STOCKHOLM — The investigational daratumumab (under development by Genmab/Janssen) has shown high and durable responses in multiple myeloma in a phase 1 trial.
As testament to the strength of the results, last month daratumumab became the first single-agent monoclonal antibody to receive a breakthrough therapy designation by the US Food and Drug Administration (FDA) for relapsed and refractory multiple myeloma.
"We've seen that 47% of patients showed benefit [with doses up to 24 mg/kg]. A response was seen in 8 of the 12 patients receiving more than 4 mg/kg, indicating that this dose provides a sufficient amount of daratumumab in the blood for an effective response," said Henk Lokhorst, MD, from the University Medical Center Utrecht, the Netherlands.
He presented findings from part 1 of a dose-escalation study here at the 18th Congress of the European Hematology Association.
Overall, increased daratumumab exposure was found to correlate with longer progression-free survival. "Daratumumab can probably induce durable responses in patients treated at the higher dose levels of 4 mg and more," he explained.
Approximately 80% of patients were double-refractory, and all patients had received a minimum of 2 previous treatment lines that included bortezomib, lenalidomide, or thalidomide. Patients had an ECOG performance status of 0 to 2, a life expectancy longer than 3 months, and no other established treatment options available to them.
Paul Richardson, MD, clinical director of the Jerome Lipper Center for Multiple Myeloma at the Dana-Farber Cancer Institute in Boston, Massachusetts, and one of the study investigators, said the results are especially compelling because they reflect single-agent activity in a difficult-to-treat population. "They are the most we have seen to date from a monoclonal antibody, and in part explain the breakthrough status given to this agent."
Anti-CD38 Monoclonal Antibody
Daratumumab is currently being tested in phase 1/2 trials for relapsed or refractory multiple myeloma. Structurally, it is a human IgG1k monoclonal antibody that targets the CD38 surface protein on myeloma cells and has a broad spectrum of anticancer activity.
Because CD38 is expressed in healthy cells and in all myeloma cells, in this study, daratumumab was started at a very low dose and then escalated to minimize toxicity.
The study was comprised of 2 parts. In part 1 of the study, a classic 3 + 3 design was used. Daratumumab infusion was started at 0.005 mg/kg and escalated to 24 mg/kg, and was administered over a 9-week period as 1 pre- and 8 full doses.
Responses were evaluated using International Myeloma Workshop Consensus Panel 1 guidelines (Blood. 2011;117:4691-4695). Levels of serum or urine M-protein or serum free light chains, which are tumor markers for myeloma, were used to assess efficacy.
Table. Response Rates
|Dose||n||Partial Response, %||Minor Response, %|
Dr. Lokhorst reported that the responses are durable. At a median follow-up of 3.8 months, median progression-free survival for patients receiving doses of at least 4 mg/kg has not been reached. However, after only 8 cycles, "we saw progression-free survival of more than 8 months, even after treatment was stopped," he noted.
Table. Serious Adverse Events Related to Daratumumab
|Adverse Event||Patients Affected (n = 32)||Grade of Event||Dose (mg/kg)|
|Aspartate aminotransferase >5.2 times the upper limit of normal||1||2/3||1.0|
|Cytokine release syndrome||1||2||0.1|
In part 2 of this study, several cohorts and dose schedules are being tested to determine the optimal schedule for administration and long-term safety.
Dr. Lokhorst noted that monoclonal antibodies have long been used in the treatment of lymphomas, but they offer a novel approach in the treatment for myeloma. "It's now important to target the myeloma cell in a different way."
Because of the synergy between monoclonal antibodies and chemotherapy, the future of daratumumab is likely not as a single agent, but in combination with chemotherapy. "In vitro studies have shown that if we combine lenalidomide with daratumumab, we get enormous killing of myeloma cells," he explained.
Dr. Richardson added that another investigational monoclonal antibody, elotuzumab (under development by Bristol-Myers Squibb), which targets CD319, has shown great promise in combination for multiple myeloma, although as a single agent, the response signal is modest. "This suggests that combinations with daratumumab are likely to be even more powerful in multiple myeloma," he said.
"I think it is fascinating that after elotuzumab, we now have another monoclonal antibody. This will certainly change the treatment landscape for myeloma patients," Jesús San Miguel, MD, from University Hospital in Salamanca, Spain, a recognized expert in multiple myeloma, told Medscape Medical News.
Given the fact that these patients had all received bortezomib and lenalidomide and were still progressing, the responses and durations of response are "gratifying" in such an early trial, Sundar Jagannath, MD, director of the multiple myeloma program at the Mount Sinai School of Medicine in New York City, told Medscape Medical News. "This is the very first time a monoclonal antibody therapy has shown such responses in myeloma. The fact these responses are noted in chemotherapy-exposed and often refractory myeloma patients has resulted in FDA breakthrough therapy status."
"This completely new class of drug with activity in this disease is welcome news for myeloma patients who have failed [other options] and are now poised to lose their battle to myeloma," he added.
Dr. Lokhorst reports working closely with Genmab and Johnson & Johnson. Dr. Richardson reports serving on advisory boards for Millennium Pharmaceuticals, Celgene, Novartis, Genmab, and Johnson & Johnson. Dr. San Miguel reports sitting on advisory boards for Millennium, Celgene, Janssen, Novartis, Onyx, among others. Dr. Jagannath reports consulting for Onyx and being on scientific advisory boards for Celgene and Millennium Pharmaceuticals (Takeda Pharmaceutical Company).
18th Congress of the European Hematology Association (EHA): Abstract S576. Presented June 15, 2013.
Medscape Medical News © 2013 WebMD, LLC
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Cite this: Daratumumab Responses High and Durable in Multiple Myeloma - Medscape - Jun 18, 2013.