Bortezomib

Article Author:
Aarushi Sharma
Article Editor:
Charles Preuss
Updated:
8/27/2019 6:02:52 PM
PubMed Link:
Bortezomib

Indications

Bortezomib is FDA-approved for use in the initial treatment of multiple myeloma in combination with cyclophosphamide and dexamethasone. It is also FDA-approved for use in the treatment of multiple myeloma in individuals who previously responded to bortezomib and relapsed at least 6 months after the completion of the prior treatment. Also, it is FDA-approved for use in the treatment of mantle cell lymphoma in individuals who have received at least one prior first-line treatment.[1][2][3]

Non-FDA-Approved Uses

  • Treatment of antibody-mediated rejection in cardiac transplantation
  • Relapsed or refractory cutaneous T-cell lymphomas
  • Relapsed or refractory follicular lymphoma
  • Relapsed or refractory peripheral T-cell lymphoma
  • Systemic light-chain amyloidosis
  • Relapsed or refractory Waldenstrom macroglobulinemia

Mechanism of Action

Bortezomib is a proteasome inhibitor. The proteasomal system plays a vital role in cellular protein turnover, which is essential for the homeostasis of cells. Bortezomib reversibly binds to the chymotrypsin-like subunit of the 26S proteasome, resulting in its inhibition and preventing the degradation of various pro-apoptotic factors.[4][5] The accumulation will eventually activate the programmed cell death via caspase-mediated pathways in the neoplastic cells that are usually dependent on suppression of pro-apoptotic pathways for their proliferation and survival.

Administration

Bortezomib is available in intravenous (IV) and subcutaneous (SQ) forms. There is no difference in the response rates between the available forms; however, the SQ form has correlations with a decreased occurrence of grade 3 or higher adverse effects. IV form administration is as a rapid push (3 to 5 seconds). The administration of SQ bortezomib (1.3 mg/m2) takes place at days 1, 4, 8, and 11 of a 21-day treatment cycle. Avoid injecting at the same site within a single cycle.  

The drug is broken down by the CYP 344 and 2C19 enzymes in the liver. The metabolites are inactive and get excreted by the kidney.

Adverse Effects

The following are adverse events seen with bortezomib[6][7][8]:

Central Nervous System: Peripheral neuropathy (IV: 35% to 54%; SQ: 37%; grade 2 or higher: 24% to 39%; grade 3 or higher: SubQ: 5% to 6%; IV: 7% to 15%; grade 4: greater than 1%), fatigue (7% to 52%), neuralgia (23%), headache (10% to 19%), paresthesia (7% to 19%), dizziness (10% to 18%).

Gastrointestinal: Diarrhea (19% to 52%), nausea (14% to 52%), constipation (24% to 34%), vomiting (9% to 29%), anorexia (14% to 21%), abdominal pain (11%), decreased appetite (11%).

Hematologic and Oncologic: Thrombocytopenia (16% to 52%; grade 3: 5% to 24%; grade 4: 3% to 7%; nadir: Day 11; recovery: By day 21), neutropenia (5% to 27%; grade 3: 8% to 18%; grade 4: 2% to 4%; nadir: Day 11; recovery: By day 21), anemia (12% to 23%; grade 3: 4% to 6%; grade 4: greater than 1%). leukopenia (18% to 20%; grade 3: 5%; grade 4: ≤1%), hemorrhage (grade 3 or higher: 2%).

Cardiovascular: Hypotension (8% to 9%; grades 3/4: 2% or less), cardiac disease (treatment emergent; 8%), acute pulmonary edema (1% or less), cardiac failure (1% or less), cardiogenic shock (1% or less), pulmonary edema (1% or less).

Respiratory: Dyspnea (11%), pneumonia (1% to 3%).

Infection: Herpes zoster (reactivation; 6% to 11% - prophylactic acyclovir can be considered), herpes simplex infection (1% to 3%), herpes zoster (1% to 2%).

Dermatologic: Skin rash (12% to 23%).

Local: Injection site reaction (mostly redness; SQ: 6%), irritation at the injection site (IV 5%), catheter infection.

Neuromuscular and Skeletal: Weakness (7% to 16%).

Hepatic: Ascites, hepatic failure, hepatic hemorrhage, hepatitis, hyperbilirubinemia.

