Bortezomib

Article Author:
Aarushi Sharma
Article Editor:
Steve Bhimji
Updated:
7/26/2018 12:12:30 AM
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. In addition, 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.

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 an important 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. 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, SQ form is associated with a decreased occurrence of grade 3 or higher adverse effects. IV form is administered as a rapid push (3 to 5 seconds). SQ bortezomib 1.3 mg/m2 is administered 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 are excreted by the kidney.

Adverse Effects

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 should not be delivered to the patient via the intrathecal route.  

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 must be thoroughly discussed 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. 

Cautions

Reactivation of hepatitis B: all patients who are treated with bortezomib should first be tested for HBsAg and HBcAb. If either of these tests is positive, the patient should be started on lamivudine for the duration of the therapy. In addition, 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 it is combined with other medications like isoniazid, amiodarone, and HMG-CoA reductase inhibitors. Thus, close examination for neurological deficits is highly recommended.

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. Hence the blood sugars must be carefully monitored. Most patients do develop hypoglycemia, and hence the dose of the oral hypoglycemic should be reduced.

Amyloidosis: Patients with amyloidosis should also be treated 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 who were treated 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 very low therapeutic window, and overdose can occur when the dose is doubled. The patient will usually present with marked thrombocytopenia and hypotension, which are very difficult to reverse. Several fatal outcomes have been reported 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.