Recommended dose adjustments for newer agents for regimen-related toxicities
| . | Thalidomide86 (IMiD) . | Lenalidomide87 (IMiD) . | Pomalidomide88 (IMiD) . | Bortezomib89 (PI) . | Carfizomib90 (PI) . |
|---|---|---|---|---|---|
| Dose | 50-200 mg once daily PO | 25 mg once daily on days 1-21 q 28 d PO | 4 mg once daily on days 1-21 q 28 d PO | 1.3 mg/m2 on days 1, 4, 8, 11 q 21 d IV/SC | 20/27 mg/m2 on days 1, 2, 8, 9, 15, 16 q 28 d IV |
| Renal impairment (RI) | No dose adjustments needed | CLcr 30-60 mL/min: 10 mg q 24 h. CLcr <30 mL/min (not requiring dialysis): 15 mg q 48 h. CLcr <30 mL/min (requiring dialysis): 5 mg once daily (to be administered after dialysis on days of dialysis) | Serum creatinine ≥3.0 mg/dL: Avoid POM per label indication. Ongoing trials in patients with moderate to severe RI | No dose adjustments needed | Serum creatinine ≥2 × baseline: withhold CFZ until renal function has recovered to G1 or to baseline. If attributable to CFZ, restart at a reduced dose.* If not, restart at the same dose. |
| Hepatic impairment (HI) | Not been determined | Mild HI: no changes Moderate to severe HI: no data available for patients | Serum bilirubin ≥2.0 mg/dL and/or AST/ALT ≥3.0 × ULN: avoid POM | Moderate or severe HI: reduce BTZ to 0.7 mg/m2 in first cycle. Dose escalation to 1.0 mg/m2 or reduction to 0.5 mg/m2 in subsequent cycles based on tolerability | ≥G3 elevation of transaminases or bilirubin: withhold CFZ until toxicity resolved or returned to baseline. After resolution, CFZ may be reinitiated at a reduced dose* |
| Neutropenia | No dose adjustments needed | ANC <1000/µL/FN: interrupt LEN, add G-CSF, follow CBC weekly. When ANC returns to ≥1000/µL no other toxicity: resume LEN at 25 mg/d. When ANC returns to ≥1000/µL and if other toxicity: resume LEN at 15 mg/d. For each subsequent drop <1000/µL: interrupt LEN. When ANC returns to ≥1000 µL: resume LEN at 5 mg less than the previous dose. | ANC <500/µL: interrupt POM, follow CBC weekly. When ANC returns to ≥500/µL: resume POM at 3 mg/d. For each subsequent drop <500/µL: interrupt POM. When ANC returns to ≥500/µL: resume POM at 1 mg less than the previous dose | G4 neutropenia: withhold BTZ. Once the symptoms of the toxicity have resolved, BTZ may be reinitiated at a 25% reduced dose (1.3 mg/m2 per dose reduced to 1 mg/m2 per dose; 1 mg/m2 per dose reduced to 0.7 mg/m2 per dose) | ≥G3 neutropenia: withhold CFZ dose. If fully recovered before next scheduled dose, continue at same dose level. If recovered to G2 neutropenia, reduce dose by one dose level* |
| Thrombocytopenia | No dose adjustments needed | Platelets <30 000/µL: interrupt LEN, follow CBC weekly. When platelets return to ≥30 000 µL: resume LEN at 15 mg/d. For each subsequent drop <30 000/µL: interrupt LEN. When ANC returns to ≥30000/µL: resume LEN at 5 mg less than the previous dose | Platelets <25 000/µL: interrupt POM, follow CBC weekly. When platelets return to ≥50 000/µL: resume POM at 3 mg/d. For each subsequent drop <25 000/µL: interrupt POM. When platelets return to ≥50 000/µL: resume POM at 1 mg less than previous dose. | G4 thrombocytopenia: withhold BTZ. Once the symptoms of the toxicity have resolved, BTZ may be reinitiated at a 25% reduced dose (1.3 mg/m2 per dose reduced to 1 mg/m2 per dose; 1 mg/m2 per dose reduced to 0.7 mg/m2 per dose) | G4 thrombocytopenia: withhold dose. If fully recovered before next scheduled dose, continue at same dose level. If recovered to G3 thrombocytopenia, reduce dose by one dose level* |
| Peripheral neuropathy (PN) | Needs dose adjustments or permanent discontinuation | No dose adjustments needed | No dose adjustments needed | G1 with pain or G2 PN: reduce BTZ to 1 mg/m2. G2 with pain or G3 PN: withhold BTZ until toxicity resolves. When toxicity resolves, reinitiate with a reduced dose of BTZ at 0.7 mg/m2 once per week. G4 PN: Discontinue | ≥G3 PN: withhold CFZ until PN resolved or returned to baseline. After resolution, CFZ may be reinitiated at a reduced dose* at the discretion of the physician |
| Absolute contraindications | Pregnancy | Pregnancy; hypersensitivity (eg, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to LEN | Pregnancy | Anaphylaxis to BTZ, boron, or mannitol. Contraindicated for intrathecal administration | None |
| Comments | At least 72 h should elapse between consecutive doses of BTZ | ≥G3 cardiac toxicity or pulmonary HTN: withhold until resolved or returned to baseline. After resolution, CFZ at a reduced dose* |
| . | Thalidomide86 (IMiD) . | Lenalidomide87 (IMiD) . | Pomalidomide88 (IMiD) . | Bortezomib89 (PI) . | Carfizomib90 (PI) . |
|---|---|---|---|---|---|
