Usual Adult Dose for Multiple Myeloma

DOSING SCHEDULE IN COMBINATION WITH LENALIDOMIDE OR POMALIDOMIDE (4-WEEK CYCLE) AND LOW-DOSE DEXAMETHASONE AND FOR MONOTHERAPY:

• Weeks 1 to 8: 16 mg/kg IV weekly (total of 8 doses)
• Weeks 9 to 24: 16 mg/kg IV every 2 weeks (total of 8 doses); first dose of the every-2-week dosing schedule is given at Week 9
• Week 25 and onwards until disease progression: 16 mg/kg IV every 4 weeks; first dose of the every-4-week dosing schedule is given at Week 25

DOSING SCHEDULE IN COMBINATION WITH BORTEZOMIB, MELPHALAN, AND PREDNISONE 6-WEEK CYCLE:

• Weeks 1 to 6: 16 mg/kg IV weekly (total of 6 doses)
• Weeks 7 to 54: 16 mg/kg IV every 3 weeks (total of 16 doses); first dose of the every-3-week dosing schedule is given at Week 7
• Week 55 onwards until disease progression: 16 mg/kg IV every 4 weeks; first dose of the every-4-week dosing schedule is given at Week 55

DOSING SCHEDULE IN COMBINATION WITH BORTEZOMIB, THALIDOMIDE, AND DEXAMETHASONE 4-WEEK CYCLE:
INDUCTION:

• Weeks 1 to 8: 16 mg/kg IV weekly (total of 8 doses)
• Weeks 9 to 16: 16 mg/kg IV every 2 weeks (total of 4 doses); first dose of every-2-week dosing schedule is given at Week 9
• Stop for high dose chemotherapy and ASCT.

CONSOLIDATION:

• Weeks 1 to 8: 16 mg/kg IV every 2 weeks; first dose of the every-2-week dosing schedule is given at Week 1 upon reinitiation of therapy following ASCT

DOSING SCHEDULE IN COMBINATION WITH BORTEZOMIB AND DEXAMETHASONE 3-WEEK CYCLE:

• Weeks 1 to 9: 16 mg/kg IV weekly (total of 9 doses)
• Weeks 10 to 24: 16 mg/kg IV every 3 weeks (total of 5 doses); first dose of every-3-week dosing schedule is given at Week 10
• Week 25 onwards until disease progression: 16 mg/kg IV every 4 weeks; first dose of the every-4-week dosing schedule is given at Week 25

DOSING SCHEDULE WITH CARFILZOMIB AND DEXAMETHASONE 4-WEEK CYCLE:

• Week 1: 8 mg/kg IV on Days 1 and 2 (total of 2 doses)
• Weeks 2 to 8: 16 mg/kg IV weekly (total of 7 doses)
• Weeks 9 to 24: 16 mg/kg IV every 2 weeks (total of 8 doses); first dose of the every-2-week dosing schedule is given at Week 9
• Week 25 onwards until disease progression: 16 mg/kg every 4 weeks; first dose of the every-4-week dosing schedule is given at Week 25

Comments:

• Dosing is based on actual body weight.
• The first 16 mg/kg dose at Week 1 may be split over 2 consecutive days (i.e., 8 mg/kg on Day 1 and Day 2, respectively.
• Pre-and post-infusion medications should be given prior to initiating therapy.

Manufacturer recommended infusion rates and management of infusion related reactions (IRRs):
OPTION 1 (SINGLE DOSE INFUSION):
Week 1 Day 1 (16 mg/kg):

• Dilution volume: 1000 mL
• Initial rate (first hour): 50 mL/hr
• Rate increment: 50 mL/hr every hour
• Maximum rate: 200 mL/hr

OPTION 2 (SPLIT DOSE INFUSION):
Week 1 Day 1 (8 mg/kg):

• Dilution volume: 500 mL
• Initial rate (first hour): 50 mL/hr
• Rate increment: 50 mL/hr every hour
• Maximum rate: 200 mL/hr

Week 1 Day 2 (8 mg/kg):

• Dilution volume: 500 mL
• Initial rate (first hour): 50 mL/hr
• Rate increment: 50 mL/hr every hour
• Maximum rate: 200 mL/hr

WEEK 2 (16 mg/kg):

• Dilution volume: 500 mL
• Initial rate (first hour): 50 mL/hr
• Rate increment: 50 mL/hr every hour
• Maximum rate: 200 mL/hr

WEEK 3 ONWARDS (16 MG/KG):

• Dilution volume: 500 mL
• Initial rate (first hour): 100 mL/hr
• Rate increment: 50 mL/hr every hour
• Maximum rate: 200 mL/hr

COMMENTS:

• Consider incremental escalation of the infusion rate only in the absence of infusion reactions.
• Use a dilution volume of 500 mL for the 16 mg/kg dose only if there were no infusion reactions the previous week; otherwise, continue to use a dilution volume of 1000 mL.
• Use a modified initial rate (100 mL/hour) for subsequent infusions (i.e., Week 3 onwards) only if there were no infusion reactions during the previous infusion; otherwise, continue to use instructions indicated for the Week 2 infusion rate.

