On June 27, 2019, daratumumab was approved for use in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation.1,2
Supporting Efficacy Data
Approval was based on findings in the open-label phase III MAIA trial (ClinicalTrials.gov identifier NCT02252172).2,3 In the trial, 737 patients were randomly assigned to receive daratumumab plus lenalidomide and low-dose dexamethasone (DRd; n = 368) or lenalidomide and low-dose dexamethasone (Rd; n = 369). Patients received 28-day cycles of lenalidomide at 25 mg on days 1 through 21 and dexamethasone at 40 mg on days 1, 8, 15, and 22. Daratumumab was given at 16 mg/kg once weekly during cycles 1 and 2, every 2 weeks during cycles 3 through 6, and every 4 weeks thereafter. Treatment was continued until disease progression or unacceptable toxicity.
The median age of patients was 73 years (range = 45–90 years; 44% aged ≥ 75 years); 92% were white; 52% were male; an Eastern Cooperative Oncology Group performance status was 0 for 34%, 1 for 50%; and ≥ 2 for 17%; the International Staging System stage was I in 27%, II in 43%, and III in 29%.
Median progression-free survival based on International Myeloma Working Group criteria was not reached in the DRd group vs 31.9 months in the Rd group (hazard ratio = 0.56, P < .0001). Overall response rate was 92.9% vs 81.3% (P < .0001), and complete response or better was achieved in 47.6% vs 24.9% (P < .0001).
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 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 CD38-positive myeloid-derived suppressor cells, regulatory T cells, and B cells is decreased by daratumumab.
How It Is Used
The recommended dose of daratumumab in combination with lenalidomide and dexamethasone in the current indication is 16 mg/kg via intravenous infusion weekly for weeks 1 to 8, every 2 weeks for weeks 9 to 24 (total 8 doses), and every 4 weeks from week 25 until disease progression. 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 can cause severe and serious infusion reactions, including anaphylactic reactions. Approximately half of all patients in clinical trials experienced an infusion reaction. 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 any grade 4 reaction.
Product labeling provides instructions on preinfusion and postinfusion medication. Patients should be premedicated with corticosteroids, antihistamines, and antipyretics. When dexamethasone is the background regimen–specific corticosteroid, the dexamethasone treatment dose will serve as premedication on daratumumab infusion days. Use of low-dose oral methylprednisolone (or its equivalent) should be considered on the day after daratumumab infusion; postinfusion medication may not be needed if a background regimen–specific corticosteroid is administered the day after daratumumab infusion. 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.
In clinical trial experience with daratumumab, the most common adverse events of any grade (≥ 20% of patients) have been infusion reactions, neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy, and upper respiratory tract infection.
In the MAIA trial, the most common adverse events of any grade in the daratumumab group occurring with a ≥ 5% higher frequency than in the Rd group were diarrhea (57% vs 46%), upper respiratory tract infection (52% vs 36%), infusion reactions (41% vs 0%), constipation (41% vs 36%), peripheral edema (41% vs 33%), fatigue (40% vs 28%), back pain (34% vs 26%), dyspnea (32% vs 20%), nausea (32% vs 23%), asthenia (32% vs 25%), cough (30% vs 18%), bronchitis (29% vs 21%), muscle spasms (29% vs 22%), and pneumonia (26% vs 14%). The most common grade 3 or 4 adverse events included pneumonia (15% vs 8%), fatigue (8% vs 4%), diarrhea (7% vs 4%), and hyperglycemia (7% vs 4%). The most common grade 3 or 4 laboratory abnormalities were neutropenia (56% vs 39%), lymphopenia (52% vs 42%), and leukopenia (35% vs 24%). Serious adverse reactions with a 2% greater incidence in the DRd group vs the Rd group were pneumonia (15% vs 8%), bronchitis (4% vs 2%), and dehydration (2% vs <1%).
Daratumumab carries warnings/precautions for infusion reactions, interference with cross-matching and red blood cell antibody screening, neutropenia, and thrombocytopenia. Patients should have a blood type and screen prior to starting treatment; if a patient needs 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. ■
1. U.S. Food and Drug Administration: FDA approves daratumumab for multiple myeloma ineligible for autologous stem cell transplant. Available at www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-multiple-myeloma-ineligible-autologous-stem-cell-transplant. Accessed July 23, 2019.
2. Darzalex (daratumumab) injection prescribing information, Janssen Biotech, June 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/761036s020lbl.pdf. Accessed July 23, 2019.
3. Facon T, Kumar S, Plesner T, et al: Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med 380:2104-2115, 2019.