Daratumumab
Overview
Daratumumab is a human IgG1κ monoclonal antibody that targets CD38, a surface protein highly expressed on multiple myeloma cells and plasma cells in AL amyloidosis. It is an immunotherapy that works by inducing cell death through complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and apoptosis. Daratumumab has significantly changed the treatment landscape for relapsed, refractory, and newly diagnosed multiple myeloma, and has also been approved for systemic AL amyloidosis. Administered intravenously or subcutaneously, it can be used alone or in combination with standard therapies such as lenalidomide, bortezomib, and dexamethasone. Its favorable efficacy and manageable safety profile have made it a preferred choice in both first-line and subsequent treatment settings.
Background and Date of Approval
Daratumumab was developed by Genmab and is marketed by Janssen Biotech under the brand name Darzalex. The United States Food and Drug Administration (FDA) first approved daratumumab in November 2015 for patients with multiple myeloma who had received at least three prior lines of therapy. Subsequent approvals expanded its use to earlier lines of treatment and for use in combination regimens. The European Medicines Agency (EMA) granted approval in 2016, and the Drug Controller General of India (DCGI) followed suit in later years. In 2021, daratumumab also received FDA approval for the treatment of adult patients with newly diagnosed systemic AL amyloidosis in combination with bortezomib, cyclophosphamide, and dexamethasone. Clinical trials such as POLLUX, CASTOR, and ANDROMEDA demonstrated substantial improvements in progression-free survival and response rates compared to standard therapies. The subcutaneous formulation, daratumumab and hyaluronidase-fihj, was approved to reduce infusion time and improve patient convenience.
Uses
Daratumumab is indicated for the treatment of adults with multiple myeloma, both in newly diagnosed and relapsed or refractory settings. In newly diagnosed patients who are ineligible for autologous stem cell transplantation, it is used in combination with lenalidomide and dexamethasone or with bortezomib, melphalan, and prednisone. In transplant-eligible patients, it may be combined with bortezomib, thalidomide, and dexamethasone as induction therapy. For relapsed or refractory multiple myeloma, daratumumab is administered as monotherapy or in combination with proteasome inhibitors or immunomodulatory drugs. In addition, it is approved for systemic AL amyloidosis in combination with bortezomib, cyclophosphamide, and dexamethasone, where it has shown marked improvement in hematologic and organ responses. Off-label, daratumumab is being investigated for other hematologic malignancies and autoimmune conditions.
Administration
Daratumumab is administered either as an intravenous infusion or as a subcutaneous injection. The intravenous route requires premedication with corticosteroids, antihistamines, and antipyretics to minimize infusion-related reactions. The typical dosing schedule for intravenous administration begins with weekly infusions, gradually reducing in frequency over the treatment course. Subcutaneous administration offers a shorter administration time of approximately five minutes and a reduced risk of infusion-related reactions. Dose modifications may be necessary for infusion reactions or hematologic toxicities, and treatment should be guided by specialist protocols.
Side Effects
Common side effects of daratumumab include infusion-related reactions, upper respiratory tract infections, fatigue, nausea, diarrhea, constipation, and peripheral edema. Infusion reactions are most likely to occur during the first dose and are usually mild to moderate in severity. Patients may also experience reduced blood counts, particularly lymphopenia and neutropenia, which require monitoring and supportive management.
Warnings
Serious adverse events may include severe infusion reactions, serious infections such as pneumonia, and hematologic toxicities like severe neutropenia. Daratumumab can interfere with blood compatibility testing by binding to CD38 on red blood cells, potentially causing false-positive indirect antiglobulin tests; blood banks should be informed prior to transfusion. It is not recommended during pregnancy unless the potential benefit outweighs the risk, and effective contraception is advised during treatment and for several months after the last dose.
Precautions
Caution is advised in patients with chronic infections, immunosuppression, or respiratory disease. Live vaccines should be avoided during treatment. Daratumumab may have additive immunosuppressive effects when used with other therapies, increasing the risk of infection. Drug–drug interactions are not significant through metabolic pathways, but overlapping toxicities with other agents should be considered. Patients should be educated about signs of infection and instructed to seek immediate medical attention if symptoms arise.
Expert Tips
Consider typing and screening for blood compatibility before initiating therapy to avoid transfusion delays. Monitor blood counts regularly and manage cytopenias proactively. Premedication and post-infusion medications help minimize reactions, and the subcutaneous route can be considered for patient convenience. Educate patients about infection prevention and the importance of adherence to combination regimens.