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Daratumumab demonstrates single-agent activity in relapsed, refractory multiple myeloma
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Daratumumab monotherapy appeared safe and effective for patients with heavily pretreated relapsed or refractory multiple myeloma, according to study results published in The New England Journal of Medicine.
“Current therapies, including proteasome inhibitors and immunomodulatory agents, have improved outcomes substantially in patients with multiple myeloma,” Henk M. Lokhorst, MD, of the department of hematology at VU University Medical Center in Amsterdam, and colleagues wrote. “Unfortunately, the majority of these patients have a relapse and have limited treatment options after exposure to these classes of agents.”
Daratumumab (Janssen Biotech and Genmab) is a monoclonal antibody that targets CD38, which is overexpressed on multiple myeloma cells.
Lokhorst and colleagues conducted a phase 1/2 trial to evaluate the use of daratumumab in patients with relapsed or relapsed and refractory — defined as receipt of at least two prior therapy lines — multiple myeloma.
In the dose-escalation phase of the trial (part 1), researchers assigned patients daratumumab at doses of 0.005 mg/kg to 24 mg/kg. In the dose-expansion phase (part 2), researchers assigned 30 patients 8-mg/kg doses and 42 patients 16-mg/kg doses administered once weekly for eight doses, twice monthly for eight doses and then monthly for up to 24 months.
Safety and efficacy served as the primary endpoints.
The researchers did not identify a maximum tolerated dose during part 1 of the trial.
Patients in part 2 of the study had a median time since diagnosis of 5.7 years. Both cohorts received a median of four prior therapy lines (range, 3-10 for the 8-mg/kg arm; range, 2-12 for the 16-mg/kg arm).
Seventy-nine percent of patients were refractory to the last therapy received, which included 64% of patients whose disease was refractory to proteasome inhibitors and immunomodulatory drugs, as well as 64% who were refractory to bortezomib (Velcade; Takeda, Millennium Pharmaceuticals) and lenalidomide (Revlimid, Celgene).
Further, 76% percent of patients previously underwent autologous stem cell transplantation.
In part 2, 15 patients in the 16-mg/kg dose cohort achieved a partial response or better, including two patients who completely responded and two patients who achieved very good partial responses, equating to an overall response rate of 36%. The overall response rate in the 8-mg/kg cohort was 10% and included three patients who achieved a partial response.
Patients assigned 16-mg/kg doses achieved a median PFS of 5.6 months (95% CI, 4.2-8.1). Further, 65% of the cohort (95% CI, 28-86) who had a response did not experience progression at 12 months.
Seventy-one percent of patients experienced an infusion-related reaction of any grade, including 1% of patients who experienced a grade 3 event. No dose-dependent adverse events occurred.
The most common grade 3 or grade 4 adverse events included pneumonia (n = 5) and thrombocytopenia (n = 4).
"Daratumumab showed single-agent antitumor activity in a population of patients with highly difficult-to-treat myeloma who had very few effective treatment options,” Lokhorst and colleagues wrote. “Its target and mechanisms of action differentiate it from existing therapy.”
Noopur Raje
Monoclonal antibodies are “game-changing” for multiple myeloma treatment due to their ability to activate the immune system without patient-specific cell manipulation and with limited toxicity, Noopur Raje, MD, associate professor of medicine at Harvard Medical School and director of the multiple myeloma program at Massachusetts General Hospital, and Dan L. Longo, MD, professor of medicine at Harvard Medical School, wrote in an accompanying editorial.
“Even with this enthusiasm, unanswered questions remain,” Raje and Longo wrote. “How do tumors escape the effects of daratumumab? Can daratumumab, like rituximab [Rituxan; Genentech, Biogen Idec] in the treatment of lymphoma, be active in many phases of treatment, such as in induction, consolidation, and maintenance therapies? Can daratumumab resistance be predicted? As we begin to tackle the complexity of these questions, it is reassuring to know that we have yet one more treatment option that will contribute in an important way to improvement in outcomes in patients with multiple myeloma.” – by Cameron Kelsall
Disclosure: Janssen R&D and Genmab funded the trial. Lokhorst reports grant support and personal fees from Genmab and Janssen and personal fees from Amgen outside the
submitted work. Please see the full study for a list of all researchers’ relevant financial disclosures. Longo reports that he is employed by The New England Journal of Medicine as Deputy Editor. Raje reports grant support from Eli Lilly and AstraZeneca, and personal fees from Celgene and Millennium/Takeda outside the submitted work.
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