Miscellaneous: Fever (8% to 23%).

Contraindications

Hypersensitivity reaction to bortezomib or any other components of the formulation like boron, mannitol, etc. is a contraindication. Bortezomib administration should never be via the intrathecal route.[9][10][11]

The drug is not recommended for use in women who are pregnant or breastfeeding. There is a definite risk of harm to the fetus if used during pregnancy. If the female is pregnant and has a life-threatening situation, the use of bortezomib requires a thorough discussion with the patient, oncologists, and members of the ethics committee.

Monitoring

Frequently check CBC with differential and platelets during the therapy as it causes myelosuppression and pancytopenia. Cell counts reach a nadir by day 11, and recovery occurs by day 21. Check liver function tests in patients with existing hepatic impairment as it can lead to hepatic failure or abscess formation. Avoid using the drug if liver enzymes are elevated 2 to 3 times the upper limit of normal. Evaluate for signs/symptoms of peripheral neuropathy. Frequently assess the volume status and check orthostatic blood pressure during the treatment. Order a baseline chest x-ray and then periodic pulmonary function testing with new or worsening pulmonary symptoms.[12][13]

Cautions

Reactivation of hepatitis B: all patients treated with bortezomib should first undergo testing for HBsAg and HBcAb. If either of these tests is positive, the patient should start on lamivudine for the duration of the therapy. Also, these patients need regular monitoring of their liver function and hepatitis B serology. Consider the decision to discontinue therapy if the levels of HBV DNA increase.

Reactivation of herpes zoster: Patients treated with bortezomib need to be managed with antiviral prophylaxis as reactivation of herpes zoster is a real possibility.

Peripheral neuropathy: Data show that bortezomib can cause peripheral neuropathy when combined with other medications like isoniazid, amiodarone, and HMG-CoA reductase inhibitors. Thus, close monitoring of neurological deficits is a strong recommendation.

Special Patient Populations

Elderly: While data are lacking, one should take great precautions when administering bortezomib to seniors, because of the risk of toxicity. However, the effect of the drug is the same as in younger patients.

Diabetes mellitus: Patients who are taking oral hypoglycemic agents are at risk for developing hypo or hyperglycemia when treated with bortezomib; therefore, the blood sugars require careful monitoring. Most patients do develop hypoglycemia, so reducing the dose of the oral hypoglycemic agent may be necessary.

Amyloidosis: Patients with amyloidosis should also receive bortezomib therapy with great caution as there are reports that use or bortezomib can lead to excess protein accumulation in many organs.

Hypertension. Since bortezomib can cause hypotension, dose adjustment of the antihypertensive drugs is required. These patients need close monitoring of their blood pressure.

There have been reports of life-threatening graft versus host disease in patients with myeloma receiving treatment with bortezomib. Thus, all patients with multiple myeloma and lymphoma should receive irradiated blood products to reduce this risk.

Toxicity

Bortezomib should be withheld at the onset of grade 3 non-hematological or grade 4 hematological toxicity until the toxicity resolves. Treatment is then treatment restarted at a lower adjusted dose. There is no antidote available to reverse the toxic effects of the drug.

Overdose

Bortezomib has a narrow therapeutic window; an overdose can occur when doubling the dose. The patient will usually present with marked thrombocytopenia and hypotension, which are very difficult to reverse. There are reports of several fatal outcomes from bortezomib overdose. If the patient experiences an overdose, close monitoring in the ICU is recommended. Aggressive hydration and maintenance of normal body temperature are vital.

Enhancing Healthcare Team Outcomes

Bortezomib is a relatively new drug for the treatment of multiple myeloma. Because of its narrow therapeutic index, the drug is used only by a few healthcare professionals. The drug is administered parenterally and requires close monitoring by the nursing staff. Besides checking the CBC, the liver function requires assessment. Before starting the drug, a baseline chest X-ray is recommended.

Bortezomib therapy requires a collaborative effort from the interprofessional healthcare team. The drug can cause hypotension, and the nurse must check the BP frequently. Nursing staff should report any signs of adverse events to the attending physician immediately, as well as checking with pharmacy. If there are any questions about the drug, one should consult with the pharmacist first. The pharmacist should also verify all dosing and consult the ordering clinician regarding any discrepancies, as well as performing full medication reconciliation. Prior to dispensing the drug, the pharmacist should ensure that the patient has no allergies and has been worked up for tuberculosis, and perform medication reconciliation. In addition, the patient must receive education regarding the potential long term adverse effects that can occur, including neuropathy.

