The incorporation of proteasome inhibitors and immunomodulatory drugs into the standard of care has improved outcomes in patients with multiple myeloma over the past 10 years, but most patients still eventually have a relapse. In the October 6, 2016, issue of the New England Journal of Medicine, Dimopoulos et al. report the results of a prespecified interim analysis of a phase 3 trial of daratumumab, lenalidomide, and dexamethasone in patients with relapsed or refractory myeloma. The addition of daratumumab to lenalidomide and dexamethasone resulted in superior response rate and progression-free survival, as compared with lenalidomide and dexamethasone alone, at a cost of more frequent neutropenia and infusion reactions.
• What is daratumumab?
Daratumumab, a human IgGκ monoclonal antibody that targets CD38, has shown substantial single-agent efficacy and a manageable safety profile in phase 1–2 studies involving patients with heavily pretreated relapsed or refractory multiple myeloma, with reported overall response rates of 29% and 36%. On the basis of these findings, daratumumab monotherapy (at a dose of 16 mg per kilogram of body weight) was approved by the Food and Drug Administration and the European Medicines Agency for these patients.
• What are the mechanisms of action of daratumumab?
The mechanisms of action of daratumumab comprise immune-mediated effects, including complement-dependent and antibody-dependent cell-mediated cytotoxic effects, antibody-dependent cellular phagocytosis, and apoptosis by means of cross-linking. Moreover, daratumumab may have a role in immunomodulation by means of depletion of CD38-positive regulator immune suppressor cells, which leads to a greater clonal expansion of T cells in patients who have a response than in those who do not.
Morning Report Questions
Q: Does the addition of daratumumab to lenalidomide and dexamethasone improve progression-free survival in patients with relapsed or refractory myeloma?
A: In the study by Dimopoulos et al., the primary end point was progression-free survival. The results showed that the addition of daratumumab to lenalidomide and dexamethasone significantly prolonged progression-free survival and was associated with a 63% lower risk of disease progression or death than lenalidomide and dexamethasone alone among patients with multiple myeloma who had received one or more lines of therapy previously. The treatment effect of daratumumab was consistent regardless of previous exposure to lenalidomide (a limitation being the relatively small number of patients with previous exposure to lenalidomide) and across all subgroups, including patients 65 years of age or older, those with disease that was refractory to proteasome inhibitors or the most recent line of therapy, those with International Staging System stage III disease, and those with previous exposure to a proteasome inhibitor or immunomodulatory drug. The treatment benefit that was associated with daratumumab was also similar in patients with one previous line of therapy and in those with one, two, or three previous lines of therapy.
Q: What were some of the notable adverse events associated with daratumumab in the study by Dimopoulos et al.?
A: In the study by Dimopoulos et al., the most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2.