Bortezomib is a cancer medicine. It is indicated in the treatment of Multiple Myeloma and Mantel cell Lymphoma. It acts by blocking the activity of proteasomes which promotes the growth of cancer cells.

Bortezomib Indications:

• Multiple Myeloma

• Mantle cell lymphoma

Bortezomib is one of the first lines of treatment used for induction chemotherapy in the treatment of multiple myeloma. The two preferred induction regimens for the treatment of multiple myeloma are:

• Bortezomib + Lenalidomide + Dexamethasone

• Bortezomib + Cyclophosphamide+ Dexamethasone (in patients with kidney impairment)

Bortezomib is also one of the key drugs in the treatment of refractory cases of multiple myeloma, along with novel drugs such as:

• Daratumumab, Lenalidomide, Bortezomib, and Dexamethasone

• Bortezomib, Doxorubicin, and Dexamethasone

• Daratumumab, Cyclophosphamide, Bortezomib, and Dexamethasone

• Daratumumab, Bortezomib, Thalidomide, and Dexamethasone

• Dexamethasone, Thalidomide, Cisplatin, Doxorubicin, Cyclophosphamide, Etoposide, Bortezomib (VTD-PACE)

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Bortezomib Dosage [Ref]

• Bortezomib Injection is given in a dose of 1.3 mg/m² as an intravenous bolus over 3 to 5 seconds.

• Treatment is indicated as a first-line along with other medicines in newly diagnosed cases. A bortezomib-containing regimen can also be used in patients who have relapsed after 6 months and who have had a good response to Bortezomib in the past.

• These patients may be started on the dose that was tolerated by the patient in the previous cycle.

Bortezomib Dose in combination with Melphalan and Prednisolone:

• The combination of Bortezomib + Oral Melphalan + Oral Prednisone was previously used. This regimen is currently replaced by newer more potent regimens.

• A total of 9 cycles, each lasting for 6 weeks are recommended

• In cycles 1 to 4, Bortezomib Injection is administered twice weekly on Days 1, 4, 8, 11, 22, 25, 29, and 32.

• In cycles 5 to 9, Bortezomib Injection is administered once weekly on Days 1, 8, 22, and 29.

• At least 72 hours should elapse between consecutive doses of Bortezomib Injection.

Before initiating this regimen, the following parameters should be looked into:

• The platelet count should be at least 70,000/ul

• The absolute neutrophil count should be at least 1000/ul.

• Reduce the melphalan dose by 25% of the recommended dose if the patient had severe hematological toxicity in the previous cycle such as Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding.

• Withhold the treatment if the platelet count is less than 30 × 10^9/L or ANC is less than 0.75 × 10^9/L on a Bortezomib Injection day (other than Day 1).

• If repeated dosing is withheld due to cytopenias, reduce the dose of Bortezomib from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2).

• In cases where the patient develops nonhematological toxicities of Grade 3 or above, the treatment should be withheld until the symptoms resolve to Grade 1. The injection may then be resumed at a lower dose (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2).

• The dose may also be reduced if the patient develops treatment-related neuropathic pain.

Bortezomib Dosage for Previously Untreated Mantle Cell Lymphoma

• Bortezomib is combined with Rituximab, Cyclophosphamide, Doxorubicin, and Oral Prednisone for treating Mantle cell lymphoma.

• It is given in a dose of 1.3 mg/m2 intravenously for 6 cycles (each lasting 3 weeks). During the first 2 weeks, it is administered twice weekly on Days 1, 4, 8, and 11 followed by a ten-day rest period from Days 12 to 21.

• For patients who respond to the treatment in cycle 6, two additional VcR-CAP cycles are recommended.

• Between two consecutive doses, a minimum of 72 hours of time-lapse is recommended​​​​​​.

Dosage Schedule:

Dosage for Patients with Previously Untreated Mantle Cell Lymphoma: Twice Weekly Bortezomib Injection (6, Three-Week Cycles)

• Week 1:

  • Day 1; Bortezomib Injection (1.3 mg/m2), Rituximab (375 mg/m2), Cyclophosphamide (750 mg/m2), Doxorubicin (50 mg/m2), Prednisone (100 mg/m2)

  • Prednisone is continued from Day 1 to 5

• Week 2:

  • Day 4: Bortezomib Injection (1.3 mg/m2),

  • Prednisone (100 mg/m2) Day 1-5

• Week 3:

  • Day 8 and Day 11: Bortezomib Injection (1.3 mg/m2)

• Dosing may continue for two more cycles (for a total of eight cycles) if a response is first seen at Cycle 6.

Note:

• The patient should have a response first documented at cycle 6 for two additional VcR-CAP cycles.

