Usage
Daratumumab is prescribed for the treatment of multiple myeloma, a cancer of plasma cells in the bone marrow. It is classified as a monoclonal antibody, specifically an IgG1 kappa human monoclonal antibody. Daratumumab targets CD38, a transmembrane glycoprotein highly expressed on myeloma cells. By binding to CD38, it induces myeloma cell death through multiple mechanisms, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and apoptosis.
Alternate Names
Daratumumab is also known by its brand name, Darzalex. Darzalex Faspro is another brand name for the subcutaneous formulation of daratumumab in combination with hyaluronidase-fihj.
How It Works
Pharmacodynamics: Daratumumab exerts its anti-myeloma effect by binding to CD38, leading to cell death through CDC, ADCC, ADCP, and apoptosis. This targeted approach effectively eliminates myeloma cells while minimizing damage to healthy cells.
Pharmacokinetics: Daratumumab is administered intravenously (IV) or subcutaneously (SC). Following IV administration, it exhibits a non-linear pharmacokinetic profile. Steady state is generally reached by cycle 3. Subcutaneous administration reaches peak serum concentrations faster than IV administration. Daratumumab is primarily eliminated through metabolic pathways, and its clearance is affected by factors like body weight and baseline CD38 expression levels.
Mode of Action: Daratumumab binds to the CD38 receptor on myeloma cells. This binding triggers a cascade of events, including complement activation, recruitment of immune effector cells (natural killer cells, macrophages), and induction of programmed cell death (apoptosis).
Elimination Pathways: The specific elimination pathways for daratumumab have not been fully elucidated, but metabolism is thought to play a major role.
Dosage
Standard Dosage
Adults:
The standard dosage of daratumumab is 16 mg/kg body weight, administered via IV infusion.
- Combination therapy with lenalidomide and dexamethasone or with bortezomib and dexamethasone (relapsed/refractory multiple myeloma): Weeks 1-8: weekly; Weeks 9-24: every two weeks; Week 25 onwards: every four weeks.
- Monotherapy (relapsed/refractory multiple myeloma): Weeks 1-8: weekly; Weeks 9-24: every two weeks; Week 25 onwards: every four weeks.
- Combination therapy with bortezomib, melphalan and prednisone (newly diagnosed, transplant-ineligible): Weeks 1-6: weekly; Weeks 7-54: every 3 weeks; Week 55 onwards: every 4 weeks.
- Subcutaneous (SC) administration: 1800 mg/30,000 units SC weekly for the first 8 weeks, then every 2 weeks for 8 doses, then every 4 weeks thereafter until disease progression.
Children:
Daratumumab is not approved for use in pediatric patients.
Special Cases:
- Elderly Patients: No specific dose adjustment is required based on age alone. However, close monitoring is recommended.
- Patients with Renal Impairment: No dose adjustment is necessary for mild to moderate renal impairment. For severe impairment, cautious use is advised, and close monitoring is required.
- Patients with Hepatic Dysfunction: No dose adjustment is needed for mild hepatic impairment. Use with caution in moderate to severe hepatic impairment.
- Patients with Comorbid Conditions: Dose adjustments may be necessary based on specific comorbidities. For example, patients with pre-existing cytopenias should be closely monitored.
Clinical Use Cases
Daratumumab is not typically used in acute clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary use is in the outpatient setting for the treatment of multiple myeloma.
Dosage Adjustments
Dose adjustments or delays may be necessary for patients experiencing severe infusion-related reactions or hematologic toxicities (neutropenia, thrombocytopenia). No dose adjustments are recommended for renal or hepatic impairment, though close monitoring is advised.
Side Effects
Common Side Effects:
Infusion-related reactions (fever, chills, cough, nausea, vomiting, shortness of breath), fatigue, diarrhea, musculoskeletal pain, upper respiratory tract infection, pneumonia, neutropenia, thrombocytopenia.
Rare but Serious Side Effects:
Severe infusion-related reactions (including bronchospasm, hypotension, angioedema), opportunistic infections (e.g., herpes zoster reactivation), thromboembolic events.
Long-Term Effects:
Long-term effects of daratumumab are still being studied. Secondary malignancies are a potential concern with long-term use of any immunomodulatory agent.
