Darzalex for Treatment of Multiple Myeloma and AL Amyloidosis

Darzalex is a subcutaneous injection combining daratumumab, a monoclonal antibody targeting CD38, with hyaluronidase to aid absorption. It is used primarily to treat adult patients with various forms of multiple myeloma, either alone or with other cancer medicines, as well as newly diagnosed light chain (AL) amyloidosis.

This medicine works by targeting cancer cells and is given by healthcare professionals under careful monitoring for side effects and infusion-related reactions.

Darzalex is approved for treating adult patients in the following conditions:

• Multiple myeloma in newly diagnosed patients eligible for autologous stem cell transplant (ASCT), given with bortezomib, lenalidomide, and dexamethasone during induction and consolidation.
• Multiple myeloma in newly diagnosed patients ineligible for ASCT, with combinations of bortezomib, lenalidomide and dexamethasone; bortezomib, melphalan, and prednisone; or bortezomib, thalidomide, and dexamethasone.
• Multiple myeloma in patients who have received at least one prior therapy:
• In combination with bortezomib and dexamethasone.
• In combination with lenalidomide and dexamethasone.
• In combination with pomalidomide and dexamethasone after prior lenalidomide and proteasome inhibitor therapy.
• In combination with carfilzomib and dexamethasone after one to three prior lines of therapy.
• As monotherapy for patients with multiple myeloma who have had at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory to both.
• As monotherapy for adult patients with high-risk smoldering multiple myeloma.
• In combination with bortezomib, cyclophosphamide, and dexamethasone for newly diagnosed light chain (AL) amyloidosis.

Limitations: It is not recommended for treating AL amyloidosis in patients with NYHA Class IIIB or IV cardiac disease or Mayo Stage IIIB outside clinical trials.

daratumumab and hyaluronidase-fihj

Darzalex contains daratumumab, an antibody that binds to CD38, a protein highly expressed on myeloma and AL amyloidosis cells. This binding triggers immune mechanisms that destroy these cancerous cells. Hyaluronidase is included to enhance the subcutaneous absorption of daratumumab, allowing for a shorter injection time.

General Dosage and Administration

Darzalex is administered as a subcutaneous injection into the abdomen at a dose of 1,800 mg daratumumab and 30,000 units hyaluronidase in 15 mL. The injection is given over approximately 3 to 5 minutes. Injection sites should be rotated and should avoid areas with scars, bruising, or redness.

Patients should receive pre-medications 1 to 3 hours before each dose, including acetaminophen, a histamine-1 receptor antagonist (eg, diphenhydramine), and corticosteroids (methylprednisolone or dexamethasone depending on regimen). Post-medications such as corticosteroids may also be administered to help reduce delayed reactions.

Dosing Schedules

Detailed dosing schedules vary by treatment setting and drug combinations, typically involving a weekly schedule initially, then every 2 weeks, and later every 3 to 4 weeks as maintenance, continuing until disease progression as follows:

• Monotherapy and combinations with lenalidomide, pomalidomide, or carfilzomib plus dexamethasone: Weekly dosing during weeks 1 to 8, every 2 weeks during weeks 9 to 24, and every 4 weeks thereafter.
• Combination with bortezomib, melphalan, and prednisone (6-week cycle): Weekly during weeks 1 to 6, then every 3 weeks during weeks 7 to 54, then every 4 weeks thereafter.
• Combination with bortezomib, thalidomide, and dexamethasone or lenalidomide, bortezomib, and dexamethasone for ASCT-eligible patients: Weekly during induction (weeks 1 to 8), every 2 weeks during weeks 9 to 16, treatment pause for ASCT, then every 2 weeks during consolidation (weeks 1 to 8).
• Combination with bortezomib, lenalidomide, and dexamethasone for ASCT-ineligible patients (3-week cycle): Weekly for 6 weeks, followed by every 3 weeks for 6 doses, then every 4 weeks until disease progression.
• Combination with bortezomib and dexamethasone: Weekly for 9 doses, then every 3 weeks for 5 doses, then every 4 weeks.
• Monotherapy for high-risk smoldering multiple myeloma: Weekly for 8 doses, every 2 weeks for 8 doses, then every 4 weeks up to 3 years or development of multiple myeloma.
• Combination with bortezomib, cyclophosphamide, and dexamethasone: Weekly for 8 doses, every 2 weeks for 8 doses, then every 4 weeks until disease progression or up to 2 years.