Bortezomib Dose Modification if side effects develop when treating Lymphoma

Before initiating each cycle, except for Cycle 1, the following conditions must be met:

• Platelet count should be ≥100,000/ul

• ANC should be ≥1500/ul

• Hemoglobin should be ≥8 g/dL (≥4.96 mmol/L)

• Nonhematologic toxicity should have resolved or recovered to Grade 1.

Bortezomib Dose Modification Guidelines:

Discontinue the treatment in severe side effects Grade 3 severity or more (other than neuropathy). Modify the dose of Bortezomib on Days 4, 8, and 11 as given below:

Hematological toxicity	Action
Grade 3 or higher neutropenia or platelet count below 25,000/ul	Withhold therapy for up to 2 weeks. Discontinue if toxicity persists. Reduce dose by one level if toxicity resolves.
Grade 3 or higher nonhematological toxicities	Withhold therapy until toxicity improves to Grade 2 or better Resume with a one-level dose reduction.

Bortezomib Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma

Information	Description
Administration Schedule	Twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a ten-day rest period (Days 12 to 21).
Extended Therapy Schedule of more than 8 cycles	Follow the standard schedule or, For relapsed multiple myeloma, on a maintenance schedule of once weekly for four weeks (Days 1, 8, 15, and 22) followed by a 13-day rest period (Days 23 to 35).
Dosing Interval	At least 72 hours should elapse between two consecutive doses of Bortezomib.

Dosage Administration for Retreated Patients

• Patients with multiple myeloma who have had a good response to the Bortezomib combination regimen and who have relapsed after 6 months may be started on a Bortezomib-containing regimen. The last dose in the previous treatment that was well tolerated should be given.

• The dose is given twice weekly (Days 1, 4, 8, and 11) every three weeks for a maximum of eight cycles.

• At least 72 hours should elapse between two consecutive doses of Bortezomib Injection.

Dose Modifications

• Withhold Bortezomib Injection if any Grade 3 nonhematological or Grade 4 hematological toxicities develop, excluding neuropathy.

• The treatment may be reinitiated at a 25% reduced dose once the toxicity resolves.

• Reduce the dose as follows:

  • 1.3 mg/m2/dose to 1 mg/m2/dose;

  • 1 mg/m2/dose to 0.7 mg/m2/dose.

Dosage Modifications for Peripheral Neuropathy: Guidelines and Severity Grading

• Peripheral neuropathy is one of the common side effects of Bortezomib treatment. It can be given to patients with preexisting neuropathy but with extreme caution.

• However, if the symptoms of neuropathy worsen, dos modification or treatment interruption may be required.

Severity Grading:

• The severity of peripheral neuropathy signs and symptoms is graded based on the NCI Common Terminology Criteria CTCAE v4.0.

Dose Modification Guidelines:

The dose and regimen modification for patients who experience neuropathic pain and/or peripheral sensory or motor neuropathy related to Bortezomib Injection.

• Grade 1 neuropathy without pain or loss of function: No action is needed

• Grade 1 neuropathy with pain or Grade 2 neuropathy that limits instrumental activities of daily living (ADL): Reduce Bortezomib Injection to 1 mg/m2

• Grade 2 neuropathy with pain or Grade 3 neuropathy that limits self-care ADL: Withhold Bortezomib Injection until toxicity resolves. Then, restart with a reduced dose of Bortezomib Injection at 0.7 mg/m2 once a week.

• Grade 4 neuropathy with life-threatening consequences that require urgent intervention: Discontinue Bortezomib Injection therapy.

Activities of Daily Living:

Instrumental ADL refers to activities such as preparing meals, shopping, using the phone, managing money, etc. Self-care ADL refers to activities such as bathing, dressing, feeding oneself, using the toilet, taking medications, and not being bedridden.

Dosage Modifications for Hepatic Impairment:

• For patients with mild hepatic impairment and if the bilirubin is between 1 to 1.5 times the ULN, no starting dose modification is required regardless of the ALT or SGOT (AST) levels.

Moderate:

• For patients with moderate hepatic impairment with bilirubin levels more than 1.5×-3× ULN and any SGOT (AST) levels, the dose of Bortezomib should be reduced to 0.7 mg/m2 in the first cycle.

Severe:

• If a patient has a bilirubin level greater than 3 times the upper limit of normal or any level of SGOT (AST), the starting dose of Bortezomib Injection should be reduced to 1 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability.

