1. The addition of daratumumab to standard therapy of lenalidomide and dexamethasone increased progression-free survival in relapsed or refractory multiple myeloma (MM).
2. Daratumumab was associated with a greater rate of infusion-related reactions and neutropenia compared to standard therapy alone.
Evidence Rating Level: 1 (Excellent)
Study Rundown: While the addition of proteasome inhibitors and immune modulators have improved outcomes for patients with MM, eventually relapse occurs. Prior phase1-2 trials with daratumumab (IgG monoclonal antibody targeting CD38) have shown improved response rates in patients with pre-treated relapsed or refractory MM using lenalidomide and dexamethasone. Given these results, this trial randomized daratumumab added to lenalidomide and dexamethasone, versus the latter two alone. The results showed a significant increase in disease-free survival, overall response and complete response or better in the daratumumab group compared to the standard group. However, there were more grade 3 or 4 adverse events in terms of neutropenia in the daratumumab group, as well as infusion related reactions compared to the control group. Nevertheless, these adverse events did not lead to higher death or treatment cessation rates. The major strengths of this trial were the large study numbers and randomization across multiple centers, and it built upon prior trials that demonstrated the added benefit of daratumumab. The main limitation was the lack of long-term data.
Relevant Reading: Targeting CD38 with daratumumab monotherapy in multiple myeloma
In-Depth [randomized controlled trial]: This study randomized 569 patients with MM, who had prior treatment with one or more lines of therapy, to either lenalidomide and dexamethasone alone (control group) or combination with daratumumab (daratumumab). The primary endpoint was progression-free survival.
Of the 569 patients enrolled in the trial, 286 were assigned to the daratumumab group and 283 to the control group. At the median follow-up time point of 13.5 months, there was a total of 169 events of disease progression or death, with 53 (18.5%) in the daratumumab group and 116 (41%) in the control group, for a HR of 0.37 (95%CI 0.27-0.52, p < 0.001). The progression-free survival at 12 months was 83.2% (95%CI 78.3-87.2) in the daratumumab group and 60.1% (95%CI 54-65.7) in the control group. The overall response rate that could be evaluated was 92% in the daratumumab group versus 76.4% in the control group (p < 0.001). In the daratumumab group, 51.9% of patients had grade 3 or 4 neutropenia, compared to 37% in the control group. Thrombocytopenia of grade 3 or 4 occurred in 12.7% of the treatment group and 13.5% of patients in the control group. The incidence of daratumumab infusion-related reaction of any grade was 47.7%, which included cough (8.5%), dyspnea (8.55%) and vomiting (5.7%).
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