In May 2018, daratumumab (Darzalex) was approved for use in combination with VMP (bortezomib, melphalan, and prednisone) in the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation.1
Supporting Efficacy Data
Approval was based on the findings of the open-label phase III ALCYONE trial, in which 706 patients were randomized to receive daratumumab plus VMP (n = 350) or VMP alone (n = 356).1,2 The median age of patients was 71 years (30% ≥ 75 years); 85% were white; 54% were female; Eastern Cooperative Oncology Group performance status was 0 in 25%, 1 in 50%, and 2 in 25%; and the International Staging System stage was I in 19%, II in 42%, and III in 38%.
Median progression-free survival was not reached in the daratumumab group vs 18 months in the VMP group (hazard ratio = 0.50, P < .0001). Overall response rates were 91% vs 74% (P < .0001), with a complete response or better in 43% vs 25%, respectively. The minimal residual disease–negativity rate was 22% vs 6% among all patients (P < .0001) and 50% vs 25% in those with a complete response or better, respectively.
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 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 VMP in the current indication is 16 mg/kg via intravenous infusion weekly for weeks 1 to 6 (total of 6 doses), every 3 weeks for weeks 7 to 54 (total of 16 doses), and every 4 weeks from week 55 until disease progression.
Daratumumab carries warnings/precautions for infusion reactions, interference with cross-matching and red blood cell antibody screening, neutropenia, and thrombocytopenia.
Daratumumab should be administered by a health-care professional, with immediate access to emergency equipment and appropriate medical support to manage infusion reactions. Product labeling 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. No dose reductions of daratumumab are recommended. Dose delay may be required to allow recovery of blood cell counts in patients experiencing hematologic toxicity.
Product labeling provides specific instructions on pre- and postinfusion medications. Premedication includes administration of dexamethasone, antipyretics, and antihistamines at 1 to 3 hours prior to each daratumumab infusion. Background regimen–specific corticosteroids (eg, prednisone) should not be taken 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) were 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 ALCYONE trial, the most common adverse events of any grade occurring in ≥ 20% of the daratumumab group with ≥ 5% frequency vs the control group were upper respiratory tract infection (48% vs 28%), infusion reactions (28% vs 0%), and peripheral edema (21% vs 14%). Serious adverse events with a ≥ 2% greater incidence in the daratumumab group were pneumonia (11% vs 4%), upper respiratory tract infection (5% vs 1%), and pulmonary edema (2% vs 0%). Grade 3 or 4 pneumonia was observed in 12% vs 5% of patients. Grade 3 and grade 4 infusion reactions were observed in 4% and 1% of daratumumab patients. The most common grade 3 or 4 hematologic abnormalities were lymphopenia (58% vs 53%), neutropenia (44% vs 43%), thrombocytopenia (38% vs 42%), and anemia (18% vs 21%, all grade 3).
Daratumumab carries 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 needs a blood transfusion, the blood bank should be informed that the patient has received daratumumab. Complete blood cell counts should be monitored periodically during treatment. Patients with neutropenia should be monitored for signs of infection. A dose delay may be necessary to allow recovery of neutrophil or platelet counts. ■
1. Darzalex (daratumumab) injection prescribing information. Janssen Biotech, Inc, May 2018. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761036s013lbl.pdf. Accessed August 6, 2018.
2. Mateos MV, Dimopoulos MA, Cavo M, et al: Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med 378:518-528, 2018.
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).