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. 2021 Mar 24;11(3):e046225. doi: 10.1136/bmjopen-2020-046225

Table 3.

Dose modifications

Cyclophosphamide Modifications are at the discretion of the investigator Renal impairment—a dose reduction of 50% for creatinine clearance of 10 mL/min is recommended Hepatic impairment—a dose reduction to 350 mg is recommended with a serum bilirubin of >2.5 times the upper limit of normal (ULN)
Bortezomib
Induction dose reductions
Regimen: first dose reduction CVRDd Cycle duration: 21 days
Drug Dose Route Days
Cyclophosphamide 500 mg PO 1 and 8
Bortezomib 1.3 mg/m2 SC 1, 8, 15
Lenalidomide 25 mg PO 1–14
Daratumumab 16 mg/kg (actual body weight) IV 1, 8, 15 (cycles 1 and 2)
1 only (cycle 3 onwards)
Dexamethasone 20–40 mg PO/IV 1, 8, 15
Postinduction dose reductions
Bortezomib schedule Dose levels
0 −1 −2 −3 −4
Twice weekly schedules 1.3 mg/m2 d 1, 4, 8, 11 1.3 mg/m2 d 1, 8, 15 1.0 mg/m2 d 1, 8, 15 1.3 mg/m2 d 1, 15 Stop
Once weekly schedules 1.3 mg/m2 d 1, 8, 15, (22) 1.0 mg/m2 d 1, 8, 15 (22) 1.0 mg/m2 d 1, 15 0.7 mg/m2 d 1, 15, Stop
Consolidation 1 1.3 mg/m2 d 1, 8, 15, 22 1.0 mg/m2 d 1, 8, 15, 22 1.0 mg/m2 d 1, 15 0.7 mg/m2 d 1, 15, Stop
Consolidation 2 1.3 mg/m2 d 1, 8, 15 1.0 mg/m2 d 1, 8, 15 1.0 mg/m2 d 1, 15 0.7 mg/m2 d 1, 15, Stop
Neuropathy- CTCAE Grade 1 with pain or grade 2—withhold bortezomib until returns to baseline. Dose reduce 1 level; CTCAE Grade 2 with pain or grade 3—withhold bortezomib until returns to baseline. Dose reduce 2 levels; CTCAE Grade 4—discontinue treatment Renal impairment—dose reduce at the discretion of the clinician Hepatic impairment—moderate or severe impairment (>1.5–3×ULN) should start on a reduced dose of 0.7 mg/m2 during the first cycle of treatment and dose escalate to 1.0 mg/m2 or dose reduce to 0.5 mg/m2 may be considered Grade 3 Non-haematological toxicity—withhold until symptoms of toxicity resolve and reduce one dose. Grade 4 haematological toxicity—withhold until symptoms of toxicity resolve and reduce one dose. Support may be given.
Lenalidomide schedule Dose levels
0 −1 −2 −3 −4 −5
25 mg 20 mg 15 mg 10 mg 5 mg 2.5 mg
Thrombocytopenia—<25×109/L stop lenalidomide for the remainder of the cycle. Return to ≥50 × 109/L decrease by 1 dose level to resume the next cycle. Neutropenia—first fall to <0.5×109/L omit lenalidomide until a return to ≥0.5 × 109/L when neutropenia is the only toxicity. Resume lenalidomide at one dose lower. For each subsequent drop to ≥0.5 × 109/L omit lenalidomide, resume lenalidomide decreased by 1 dose level at the next cycle. Renal impairment—30–50 mL/min 10 mg daily;<30 mL/min, not requiring dialysis 7.5 mg daily or 15 mg every other day; <30 mL/min, requiring dialysis 5 mg daily administered following dialysis Other non-haematological toxicities: CTCAE grade 3 and 4 related to lenalidomide should be stopped and started 1 dose lower when toxicity has resolved to grade 2 at clinicians discretion. Rash—interrupt or discontinue for grade 2 or 3. Grade 4 rash discontinue including angioedema, exfoliative or bullous rash or Steven Johnson syndrome or toxic epidermal necrosis.
Daratumumab schedule Frequency Dose held Dosing restart
Induction cycles 1 and 2 Weekly >3 days Next planned weekly dose
Induction cycles 3–6 Monthly >1 week Next planned weekly dose
Consolidation 1, Consolidation 2, Maintenance Monthly >2 weeks Next planned weekly dose
Follow the daratumumab SPC. The daratumumab infusion must be withheld to allow for recovery from toxicity ONLY where any of the following criteria are met and the event cannot be ascribed to lenalidomide or cyclophosphamide.

  • Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding.

  • Grade 4 neutropenia, if this is the second occurrence despite growth factor support.

  • Febrile neutropenia of any grade.

  • Neutropenia with infection, of any grade.

  • Grade 3 or higher non-haematological toxicities with the following exceptions:

    • Grade 3 nausea that responds to antiemetic treatment within 8 days.

    • Grade 3 vomiting that responds to antiemetic treatment within 8 days.

    • Grade 3 diarrhoea that responds to anti-diarrhoeal treatment within 8 days.

    • Grade 3 fatigue that was present at baseline or that lasts for<8 days after the previous administration of daratumumab.

    • Grade 3 asthenia that was present at baseline or that lasts for<8 days after the previous administration of daratumumab.

Dexamethasone Occasionally patients will not be able to tolerate because of corticosteroid effects. Dose reductions from 40 to 20 mg daily. Further dose reductions to 10 mg daily is acceptable followed by the omission of dexamethasone If the bortezomib schedule changes, dexamethasone should change in line with it.
Melphalan Dose may be adjusted based on performance status and clinical judgement in discussion with the Chief Investigator GFR measured by Cockcroft & Gault formula or EDTA—>50 mL/min 200 mg/m2; 30–50 mL/min 140 mg/m2;<30 mL/min 100 mg/m2

CTCAE, common terminology criteria for adverse events; CVRDd, Cyclophosphamide, bortezomib (Velcade), lenalidomide (Revlimid), daratumumab (Darzalex), dexamethasone; GFR, glomerular filtration rate; IV, intravenous; SC, subcutaneous; SPC, summary of product characteristics.