treated with lenalidomide and weekly dexametha- sone. He relapsed for the second time after 15 months of lenalidomide and dexamethasone treatment. Serum creati- nine increased and daily urine output decreased. He had a blood urea nitrogen (BUN) to creatinine ratio of 114:8.1 mg/ dL. Hemodialysis was started immediately and then pro- vided regularly 2 times per week. He remained dialysis- dependent with the second relapse. He was given VCD and
after 4 cycles he achieved stable disease. A deletion in 17p13.1 was detected in 18% of cells. Bone marrow exami- nation showed 20% plasma cell infiltration. PET/CT revealed no FDG involvement. Laboratory analysis revealed BUN 53 mg/dL, serum creatinine 3.24 mg/dL, uric acid 5.1 mg/dL, total protein 7.1 g/dL, serum albumin 3.1 g/dL, calcium 9.8 mg/dL, phosphate 5.8 mg/dL, potassium 5.1 mmol/L, lactate dehydrogenase (LDH) 320 IU/L, white cell count 7,200 mm3/μL, hemoglobin 8.2 g/dL, hematocrit 24%, platelet count 114,000/mm3/μL, β2 microglobulin 15.6 mg/L. Serum protein immunofixation revealed IgG–kappa mono- clonal gammopathy. IgG was 2,531 mg/dL, kappa light chain was 593 mg/dL, and free serum kappa/lambda ratio was 56. Immunofixation of his urine showed kappa light chain 1,240 mg/d. He was scheduled to receive carfilzomib and dexamethasone. Carfilzomib dose was reduced because the patient had end-stage renal disease (dialysis-dependent). The patient was treated with carfilzomib with a 15 mg/ m2 dose (days 1, 2, 8, 9, 15, and 16) in cycle 1. Prior to dos- ing in cycle 1, he was hydrated with 250 mL intravenous fluid. He developed generalized weakness, severe dyspnea, and bilateral swelling in his legs, feet, and arms. Three days later, he had received the second dose of carfilzomib in cycle 1. On physical examination, the patient was alert and appeared in poor general condition and he had bilateral inspiratory basal crackles with reduced breath sound and bilateral +2 generalized edema. Arterial blood gas analysis showed severe metabolic acidosis. Renal ultrasound showed no evidence of renal tract obstruction. Laboratory results are shown in Table 1. Carfilzomib-induced TLS with acute-on- chronic renal failure was diagnosed. He was treated with intravenous fluid hydration, urinary alkalization with sodium bicarbonate, allopurinol 150 mg daily, and calcium gluconate. Daily hemodialysis was started. Nevertheless, the patient’s condition deteriorated as he experienced car- diac arrhythmias, hypotension, and increasing pulmonary and peripheral edema, and he died 6 days after receiving the second dose of carfilzomib.
A 65-year-old woman was diagnosed with immunoglobulin A (IgA)–kappa MM, International Staging System stage II,after presenting with anemia, hypercalcemia, and multiple lytic bone lesions. At diagnosis, she had type 2 diabetes mel- litus and hypertension and an Eastern Cooperative Oncology Group performance status of 2. ASCT was not feasible for her. She was given 6 cycles VCD chemotherapy, resulting in stable disease. Then she was treated with lenalidomide and weekly dexamethasone for 1 year until she had disease pro- gression. At progression, laboratory analysis revealed BUN 20 mg/dL, serum creatinine 0.8 mg/dL, uric acid 4.4 mg/dL, total protein 9.8 g/dL, serum albumin 3.0 g/dL, calcium 9.9 mg/dL, phosphate 4 mg/dL, potassium 4.5 mmol/L, LDH 110 IU/L, white cell count 9,000 mm3/μL, hemoglobin 8.7 g/dL, hematocrit 25%, platelet count 58,000/mm3/μL, β2 microglobulin 6.5 mg/L. Anemia and thrombocytopenia were thought to be associated with myeloma. Serum protein immunofixation revealed IgA–Kappa monoclonal gam- mopathy. IgA was 6,292 mg/dL, kappa light chain was 1,479 mg/dL, and free serum kappa/lambda ratio was 452. Bone marrow examination showed 50% plasma cell infiltra- tion. Deletion of 13q14.3 was detected in 14% of the ana- lyzed cells by fluorescent in situ hybridization analysis. PET/CT revealed a lytic lesion in the L2 vertebrae and dif- fuse marrow infiltration. Treatment with carfilzomib and dexamethasone was planned. She was treated with carfil- zomib with a dose of 20 mg/m2 (days 1, 2, 8, 9, 15, and 16) in cycle 1. Prior to dosing in cycle 1, she was hydrated with 500 mL intravenous fluid. After the second dose of carfil- zomib in cycle 1, she was admitted to the emergency room with 1 day history of shortness of breath, nausea, vomiting, and decreased urine output. Laboratory results are shown in Table 1. Renal ultrasound revealed no evidence of obstruc- tion. Laboratory tests were consistent with TLS. Carfilzomib- induced TLS was diagnosed according to the Cairo and Bishop criteria. The patient was started on aggressive intra- venous hydration with sodium bicarbonate to maintain a urine pH of >7.0 and furosemide for forced diuresis and allopurinol 150 mg daily. Hemodialysis was performed one time and in the following days, her clinical symptoms improved, and the laboratory results returned to normal. Later on, 4 cycles of carfilzomib treatment were completed with allopurinol prophylaxis. She was evaluated to have sta- ble disease after 4 cycles of carfilzomib treatment. The patient refused any further treatment.
