Carfilzomib‐Associated Tumor Lysis Syndrome

Abstract

Multiple myeloma is the second most common type of hematologic malignancy. It is a B-cell malignancy that affects the bone marrow and often results in thrombocytopenia as well as renal dysfunction. Treatment options range from oral and intravenous chemotherapy to bone marrow transplantation and supportive care. Carfilzomib was approved by the U.S. Food and Drug Administration in 2012 as a treatment option for patients with refractory multiple myeloma who have received at least two previous therapies and have demonstrated recent disease progression. According to the product labeling, the frequency of tumor lysis syndrome (TLS) is less than 1% in patients treated with carfilzomib. To our knowledge, no postmarketing events of TLS have been reported or published. We describe a 55-year-old man with relapsed multiple myeloma who developed a case of TLS that occurred after he received his first two doses of carfilzomib therapy on days 1 and 2; he also had chronic kidney disease secondary to his neoplastic disease. Beginning on day 4, his uric acid levels spiked to critical levels, prompting the use of rasburicase, which returned the levels to within normal limits. His phosphorus and creatinine levels increased during days 5 and 6. On day 8, the patient died, likely due to a combination of disease progression and the adverse effects of treatment. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 6) between the patient's development of TLS and carfilzomib therapy. The Hill criteria were used as a secondary measure to ensure causality, which also suggested a link between the patient's development of TLS and the administration of carfilzomib. This case report shows that even the most unlikely of adverse events may occur with medications, especially in the case of a new or recently approved medication. Caution must be taken when deciding to treat and when choosing hydration and premedications with regard to biologic and chemotherapeutic medications. In this case, additional hydration may have been considered. Although given the extent of the adverse reaction combined with the patient's underlying renal dysfunction, extra fluid may or may not have proven beneficial. The use of prophylactic rasburicase or allopurinol could have been considered, but these measures are not typically used with multiple myeloma due to the low incidence of TLS. All things considered, this unlikely adverse reaction may occur in certain patients. If other cases such as this occur, it may be advisable to use TLS prophylaxis in the future in certain patient populations, including those with renal dysfunction or worsening disease states.

Improving the efficacy of proteasome inhibitors in the treatment of renal cell carcinoma by combination with the human immunodeficiency virus (HIV)‐protease inhibitors lopinavir or nelfinavir

“…Although acute renal failure occurred in 4.2% of patients undergoing carfilzomib treatment for myeloma in an integrated safety analysis , carfilzomib proved to be safe in patients with myeloma with renal impairment, and was well tolerated and demonstrated promising efficacy . Moreover, acute renal failure and tumour lysis syndrome, described within case reports of individual patients undergoing carfilzomib‐based therapy, were well manageable if properly monitored .…”

Acute Tubular Necrosis in a Patient With Myeloma Treated With Carfilzomib

“… 1 Most of the cases of AKI in this phase II trial were attributed to carfilzomib, as no other precipitating cause could be identified; however, the mechanism of AKI was not determined. There have also been a number of case reports 2 , 3 , 4 , 5 , 6 , 7 attributing AKI to carfilzomib, some suggesting that thrombotic microangiopathy may have been the mechanism of injury based on clinical presentation and evidence from kidney biopsies, but definitive causality was not established. 4 , 5 …”

“…There have been several case reports providing evidence of AKI secondary to carfilzomib. 2 , 3 , 4 , 5 , 6 , 7 Two recent reports describe thrombotic microangiopathy associated with carfilzomib administration, although causality was not definitively established. 4 , 5 To our knowledge this is the first case report of biopsy-proven acute tubular necrosis (ATN) in a patient with multiple myeloma who was treated with carfilzomib.…”

Renal Toxicities of Novel Agents Used for Treatment of Multiple Myeloma

“…Although the majority of the kidney adverse effects were mild, progressive kidney disease was reported in 3.8% of patients, leading to discontinuation of the drug in two patients (22). There are now additional cases of AKI from carfilzomib reported in the literature (23)(24)(25)(26)(27). The possible mechanisms listed are diverse and summarized in Table 2.…”

“…The possible mechanisms listed are diverse and summarized in Table 2. They range from prerenal insults, tumor lysis-like phenomenon, to biopsy-proven TMA (23)(24)(25)(26). In the initial two cases (23,24), AKI was transient and was clinically consistent with a 'prerenal' insult.…”