Daratumumab - Drug Monograph

Introduction

Daratumumab is a first-in-class human IgG1κ monoclonal antibody that targets CD38, a cell surface protein highly expressed on multiple myeloma cells. It represents a significant advancement in the treatment of multiple myeloma, offering a novel mechanism of action for patients with relapsed or refractory disease. Approved by the FDA in 2015, daratumumab has since expanded its indications and transformed the treatment landscape for multiple myeloma.

Mechanism of Action

Daratumumab binds specifically to CD38, a transmembrane glycoprotein expressed on the surface of multiple myeloma cells and various other cell types. Its mechanism of action involves multiple immunologic pathways:

• Antibody-dependent cellular cytotoxicity (ADCC)
• Antibody-dependent cellular phagocytosis (ADCP)
• Complement-dependent cytotoxicity (CDC)
• Direct apoptosis through cross-linking
• Modulation of CD38 enzymatic activity
• Depletion of CD38+ immunosuppressive regulatory cells

This multifaceted approach results in potent antitumor activity against CD38-expressing malignant cells.

Indications

Daratumumab is FDA-approved for: 1. Multiple myeloma: - In combination with lenalidomide and dexamethasone for newly diagnosed patients who are ineligible for autologous stem cell transplant - In combination with bortezomib, melphalan, and prednisone for newly diagnosed patients who are ineligible for autologous stem cell transplant - In combination with bortezomib, thalidomide, and dexamethasone for newly diagnosed patients who are eligible for autologous stem cell transplant - In combination with bortezomib and dexamethasone for patients who have received at least one prior therapy - As monotherapy for patients who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent 2. Light chain (AL) amyloidosis: - In combination with cyclophosphamide, bortezomib, and dexamethasone for newly diagnosed patients

Dosage and Administration

• 16 mg/kg administered intravenously
• Weekly for cycles 1-2 (weeks 1-8)
• Every 2 weeks for cycles 3-6 (weeks 9-24)
• Every 4 weeks thereafter until disease progression

• Pre-medication required: corticosteroids, antipyretics, and antihistamines
• Infusion rate: Initial dose at 50 mL/hour, gradually increasing if no infusion reactions
• Subsequent infusions may be administered at higher rates if tolerated

• Renal impairment: No dosage adjustment required
• Hepatic impairment: No specific recommendations; use with caution
• Elderly: No dosage adjustment required

Pharmacokinetics

Contraindications

1. History of severe hypersensitivity to daratumumab or any of its excipients 2. No other absolute contraindications exist beyond hypersensitivity

Warnings and Precautions

1. Infusion-related reactions: Occur in up to 50% of patients, typically during first infusion 2. Hematologic toxicity: Neutropenia, thrombocytopenia, lymphopenia 3. Interference with serologic testing: May cause false-positive indirect antiglobulin tests 4. Hepatitis B virus reactivation: Screen patients before initiation 5. Interference with determination of complete response: May affect assessment due to daratumumab binding to CD38 on non-malignant cells 6. Embryo-fetal toxicity: May cause fetal harm; advise women of reproductive potential to use effective contraception

Drug Interactions

1. Interference with blood bank compatibility testing: Requires special handling and communication with blood bank 2. No clinically significant pharmacokinetic interactions with: - Bortezomib - Lenalidomide - Dexamethasone - Melphalan - Prednisone 3. Potential for increased immunosuppression when combined with other immunosuppressive agents

Adverse Effects

• Infusion-related reactions (48%)
• Fatigue (39%)
• Nausea (24%)
• Back pain (23%)
• Pyrexia (21%)
• Cough (21%)
• Dyspnea (20%)
• Neutropenia (20%)
• Thrombocytopenia (19%)

• Pneumonia (12%)
• Sepsis (5%)
• Upper respiratory tract infections (7%)
• Infusion reactions (2% severe)
• Hepatitis B reactivation
• Hematologic toxicity requiring dose modifications

Monitoring Parameters

1. Prior to initiation: - Hepatitis B screening - Complete blood count with differential - Comprehensive metabolic panel - Serum immunofixation electrophoresis - Quantitative immunoglobulins

2. During therapy: - Vital signs during infusion - CBC weekly for first 2 months, then monthly - Liver function tests regularly - Signs of infection - Infusion reactions monitoring - Response assessment per IMWG criteria

3. Long-term monitoring: - Regular assessment for secondary malignancies - Immunoglobulin levels - Renal function

Patient Education

1. Report any signs of infusion reactions during and after treatment 2. Notify healthcare team of any fever, chills, or signs of infection 3. Understand the importance of pre-medications before each infusion 4. Be aware of potential interference with blood compatibility testing 5. Use effective contraception during treatment and for 3 months after last dose 6. Report any unusual bleeding or bruising 7. Maintain regular follow-up appointments for monitoring 8. Inform all healthcare providers about daratumumab therapy 9. Understand the schedule and commitment required for treatment

References

1. FDA Prescribing Information: Darzalex (daratumumab) 2. Lokhorst HM, et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015;373(13):1207-1219 3. Palumbo A, et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375(8):754-766 4. Dimopoulos MA, et al. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375(14):1319-1331 5. Mateos MV, et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2018;378(6):518-528 6. NCCN Guidelines Multiple Myeloma Version 4.2023 7. ClinicalTrials.gov identifiers: NCT01615029, NCT02195479, NCT02252172