Bortezomib

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 the 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 correlates with a decreased occurrence of grade 3 or higher adverse effects. IV form administration is as a rapid push (3 to 5 seconds). The dosing regimens below will reference IV administration.

For previously untreated multiple myeloma, bortezomib dosing is 1.3 mg/m^2 X 1 IV on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle for the first 4 cycles; doses must be at least 72 hours apart. Subsequent dosing is 1.3 mg/m^2 X 1 IV on days 1, 8, 22, and 29 of a 42-day cycle. Bortezomib is given as part of a multi-drug regimen.

For previously relapsing multiple myeloma, bortezomib dosing is 1.3 mg/m^2 X 1 IV on days 1, 4, 8, and 11 of a 21-day cycle. If the patient has previously received bortezomib therapy, give up to 8 cycles, then starting with cycle 9, dosing can be 1.3 mg/m^2 X 1 IV on days 1, 8, 15, and 22 of a 35-day cycle; doses must be at least 72 hours apart. In this regimen, bortezomib can be given with dexamethasone or as monotherapy.[6]

For mantle cell lymphoma, bortezomib is dosed at 1.3 mg/m^2 x 1 IV on days 1, 4, 8, and 11 of a 21-day treatment cycle, with a minimum of 72 hours between doses. Avoid injecting at the same site within a single cycle.  

The drug is metabolized by the CYP3A4 and CYP2C19 enzymes in the liver. The metabolites are inactive and are excreted by the kidney.

Adverse Effects

The following are adverse events seen with bortezomib[7][8][9]:

Central Nervous System: Peripheral neuropathy (IV: 35% to 54%; SQ: 37%; grade 2 or higher: 24% to 39%; grade 3 or higher: SQ: 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: 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.[10][11][12]

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 increase to 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.[13][14]

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 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 the use of bortezomib can lead to excess protein accumulation in many organs.

Hypotension: 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. Ordering should be under the direction of an oncology specialist who is well-versed in the use of the drug.  The drug is administered parenterally and requires close monitoring by the nursing staff. Besides checking the CBC, the liver function involves 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 clinician immediately and check with the pharmacist. 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. Before dispensing the drug, the pharmacist should ensure that the patient has no allergies and has been worked up for tuberculosis and perform medication reconciliation. Also, the patient must receive education regarding the potential long-term adverse effects that can occur, including neuropathy.

It is through this type of interprofessional effort between physicians, nurses, and pharmacists that bortezomib therapy can achieve optimal therapeutic outcomes for patients while minimizing the potential for adverse events. [Level 5]