In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On November 16, 2015, daratumumab injection (Darzalex) was granted accelerated approval for treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.1,2 Daratumumab is the first monoclonal antibody approved for the treatment of multiple myeloma.
The manufacturer, Janssen, is required to conduct a multicenter randomized trial establishing the superiority of daratumumab over standard therapy and has several ongoing multicenter randomized trials in patients with multiple myeloma with a primary endpoint of progression-free survival.
Supporting Efficacy Data
Approval was based on response rate in a multicenter open-label study in which 106 patients with relapsed or refractory multiple myeloma received daratumumab monotherapy via intravenous infusion at 16 mg/kg once every week for 8 weeks followed by once every 2 weeks for 16 weeks and once every 4 weeks until unacceptable toxicity or disease progression.2 Treatment was administered with pre- and postinfusion medication.
Study patients had a median age of 63.5 years (range = 31–84 years), 51% were female, and 79% were white. Patients had received a median of five prior lines of therapy, 80% had received autologous stem cell transplantation, and prior therapies included bortezomib (Velcade, 99%), lenalidomide (Revlimid, 99%), pomalidomide (Pomalyst, 63%) and carfilzomib (Kyprolis, 50%).
The objective response rate was 29% (95% confidence interval = 21%–39%), including stringent complete response in 2.8%, very good partial response in 9.4%, and partial response in 17.0%. Median time to response was 1 month (range = 0.9–5.6 months) and median duration of response was 7.4 months (range = 1.2–13.1+ 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, 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 inducing immune-mediated tumor cell lysis through complement- dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis. Myeloid-derived suppressor cells and a subset of regulatory T cells (CD38-positive Tregs) express CD38 and are susceptible to daratumumab-mediated cell lysis.
How It Is Used
The recommended dose of daratumumab is 16 mg/kg via intravenous 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. Pre- and postinfusion medication must be given.
The maximum infusion rate for all infusions is 200 mL/h. For first infusion, the dilution volume should be 1,000 mL, with an infusion rate during the first hour of 50 mL/h and a rate increment of 50 mL/h every hour. For the second infusion, infusion volume should be 500 mL, infusion rate 50 mL/h, and rate increment 50 mL/h every hour, with escalation occurring only if there were no grade ≥ 1 infusion reactions during the first 3 hours of the first infusion. For subsequent infusions, the dilution volume should be 500 mL, infusion rate 100 mL/h, and rate increment 50 mL/h every hour, with escalation only if there were no grade ≥ 1 infusion reactions during a final infusion rate of 100 mL/h in the first two infusions.
Treatment should be immediately interrupted for infusion reactions of any grade. For grade 1 or 2 reactions that resolve and for the first two occurrences of a grade 3 reaction that improves to grade ≤ 2, infusion may be resumed at no more than half the rate at which the reaction occurred. If the patient does not experience any further reaction symptoms, infusion rate escalation may resume at the specified increments and intervals. Treatment should be permanently discontinued for the third occurrence of a grade 3 reaction and for grade 4 reactions.
Preinfusion medications should be given about 1 hour prior to every infusion as follows: intravenous corticosteroid (methylprednisolone at 100 mg or equivalent dose of an intermediate-acting or long-acting corticosteroid), oral antipyretics (acetaminophen at 650 to 1,000 mg), oral or intravenous antihistamine (diphenhydramine at 25 to 50 mg or equivalent). After the second infusion, the corticosteroid dose may be reduced (methylprednisolone at 60 mg intravenously).
Postinfusion medication should be given as follows: oral corticosteroid on the first and second days after each infusion. Postinfusion medications such as short- and long-acting bronchodilators and inhaled corticosteroids should be considered in patients with a history of obstructive pulmonary disorder. These additional medications can be discontinued if no major infusion reaction occurs during the first four infusions. Antiviral prophylaxis to prevent herpes zoster reactivation should be given within 1 week of starting treatment and continued for 3 months following treatment.
Safety data are from 156 patients who received daratumumab at 16 mg/kg in three open-label trials. The most common adverse events of any grade were infusion reaction (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). The most common grade 3 or 4 adverse events (all grade 3) were pneumonia (6%), hypertension (5%), and infusion reaction (3%). The most common grade 3 or 4 laboratory abnormalities were lymphopenia, neutropenia, anemia, and thrombocytopenia.
Serious adverse events occurred in 33% of patients, with the most common being pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%). Adverse events resulted in treatment delay in 15%, most frequently for infections, and treatment discontinuation in 4%.
The incidence of infusion reactions was 46% with the first infusion, 5% with the second infusion, and 4% with subsequent infusions; all reactions with second or subsequent infusions were grade ≤ 2. Severe infusion reactions included bronchospasm, dyspnea, hypoxia, and hypertension (< 2% each).
Median time to onset of reaction was 1.5 hours. The incidence of infusion interruptions due to reactions was 37%. Systemic antiviral medication was used in 73% of patients.
Daratumumab carries warnings/precautions for infusion reactions and interference with cross-matching and red blood cell antibody screening. ■
1. U.S. Food and Drug Administration: Daratumumab injection. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm472904.htm. Accessed December 2, 2015.
2. Darzalex (daratumumab) injection, prescribing information. Janssen Biotech, November 2015. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2015/761036s000lbl.pdf. Accessed December 2, 2015.