Medical Director, Sidney Kimmel Comprehensive Cancer Center
Associate Professor of Medicine and Oncology
Multiple Myeloma Program
Johns Hopkins University
Carol Ann Huff, MD, has disclosed that she has received consulting fees from Celgene.
Multiple myeloma remains an incurable disease, but we have made dramatic progress in recent years, particularly with the introduction of monoclonal antibody–based therapies. In this commentary, I focus on the use of one of these therapies, daratumumab, in the treatment of patients with recurrent myeloma.
In myeloma, daratumumab works in 3 different ways: through antibody-dependent cellular cytotoxicity (or ADCC), linking effector cells with myeloma plasma cells by way of the anti-CD38 antibody; by causing complement-dependent cytotoxicity; and by causing apoptosis and growth arrest through targeting signaling pathways.
Daratumumab: Studies and Approvals
Daratumumab was first approved by the FDA for myeloma in November 2015 as a single agent based on results from the SIRIUS study and GEN501, which examined the use of daratumumab monotherapy in heavily pretreated patients who had received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who were double refractory to a proteasome inhibitor and an immunomodulatory agent. The SIRIUS trial demonstrated a ~ 30% response rate, a median PFS of approximately 3.7 months, and a 1-year OS of 65%—rather remarkable in a patient population that was refractory to multiple previous therapies, including some patients refractory to all known therapies. Daratumumab is generally very well tolerated, with infusion-related reactions being the most common adverse event, occurring in approximately one third of patients.
Studies of daratumumab-based combinations have led to 3 additional FDA approvals. The CASTOR trial showed that daratumumab combined with bortezomib and dexamethasone in patients with myeloma and at least 1 previous line of therapy had a 1-year PFS rate of 61% vs just 27% with bortezomib and dexamethasone alone. This was a significant improvement in outcomes and led to the approval of this daratumumab combination for patients with at least 1 previous line of therapy.
The POLLUX trial studied lenalidomide plus dexamethasone with or without daratumumab in patients with myeloma and at least 1 previous line of therapy. It showed a significant improvement in 1-year PFS in the daratumumab group, 78% PFS at 18 months, and a 63% reduction in the risk of progression or death, leading to the approval of this combination in patients who have received at least 1 prior therapy.
The most recent FDA approval of a daratumumab combination for a myeloma indication is that of daratumumab plus pomalidomide and dexamethasone in patients who have received at least 3 previous lines of therapy, based on the EQUULEUS study led by Chari and colleagues. This phase II trial showed that 59% of heavily pretreated patients receiving this 3-drug regimen achieved a PR or better, with a median PFS of approximately 8.9 months.
Daratumumab has opened a new avenue of well-tolerated therapies for patients with recurrent myeloma and has led to new and novel ways of targeting the disease. With these novel treatments, however, there are important factors for clinicians to consider.
Key Points When Using Daratumumab
Infusion-related reactions are the most common adverse event of daratumumab. The recommendation is to give an antipyretic and an antihistamine as premedication, but many centers, ours included, have added corticosteroids and montelukast to the premedication regimen. Using this additional preventive premedication strategy has further reduced the incidence of infusion reactions in patients receiving daratumumab to approximately 10% to 15%, making it quite well tolerated. There are also ongoing investigational studies of alternate premedication preparations and infusion schedules and preparations, including SC administration; we await results from these trials.
Daratumumab can interfere with red blood cell (RBC) typing and cross-match analysis within blood banks. RBCs express CD38, and when daratumumab is given to patients, it binds to the CD38 on the surface of these cells, leading to an agglutination of RBCs and a false-positive, indirect Coombs test on analysis. Thus, it is recommended that all patients have RBC phenotyping prior to their first dose of daratumumab and that they receive phenotypically matched blood for up to 1 year following their last daratumumab infusion. The RBCs can be treated with dithiothreitol to denature the CD38, preventing daratumumab binding, but the lab needs to be aware of this. In our center, we obtain a baseline type and screen in all patients who are being given daratumumab and we alert the blood bank of their treatment with daratumumab to help facilitate care. That said, cross-matching blood for patients receiving daratumumab requires extra time and can delay the availability of RBC products.
It is important to note that daratumumab is an IgG kappa antibody, so in patients with IgG kappa myeloma, daratumumab may interfere with the serum protein electrophoresis and immunofixation analyses. The FDA has recently approved an assay that mitigates the daratumumab-mediated interference seen in immunofixation analyses, through use of gel-shift technology and an anti-daratumumab antibody, to shift the migration of the daratumumab away from the M proteins and confirm the achievement of a complete remission. When the patient has persistent detectable disease, this extra step is generally not required, but it is important to remember that daratumumab is an IgG kappa antibody when interpreting immunoelectrophoresis testing.
In most patients with relapsed/refractory myeloma, I recommend daratumumab plus dexamethasone in combination with either lenalidomide, bortezomib, or pomalidomide because of the significantly improved response rate and survival of these combinations vs 2-drug combinations. In patients too frail to tolerate 3-drug therapy, single-agent daratumumab has shown activity and may be an option.
The adverse event profile of daratumumab is quite well tolerated despite infusion time concerns and, combined with its efficacy, has contributed to widespread uptake in the community and tolerability by patients, many of whom report that they “haven’t felt this well in years” while receiving a daratumumab regimen. Daratumumab therapy has made a big difference for our patients; ongoing trials are exploring the use of daratumumab in earlier lines of therapy. What the ultimate role of daratumumab will be in first-line treatment, in maintenance regimens, and in the treatment of other cancers remains to be seen.
What has been your experience in treating your patients with daratumumab? Let us know in the comment section below.