Daratumumab monotherapy yielded impressive results in patients with heavily pretreated and refractory multiple myeloma, according to the full results of a phase I/II study published online by the New England Journal of Medicine.

Among 42 patients receiving 16 mg/kg of daratumumab in part 2 of the study, the overall response rate was 36%, including 2 complete responses, 2 very good partial responses, and 11 partial responses.

Median progression-free survival was 5.6 months. Responses deepened over time, with 65% of responders remaining progression-free at 12 months, study author Dr. Henk M. Lokhorst , of University Medical Center Utrecht, and the VU University Medical Center, Amsterdam, both in the Netherlands, and his associates reported (N Engl J Med. 2015 Aug. 26 [ doi:10.1056/NEJMoa1506348 ]).

In 30 patients given daratumumab 8 mg/kg, the response rate was 10%, including three partial responses.

Patients in part 2 of the study were heavily pretreated with a median of four prior lines of therapy (range 2-12) and 64% were refractory to the current standard treatment of protease inhibitors (PIs) and immunomodulatory agents (IMiDs). Such patients have a poor prognosis, with an estimated median overall survival of 9 months and estimated event-free survival of 5 months at best, Dr. Lokhorst and his associates noted.

“Daratumumab showed single-agent antitumor activity in a population of patients with highly difficult-to-treat myeloma who had very few effective treatment options,” the investigators concluded. “Its target and mechanisms of action differentiate it from existing therapies.”

Daratumumab is a human monoclonal antibody that targets CD38, which is uniformly overexpressed in multiple myeloma cells.

In part 1, the dose-escalation phase of the study, no maximum-tolerated dose was identified at doses up to 24 mg/kg in 32 patients. Two dose-limiting toxicities – grade 3 anemia and grade 3 elevated aspartate aminotransferase levels – occurred at 0.1 mg/kg and 1 mg/kg, but no further events were seen with dose escalation, Dr. Lokhorst and associates reported.

The most-common adverse events in part 2 of the study – occurring in at least 25% of patients – were fatigue, allergic rhinitis, and pyrexia. Infusion-related reactions were mild and were seen in 71% of patients, typically during the first infusion.

The most-common grade 3/4 events were pneumonia (five patients) and thrombocytopenia (four patients). Neutropenia, leukopenia, anemia, and hyperglycemia occurred in two patients each. There was one grade 5 pneumonia, but investigators did not think it was related to the study drug, they wrote.

Exploratory subgroup analyses revealed that response rates were similar in patients with disease refractory to both bortezomib (Velcade) and lenalidomide (Revlimid) and the total population, but were higher in patients with two or three prior lines of therapy vs. more heavily pretreated patients (56% vs. 23%).

Data from the study were included in a Biologics License Application submitted in July 2015 to the U.S. Food and Drug Administration for daratumumab as a treatment for patients with multiple myeloma who have received at least three prior lines of therapy including both a PI and an IMiD or who are double refractory to a PI and an IMiD, according to Genmab .

Daratumumab, which has already been granted breakthrough therapy status by the FDA, is being develop by Janssen Biotech, under an exclusive license from Genmab.

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