| Dose | 50-200 mg once daily PO | 25 mg once daily on days 1-21 q 28 d PO | 4 mg once daily on days 1-21 q 28 d PO | 1.3 mg/m2 on days 1, 4, 8, 11 q 21 d IV/SC | 20/27 mg/m2 on days 1, 2, 8, 9, 15, 16 q 28 d IV |
| Renal impairment (RI) | No dose adjustments needed | CLcr 30-60 mL/min: 10 mg q 24 h. CLcr <30 mL/min (not requiring dialysis): 15 mg q 48 h. CLcr <30 mL/min (requiring dialysis): 5 mg once daily (to be administered after dialysis on days of dialysis) | Serum creatinine ≥3.0 mg/dL: Avoid POM per label indication. Ongoing trials in patients with moderate to severe RI | No dose adjustments needed | Serum creatinine ≥2 × baseline: withhold CFZ until renal function has recovered to G1 or to baseline. If attributable to CFZ, restart at a reduced dose.* If not, restart at the same dose. |
| Hepatic impairment (HI) | Not been determined | Mild HI: no changes Moderate to severe HI: no data available for patients | Serum bilirubin ≥2.0 mg/dL and/or AST/ALT ≥3.0 × ULN: avoid POM | Moderate or severe HI: reduce BTZ to 0.7 mg/m2 in first cycle. Dose escalation to 1.0 mg/m2 or reduction to 0.5 mg/m2 in subsequent cycles based on tolerability | ≥G3 elevation of transaminases or bilirubin: withhold CFZ until toxicity resolved or returned to baseline. After resolution, CFZ may be reinitiated at a reduced dose* |
| Neutropenia | No dose adjustments needed | ANC <1000/µL/FN: interrupt LEN, add G-CSF, follow CBC weekly. When ANC returns to ≥1000/µL no other toxicity: resume LEN at 25 mg/d. When ANC returns to ≥1000/µL and if other toxicity: resume LEN at 15 mg/d. For each subsequent drop <1000/µL: interrupt LEN. When ANC returns to ≥1000 µL: resume LEN at 5 mg less than the previous dose. | ANC <500/µL: interrupt POM, follow CBC weekly. When ANC returns to ≥500/µL: resume POM at 3 mg/d. For each subsequent drop <500/µL: interrupt POM. When ANC returns to ≥500/µL: resume POM at 1 mg less than the previous dose | G4 neutropenia: withhold BTZ. Once the symptoms of the toxicity have resolved, BTZ may be reinitiated at a 25% reduced dose (1.3 mg/m2 per dose reduced to 1 mg/m2 per dose; 1 mg/m2 per dose reduced to 0.7 mg/m2 per dose) | ≥G3 neutropenia: withhold CFZ dose. If fully recovered before next scheduled dose, continue at same dose level. If recovered to G2 neutropenia, reduce dose by one dose level* |
| Thrombocytopenia | No dose adjustments needed | Platelets <30 000/µL: interrupt LEN, follow CBC weekly. When platelets return to ≥30 000 µL: resume LEN at 15 mg/d. For each subsequent drop <30 000/µL: interrupt LEN. When ANC returns to ≥30000/µL: resume LEN at 5 mg less than the previous dose | Platelets <25 000/µL: interrupt POM, follow CBC weekly. When platelets return to ≥50 000/µL: resume POM at 3 mg/d. For each subsequent drop <25 000/µL: interrupt POM. When platelets return to ≥50 000/µL: resume POM at 1 mg less than previous dose. | G4 thrombocytopenia: withhold BTZ. Once the symptoms of the toxicity have resolved, BTZ may be reinitiated at a 25% reduced dose (1.3 mg/m2 per dose reduced to 1 mg/m2 per dose; 1 mg/m2 per dose reduced to 0.7 mg/m2 per dose) | G4 thrombocytopenia: withhold dose. If fully recovered before next scheduled dose, continue at same dose level. If recovered to G3 thrombocytopenia, reduce dose by one dose level* |
| Peripheral neuropathy (PN) | Needs dose adjustments or permanent discontinuation | No dose adjustments needed | No dose adjustments needed | G1 with pain or G2 PN: reduce BTZ to 1 mg/m2. G2 with pain or G3 PN: withhold BTZ until toxicity resolves. When toxicity resolves, reinitiate with a reduced dose of BTZ at 0.7 mg/m2 once per week. G4 PN: Discontinue | ≥G3 PN: withhold CFZ until PN resolved or returned to baseline. After resolution, CFZ may be reinitiated at a reduced dose* at the discretion of the physician |
| Absolute contraindications | Pregnancy | Pregnancy; hypersensitivity (eg, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to LEN | Pregnancy | Anaphylaxis to BTZ, boron, or mannitol. Contraindicated for intrathecal administration | None |
| Comments | At least 72 h should elapse between consecutive doses of BTZ | ≥G3 cardiac toxicity or pulmonary HTN: withhold until resolved or returned to baseline. After resolution, CFZ at a reduced dose* |
ALT, alanine transaminase; ANC, absolute neutrophil count; AST, aspartate transaminase; BTZ, bortezomib; CFZ, carfilzomib; CLCr, creatinine clearance; FN, febrile neutropenia; G, grade; HI, hepatic impairment; HTN, hypertension; IMiD, immunomodulatory agent; IV, intravenous; LEN, lenalidomide; PI, proteasome inhibitor; PN, peripheral neuropathy; PO, per os; POM, pomalidomide; RI, renal impairment; SC, subcutaneous.
Reduced dose of CFZ: from 27 mg/m2 to 20 mg/m2 OR from 20 mg/m2 to 15 mg/m2.