A three-drug therapy combination consisting of Darzalex (daratumumab) with Revlimid (lenalidomide) and Decadron (dexamethasone) shows real potential in increasing survival in patients with relapsed or refractory multiple myeloma, according to an interim analysis of a Phase 3 trial.
But the data in the study, “Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma,” published in The New England Journal of Medicine, shows that the combination increases the incidence of treatment-related adverse events.
Approved in 2015 by the U.S. Food and Drug Administration (FDA), Darzalex has been showing promising safety and anticancer effects in multiple myeloma, both as a single agent and in combination with other standard of care therapies.
A Phase 1/2 trial (NCT01615029) assessing the safety and effectiveness of Darzalex in combination with Revlimid and Decadron showed potential in myeloma patients, with an 81 percent overall response rate; 72 percent 18-month progression-free survival (PFS); and 90 percent 18-month overall survival.
Based on those results, Dr. Meletios A. Dimopoulos, MD, professor and chairman of the Department of Clinical Therapeutics at the University Athens School of Medicine in Greece and his colleagues designed a Phase 3 trial to assess the effectiveness of adding Darzalex to Revlimid and Decadron.
The randomized, open-label, Phase 3 POLLUX study (NCT02076009) enrolled 596 patients (median age 65 years) with relapsed or refractory multiple myeloma who had received at least one prior therapy, and 19.2 percent of patients had received three or more previous lines of therapy.
Participants were randomized to receive Revlimid (25 mg on days 1-21) plus Decadron (40 mg weekly), with or without Darzalex (16 mg/kg weekly in the first eight weeks for cycles 1 and 2, and every two weeks for cycles 3 through 6, and every four weeks thereafter).
After 13.5 months of follow-up, when the interim analysis was conducted, 169 patients experienced disease progression or had died. These events, however, were more common in the control group than in the Darzalex group (41% vs. 18.5%).
Progression-free survival at 12 months was higher in the Darzalex group, as was overall survival. Indeed, patients on the Darzalex arm showed an 83.2% 12-month PFS compared to 60.1% in the control group. Median PFS was 18.4 months in the control group and had not been reached at the time of data cutoff.
The Darzalex triple therapy showed superiority to the Revlimid plus Decadron regimen regardless of the number of prior therapies or whether patients had already received Revlimid therapy.
The Darzalex group also showed superiority in patients’ 12-month overall survival, with 92.1 percent of patients alive at 18 months, compared to only 86.8 percent in the control group.
More patients in the Darzalex group responded to therapy (92.9% vs. 76.4%), and achieved a complete response (43.1% vs. 19.2%), and more patients achieved the threshold of minimal residual disease (22.4% vs. 4.6%), which is defined as having less than one tumor cell per 100,000 white blood cells.
However, the Darzalex group also had more common adverse events than the control group. The most common adverse events were low levels of neutrophils — a type of immune cells — along with diarrhea, upper respiratory tract infection, and cough, all of which were higher in the Darzalex group.
Nearly half of patients in the Darzalex arm had infusion-related reactions of grade 1 or grade 2.
But despite having higher incidence of adverse events, the control arm had more patients withdrawing from therapy due to adverse events (7.8% vs. 6.7%), and more patients died in that group due to adverse events (5.3% vs. 3.9%).
“Although higher rates of neutropenia and infusion-related reactions (primarily during the first infusion) were observed with this combination than with [Revlimid] and [Decadron] alone, these events did not result in higher rates of treatment discontinuation or death,” the researchers wrote.
In an accompanying editorial, Dr. S. Vincent Rajkumar, MD, and Dr. Robert A. Kyle, MD, both of the division of hematology at Mayo Clinic in Rochester, Minnesota, said that incorporating Darzalex into the therapy is a “landmark advance” for this disease, but that comparisons must be made to understand which regimen yields best results in effectiveness, safety, ease of use, and cost.
Still, it is likely that Darzalex will be “incorporated into the treatment of all stages of the disease over the next several years,” Rajkumar and Kyle wrote.
“The challenge will be to prevent unnecessary use, since it will be hard to isolate the effect of [Darzalex] when it is combined with multiple other active agents. It will be important for future randomized trials to compare the various triplet regimens so that we can make more informed decisions,” they wrote.
Based on the POLLUX and CASTOR Phase 3 studies, the FDA has recently granted priority review to the application requesting the approval of Darzalex in combination with either Revlimid and Decadron, or Velcade (bortezomib) and Decadron. The action date is set for June 17, 2017.