Daratumumab

Daratumumab is a human IgG1 kappa monoclonal antibody and a CD38-directed anticancer medicine used primarily in plasma-cell disorders. It binds to CD38, a surface protein expressed at high levels on abnormal plasma cells in multiple myeloma and in plasma cells involved in light chain amyloidosis. Daratumumab can inhibit tumor cells through several mechanisms, including direct apoptosis and immune-mediated cell killing through complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis. It may also reduce certain CD38-positive immune-regulatory cell populations. Daratumumab is available as an intravenous formulation and, in combination with recombinant human hyaluronidase, as a subcutaneous formulation. Depending on the indication, it may be administered alone or combined with medicines such as lenalidomide, bortezomib, dexamethasone, pomalidomide, carfilzomib, or other standard treatment agents. Its clinical importance comes from its ability to target CD38-positive plasma cells and to be incorporated into treatment regimens across newly diagnosed and relapsed or refractory multiple myeloma, as well as selected related plasma-cell disorders.

Daratumumab was developed as a monoclonal antibody targeting CD38, a cell-surface protein expressed on plasma cells and several other hematopoietic cells. The U.S. Food and Drug Administration granted the first approval for daratumumab in November 2015 for heavily pretreated multiple myeloma, making it the first CD38-directed monoclonal antibody approved for this disease. Subsequent FDA approvals expanded its use into combination regimens for patients with newly diagnosed and relapsed or refractory multiple myeloma. The European Medicines Agency granted an initial conditional marketing authorisation for Darzalex in May 2016, which was converted to a standard marketing authorisation in April 2017. Regulatory development subsequently included both intravenous daratumumab and the subcutaneous daratumumab and hyaluronidase formulation. In the United States, the subcutaneous formulation is approved for multiple myeloma, high-risk smoldering multiple myeloma, and newly diagnosed light chain AL amyloidosis, with additional multiple myeloma combinations added over time. Major clinical programs supporting development include GEN501 and SIRIUS for early monotherapy development, CASTOR and POLLUX for relapsed or refractory multiple myeloma, MAIA and ALCYONE for newly diagnosed disease, COLUMBA for subcutaneous administration, PERSEUS and CEPHEUS for daratumumab-containing frontline regimens, and ANDROMEDA for AL amyloidosis.

Daratumumab is used in adults with multiple myeloma in both newly diagnosed and relapsed or refractory settings, with the specific combination determined by transplant eligibility, previous treatment, disease status, and the applicable regulatory indication. Current U.S. labeling for the intravenous formulation includes combination treatment with lenalidomide and dexamethasone, bortezomib with melphalan and prednisone, bortezomib with thalidomide and dexamethasone, bortezomib and dexamethasone, carfilzomib and dexamethasone, or pomalidomide and dexamethasone, as well as monotherapy in selected heavily pretreated or double-refractory patients. The subcutaneous daratumumab and hyaluronidase formulation has additional U.S. indications, including combination with bortezomib, lenalidomide and dexamethasone for newly diagnosed multiple myeloma, including induction and consolidation in transplant-eligible patients, and monotherapy for adults with high-risk smoldering multiple myeloma. It is also approved in combination with bortezomib, cyclophosphamide and dexamethasone for newly diagnosed systemic light chain AL amyloidosis. European indications include multiple myeloma combinations and monotherapy as well as high-risk smoldering multiple myeloma and AL amyloidosis, with exact indications depending on the current regional authorization.

Daratumumab dosing depends on the formulation and treatment regimen. Intravenous daratumumab is generally administered at 16 mg/kg based on actual body weight, with an initially frequent schedule that subsequently becomes less frequent as treatment continues. Depending on the combination regimen, administration may transition from weekly dosing to every two weeks and then every four weeks, while certain regimens use different schedules during induction, consolidation, or treatment cycles. The subcutaneous daratumumab and hyaluronidase formulation is administered as a fixed dose of 1,800 mg daratumumab with 30,000 units of hyaluronidase, with schedules varying according to the disease and treatment combination. In high-risk smoldering multiple myeloma, the regimen begins with frequent administration followed by less frequent administration according to the approved treatment schedule. In AL amyloidosis, treatment is given with bortezomib, cyclophosphamide and dexamethasone according to the approved regimen. Treatment is generally continued according to the relevant indication until disease progression, unacceptable toxicity, completion of a defined treatment period, or another clinically appropriate stopping point. Premedication and post-treatment medication are required to reduce administration-related reactions, particularly with intravenous treatment.

