| Cycle length: 21 days. |
| Drug | Dose and route | Administration | Given on days |
| Bortezomib | 1.3 mg/m2 SC* | Given as a single SC injection. | Days 1, 8, and 15[3,4] |
| Lenalidomide¶ | 25 mgΔ by mouth | Administer with water. Swallow capsule whole; do not break, open, or chew. | Daily, on days 1 through 14 |
| Dexamethasone | 40 mgΔ by mouth | Take with food (after meals or with food or milk) in the morning. | Days 1, 8, and 15[3] |
| Pretreatment considerations: |
| Emesis risk | - MINIMAL TO 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 (not including local reactions) occurs with bortezomib or lenalidomide, then neither drug should be readministered.
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| Antithrombotic prophylaxis | - Routine antithrombotic prophylaxis is warranted. Thromboembolism was reported in 2 to 6% of patients in clinical trials receiving VRd despite antithrombotic prophylaxis.[1,2] The risk of thromboembolism was over 10% with another lenalidomide and high-dose dexamethasone (RD) regimen.[5]
- Refer to UpToDate topics on thrombotic complications following treatment of multiple myeloma with immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide).
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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 VRd. Some clinicians also administer prophylactic trimethoprim-sulfamethoxazole (eg, one double-strength tablet once daily on Mondays, Wednesdays, and Fridays) during treatment.[1,2] Primary prophylaxis with G-CSF is not indicated.
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| Vesicant/irritant properties | - Bortezomib is an irritant.
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
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| Dose adjustment for baseline liver or renal dysfunction | - Bortezomib: No dosage adjustment for bortezomib secondary to renal insufficiency is necessary.[6] For patients undergoing hemodialysis, bortezomib should be administered after dialysis. Patients with moderate or severe hepatic impairment (serum bilirubin level >1.5 times the ULN) 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.
- Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents and chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents.
- Lenalidomide: Patients with renal insufficiency experience more neutropenia with lenalidomide.[7] Dose adjustment is recommended for patients with CrCl <60 mL/min.[8] At this time, studies have not been conducted in patients with hepatic impairment.
- 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 agent; and chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency, conventional cytotoxic agents.
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| Monitoring parameters: |
- Assess CBC with differential, electrolytes, renal function, and liver function prior to starting each cycle. A CBC should also be performed prior to the day 8 and 15 doses of bortezomib during induction therapy.
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- Weekly assessment for peripheral neuropathy and/or neuropathic pain.
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- Monitor for hypotension during bortezomib therapy; adjustment of antihypertensives and/or administration of IV hydration may be needed.
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - A cycle of VRd should not be started unless the ANC is ≥1000/microL and the platelet count is ≥70,000/microL.[1,2,6] If platelets are <50,000/microL or the ANC is <1000/microL on day 15, hold day 15 bortezomib dose. 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 daily dose of lenalidomide by 5 mg. Growth factor support can be given on day 8 of the second and subsequent cycles for ANC <500/m2 lasting >7 days or for an episode of febrile neutropenia.[1,2]
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| Neuropathy | - Dose adjustment guidelines for bortezomib in patients who develop peripheral neuropathy or neuropathic pain are available:[6]
- 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 with 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.
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| Thrombotic microangiopathy | - Rarely, bortezomib has been associated with TMA, which can present with Coombs-negative hemolysis, thrombocytopenia, renal failure, and/or neurologic findings.[6] 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, hold lenalidomide and bortezomib. Once symptoms have resolved to grade 1 or baseline, reinitiate therapy with lower doses. Reduce dexamethasone dose 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. |
