On June 16, 2017, daratumumab -(Darzalex) was approved for use in combination with pomalidomide (Pomalyst) and dexamethasone for treatment of patients with multiple myeloma who have received at least two prior therapies including lenalidomide (Revlimid) and a proteasome inhibitor.1,2
Supporting Efficacy Data
Approval was based on the finding of durable responses in a study in which 103 patients received intravenous (IV) daratumu-mab at 16 mg/kg at the recommended dosing schedule in combination with pomalidomide (4 mg once daily orally on days 1–21 of repeated 28-day cycles) and low-dose oral or IV dexamethasone (40 mg/wk or 20 mg/wk in patients aged > 75 years or with a body mass index < 18.5 kg/m2) until disease progression. On daratumumab infusion days, 20 mg of the dexamethasone dose was given as a preinfusion medication and the remainder was given the day after the infusion; for patients on a reduced dexamethasone dose, the entire 20-mg dose was given as a preinfusion medication.
Daratumumab carries warnings/precautions for infusion reactions, interference with cross-matching and red blood cell antibody screening, neutropenia, and thrombocytopenia.
The median age of patients was 64 years (range = 35–86 years, 8% ≥ 75 years). The median number of prior lines of therapy was 4, and 74% had received autologous stem cell transplantation. A total of 98% had received bortezomib (Velcade); 33% had received carfilzomib (Kyprolis); all had received lenalidomide (98% received the combination of bortezomib and lenalidomide); and 89% were refractory to lenalidomide, 71% were refractory to bortezomib, and 64% were refractory to both.
Response on independent review committee assessment using International Myeloma Working Group criteria occurred in 61 patients (59%), with a stringent complete response reported in 8 (8%), a complete response reported in 6 (6%), a very good partial response reported in 29 (28%), and a partial response reported in 18 (18%). The median time to response was 1 month (range =
0.9–2.8 months). The median duration of response was 13.6 months (range = 0.9+ to 14.6+ months).
How It Works
The transmembrane glycoprotein CD38 is expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types and tissues; 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
For use in combination with pomalidomide and low-dose dexamethasone in a 4-week cycle regimen, the recommended dose of daratumumab is 16 mg/kg via IV infusion weekly for weeks 1 to 8, every 2 weeks for weeks 9 to 24, and every 4 weeks from week 25 until disease progression. Daratumumab should be administered by a health-care professional, with immediate access to emergency equipment and appropriate medical support to manage infusion reactions. No dose reductions of daratumumab are recommended. Dose delay may be required to allow recovery of blood cell counts in cases of hematologic toxicity.
Preinfusion medications should be given to all patients 1 to 3 hours before every infusion of daratumumab. They consist of 20 mg of dexamethasone (IV prior to the first infusion, with consideration of oral administration prior to subsequent infusions), an antipyretic (oral acetaminophen at 650–1,000 mg), and an antihistamine (oral or IV diphenhydramine at 25 to 50 mg or equivalent). For postinfusion medication, low-dose oral methylprednisolone (≤ 20 mg) or equivalent on the day after the daratumumab infusion should be considered; if a background regimen–specific corticosteroid (eg, dexamethasone) is administered the day after the daratumumab infusion, additional postinfusion medications may not be needed.
Postinfusion medications such as short- and long-acting bronchodilators and inhaled corticosteroids should be considered for any patient with a history of chronic obstructive pulmonary disease. Antiviral prophylaxis to prevent herpes zoster reactivation should be started within 1 week after starting daratumumab and continued for 3 months following treatment.
Guidelines for infusion, including volume dilution, initial infusion rates, incremental increases in infusion rate in the absence of infusion reactions, and maximum infusion rate, are detailed in the product labeling. Treatment should be immediately interrupted for infusion reactions of any grade. For grade 1 or 2 reactions that resolve, infusion should resume at no more than half the rate at which the reaction occurred. If no further reactions occur, escalation of the infusion rate may resume. For the first two occurrences of grade 3 reactions, restarting the infusion at no more than half the rate at which the reaction occurred may be considered if symptoms resolve. Treatment should be permanently discontinued for a third occurrence of a grade ≥ 3 reaction and for a first occurrence of a grade 4 reaction.
Among 103 patients receiving daratumumab plus pomalidomide/dexamethasone in the study supporting efficacy, the most common adverse events of any grade were infusion reactions (50%), fatigue (50%), upper respiratory tract infection (50%), cough (43%), diarrhea (38%), constipation (33%), dyspnea (33%), and nausea (30%). The most common grade 3 or 4 adverse events were fatigue (10%), pneumonia (10%), and dyspnea (7%); grade 3 infusion reactions occurred in 4% of patients. Grade 3 or 4 laboratory abnormalities included neutropenia in 82% (grade 4 in 46%), lymphopenia in 71% (grade 4 in 26%), anemia in 30% (all grade 3), and thrombocytopenia in 20% (grade 4 in 10%). Serious adverse events occurred in 49%, with the most common being pneumonia (7%). Adverse events resulted in discontinuation of treatment in 13% of patients.
Daratumumab carries warnings/precautions for infusion reactions, interference with cross-matching and red blood cell antibody screening, neutropenia, and thrombocytopenia. Patients should be typed and screened 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. Patients with neutropenia should be monitored for signs of infection. Dose delay may be necessary to allow recovery of neutrophil or platelet counts. ■
1. Darzalex (daratumumab) injection prescribing information. Janssen Biotech, Inc, June 2017. Available at www.janssenmd.com/pdf/darzalex/darzalex_pi.pdf. Accessed January 22, 2018.
2. Chari A, Suvannasankha A, Fay JW, et al: Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood 130:974-981, 2017.