Carfilzomib is an irreversible proteasome inhibitor and antineoplastic agent that is used in treatment of refractory multiple myeloma. Carfilzomib is associated with a low rate of serum enzyme elevations during treatment and has been implicated to rare instances of clinically apparent, acute liver injury some of which have been fatal.
Carfilzomib (kar filz’ oh mib) is an orally available, small molecule inhibitor of the 26S proteasome, the intracellular complex that degrades proteins involved in cell signaling and cell cycle regulation. Blocking proteasome activity prevents activation of factors involved in cell growth and resistance to chemotherapy induced apoptosis, leading to cancer cell death. Carfilzomib was the second proteasome inhibitor developed as an antineoplastic agent, differing from the initial (bortezomib) in being an irreversible inhibitor and not being metabolized by the CYP 3A4 system. Clinical trials of carfilzomib in patients with multiple myeloma showed at least partial responses in patients who were resistant to other antineoplastic agents including bortezomib. Carfilzomib received accelerated approval for use in the United States in 2012 for therapy of previously treated, refractory or relapsing multiple myeloma. Carfilzomib is available in powdered form in single use vials of 60 mg under the brand name Kyprolis. The typical starting dose is 20 mg per meter-squared per day intravenously for two days each week for 3 weeks, and then in cycles after a rest period. It is typically administered with dexamethasone with or without lenalidomide. Common side effects include fatigue, nausea, diarrhea, constipation, anorexia, fatigue, dyspnea, thrombocytopenia, neutropenia, anemia peripheral neuropathy, rash and fever. Infusion reactions are not uncommon with the first cycle of carfilzomib and dexamethasone pretreatment is recommended. Other uncommon, but potentially severe side effects include peripheral neuropathy, cardiac and pulmonary toxicity, bone marrow suppression and tumor lysis syndrome.
In large clinical trials of carfilzomib, elevations in serum aminotransferase levels were common, occurring in 8% to 13% of patients. However, values greater than 5 times the upper limit of normal (ULN) were uncommon, occurring in 1% to 2% of recipients. In several studies there were reports of clinically apparent liver injury including acute liver failure in patients receiving carfilzomib; however, in most instances multiple concomitant medications were being taken (such as lenalidomide) and the specific role of carfilzomib in causing the liver injury was not always clear. The onset of injury was typically during the first cycle of therapy. The clinical features and pattern of injury in clinically apparent cases of liver injury due to carfilzomib have not been described in the published literature. Hepatotoxicity is listed as a warning in the product label for carfilzomib and monitoring of serum enzymes during treatment is recommended.
Likelihood score: D (Possible cause of clinically apparent liver injury).
Mechanism of Injury
The mechanisms of liver injury accounting for serum enzyme elevations and hepatic toxicity during carfilzomib therapy are not known. Carfilzomib is metabolized peripherally by plasma peptidases and only a proportion is metabolized in the liver through the CYP 3A4 pathway. Carfilzomib has minimal effect on CYP 3A4 activity and does not appear to be susceptible to drug-drug interactions with agents that inhibit or induce hepatic CYP 3A4 activity.
Outcome and Management
Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) should lead to dose reduction or temporary cessation. Clinically apparent liver injury should prompt immediate interruption of carfilzomib therapy. There is little information on cross reactivity in risk for hepatic injury between carfilzomib and other cancer chemotherapeutic agents, including the tyrosine kinase inhibitors and other proteasome inhibitors such as bortezomib.
REPRESENTATIVE TRADE NAMES
Carfilzomib – Kyprolis®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 17 January 2017
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Jagannath S, Vij R, Stewart AK, Trudel S, Jakubowiak AJ, Reiman T, Somlo G, Bahlis N, et al. An open-label single-arm pilot phase II study (PX-171-003-A0) of low-dose, single-agent carfilzomib in patients with relapsed and refractory multiple myeloma. Clin Lymphoma Myeloma Leuk 2012; 12: 310-8. PubMed Citation (Among 46 patients with refractory multiple myeloma treated with carfilzomib, 7 were partial responders; side effects included anemia [74%], fatigue [70%] and thrombocytopenia [50%]; no mention of ALT elevations or hepatotoxicity and no deaths were considered secondary to therapy).
Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, Trudel S, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 2012; 120: 2817-25. PubMed Citation (Among 266 patients with refractory multiple myeloma treated with carfilzomib, the overall response rate was 24% and side effects included fatigue, anemia, nausea, thrombocytopenia, and peripheral neuropathy; among 12 deaths were 2 from hepatic failure, one of which was considered possibly or probably related to carfilzomib therapy).
Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, Al-Zoubi A, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 2012; 120: 1801-9. PubMed Citation (Among 53 patients with multiple myeloma treated with carfilzomib, lenalidomide and dexamethasone in 28 day cycles, elevated liver tests occurred in 8% of patients).
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Herndon TM, Deisseroth A, Kaminskas E, Kane RC, Koti KM, Rothmann MD, Habtemariam B, et al. U.S. Food and Drug Administration approval: carfilzomib for the treatment of multiple myeloma. Clin Cancer Res 2013; 19: 4559-63. PubMed Citation (Description of the accelerated approval of carfilzomib as therapy for multiple myeloma from the FDA; review of adverse reactions among 526 treated patients mentions AST elevations occurring in 66 [13%], with 6 [~1%] above 5 times ULN, and that 2 patients died of hepatic failure having entered the study with normal liver tests).
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Harvey RD. Incidence and management of adverse events in patients with relapsed and/or refractory multiple myeloma receiving single-agent carfilzomib. Clin Pharmacol 2014; 6: 87-96. PubMed Citation (Review of the published adverse reactions of carfilzomib therapy and recommendations for their management; among 37 deaths occurring during or shortly after therapy, seven were considered at least possibly related to carfilzomib, including one due to hepatic failure).
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Wang H, Guan F, Chen D, Dou QP, Yang H. An analysis of the safety profile of proteasome inhibitors for treating various cancers. Expert Opin Drug Saf 2014: 13: 1043-54. PubMed Citation (Review of efficacy and safety of bortezomib and second generation proteasome inhibitors including carfilzomib, marizomib, ixazomib and oprozomib, states that "Carfilzomib has a favorable and tolerable safety profile"; no discussion of hepatotoxicity or serum enzyme elevations).
Lendvai N, Hilden P, Devlin S, Landau H, Hassoun H, Lesokhin AM, Tsakos I, et al. A phase 2 single-center study of carfilzomib 56 mg/m2 with or without low-dose dexamethasone in relapsed or refractory multiple myeloma. Blood 2014 Jun 24. [Epub ahead of print] PubMed Citation (Among 44 patient with refractory multiple myeloma previously treated with bortezomib given carfilzomib, 55% had at least a partial response and side effects included lymphopenia [55%], thrombocytopenia [32%], hypertension [25%], pneumonia [18%] and heart failure [11%]; no mention of ALT elevations or hepatotoxicity).
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patients: a multicentre retrospective observational study. Br J Haematol 2016; 172: 89-96. PubMed Citation (Among 135 patients with relapsed or refractory multiple myeloma treated with carfilzomib usually in combination with dexamethasone and often with lenilidamide, the overall response rate was 47% and adverse events included liver enzyme elevations in 19% which were above 5 times ULN in 4% and 1 of 7 deaths was attributed to acute hepatic failure death considered related to therapy).
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and dexamethasone versus bortezomib and dexamethasone for patients with relapsed
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multicentre study. Lancet Oncol 2016; 17: 27-38. PubMed Citation (Among 929 patients with refractory multiple myeloma treated with dexamethasone and carfilzomib or bortezomib, progression-free but not overall survival was longer with carfilzomib than bortezomib, while adverse event rates were similar, ALT elevations occurring in 4.5% vs 3.9% and rising above 5 times ULN in 1.1% vs 0.4%).
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