Daratumumab Improves Progression-Free Survival for Patients with Multiple Myeloma

The addition of daratumumab (Darzalex®) to lenalidomide (Revlimid®) and dexamethasone increased progression-free survival among patients with relapsed or refractory multiple myeloma, compared with lenalidomide and dexamethasone alone, according to the results of a phase III clinical trial.

Meletios A. Dimopoulos, M.D., of the University of Athens, and his colleagues reported their findings from the POLLUX trial at the 21st Congress of the European Hematology Association in June. The results appeared in the New England Journal of Medicine on October 6.

Daratumumab is a monoclonal antibody that targets the CD38 protein. In November 2015, the Food and Drug Administration (FDA) granted accelerated approval for daratumumab to treat patients with multiple myeloma who have received at least three prior treatments. That decision was one of several recent drug approvals for patients with multiple myeloma.

“It’s really remarkable,” said Richard Little, M.D., of NCI’s Cancer Therapy Evaluation Program. “In just the last few years, a number of new therapies for multiple myeloma have emerged, and they are helping many patients. The field is terribly excited about these drugs.”

In August, Dr. Dimopoulos and his colleagues published the results of another phase III study of daratumumab in the New England Journal of Medicine. The CASTOR trial evaluated daratumumab with or without subcutaneous bortezomib (Velcade®) and dexamethasone in patients with relapsed or refractory multiple myeloma.

Based on data from the CASTOR and POLLUX trials, the FDA in July granted breakthrough status for daratumumab in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. And in November 2016, daratumumab was approved for that indication.

The POLLUX study included 569 patients with multiple myeloma who had received at least one prior therapy. Participants were randomly assigned to receive lenalidomide and dexamethasone with or without daratumumab. The primary end point was progression-free survival.

The median progression-free survival for patients in the daratumumab group had not been reached when the results were reported, whereas the estimated median progression-free survival for patients who received lenalidomide and dexamethasone alone was 18.4 months.

At a median follow-up of 13.5 months, 53 of 286 patients (18.5%) in the daratumumab group experienced disease progression or died versus 116 of 283 (41.0%) in the control group. The daratumumab group had a higher rate of overall response than the control group (92.9% versus 76.4%) and also a higher rate of complete response (43.1% versus 19.2%).

The most common side effects included neutropenia (in 51.9% of the patients in the daratumumab group versus 37.0% of patients in the control group), thrombocytopenia (in 12.7% versus 13.5%), and anemia (in 12.4% versus 19.6%). Infusion-related reactions associated with daratumumab occurred in 47.7% of the patients, primarily during the first infusions.

The rates of treatment discontinuation were similar in the daratumumab group and the control group (6.7% versus 7.8%), the study authors noted. Eleven patients (3.9%) in the daratumumab group and 15 (5.3%) in the control group died from adverse events, including acute kidney injury, septic shock, and pneumonia.

“Daratumumab appears to be an important advance for patients with multiple myeloma,” said Dr. Little, noting that it is too soon to known whether there is an improvement in overall survival associated with the treatment.

The three-drug combination was reasonably well tolerated, but the higher rates of neutropenia and infectious complications in the daratumumab group “are always concerns for patients undergoing treatment for multiple myeloma,” he added.

In an editorial accompanying the POLLUX results, S. Vincent Rajkumar, M.D., and Robert A. Kyle, M.D., of the Mayo Clinic wrote that daratumumab “is likely to be incorporated into the treatment of all stages of the disease over the next several years.”

A challenge for physicians will be to prevent the unnecessary use of daratumumab, because it will be difficult to isolate the drug’s effects when daratumumab is combined with multiple other active agents, the editorialists noted. “It will be important for future randomized trials to compare the various triplet regimens so that we can make more informed decisions,” they wrote.

The new findings have raised other important questions, added Dr. Little. For instance, “researchers do not yet know whether these drugs need to be given continuously or whether patients can take ‘drug holidays,’” he said. Another question is whether certain subgroups of patients can get the same therapeutic benefit from shorter courses of treatment as from longer ones.

“A lot of work needs to be done to learn how best to use these medicines so that individual patients achieve the most benefit,” said Dr. Little.