CHICAGO—The anti-CD38 antibody daratumumab is effective as a stand-alone therapy for heavily pretreated multiple myeloma patients, according to the results of an open-label, international, multicenter Phase II trial reported here the American Society of Clinical Oncology Annual Meeting (Abstract LBA8512).
“This is the first monoclonal antibody in myeloma that has shown single-agent activity,” study coauthor Saad Z. Usmani, MD, a hematologist at the Levine Cancer Institute/Carolinas Healthcare System, said at a news briefing that highlighted noteworthy targeted therapy research. “One in three patients in this study benefited from getting the drug—that truly is unprecedented.”
Multiple myeloma remains an incurable disease, and patients whose disease relapses after treatment with proteasome inhibitors and/or immunomodulatory drugs (IMiDs) have poor prognoses and few treatment options. CD38 is highly expressed on myeloma cells and is a promising therapeutic target, Usmani said. Daratumumab binds to CD38-expressing cancer cells and induces cell death through multiple mechanisms.
The study included patients with a median age of 63 who had received at least three prior lines of therapy, including proteasome inhibitors and IMiDs, or were refractory to their most recent proteasome inhibitor and IMiD. In part 1 of this ongoing trial, 18 patients were randomized to receive either 8 mg/kg of daratumumab once every four weeks and 16 patients received 16 mg/kg of daratumumab once a week for eight weeks and then once a week every two weeks for 16 weeks and once every four weeks until disease progression or unacceptable toxicity.
In part 2, an additional 90 patients received 16 mg/kg of daratumumab on the same dosing schedule as part 1. The primary endpoint was overall response rate.
After a median follow-up of 9.4 months, 29 percent of the patients responded to daratumumab, including three patients who had stringent complete responses (defined as the usual criteria for a complete response as well as a normal free light chain ratio in the serum and no clonal cells in the bone marrow as determined by either immunofluorescence or immunohistochemistry), 10 very good partial responses, and 18 partial responses.
The median duration of response was 7.4 months, the median time to disease progression was 3.7 months, and the estimated overall one-year survival rate was 65 percent.
Nearly half (45%) of the responders remain on therapy, Usmani said, adding that the responses were consistent among various subgroups.
‘Rapid, Durable, and Deepened Over Time’
“The responses were rapid, durable, and deepened over time,” said the study's lead author, Sagar Lonial, MD, Chief Medical Officer of Winship Cancer Institute of Emory University and Professor and Executive Vice Chair of the Department of Hematology and Medical Oncology at Emory University School of Medicine, who presented the detailed results at an oral session.
“The depth of response may translate to prolonged overall survival. Daratumumab represents a new standard of care in this setting. It is particularly noteworthy to see this level of response with a single agent in this heavily pretreated population.”
Lonial noted that 97 percent of the patients were refractory to their last line of therapy and 95 percent were double refractory to both a proteasome inhibitor and an IMiD.
Daratumumab was considered to be well-tolerated: Five patients (4.7%) had to discontinue treatment due to adverse events, but none were considered drug-related. The most common adverse events were fatigue (occurring in 40% of patients), anemia (33%), nausea (29%), thrombocytopenia (25.5%), neutropenia (23%), back pain (23%), and cough (21%).
The major side effect of daratumumab was infusion reaction, which typically occurred early in the course of the treatment and was generally well managed with standard of care and slower infusion rates, Lonial continued.
Infusion-related reactions were reported in 42.5 percent of patients and were predominantly grade 1 or 2, the most common of which were nasal congestion (occurring in 12% of patients), throat irritation (7%), and cough, dyspnea, chills, and vomiting (6% each).
“These findings speak to the potential of daratumumab as an effective and tolerable option for people with multiple myeloma who have exhausted other available treatment options,” Lonial said.
Usmani added: “The efficacy we are 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. Our hope is that daratumumab will help fill the unmet clinical need of patients who have exhausted available treatment approaches.”
In 2013, the FDA granted breakthrough therapy designation to daratumumab for the treatment of multiple myeloma in patients who have received at least three prior lines of therapy (OT 5/25/13 issue). The drug's manufacturer, Janssen, has said that it plans to submit a Biologics License Application to the FDA for daratumumab this year, based on the results of this trial.
Multiple Ongoing Phase III Trials
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, Lonial noted. “The future hope for daratumumab is in our ability to bring this active agent to earlier lines of therapy and combine it with drugs where you may get synergy.”
Several Phase III clinical trials are examining daratumumab in various treatment settings in a number of combination studies. Currently, there are five large Phase III studies that are evaluating daratumumab in combination with existing therapies, with three of the five in the frontline setting, Usmani said.
An early study assessed daratumumab along with lenalidomide and dexamethasone in pretreated multiple myeloma patients. The response rate was 75 percent; and in an expansion cohort, patients received the 16 mg/kg dose of daratumumab, and the response rate improved to 92.3 percent.
In the frontline setting, a combination of daratumumab with the proteasome inhibitor bortezomib and other therapies led to a 100 percent response rate. The only safety issues were infusion-related reactions.
A Phase III study of daratumumab, lenalidomide, and dexamethasone compared with lenalidomide and dexamethasone in the frontline setting has already accrued 500 patients, Usmani said. The results of this trial are still several years away, though.
Merry-Jennifer Markham, MD, an ASCO designated expert commenting at the news conference, who is Assistant Professor of Medicine in the Division of Hematology & Oncology at the University of Florida, noted that there have been substantial treatment advances in multiple myeloma over the last decade, and daratumumab will be an important addition to the list of options—“This therapy may offer a glimmer of hope for those myeloma patients who have run out of treatment options,” she said.
And the study's Discussant, Suzanne Lentzsch, MD, Director of the Multiple Myeloma and Amyloidosis Program at the College of Physicians and Surgeons of Columbia University, said: “Daratumumab has significant single-agent activity in multiple myeloma with complete responses and very good partial responses in double refractory patients. The mechanism of action of daratumumab results in responses independent of the number and type of prior therapies. Responses were rapid within four weeks, and many improved over time.”
She pointed to the one-year survival rate of 65 percent in the trial as especially noteworthy.
She added that the 16 mg/kg dose of daratumumab was well-tolerated and that no patients discontinued treatment due to adverse events related to the drug.
“Studies have found dramatic increases in response to monoclonal antibodies when combined with ImiDs,” Lentzsch said. “Monoclonal antibodies will be the backbone of multiple myeloma treatments. ... With monoclonal antibodies, it is time for ‘R-CHOP’ in multiple myeloma.”