The CD38-targeted monoclonal antibody daratumumab shows promising single-agent activity in patients with heavily pretreated relapsed and refractory multiple myeloma, suggest results of the open-label, international phase II Sirius trial (Abstract LBA8512). Data were presented by Sagar Lonial, MD, of the Winship Cancer Institute at Emory University, on Tuesday, June 2, during the Myeloma Oral Abstract Session.
In 2013, daratumumab was granted a breakthrough therapy designation by the U.S. Food and Drug Administration based on preliminary data from a phase I/II trial.
The subsequent Sirius trial enrolled patients who had received at least three prior lines of therapy or had disease that was refractory to both a proteasome inhibitor and an immunomodulatory agent. In the first stage of the study, 34 patients were randomly assigned to receive 8 mg/kg (18 patients) or 16 mg/kg (16 patients) of daratumumab. After the higher dose was established as the recommended dose, an additional 90 patients were enrolled at this dosage. Dr. Lonial presented findings from all 106 patients who received 16 mg/kg of daratumumab, which was administered every week for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks thereafter.
Dr. Sagar Lonial
In 106 patients with relapsed/refractory multiple myeloma who had received a median of five prior lines of therapy (range: 2-14) over a median of 5 years, single-agent daratumumab was associated with an overall response rate (ORR) of 29%.
“What I think is striking about this,” Dr. Lonial said, “is not just that one in three patients with refractory—one would argue almost end-stage—myeloma had responses, but that we actually saw stringent complete responses.” Three percent of patients had a stringent complete response, and 12% had a very good partial response or better; the clinical benefit rate (ORR plus minimal response) was 34%.
Dr. Lonial suggested that daratumumab’s novel mechanism of action might play an important role in its activity in this patient population. The median duration of response was 7.4 months; deepening of response was observed in some patients with continued therapy. Responses were observed across subgroups of age, number and types of lines of prior therapy, and presence/absence of extramedullary disease. Daratumumab was associated with a median progression-free survival of 3.7 months (95% CI [2.8, 4.6]) and a 1-year overall survival (OS) rate of 65% (95% CI [51.2, 75.5]); the median OS has not been reached.
Regarding safety, the most common adverse events were fatigue, anemia, nausea, thrombocytopenia, and neutropenia. No patients discontinued treatment because of adverse events, and no cases of febrile neutropenia were reported. Infusion reactions, which were reported in 43% of patients, were primarily grade 1/2 and occurred predominantly during the first infusion.
Dr. Lonial noted that the trial had wider eligibility criteria with regard to blood counts and creatinine clearance than is typical for first-line trials. “I think this potentially speaks to the safety of doing immunotherapy—monoclonal antibody-based therapy—in the context of relapsed/refractory disease,” he said.
Discussant Suzanne Lentzsch, MD, PhD, of Columbia University, concluded, “monoclonal antibodies will be the backbone of multiple myeloma [therapy] in the future, and I think it’s really time to develop an ‘R-CHOP’ for multiple myeloma.”
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