CHICAGO—The anti-CD38 monoclonal antibody daratumumab is effective and safe as a standalone therapy for multiple myeloma patients whose disease has failed to improve after three prior treatments, according to results from the phase II SIRIUS trial. Nearly 30 percent of these hard-to-treat patients responded to treatment with daratumumab.
“Daratumumab is a human monoclonal antibody targeting CD38, which is a surface marker on myeloma cells that is highly expressed,” lead study author Saad Zafar Usmani, MD, explained in an interview with ASH Clinical News. “It kills the myeloma cells by direct cell death mechanisms as well as immune-mediated cell death mechanisms.” The FDA previously granted daratumumab breakthrough therapy designation for the treatment of multiple myeloma.
The 106 patients enrolled in this phase II study had been treated with at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or were double-refractory to drugs from either of these classes. SIRIUS is the largest study to show impressive activity of a monoclonal antibody as a standalone therapy for treatment-resistant multiple myeloma.
“The efficacy we’re seeing is quite impressive for a clinical trial of refractory multiple myeloma, given that many patients had already undergone five or more types of treatment,” said Dr. Usmani, from the Levine Cancer Institute/Carolinas Healthcare System in Charlotte, North Carolina. “Our hope is that daratumumab will help fill the unmet clinical need of patients who have exhausted available treatment approaches.”
In order to help investigators determine the most effective dose, patients were selected to receive either 8 mg/kg daratumumab (n=18) every four weeks or 16 mg/kg daratumumab (n = 16) every week for eight weeks, followed by every two weeks for 16 weeks, and then every four weeks. Subsequently, 90 additional patients were enrolled in the 16 mg/kg daratumumab group.
Preliminary results presented by Dr. Usmani at the 2015 ASCO Annual Meeting showed that, after a median follow-up period of 9.4 months, 29.2 percent of patients responded to daratumumab. Responses were categorized as:
- Complete remission in three patients
- Very good partial response in 10 patients
- Partial response in 18 patients
These responses were consistent across clinically relevant subgroups and durable (lasting an average of 7.4 months), and the monoclonal antibody also delayed disease progression (median time to progression = 3.7 months).
While the median overall survival had not yet been reached, the estimated one-year overall survival rate was 65 percent.
After a median follow up of 9.4 months, 14 of 31 responders (45.2%) remain on therapy, the researchers reported. Five patients (4.7%) had discontinued therapy due to adverse events; however, the researchers did not determine these events to be drug-related.
The major side effect of daratumumab was infusion reactions (42%) – the majority of which occurred early in the course of the treatment and were grade 1 or 2. The most common adverse events included fatigue (39.6%), anemia (33%), nausea (29.2%), thrombocytopenia (25.5%), back pain (22.6%), neutropenia (22.6%), and cough (20.8%).
Ongoing phase III trials are exploring daratumumab in combination with various existing treatments to further solidify the role of this antibody across all stages of the disease.
“It is an area of unmet clinical need – we do run out of options for those patients and even if they are in good physical shape it is difficult to have that discussion with patients,” Dr. Usmani said. “We have seen a big boom in immunotherapies being developed for several solid tumors as well as hematologic malignancies, and daratumumab is an exciting addition to the armamentarium of myeloma treatment for physicians.”
Source: Sagar L, Weiss BM, Usmani SZ, et al. Phase II study of daratumumab (DARA) monotherapy in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius). Abstract #LBA8512. Presented at the 2015 American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 2, 2015.