PREMEDICATIONS:
Premedicate approximately 1 to 3 hours prior to every infusion:
1) Corticosteroid (long- or intermediate-acting);

• Monotherapy: Methylprednisolone (or equivalent) 100 mg IV; following the second infusion, consider reducing the dose to 60 mg (or equivalent) IV or orally.
• Combination therapy: Administer 20 mg dexamethasone (or equivalent) IV or orally. When dexamethasone is the background regimen specific corticosteroid, the dexamethasone dose that is part of the background regimen will serve as premedication on daratumumab infusion days.
• Do not administer background regimen-specific corticosteroids (e.g., prednisone) on daratumumab infusion day.
• Daratumumab infusion days when patients have received dexamethasone (or equivalent) as a premedication.

2) Antipyretic: Acetaminophen 650 to 1000 mg orally
3) Antihistamine: Diphenhydramine (or equivalent) 25 to 50 mg IV or orally

POST-INFUSION MEDICATION:
MONOTHERAPY: Administer methylprednisolone 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) orally for 2 days starting the day after the administration of daratumumab.
IN COMBINATION: Consider administering oral methylprednisolone at a dose of less than or equal to 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) beginning the day after the administration of daratumumab.
If a background regimen-specific corticosteroid (e.g., dexamethasone, prednisone) is administered the day after the daratumumab infusion, additional corticosteroids may not be needed.

• For patients with a history of chronic obstructive pulmonary disease, consider prescribing short and long-acting bronchodilators and inhaled corticosteroids. Following the first 4 daratumumab infusions, consider discontinuing these additional post-infusion medications if the patient does not experience a major infusion-related reaction.

PROPHYLAXIS FOR HERPES ZOSTER REACTIVATION:

• Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting daratumumab and continue for 3 months after.

Comments:

• For dosing instructions of combination agents administered with this drug see the manufacturer product information.

Uses:

• In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant or with relapsed or refractory multiple myeloma who have received at least 1 prior therapy
• In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant (ASCT)
• In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
• In combination with bortezomib and dexamethasone in patients who have received at least 1 prior therapy
• In combination with pomalidomide and dexamethasone in patients who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor
• As monotherapy, in patients who have received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent

Renal Dose Adjustments

No adjustment recommended.

Liver Dose Adjustments

Mild hepatic impairment: No adjustment recommended.
Moderate to severe hepatic impairment: Data not available

Dose Adjustments

No dose reductions of daratumumab are recommended. Consider withholding therapy to allow recovery of blood cell counts in the event of myelosuppression.

INFUSION-RELATED REACTIONS (IRRs):
For infusion related reactions (IRRs) of any grade/severity, interrupt the infusion and manage symptoms (this may require further reduction in the rate of infusion or discontinuation of therapy):

• Grade 1 to 2 (mild to moderate): After symptoms resolve, resume the infusion at no more than half the rate at which the IRR occurred; if the patient experiences no further IRRs, infusion rate escalation may resume at increments up to the maximum rate of 200 mL/hour.
• Grade 3 (severe): After symptoms resolve, restart the infusion at no more than half the rate at which the IRR occurred; if the patient experiences no further IRRs, resume infusion rate escalation as outlined in the "Manufacturer recommended infusion rates and management of IRRs". Repeat this procedure in the event of recurrence of Grade 3 symptoms. Permanently discontinue therapy upon the third occurrence of a Grade 3 or greater IRR.
• Grade 4 (life threatening): Permanently discontinue therapy.

Precautions

CONTRAINDICATIONS:

• None

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• This drug should be administered by a healthcare professional, with immediate access to emergency equipment and appropriate medical support to manage IRRs.
• Administer only as an IV infusion after dilution.
• For dosing instructions of combination agents administered with this drug see the manufacturer product information.
• If a dose is missed, administer as soon as possible and adjust the dosing schedule accordingly maintaining the treatment interval.

Reconstitution/preparation/storage advice:

• The manufacturer product information should be consulted.

Patient advice:

• The patient should be instructed to read the patient labeling.
• Patients should be advised to seek immediate medical attention for any signs of infusion reactions (i.e., itchy, runny or blocked nose, chills, nausea, throat irritation, cough, headache, shortness of breath, or difficulty breathing).
• Patients should be advised to inform healthcare providers including blood transfusion centers/personnel that they are taking this drug, in the event of a planned transfusion.

Frequently asked questions

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