Only through this type of interprofessional effort between physicians, nurses, and pharmacists can bortezomib therapy achieve optimal therapeutic outcomes for patients. [Level V]


References

[1] Yimer H,Melear J,Faber E,Bensinger WI,Burke JM,Narang M,Stevens D,Gunawardena S,Lutska Y,Qi K,Ukropec J,Qi M,Lin TS,Rifkin RM, Daratumumab, bortezomib, cyclophosphamide and dexamethasone in newly diagnosed and relapsed multiple myeloma: LYRA study. British journal of haematology. 2019 Mar 3;     [PubMed PMID: 30828799]
[2] Facon T,Lee JH,Moreau P,Niesvizky R,Dimopoulos M,Hajek R,Pour L,Jurczyszyn A,Qiu L,Klippel Z,Zahlten-Kumeli A,Osman M,Paiva B,San-Miguel J, Randomized phase 3 study of carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible, NDMM patients. Blood. 2019 Feb 28;     [PubMed PMID: 30819926]
[3] Ludman T,Melemedjian O, [EXPRESS] Bortezomib-induced aerobic glycolysis contributes to chemotherapy-induced painful peripheral neuropathy. Molecular pain. 2019 Feb 27;     [PubMed PMID: 30810076]
[4] Fu Z,Lu C,Zhang C,Qiao B, PSMA5 promotes the tumorigenic process of prostate cancer and is related to bortezomib resistance. Anti-cancer drugs. 2019 Feb 21;     [PubMed PMID: 30807553]
[5] Liu Y,Wang X,Zhu T,Zhang N,Wang L,Huang T,Cao Y,Li W,Zhang J, Resistance to bortezomib in breast cancer cells that downregulate Bim through FOXA1 O-GlcNAcylation. Journal of cellular physiology. 2019 Feb 21;     [PubMed PMID: 30793308]
[6] Burkhart T,Keith MCL,Lenneman CAG,Fernando RR, Bortezomib-Induced Cardiac Tamponade in a 49-Year-Old Man. Texas Heart Institute journal. 2018 Aug;     [PubMed PMID: 30374242]
[7] Zajączkowska R,Kocot-Kępska M,Leppert W,Wrzosek A,Mika J,Wordliczek J, Mechanisms of Chemotherapy-Induced Peripheral Neuropathy. International journal of molecular sciences. 2019 Mar 22;     [PubMed PMID: 30909387]
[8] Kohler S,Märschenz S,Grittner U,Alexander T,Hiepe F,Meisel A, Bortezomib in antibody-mediated autoimmune diseases (TAVAB): study protocol for a unicentric, non-randomised, non-placebo controlled trial. BMJ open. 2019 Jan 28;     [PubMed PMID: 30696682]
[9] Zanwar S,Abeykoon JP,Kapoor P, Challenges and Strategies in the Management of Multiple Myeloma in the Elderly Population. Current hematologic malignancy reports. 2019 Feb 28;     [PubMed PMID: 30820879]
[10] Hungria VTM,Crusoé EQ,Bittencourt RI,Maiolino A,Magalhães RJP,Sobrinho JDN,Pinto JV,Fortes RC,Moreira ES,Tanaka PY, New proteasome inhibitors in the treatment of multiple myeloma. Hematology, transfusion and cell therapy. 2019 Jan-Mar;     [PubMed PMID: 30793108]
[11] Ladha A,Zhao J,Epner EM,Pu JJ, Mantle cell lymphoma and its management: where are we now? Experimental hematology     [PubMed PMID: 30733891]
[12] Heckmann MB,Doroudgar S,Katus HA,Lehmann LH, Cardiovascular adverse events in multiple myeloma patients. Journal of thoracic disease. 2018 Dec;     [PubMed PMID: 30701098]
[13] Hassan Zafar MS,Khan AA,Aggarwal S,Bhargava M, Efficacy and tolerability of bortezomib and dexamethasone in newly diagnosed multiple myeloma. South Asian journal of cancer. 2018 Jan-Mar;     [PubMed PMID: 29600238]