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Instructions for Intravenous Administration

• Calculate the dose based on BSA according to the formula:

  • ​​DuBois BSA formula (m²): 0.20247 × height(m)^0.725 × weight(kg)^0.425

  • Mosteller BSA formula (m²): (height(cm) x weight(kg))^(1/2) / 3600

  • Haycock BSA formula (m²): 0.024265 x height(cm)^0.3964 x weight(kg)^0.5378

Visual Inspection:

• Inspect the vials before injecting them for discoloration and particulate matter. Discard if any discoloration or particulate matter is noted

Stability:

• Keep Bortezomib Injection refrigerated at 2 to 8°C (36℉ to 46℉). Unopened vials may be stored at room temperature (20℃ to 25℃ [68℉ to 77 ℉) for up to 7 days.

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Contraindications to Bortezomib:

Bortezomib Injection should not be used in the following situations:

• Allergic reactions that are severe including anaphylaxis to bortezomib, boron, or mannitol.

• Intrathecal use

Warning & Precautions:

Peripheral Neuropathy:

• Monitor for symptoms of neuropathy. The dose may need to be reduced based on the severity of neuropathy.

Hypotension:

• Watch out for hypotension. The dose of antihypertensive medications may need to be reduced.

Cardiac Toxicity:

• Bortezomib may cause acute heart failure. It should be cautiously advised to patients with preexisting cardiac diseases. Close monitoring is recommended during the treatment.

• Very rarely, it can also result in the prolongation of the QT interval.

Pulmonary Toxicity:

• ARDS, pneumonitis, and pulmonary hypertension have been reported. The treatment may need to be stopped in such cases. Patients should be evaluated for new-onset cardiac or lung-related symptoms.

Posterior Reversible Encephalopathy Syndrome (PRES):

• PRES syndrome manifesting as seizure, headache, confusion, and blindness may develop during the treatment. In such cases, the treatment should be discontinued.

Gastrointestinal Toxicity:

• Nausea, diarrhea, constipation, vomiting, and ileus can occur with the treatment. Symptomatic treatment and hydration may be necessary. In severe cases, the treatment may need to be stopped.

Thrombocytopenia/Neutropenia

• Thrombocytopenia and neutropenia are common. In mild cases, the counts improve before the next scheduled dose.

• In severe cases, dose adjustment and treatment interruption may be needed. Checking for blood counts before the next scheduled dose is recommended.

Bortezomib vs Dexamethasone Study:

	Platelet count nadir	Incidence of bleeding (≥Grade 3)
Bortezomib	Decreased to 40% of baseline	2%
Dexamethasone	Less than 1%	Less than 1%

Bortezomib + Rituximab + Chemotherapy Study:

	Thrombocytopenia (≥Grade 4)	Platelet Transfusions	Neutropenia (≥Grade 4)	Febrile Neutropenia (≥Grade 4)	Myeloid Growth Factor Support
VcR-CAP	32%	23%	70%	5%	78%
R-CHOP	1%	3%	52%	6%	61%

Tumor Lysis Syndrome

• Bortezomib therapy can cause tumor lysis syndrome, especially in patients with high tumor burden before treatment

• Take necessary measures to prevent and treat this condition.

Hepatic Toxicity

• Taking Bortezomib Injection with other medications and underlying medical conditions may increase the risk of acute liver failure and other hepatic reactions.

• Monitor liver function during therapy and interrupt Bortezomib Injection if needed to assess reversibility.

• Re-challenging patients who had hepatic reactions is not well-studied.

Thrombotic Microangiopathy

• Thrombotic microangiopathy, including TTP and HUS, may develop during Bortezomib treatment.

• In such cases, the treatment may need to be stopped. Re-challenging the patient again, after the resolution of TTP/HUS is not clear.

Embryo-fetal Toxicity

• Bortezomib Injection can harm the fetus if given to pregnant women, based on animal studies.

• Use effective contraception during and after Bortezomib Injection treatment for women who may conceive and their male partners.

• Discuss the risk and benefits of Bortezomib Injection in pregnancy or breastfeeding with the patient and the healthcare provider.

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Side Effects of Bortezomib:

Side Effect	Frequency	Severity
Tumor Lysis Syndrome	Common	High
Hepatic Toxicity	Common	Moderate
Thrombotic Microangiopathy	Common	High
Embryo-Fetal Toxicity	Common	High
Nausea/Vomiting	Very Common	Mild
Diarrhea	Very Common	Mild
Constipation	Common	Mild
Fatigue	Common	Mild
Neuropathy	Common	Moderate
Pyrexia	Common	Mild
Thrombocytopenia	Common	Moderate
Anemia	Common	Moderate
Peripheral Edema	Common	Mild
Neutropenia	Common	Moderate
Headache	Common	Mild
Rash	Common	Mild
Insomnia	Common	Mild

Note: This table is not exhaustive and other side effects may also occur. The frequency and severity of these side effects may vary depending on the individual patient's medical history and other factors.

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Bortezomib Drug Interactions:

Interactions of Bortezomib Injection with Other Drugs

Bortezomib Injection may increase or decrease the efficacy of other drugs when combined. In addition, the risk of side effects may increase with certain medications.

