On September 26, 2019, daratumu-mab (Darzalex) was approved in combination with bortezomib, thalidomide, and dexamethasone for the treatment of multiple myeloma in newly diagnosed adult patients eligible for autologous stem cell transplantation (ASCT).^1,2

Supporting Efficacy Data

Approval was based on findings from the open-label phase III CASSIOPEIA trial (ClinicalTrials.gov identifier NCT02541383),^2,3 which compared induction and consolidation treatment with daratumumab at 16 mg/kg in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) vs bortezomib, thalidomide, and dexamethasone (VTd) in patients aged ≤ 65 years with newly diagnosed multiple myeloma who were eligible for ASCT. The consolidation phase of treatment began a minimum of 30 days after ASCT, when patients had recovered sufficiently and engraftment was complete. Overall, 1,085 patients were randomly assigned to D-VTd (n = 543) or VTd (n = 542). The median age of study patients was 58 (range = 22–65 years); 59% were male; the Eastern Cooperative Oncology Group performance status was 0 for 48%, 1 for 42%, and 2 for 10%; and the International Staging System disease stage was I in 40%, II in 45%, and III in 15%.

With median follow-up of 18.8 months, the median progression-free survival had not been reached in either group. Treatment with D-VTd was associated with a significant reduction in the risk of disease progression or death (hazard ratio = 0.47, P < .0001). The rate of stringent complete response at 100 days after ASCT was 28.9% in the D-VTd group vs 20.3% in the VTd group (P = .0010). The rate of complete response at 100 days after ASCT was 9.9% vs 5.7%.

How It Works

The transmembrane glycoprotein CD38 is expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types and tissues, and it has multiple functions, including receptor-mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. Daratumumab is an IgG1κ human monoclonal antibody that binds to CD38 and inhibits the growth of CD38-expressing tumor cells by inducing apoptosis directly through Fc-mediated cross linking, as well as by inducing immune-mediated tumor cell lysis through complement- dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis. A subset of myeloid-derived suppressor cells, regulatory T cells, and B cells are decreased by daratumumab.

How It Is Used

The recommended dose of daratumumab in combination with VTd (4-week cycle regimen) in patients with newly diagnosed multiple myeloma eligible for ASCT is 16 mg/kg via intravenous infusion according to the following dosing schedule. For induction, it is given weekly for weeks 1 to 8 (total of 8 doses) and every 2 weeks during weeks 9 to 16 (total of 4 doses). Treatment is stopped for administration of high-dose chemotherapy and ASCT. For consolidation treatment, it is given every 2 weeks for weeks 1 to 8 (total of 4 doses). For dosing instructions of combination agents administered with daratumumab, the manufacturer’s prescribing information should be consulted. No dose reductions of daratumumab are recommended. Dose delay may be required to allow recovery of blood cell counts in patients experiencing hematologic toxicity.

Daratumumab should be administered by a health-care professional, with immediate access to emergency equipment and appropriate medical support to manage infusion reactions. Full prescribing information provides detailed instructions on infusion rates and management of infusion-related reactions. Infusion should be interrupted for reactions of any grade and permanently discontinued for grade 4 reactions.

Product labeling provides instructions on preinfusion treatment including corticosteroids, antihistamines, and antipyretics and postinfusion corticosteroid treatment. Use of postinfusion medications such as short- and long-acting bronchodilators and inhaled corticosteroids should be considered in patients with a history of chronic obstructive pulmonary disease. Antiviral prophylaxis for herpes zoster reactivation should be given within 1 week after starting daratumumab and continued for 3 months after treatment.

Safety Profile

The most frequently reported adverse events of any grade (incidence ≥ 20%) in patients receiving daratumumab in clinical trials have been infusion reactions, neutropenia, thrombocytopenia, fatigue, asthenia, nausea, diarrhea, constipation, decreased appetite, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy, bronchitis, pneumonia, and upper respiratory tract infection.

In the CASSIOPEIA trial, the median duration of induction/ASCT/consolidation treatment was 8.9 months in the D-VTd group and 8.7 months in the VTd group. The most common adverse events of any grade occurring in more than 20% of the D-VTd group with at least 5% greater frequency vs the VTd group were infusion reactions (35% vs 0%) , nausea (30% vs 24%), upper respiratory tract infection (27% vs 17%), pyrexia (26% vs 21%), and bronchitis (20% vs 13%). The most common grade 3 or 4 adverse events in the D-VTd group included infusion reactions, nausea, and hypertension. Serious adverse events with a ≥ 2% greater incidence in the D-VTd group were bronchitis and pneumonia. The most common grade 3 or 4 hematologic abnormalities in the D-VTd group were lymphopenia, neutropenia, leukopenia, and thrombocytopenia.

Daratumumab has warnings/precautions for infusion reactions, interference with cross-matching and red blood cell antibody screening, neutropenia, and thrombocytopenia. Patients should be blood typed and screened prior to starting treatment; if a patient requires a blood transfusion, the blood bank should be informed that a patient has received daratumumab. Complete blood cell counts should be monitored periodically during treatment. Daratumumab is contraindicated in patients with a history of severe hypersensitivity to daratumumab or any of the components of the formulation. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves daratumumab for transplant-eligible multiple myeloma. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-transplant-eligible-multiple-myeloma. Accessed October 25, 2019.

2. Darzalex (daratumumab) injection prescribing information, Janssen Biotech, Inc, September 2019. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761036s024lbl.pdf. Accessed October 25, 2019.

3. Moreau P, Attal M, Hulin C, et al: Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): A randomised, open-label, phase 3 study. Lancet 394:29-38, 2019.