| Cycle length: 28 days. |
| Drug | Dose and route | Administration | Given on days |
| Ixazomib | 4 mg by mouth | Take at least one hour prior to or two hours following a meal. Swallow capsule whole; do not break, open, or chew. | Days 1, 8, and 15 |
| Lenalidomide* | 25 mg¶ by mouth | Take with water. Swallow capsule whole; do not break, open, or chew. | Daily, on days 1 through 21 |
| Dexamethasone | 40 mg¶ by mouth | Take with food (after meals or with food or milk) in the morning. | Days 1, 8, 15, and 22 |
| Pretreatment considerations: |
| Emesis risk | - LOW (10 to 30% risk of emesis).
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
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| Antithrombotic prophylaxis | - Routine antithrombotic prophylaxis is warranted. The risk of thromboembolism was over 10% with another lenalidomide and high-dose dexamethasone (RD) regimen.[2]
- Refer to UpToDate topics on thrombotic complications following treatment of multiple myeloma with immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide.
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| Dose adjustment for baseline liver or renal dysfunction | - Ixazomib: Reduce ixazomib dose to 3 mg orally on days 1, 8, and 15 in patients with moderate (total bilirubin >1.5 to 3 times ULN) or severe (total bilirubin >3 times ULN) hepatic impairment and in those with severe renal impairment (creatinine clearance <30 mL/min) or end-stage kidney disease requiring dialysis. Since the drug is not dialyzable, it may be administered without regard to the timing of dialysis.
- Lenalidomide: Patients with renal insufficiency experience more neutropenia with lenalidomide. Dose adjustment is recommended for patients with CrCl <60 mL/min. 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 agents; and chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency, conventional cytotoxic agents.
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| Monitoring parameters |
- CBC with differential and platelet count at baseline, every seven days for the first two cycles, days 1 and 15 in cycle 3, and every 28 days thereafter.[3]
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- Electrolytes, renal, and hepatic function at baseline and the start of each cycle.
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- Assessment for peripheral neuropathy and/or neuropathic pain at baseline and prior to the start of each cycle.
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- Monitor for signs of hypovolemia secondary to diarrhea and/or vomiting prior to each cycle.
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- Monitor for rash prior to each cycle.
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| Suggested dose modifications for toxicity: |
| Myelosuppression | - A cycle of IRd should not be started unless the ANC is ≥1000/microL and the platelet count is ≥75,000/microL.[4] If platelets are <30,000/microL and/or the ANC is <500/microL, hold ixazomib and lenalidomide until platelet count is at least 30,000/mm3 and the ANC is at least 500/mm3. Consider prophylactic G-CSF in subsequent cycles for those with ANC <500/microL. Following recovery, reduce lenalidomide dose by 5 mg and resume ixazomib at its most recent dose.[3] If platelet count and/or ANC falls to this level again, withhold both ixazomib and lenalidomide. Following recovery, reduce ixazomib by one dose level (from 4 mg to 3 mg; from 3 mg to 2.3 mg) and resume lenalidomide at its most recent dose.[2]
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| Rash | - If grade 2 or 3, withhold lenalidomide until rash recovers to grade 1 or lower. Following recovery, reduce lenalidomide dose by 5 mg. If grade 2 or 3 rash recurs, withhold lenalidomide and ixazomib. Following recovery to grade 1 or lower, resume ixazomib at next lower dose (from 4 mg to 3 mg; from 3 mg to 2.3 mg) and lenalidomide at its most recent dose. If grade 4 rash develops, discontinue treatment regimen.[3]
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| Peripheral neuropathy | - If grade 1 with pain or grade 2, withhold ixazomib until neuropathy recovers to grade 1 or lower without pain or patient's baseline, and resume ixazomib at its most recent dose. For grade 2 with pain or grade 3, withhold ixazomib until recovery to patient's baseline condition or grade 1 or lower, and resume ixazomib at a dose reduced by one dose level (from 4 mg to 3 mg; from 3 mg to 2.3 mg). For grade 4 peripheral neuropathy, discontinue treatment regimen.[4]
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| Thrombotic microangiopathy | - Rarely, ixazomib has been associated with TMA, which can present with Coombs-negative hemolysis, thrombocytopenia, renal failure, and/or neurologic findings.[4] If TMA is suspected, stop ixazomib and evaluate.
- Refer to UpToDate topics on drug-induced thrombotic microangiopathy.
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| Other nonhematologic toxicities | - If grade 3 or 4, withhold ixazomib and upon recovery to patient's baseline or grade 1 or lower, resume ixazomib at its most recent dose. If toxicity believed to be attributable to ixazomib, resume at next lower dose (from 4 mg to 3 mg; from 3 mg to 2.3 mg).
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