Additional

• If a dose is missed, administer as soon as possible and adjust the schedule to maintain intervals.
• No dose reduction of Darzalex is recommended; dose delays may be considered for myelosuppression recovery.
• Type and screen patients before starting therapy due to interference with blood compatibility testing.

• Patients with a history of severe hypersensitivity reactions to daratumumab, hyaluronidase, or any component of Darzalex Faspro.

Serious Allergic and Administration Reactions

Hypersensitivity and severe administration-related reactions can occur, including life-threatening reactions. Permanently discontinue Darzalex Faspro after any serious or life-threatening reaction.

Ocular adverse events such as acute myopia and angle closure glaucoma due to ciliochoroidal effusions have been reported. Interrupt treatment and seek ophthalmologic evaluation if ocular symptoms develop.

Cardiac Toxicity in AL Amyloidosis

Serious and fatal cardiac adverse reactions have occurred in patients with AL amyloidosis receiving Darzalex Faspro with bortezomib, cyclophosphamide, and dexamethasone. Patients with NYHA Class IIIA or Mayo Stage IIIA require close monitoring; patients with worse cardiac function were not studied.

Infections

Darzalex Faspro can cause serious, sometimes fatal infections, including opportunistic infections. Monitor and treat infections promptly. Initiate herpes zoster prophylaxis within one week of starting therapy and continue for 3 months after treatment ends.

Myelosuppression

Neutropenia and thrombocytopenia can occur. Regularly monitor blood counts and consider dose withholding until recovery.

Embryo-Fetal Toxicity

Darzalex may cause fetal harm. Advise women of reproductive potential regarding effective contraception during treatment and for 3 months after the last dose. It is contraindicated to combine with lenalidomide, thalidomide, or pomalidomide in pregnant women due to teratogenicity of these agents.

Interference with Blood Testing

Darzalex binds CD38 on red blood cells causing positive indirect antiglobulin tests, interfering with blood compatibility testing for up to six months after treatment. It also can interfere with serum protein assays used to monitor myeloma proteins. Inform blood banks and screen patients prior to therapy.

Common side effects vary by treatment combination but often include:

• Upper respiratory tract infections
• Fatigue
• Peripheral neuropathy
• Constipation and diarrhea
• Musculoskeletal pain and muscle spasms
• Rash and injection site reactions
• Pyrexia (fever)
• Edema
• Insomnia
• Cough and dyspnea
• Nausea and vomiting
• Headache and dizziness

Laboratory abnormalities frequently include decreased leukocytes, lymphocytes, neutrophils, platelets, and hemoglobin.

Serious adverse reactions include severe infections, pneumonia, sepsis, and hypersensitivity reactions.

Daratumumab causes interference with blood compatibility testing due to binding of CD38 on red blood cells. Inform blood banks that a patient has received Darzalex Faspro for appropriate management.

Darzalex may interfere with serum protein electrophoresis and immunofixation assays, affecting monitoring of IgG kappa myeloma proteins.

The combination of Darzalex Faspro with lenalidomide, thalidomide, or pomalidomide is contraindicated in pregnancy due to the teratogenicity of these agents.

Pregnancy

Darzalex Faspro can cause fetal harm including immune cell depletion and decreased bone density. Women of childbearing potential should use effective contraception during treatment and for 3 months after the last dose.

Use in combination with lenalidomide, thalidomide, or pomalidomide is contraindicated in pregnant women due to risk of severe birth defects and fetal death from these agents.

Lactation

No specific data provided regarding breastfeeding; a decision should be made to discontinue breastfeeding or treatment considering potential benefits and risks.

Store Darzalex Faspro vials refrigerated at 2°C to 8°C (36°F to 46°F). Before injection, allow the vial to reach room temperature (15°C to 30°C / 59°F to 86°F) without shaking.

After withdrawal into a syringe, if not used immediately, store refrigerated (2°C to 8°C) for up to 24 hours or at room temperature (15°C to 25°C / 59°F to 77°F) for up to 12 hours, protected from light.

Discard if storage times are exceeded or if particles or discoloration are present.