The investigational anti-CD38 monoclonal antibody daratumumab (HuMax-CD38, Genmab/Janssen) has demonstrated promising single-agent activity in patients with difficult-to-treat multiple myeloma.
Clinical trial results from early trials in a total of 114 patients showed that daratumumab produced a response in about one-third of patients with relapsed myeloma or relapsed disease that proved refractory to two or more previous lines of therapy.
The product has already moved on to phase 3 clinical trials, and has been granted breakthrough designation by the US Food and Drug Administration (FDA). The manufacturer is submitting clinical trial data to the FDA as it becomes available, in a rolling submission.
The clinical trial results were published online August 26 in the New England Journal of Medicine.
"Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma," said lead investigator Paul Richardson, MD, director of clinical research at the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, and R.J. Corman professor at Harvard Medical School in Boston.
"This agent is unique as far as the mechanism of action in myeloma treatment," he told Medscape Medical News.
On the basis of positive results from early trials and results from this trial, daratumumab has already moved into phase 3 trials, and the data so far look "very promising," Dr Richardson said.
"The introduction of monoclonal antibodies into the arsenal against myeloma is game-changing in multiple myeloma treatment," according to the authors of an accompanying editorial.
"These agents have the advantage of an immune-based approach without the need for patient-specific cell manipulation," and their limited toxicity "allows for easy combining with existing therapies," write editorialists Noopur Raje, MD, from the Massachusetts General Hospital Cancer Center, and Dan L. Longo, MD, from Harvard Medical School.
Encouraging Activity in Refractory Myeloma
Initial results from the clinical trial were presented at the European Hematology Association in 2013, as reported at the time by Medscape Medical News.
In part 1 of the phase 1/2, open-label, multicenter trial, dose-escalation was assessed in 32 patients. Doses of daratumumab ranged from 0.005 to 24 mg/kg.
In part 2 of the trial, dose expansion was assessed in 72 patients. Daratumumab 8 mg/kg and 16 mg/kg were administered in different schedules.
The primary end point was safety. Secondary end points included pharmacokinetics, objective response, time to disease progression, duration of response, progression-free survival, and overall survival.
Patients in part 2 had received a median of four previous treatments, and 79% were refractory to the last therapy they had received. Of these, 64% had disease refractory to proteasome inhibitors and immunomodulatory drugs, and 64% had disease refractory to bortezomib (Velcade, Millennium) and lenalidomide (Revlimid, Celgene).
In addition, 76% of patients in part 2 had already undergone autologous stem-cell transplantation.
In part 1, 4 of 12 (33%) patients achieved a partial response after doses of daratumumab ranging from 4 to 24 mg/kg, which is the range in which consistent clinical responses were observed, the investigators note.
In part 1, 4 of 12 patients (33%) had a partial response when they received doses in the range of 4 to 24 mg/kg. This was the range in which consistent clinical responses were observed, they note.
For patients in part 2 who received 16 mg/kg, two achieved a very good partial response and 11 achieved a partial response. For patients in part 2 who received 8 mg/kg, 10% achieved a response (three patients achieved a partial response).
In the 8 mg/kg group, the estimated median duration of response was 6.9 months (95% CI, 6.2 - 10.6). In the 16 mg/kg group, the median duration of response has not yet been reached.
The overall survival rate at 12 months was 77% in the 8 mg/kg group and in the 16 mg/kg group.
Acceptable Toxicity Profile
The most common adverse events were infusion-related reactions, which occurred in 71% of the patients but were primarily grade 1 or 2, as were most of the events observed during the study.
Grade 3 or 4 adverse events were reported in 53% of patients in the 8 mg/kg group and in 26% of patients in the 16 mg/kg group. These events included pneumonia in five patients, thrombocytopenia in four patients, and, in two patients each, neutropenia, leukopenia, anemia, and hyperglycemia.
Serious adverse events occurred in 40% of patients in the 8 mg/kg group and in 33% in the 16 mg/kg group. In the 8 mg/kg and 16 mg/kg groups, the most frequent events were infection-related events (17% vs 10%)
Exciting Results But Questions Remain
"The single-agent activity of daratumumab, including complete responses, in this patient population is surprising and very encouraging," Drs Raje and Longo explain in their editorial. "These results are probably due to its pleiotropic mechanisms of action against myeloma."
They describe the activity as "impressive," but caution that many questions remain. For example, they note, "how do tumors escape the effects of daratumumab? Can daratumumab, like rituximab in the treatment of lymphoma, be active in many phases of treatment, such as in induction, consolidation, and maintenance therapies?"
Another question is whether daratumumab resistance can 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 myeloma," they say.
The study was sponsored by Genmab A/S and Janssen Research & Development, LLC. Dr Richardson reports receiving support from Genmab outside the submitted work. Several coauthors report relationships with industry. Dr Longo is deputy editor of the New England Journal of Medicine. Dr Raje reports receiving grant support from Eli Lilly and AstraZeneca, and personal fees from Celgene and Millennium/Takeda outside the submitted work.
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