OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Bortezomib	179324-69-7	C19-H25-B-N4-O4

ANNOTATED BIBLIOGRAPHY

References updated: 30 September 2017

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999 before the availability of proteasome inhibitors such as bortezomib).
• DeLeve LD. Erlotinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556.

  (Review of hepatotoxicity of cancer chemotherapeutic agents published; bortezomib is listed as being implicated in causing hepatocellular injury).
• Chabner BA, Barnes J, Neal J, Olson E, Mujagic H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-54.

  (Textbook of pharmacology and therapeutics).
• Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348: 2609-17. [PubMed: 12826635]

  (Among 193 patients with refractory multiple myeloma treated with bortezomib in cycles for up to 24 weeks, a clinical response occurred in 35% of patients and common side effects were nausea, diarrhea, fatigue, thrombocytopenia and neuropathy; no mention of ALT elevations or hepatotoxicity).
• Bortezomib (Velcade) for multiple myeloma. Med Lett Drugs Ther 2003; 45 (1161): 57-8. [PubMed: 12865865]

  (Concise review of mechanism of action, efficacy, safety and cost of bortezomib shortly after its approval for use in the US; does not mention hepatotoxicity or serum enzyme elevations).
• Rosiñol L, Montoto S, Cibeira MT, Bladé. Bortezomib-induced severe hepatitis in multiple myeloma: a case report. Arch Intern Med 2005; 165: 464-5. [PubMed: 15738379]

  (68 year old man with advanced refractory multiple myeloma developed septic shock on the 6th day of cycle 1 of therapy, with subsequent increase in liver enzymes [ALT 2865 U/L, LDH 6448 U/L] followed by rapid recovery, but recurrence with two subsequent cycles [peak bilirubin 2.8 mg/dL, ALT 2750 U/L, LDH 6129 U/L] and rapid recovery each time).
• Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, et al.; Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352: 2487-98. [PubMed: 15958804]

  (Among 669 patients with refractory multiple myeloma treated with multiple cycles of bortezomib or dexamethasone, response rates and survival were greater with bortezomib; common side effects were diarrhea, nausea, fatigue, constipation, peripheral neuropathy and thrombocytopenia; no mention of hepatotoxicity or ALT elevations).
• Cornelis T, Beckers EA, Driessen AL, van der Sande FM, Koek GH. Bortezomib-associated fatal liver failure in a haemodialysis patient with multiple myeloma. Clin Toxicol (Phila) 2012; 50: 444-5. [PubMed: 22462599]

  (70 year old man with renal failure on hemodialysis and multiple myeloma developed jaundice ten days after the first dose of bortezomib and dexamethasone [bilirubin 8.0 mg/dL, ALT 114 U/L, Alk P 461 U/L], with progression to hepatic failure and death 2 months later).
• Paudice N, Farsetti S, Caroti L, Bandini S, Ciuti G, Tempestini A, Perfetto F, et al. [Severe recurrent intrahepatic cholestasis in systemic AL amyloidosis without obvious liver involvement: unexplained hepatic toxicity or a case of misdiagnosed liver amyloidosis?]. G Ital Nefrol 2012 Jan-Feb; 29 (1): 92-7. Italian.

  (50 year old woman with renal failure, multiple myeloma and amyloidosis developed jaundice 10 days after starting bortezomib and dexamethasone, which resolved despite continuing bortezomib, but recurred after stopping and was suspected to be due to amyloidosis).
• Kim GP, Mahoney MR, Szydlo D, Mok TS, Marshke R, Holen K, Picus J, et al. An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma. Invest New Drugs 2012; 30: 387-94. [PMC free article: PMC3896232] [PubMed: 20839030]

  (Among 35 patients with hepatocellular carcinoma treated with 1 to 12 cycles of bortezomib, the confirmed response rate was only 4% and toxicity was common; ALT elevations above 5 times ULN occurred in 2 patients and one died to hepatic failure).
• Laubach J, Hideshima T, Richardson P, Anderson K. Clinical translation in multiple myeloma: from bench to bedside. Semin Oncol 2013; 40: 549-53. [PubMed: 24135399]

  (Review of recent development of new agents to treat multiple myeloma, including bortezomib which showed activity against myeloma cell lines and was then evaluated clinically).
• 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: 25005844]

  (Review of efficacy and safety of bortezomib and several second generation proteasome inhibitors including carfilzomib, marizomib, ixazomib and oprozomib; no discussion of hepatotoxicity or serum enzyme elevations).
• Till BG, Li H, Bernstein SH, Fisher RI, Burack WR, Rimsza LM, Floyd JD, DaSilva MA, et al. Phase II trial of R-CHOP plus bortezomib induction therapy followed by bortezomib maintenance for newly diagnosed mantle cell lymphoma: SWOG S0601. Br J Haematol 2016; 172: 208-18. [PMC free article: PMC4710555] [PubMed: 26492567]

  (Among 65 patients with mantle cell lymphoma treated with 6 cycles of CHOP with bortezomib followed by bortezomib maintenance, during which adverse events included neuropathy in 72% of patients; no mention of ALT elevations or hepatotoxicity).
• Lu J, Chen WM, Geng CY, Durie BG, Huang XJ. Efficacy and safety of bortezomib in multiple myeloma patients with hepatitis B: a multicenter retrospective study. Chin Med J (Engl) 2016; 129: 274-8. [PMC free article: PMC4799569] [PubMed: 26831227]

  (Retrospective review of outcome of bortezomib therapy in 25 HBsAg-positive patients with multiple myeloma [20 treated with nucleoside analogues for HBV] found no evidence of reactivation, ALT and HBV DNA levels remaining normal or negative).
• Jain A, Malhotra P, Suri V, Varma S, Das A, Mitra S. Cholestasis in a patient of multiple myeloma: a rare occurrence of bortezomib induced liver injury. Indian J Hematol Blood Transfus 2016; 32 (Suppl 1): 181-3. [PMC free article: PMC4925560] [PubMed: 27408386]

  (A 54 year old man with multiple myeloma developed jaundice a few days into a second 4-week cycle of cyclosphosphamide, dexamethasone and bortezomib [bilirubin 15.5 mg/dL, ALT 367 U/L, Alk P 2456 U/L], recovering in 4 weeks and later tolerating cyclophosphamide and thalidomide).