Strong CYP3A4 Inducers

• Reduce the efficacy of Bortezomib.

• Avoid the combined use of Bortezomib with CYP3A4 inducers.

Strong CYP3A4 Inhibitors

• There is an increased risk of Bortezomib-associated side effects.

• Monitor for side effects. In addition, the dose may be reduced.

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Use in Specific Populations:

Pregnancy and Lactation:

• Bortezomib Injection can be harmful to a fetus and may cause embryo-fetal lethality in pregnant women. There are no studies on the use of bortezomib in pregnant or breastfeeding women, and potential adverse outcomes in pregnancy can occur despite maternal health or medication use.

• Pregnant and nursing women should be warned about the potential risks, and nursing women should avoid breastfeeding while receiving Bortezomib Injections and for two months after treatment.

Females and Males of Reproductive Potential

• Bortezomib Injection may harm fetuses when given to pregnant women. Females of reproductive potential must have a pregnancy test before treatment and use effective contraception during and after treatment. The drug may also affect fertility in both males and females.

Pediatric and Geriatric Use

• Limited data in children. In older people, the risk of side effects may increase. Need to monitor more closely for adverse events.

Renal Impairment

• There is no consensus on the starting dosage in kidney impairment. If the patient is on dialysis, the dose should be administered after the procedure.

Hepatic Impairment

• In severe hepatic impairment, reduce the dose. No adjustment in the dose is recommended in mild hepatic impairment.

Patients with Diabetes

• Monitor diabetic patients on antidiabetic treatment for dysglycemia (both hypo and hyperglycemia can occur).

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Mechanism of Action (MOA) of Bortezomib:

Bortezomib Injection is a proteasome inhibitor. It stops a protein called 26S proteasome from working. The 26S proteasome helps remove certain proteins from the cell to keep things balanced.

Stopping 26S proteasome can affect many cell signals and cause the cell to die. Studies show that bortezomib Injection can kill cancer cells and slow tumor growth in patients with multiple myeloma

Pharmacodynamics:

• Proteasome inhibition is very rapid and occurs within 5 minutes of the infusion.

Pharmacokinetics	Data
Protein binding	83%
Half-life	40 – 193 hours
Metabolism	Via CYP enzymes 3A4, 2C19, and 1A2, and to a lesser extent by 2D6 and 2C9

How Supplied/Storage And Handling

Bortezomib is available as 5 ml and 2 ml injection vials containing 3.5 mg/3.5 ml (1mg/1ml) and 3.5 mg/1.4 ml (2.5 mg/ml) respectively.

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Patient Counselling Information

Before taking Bortezomib Injection, patients should discuss the following with their healthcare provider:

Peripheral Neuropathy

• Report numbness, tingling, or pain in hands and feet.

Hypotension

• Drink lots of fluids to avoid dehydration. Notify symptoms of low blood pressure such as dizziness, fainting, or muscle cramps.

Cardiac Toxicity

• Report shortness of breath or swelling, indicative of heart failure.

Pulmonary Toxicity

• Report chest symptoms like cough and shortness of breath indicating ARDS, pulmonary hypertension, pneumonitis, or pneumonia.

Posterior Reversible Encephalopathy Syndrome (PRES)

• Report new onset symptoms of headache or drowsiness, suggesting PRES.

Gastrointestinal Toxicity

• Report nausea, vomiting, and diarrhea. Drink lots of fluids to avoid dehydration.

Thrombocytopenia/Neutropenia

• Report any signs or symptoms of bleeding or infection.

Tumor Lysis Syndrome

• Take liberal fluids to avoid dehydration so as to reduce the risk of tumor lysis syndrome.

Hepatic Toxicity

• Report jaundice or right upper quadrant pain.

Thrombotic Microangiopathy

• Report signs or symptoms of thrombotic microangiopathy such as black-colored urine, reduced urination, and limb weakness.

Ability to Drive or Operate Machinery or Impairment of Mental Ability

• Avoid driving or operating heavy machinery if you experience fatigue, dizziness, syncope, or orthostatic/postural hypotension.

Embryo-fetal Toxicity

• Avoid getting pregnant during the treatment.

Lactation

• Avoid breastfeeding while receiving Bortezomib Injection and for two months after the last dose.

Concomitant Medications

• Give a list of the medications you are taking to your doctor to avoid drug interactions that can be serious.

Diabetic Patients

• Monitor blood sugars frequently to avoid hypo and hyperglycemia.

Dermal

• Report if you experience a rash, injection site reactions, or skin pain.

Other

• Report hypertension, hypotension, bleeding, fever, constipation, or decreased appetite.

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Bortezomib Injection Brand Names:

Velcade