Discussion
TLS is a serious oncologic emergency characterized by hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcaemia. Cairo and Bishop is the most widely accepted classification system. TLS can be classified as lab- oratory or clinical TLS and the severity of TLS can be assessed with this system. Laboratory TLS (LTLS) is defined as a 25% decline from baseline in serum calcium and/or 25% increase from baseline in the serum values of uric acid, potassium, and phosphorous within 3 days or 7 days after the initiation of chemotherapy. Clinical TLS (CTLS) is defined as the presence of LTLS and one or more clinical manifesta- tions such as creatinine ⩾1.5 times greater than upper limit of normal, seizures, and arrhythmia/sudden death.1,2 In our 2 cases, both LTLS and CTLS criteria were met.
Carfilzomib is a next-generation proteasome inhibitor that binds irreversibly and selectively to its target.4 The Food and Drug Administration approved carfilzomib for the treat- ment of relapsed or refractory MM in patients who received at least 2 prior lines of therapies (including bortezomib and an immunomodulatory agent) in 2012.5 Carfilzomib is now also Food and Drug Administration approved for second-line treatment. The most common side effects of carfilzomib were fatigue, nausea, anemia, and thrombocytopenia.4 TLS is rarely observed in MM due to the low proliferation rate of plasma cells. Nevertheless, recently published data revealed that TLS may occur after novel treatment modalities. Novel treatments (including proteasome inhibitors and immu- nomodulatory drugs) are more effective compared with con- ventional therapies in MM.
It has been shown that deep, rapid, and sustainable responses can be obtained with carfilzomib-based combi- nations.7 Carfilzomib, inducing more rapid and deeper responses, is associated with a higher risk of TLS com- pared with other drugs that act more slowly. Two Phase II studies and one phase I/II study of carfilzomib in relapsed/ refractory MM reported TLS incidence as 0.4%, 1%, and 2.7%, respectively.4,8,9 In two studies, patients at risk for TLS or with a high tumor burden were allowed to receive allopurinol prophylaxis.4,8 However, in these studies, risk factors for TLS are not exactly defined.Risk factors for TLS in patients with MM are high tumor burden, plasmablastic morphology, poor cytogenetic status, high proliferative index of plasma cells, advanced stage disease, and the classical risk factors such as high LDH level, high uric acid level, and preexisting renal failure.3,10,11 There is no relationship between a specific cytogenetic sta- tus and TLS, but higher frequency of cytogenetic changes including del13q, del17p, t(4,14) has been shown in patients with MM with TLS.11,12 Shely and Ratliff13 reported a case of a patient with MM who developed carfilzomib-associ- ated TLS following the first cycle of carfilzomib treatment. This patient had high creatinine before carfilzomib admin- istration. Similarly, our two patients developed TLS during the first cycle of carfilzomib treatment.
However, there is no widely accepted risk factor classification for TLS in MM. At present, guidelines recommend us to give 250 mL to 500 mL of intravenous fluid to reduce the risk of kidney toxicity and TLS during carfilzomib treatment in the first cycle. Allopurinol is not recommended as a routine treat- ment of carfilzomib.5 Revised prescribing information in 2018 indicates that uric acid-lowering drugs may be con- sidered in patients at high risk for TLS. However, risk fac- tors for TLS are not exactly defined.TLS is rare in patients with MM. Recently, it has been increasingly described after treatment with proteasome inhibitors. Clinicians should consider the potential risk factors of TLS before treatment, and monitor the patient closely for laboratory and clinical findings of TLS. In both of our cases, TLS developed during the first cycle of carfil- zomib treatment. Allopurinol prophylaxis during the first cycle of carfilzomib treatment may be an option to prevent TLS. Risk factors for development of TLS and role of allopurinol prophylaxis during carfilzomib treatment in MM should be clarified in future Carfilzomib studies.