Daratumumab

Introduction to Daratumumab

Daratumumab (brand names: Darzalex, Darzalex Faspro) is a human IgG1κ monoclonal antibody approved by the FDA in 2015. It targets CD38, a transmembrane glycoprotein highly expressed on multiple myeloma cells. Daratumumab has revolutionized the treatment of multiple myeloma, showing efficacy in both newly diagnosed and relapsed/refractory settings. It's available in two formulations: intravenous (Darzalex) and subcutaneous (Darzalex Faspro).

Mechanism of Action

Daratumumab works through multiple mechanisms:

  • Direct mechanisms:
    • Antibody-dependent cellular cytotoxicity (ADCC)
    • Complement-dependent cytotoxicity (CDC)
    • Antibody-dependent cellular phagocytosis (ADCP)
    • Direct induction of apoptosis upon cross-linking
  • Immunomodulatory effects:
    • Depletion of CD38-positive regulatory T cells, regulatory B cells, and myeloid-derived suppressor cells
    • Increased T-cell clonality and enhanced T-cell mediated killing

The multi-faceted mechanism of daratumumab contributes to its efficacy across various stages of multiple myeloma and potentially in other hematological malignancies expressing CD38.

Clinical Applications

Daratumumab is FDA-approved for:

  • Newly diagnosed multiple myeloma:
    • In combination with bortezomib, melphalan, and prednisone in transplant-ineligible patients
    • In combination with lenalidomide and dexamethasone in transplant-ineligible patients
    • In combination with bortezomib, thalidomide, and dexamethasone in transplant-eligible patients
  • Relapsed or refractory multiple myeloma:
    • As monotherapy in heavily pretreated patients
    • In various combinations with standard-of-care regimens
  • Light chain (AL) amyloidosis:
    • In combination with bortezomib, cyclophosphamide, and dexamethasone

Key clinical trial results:

  • MAIA trial: Showed improved progression-free survival (PFS) in newly diagnosed, transplant-ineligible patients when added to lenalidomide and dexamethasone
  • CASSIOPEIA trial: Demonstrated improved stringent complete response rates and PFS in transplant-eligible patients
  • POLLUX and CASTOR trials: Showed significant PFS improvement in relapsed/refractory settings

While primarily used in adults, research is ongoing to evaluate its potential in pediatric populations with relapsed or refractory CD38-positive hematologic malignancies.

Dosage and Administration

Daratumumab is available in two formulations:

  • Intravenous (IV) formulation (Darzalex):
    • Typical dose: 16 mg/kg actual body weight
    • Schedule varies based on the combination regimen and stage of treatment (weekly, every two weeks, or every four weeks)
  • Subcutaneous (SC) formulation (Darzalex Faspro):
    • Fixed dose: 1,800 mg daratumumab and 30,000 units hyaluronidase
    • Administered subcutaneously over approximately 3-5 minutes
    • Schedule similar to IV formulation

Pre-medication and post-medication:

  • Pre-infusion: Corticosteroids, antipyretics, and antihistamines to reduce the risk of infusion reactions
  • Post-infusion: Oral corticosteroids to reduce the risk of delayed infusion reactions

Special considerations:

  • Split first dose over two consecutive days for IV formulation to reduce infusion reaction risk
  • Monitor for infusion reactions, especially during the first and second infusions
  • Administer antiviral prophylaxis to prevent herpes zoster reactivation

Side Effects and Precautions

Common side effects include:

  • Fatigue
  • Nausea
  • Diarrhea
  • Constipation
  • Back pain
  • Peripheral edema
  • Upper respiratory tract infection

Serious adverse events to be aware of:

  • Infusion-related reactions: More common with IV formulation, especially during first infusion
  • Neutropenia and thrombocytopenia: Monitor complete blood counts periodically
  • Infections: Increased risk, including pneumonia and sepsis
  • Hepatitis B virus (HBV) reactivation: Screen for HBV before initiating treatment
  • Interference with cross-matching and red blood cell antibody screening: Type and screen patients before starting treatment

Precautions:

  • Pregnancy: May cause fetal harm; effective contraception required during and for 3 months after treatment
  • Breastfeeding: Not recommended during treatment and for at least 3 months after the last dose
  • Pediatric use: Safety and efficacy not established in children
  • Interference with determination of complete response: May interfere with serum protein electrophoresis and immunofixation assays



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