| Cycle length: 28 days. |
| Drug | Dose and route | Administration | Given on days |
| Bortezomib | 1.5 mg/m2 SC or IV* | Given subcutaneously or as a rapid IV bolus over three to five seconds. | Days 1, 8, 15, and 22 |
| Cyclophosphamide | 300 mg/m2 by mouth, once weekly | Dose rounding to the nearest 50 mg. Do not cut or crush. Take during or after meal in the morning. | Days 1, 8, 15, and 22 |
| Dexamethasone | 40 mg by mouth, once weekly | Take with food (after meals or with food or milk) in the morning. | Days 1, 8, 15, and 22 |
| Pretreatment considerations: |
| Hydration | - Patients receiving cyclophosphamide should maintain adequate oral hydration (2 to 3 L/day during administration and for one to two days thereafter) and void every two to three hours to reduce the risk of hemorrhagic cystitis.[2] Risk of bladder irritation is also decreased by avoiding bedtime administration.
- Refer to UpToDate topics on hemorrhagic cystitis in cancer patients.
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| Emesis risk | - LOW or VERY LOW.
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
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| Prophylaxis for infusion reactions | - Routine premedication is not indicated. If a hypersensitivity reaction occurs with cyclophosphamide, then neither oral nor IV cyclophosphamide should be readministered.
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| Infection prophylaxis | - Bortezomib therapy may be associated with an increased risk of herpes zoster and infections not related to neutropenia. Antiviral prophylaxis (eg, acyclovir 400 mg orally twice a day) should be administered to all patients receiving VCD/CyBorD. Some clinicians also administer trimethoprim-sulfamethoxazole double strength once daily on Mondays, Wednesdays, and Fridays during treatment. Primary prophylaxis with G-CSF is not indicated.
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| Antithrombotic prophylaxis | - While patients with multiple myeloma have an increased risk of thrombosis, the risk of thrombosis with the VCD/CyBorD regimen was ≤7% in two trials.[3,4] Routine antithrombotic prophylaxis is not warranted.
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| Dose adjustment for baseline liver or kidney dysfunction | - Bortezomib: No dosage adjustment for bortezomib secondary to kidney impairment is necessary. For patients undergoing hemodialysis, bortezomib should be administered after dialysis. Patients with moderate or severe hepatic impairment (serum bilirubin level >1.5 times the upper limit of normal) should be started on bortezomib at a reduced dose of 0.7 mg/m2 per injection during the first cycle, with further dose modifications based upon patient tolerance.
- Cyclophosphamide: For patients with preexisting hepatic impairment, dose adjustments in cyclophosphamide dose may be needed. The need for cyclophosphamide dose reduction in patients with kidney impairment is controversial; some suggest dose reduction if the creatinine clearance is <30 mL/minute.
- Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents; chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents; and chemotherapy nephrotoxicity and dose modification in patients with kidney impairment, conventional cytotoxic agents.
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| Monitoring parameters: |
- Assess CBC with differential, electrolytes, kidney function, liver function, and M protein prior to starting each cycle. A CBC should also be performed prior to the day 15 dose of bortezomib.
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- Weekly assessment for peripheral neuropathy and/or neuropathic pain.
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- Monitor for hypotension during therapy; adjustment of antihypertensives and/or administration of IV hydration may be needed.
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - If platelets are <50,000/microL or the absolute neutrophil count is <1000/microL on day 15, hold bortezomib and cyclophosphamide.[3] If several doses are held, reduce bortezomib dose by one level (from 1.5 mg/m2 to 1.3 mg/m2; or from 1.3 mg/m2 to 1 mg/m2; or from 1 mg/m2 to 0.7 mg/m2) and decrease the number of doses of cyclophosphamide given each cycle by one level (serial levels are: Days 1, 8, 15, and 22; days 1, 8, and 15; days 1 and 8; day 1 only).
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| Neuropathy | - Dose adjustment guidelines for bortezomib in patients who develop peripheral neuropathy or neuropathic pain are available:[5]
- Grade 1 (asymptomatic, loss of deep tendon reflexes or paresthesia without pain or loss of function): No action required.
- Grade 1 (with pain) or Grade 2 (interfering function but not activities of daily living): Reduce by one level (from 1.5 mg/m2 to 1.3 mg/m2; or from 1.3 mg/m2 to 1 mg/m2; or from 1 mg/m2 to 0.7 mg/m2).
- Grade 2 (with pain) or Grade 3 (interfering with activities of daily living): Hold until resolution, may reinitiate at 0.7 mg/m2 once weekly.
- Grade 4 (life-threatening, disabling, eg, paralysis): Discontinue.
- Rarely, bortezomib has been associated with RPLS, which can present with seizures, hypertension, headache, lethargy, confusion, blindness, or as other visual or neurological disturbances. Bortezomib should be discontinued if the diagnosis of RPLS is confirmed on brain MRI.
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| Cystitis | - For grades 1 or 2 cystitis (minor symptoms responding to outpatient management), decrease the number of doses of cyclophosphamide given each cycle by one level (serial levels are: Days 1, 8, 15, and 22; days 1, 8, and 15; days 1 and 8; day 1 only).[2] Cyclophosphamide should be discontinued if cystitis symptoms are distressing or affect lifestyle (grade 3 or 4).
- Refer to UpToDate topics on hemorrhagic cystitis in cancer patients.
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| Thrombotic microangiopathy | - Rarely, bortezomib has been associated with TMA, which can present with Coombs-negative hemolysis, thrombocytopenia, kidney failure, and/or neurologic findings.[5] If TMA is suspected, stop bortezomib and evaluate.
- Refer to UpToDate topics on drug-induced thrombotic microangiopathy.
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| Other nonhematologic toxicity | - For grade 3 or 4 nonhematologic toxicity other than neuropathy, bortezomib should be held. Once symptoms have resolved to grade 1 or baseline, bortezomib may be reinitiated with one dose level reduction (from 1.3 mg/m2 to 1 mg/m2; or from 1 mg/m2 to 0.7 mg/m2). Dexamethasone dose should be reduced for grade 2 muscle weakness, grade 3 gastrointestinal tract toxicity, hyperglycemia, confusion or mood alterations.
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