Adverse Drug Reactions (ADR):
Clinically significant ADRs include severe infusion reactions, severe infections, and cardiac events (e.g., atrial fibrillation).
Contraindications
- History of severe hypersensitivity reaction to daratumumab.
Drug Interactions
Daratumumab may interact with live attenuated vaccines. Patients should not receive live vaccines during daratumumab treatment and for a period of time after treatment discontinuation. Consult current guidelines for recommendations on vaccination timing. Daratumumab can interfere with the indirect antiglobulin (Coombs) test. This can cause false positive results and complicate blood transfusions. It is essential to inform the blood bank of daratumumab treatment prior to any transfusion. For a full list of drug interactions, refer to the latest drug information resources.
Pregnancy and Breastfeeding
Daratumumab is not recommended during pregnancy. It is classified as Pregnancy Category C. Adequate contraception should be used during treatment and for at least 3 months after the last dose. It is unknown if daratumumab is excreted in breast milk. Breastfeeding is generally not recommended while receiving daratumumab.
Drug Profile Summary
- Mechanism of Action: IgG1 kappa human monoclonal antibody targeting CD38 on myeloma cells, leading to cell death through CDC, ADCC, ADCP, and apoptosis.
- Side Effects: Infusion-related reactions, neutropenia, thrombocytopenia, fatigue, diarrhea, infections.
- Contraindications: Severe hypersensitivity to daratumumab.
- Drug Interactions: Live attenuated vaccines, drugs affecting blood counts. Interference with Coombs test.
- Pregnancy & Breastfeeding: Not recommended during pregnancy or breastfeeding.
- Dosage: 16 mg/kg IV or 1800mg/30,000 units SC, with varying schedules depending on treatment regimen.
- Monitoring Parameters: Complete blood counts, renal and hepatic function, signs of infection.
Popular Combinations
Daratumumab is often used in combination with other anti-myeloma agents such as lenalidomide, bortezomib, dexamethasone, melphalan, and prednisone. The specific combination depends on factors like disease stage, prior treatment, and patient eligibility for transplant.
Precautions
- Infusion-related reactions can occur; premedication is recommended. Monitor closely during infusion, especially the first and second infusions.
- Increased risk of infection. Monitor for signs and symptoms of infection. Prophylactic antiviral medication for herpes zoster is recommended.
- Thrombocytopenia and bleeding are possible. Monitor platelet counts and advise patients about signs of bleeding.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Daratumumab?
A: The standard dose is 16 mg/kg IV or 1800 mg/30,000 units SC. Specific dosing schedules vary based on the treatment regimen.
Q2: What are the most common side effects of Daratumumab?
A: Infusion-related reactions, neutropenia, thrombocytopenia, fatigue, and diarrhea are common side effects.
A: Premedication with antihistamines, corticosteroids, and antipyretics is recommended. Slow the infusion rate or interrupt the infusion if a reaction occurs.
Q4: Can Daratumumab be used in patients with renal impairment?
A: Yes, dose adjustment is typically not required for mild to moderate renal impairment. Caution and close monitoring are advised for severe impairment.
Q5: What are the contraindications to using Daratumumab?
A: A history of severe hypersensitivity to daratumumab is a contraindication.
Q6: Does Daratumumab interact with other medications?
A: Yes, it can interact with live vaccines and some immunosuppressants. Daratumumab interferes with the indirect antiglobulin (Coombs) test. Refer to up-to-date drug interaction resources for a full list of interactions.
Q7: Can Daratumumab be used during pregnancy or breastfeeding?
A: Daratumumab is not recommended during pregnancy or breastfeeding. Effective contraception should be used during and for at least 3 months after treatment.
Q8: What is the mechanism of action of Daratumumab?
A: Daratumumab targets CD38 on myeloma cells and triggers cell death via CDC, ADCC, ADCP, and apoptosis.
Q9: How is Daratumumab administered?
A: Daratumumab can be administered intravenously or subcutaneously.
Q10: What monitoring is required during Daratumumab treatment?
A: Regular monitoring of complete blood counts, renal and hepatic function tests, and monitoring for signs of infection are necessary.
