Roxanne Nelson

June 02, 2015

CHICAGO ― A novel investigational agent has produced unprecedented responses when used as monotherapy in patients heavily treated with multiple myeloma. The drug, daratumumab, is a novel anti-CD38 antibody.

Daratumumab "produced unprecedented overall responses that deepened over time," said lead author Saad Zafar Usmani, MD, a hematologist at Levine Cancer Institute/Carolinas Healthcare System, in Charlotte, North Carolina.

"These results highlight the potential of daratumumab as a novel, well-tolerated, single-agent therapy in various stages of myeloma treatment," Dr Usmani said during a press briefing held at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting.

At a median follow-up period of 9.4 months, 29.2% of patients responded to daratumumab, including three who experienced complete remissions. The responses were also durable, lasting 7.4 months on average. Overall, the median time to disease progression was 3.7 months, and the estimated overall survival rate at 1 year was 65%.

"What is striking about this study is that daratumumab, given as a single agent, produced responses in 29% of the patients on the study, even though 95% of those who participated had disease that was resistant to both their last proteasome inhibitor and lenalidomide [Revlimid, Celgene Corporation] or pomalidomide [Pomalyst, Celgene Corporation]–based regimen," said Peter Voorhees, MD, senior author of that study and an associate professor in the Division of Hematology and Oncology at the University of North Carolina School of Medicine, in Chapel Hill.

"These are patients who otherwise have very few, if any, good treatment options," he told Medscape Medical News. "Additionally, the responses were often durable, and just as importantly, although the patients enrolled in this study had been through many prior therapies and multiple relapses of their disease, no one had to stop treatment because of daratumumab-related side effects."

Daratumumab is a first-in-class human monoclonal antibody that binds to CD38-expressing cancer cells and induces cell death through multiple mechanisms. In May 2013, the US Food and Drug Administration (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.

Last month, Janssen announced plans to submit a biologics license application to the FDA and the European Medicines Agency (EMA) for daratumumab this year on the basis of these data.

Durable Responses

There is a need for new therapies in this disease, explained Dr Usmani, because multiple myeloma remains incurable, and patient who relapse after therapy with protease inhibitors and/or immunomodulatory drugs have a poor prognosis and few options.

In this open-label, international, multicenter study, eligible patients had received three or more prior lines of therapy, including proteasome inhibitors and/or immunomodulatory drugs, or were refractory to their most recent treatment with these agents.

Patients were initially randomly assigned to receive either 8 mg/kg of daratumumab (n =18) or 16 mg/kg of daratumumab (n = 16) for dose selection; subsequently, an additional 90 patients were enrolled to receive 16 mg/kg.

Dr Usmani reported on 106 patients treated with 16 mg/kg of daratumumub.

The primary endpoint was overall response rate.

Within this cohort, 96% were refractory to their last line of therapy, 95% to protease inhibitors and/or immunomodulatory drugs, 63% to pomalidomide, 48% to carfilzomib (Kyprolis, Onyx Pharmaceuticals, Inc), and 78% to alkylating agents.

The median overall survival has not yet been reached, and the estimated 1-year overall survival rate was 65%. In addition to three patients who achieved complete responses, 10 patients achieved a very good partial response, and 18 had a partial response.

After a median follow-up period of 9.4 months. 14 of 31 (45.2%) of responders remain on therapy.

The major side effect of daratumumab was infusion reactions (42.5%), which were mainly of grade 1/2 (grade 3, 4.7%; no grade 4). They typically occurred early in the course of the treatment and were generally well managed. Other adverse events (≥20%) included fatigue (39.6%), anemia (33.0%), nausea (29.2%), thrombocytopenia (25.5%), back pain (22.6%), neutropenia (22.6%), and cough (20.8%).

No patients discontinued therapy because of infusion reactions; 4.7% discontinued therapy because of other adverse events.

Up-front and in Combination

"A response lasting 7.4 months in this population is quite remarkable," commented Suzanne Lentzsch, MD, PhD, director of the Multiple Myeloma and Amyloidosis Service at New York–Presbyterian Hospital/Columbia University Medical Center, in New York City. "This shows its potency in a heavily pretreated population."

"This is a study of 106 patients, which is fairly large and straightforward and gives us insight into the single-drug activity with this agent," said Dr Lentzsch, who was approached by Medscape Medical News for independent commentary.

However, Dr Lentzsch believes that daratumumab will probably not be used as a single agent but as part of combination therapy. Daratumumab is currently being studied in several ongoing phase 3 trials that are exploring daratumumab in combination with various existing regimens in different stages of the disease.

"The next step is to establish efficacy in combination with other agents and to bring it to frontline therapy," she said.

This study was funded by Janssen. Several of the authors have declared relationships with industry, including Janssen.

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting. Abstract LBA8512. Presented May 30, 2015.

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