Common adverse effects associated with daratumumab vary according to the formulation and combination regimen. Frequently reported effects include upper respiratory tract infections, neutropenia, thrombocytopenia, anemia, fatigue, diarrhea, constipation, nausea, peripheral sensory neuropathy, peripheral edema, cough, fever, shortness of breath, and administration-related or infusion-related reactions. With subcutaneous administration, injection-site reactions can occur and may include local redness, swelling, pain, itching, or rash. Blood-count abnormalities may occur more frequently when daratumumab is combined with other myeloma medicines that also suppress bone marrow function. Many adverse effects can be monitored and managed with supportive treatment, treatment interruption, or modification of accompanying medicines under appropriate medical supervision.

Important risks include severe infusion-related or administration-related reactions, serious infections, neutropenia, thrombocytopenia, and embryo-fetal toxicity. Intravenous daratumumab can cause severe or life-threatening infusion-related reactions, particularly during the first administration, and the infusion should be interrupted if a reaction occurs. Subcutaneous treatment can also cause serious administration-related reactions, although the administration profile differs from intravenous treatment. Daratumumab can interfere with blood-bank serological testing because it binds to CD38 on red blood cells and may cause false-positive indirect antiglobulin test results; patients should therefore have appropriate blood typing and screening before treatment and blood banks should be informed that the patient is receiving daratumumab. In AL amyloidosis, serious and sometimes fatal cardiac adverse reactions have been reported, particularly in patients with cardiac involvement, and patients with more advanced cardiac disease require careful assessment because some severe cardiac stages were not studied. Treatment may need to be interrupted or discontinued for significant reactions, and severe hypersensitivity to daratumumab or its formulation components is a contraindication.

Before treatment, clinicians should establish the diagnosis and treatment setting and assess baseline blood counts, renal and hepatic parameters, infection status, and other factors relevant to the planned combination regimen. Blood type and antibody screening should be performed before starting daratumumab because treatment can interfere with compatibility testing for transfusions for several months after administration. Patients should be monitored for infections and for neutropenia or thrombocytopenia, particularly when daratumumab is combined with other myelosuppressive medicines. Antiviral prophylaxis against herpes zoster reactivation is recommended according to the prescribing information. In AL amyloidosis, baseline and ongoing assessment of cardiac involvement is particularly important. Daratumumab is a monoclonal antibody and does not generally produce the classic small-molecule metabolic drug interactions associated with CYP enzyme inhibition or induction; however, interactions with laboratory testing and blood transfusion compatibility are clinically important. Pregnancy should be avoided when appropriate because daratumumab can cause fetal harm, and reproductive counselling should be provided. Vaccination plans and infection prevention should be reviewed according to the patient's treatment regimen and immune status.

Prescribers should confirm the exact indication and selected daratumumab formulation before treatment and coordinate administration with the accompanying myeloma or amyloidosis regimen. For intravenous therapy, ensure that appropriate premedication is given and that emergency treatment facilities are immediately available during administration because serious infusion reactions can occur. For subcutaneous daratumumab and hyaluronidase, monitor the administration site and observe patients for systemic administration-related reactions. Blood-group testing and antibody screening should be completed before the first dose, and the transfusion service should be informed that the patient is receiving daratumumab. Complete blood counts should be monitored throughout therapy, with particular attention to neutropenia, thrombocytopenia, and infection. Patients should be counselled to report fever, respiratory symptoms, allergic symptoms, unusual bleeding, or other signs of infection promptly. In AL amyloidosis, close coordination with cardiology or other relevant specialists may be appropriate because cardiac involvement can substantially affect treatment risk. Pharmacists should also review the complete combination regimen for additive hematologic toxicity, infection risk, and corticosteroid-related effects.