Results of the phase 3 POLLUX trial suggest that adding daratumumab to treatment with lenalidomide and dexamethasone can improve progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma (MM).
Compared to patients who received only lenalidomide and dexamethasone, those who received daratumumab as well had a significantly higher response rate and longer PFS.
Treatment with daratumumab was also associated with infusion-related reactions and a higher incidence of neutropenia.
These results were published in NEJM. They were previously presented at the 21st Congress of the European Hematology Association. The POLLUX trial was funded by Janssen Research and Development.
POLLUX enrolled 569 patients who had relapsed or refractory MM. The patients were randomized to receive either daratumumab, lenalidomide, and dexamethasone (DRd, n=286) or lenalidomide and dexamethasone alone (Rd, n=283).
Patient characteristics were similar between the treatment arms. The median age was 65 in both arms (overall range, 34-89). About half of patients in each arm had ISS stage I disease, about half had an ECOG performance score of 1 or 2, and patients were, roughly, a median of 4 years from diagnosis.
In both arms, patients had a median of 1 prior lines of therapy (overall range, 1-11).
More than 60% of patients in both arms (63%-64%) had received a prior transplant; 86% had received a proteasome inhibitor; 55% had received an immunomodulatory agent; 44% had received a proteasome inhibitor and an immunomodulatory agent; and 41%-43% had received a proteasome inhibitor, an immunomodulatory agent, and an alkylating agent.
Discontinuation
At the clinical cutoff date on March 7, 2016, 23.3% (n=66) of patients in the DRd arm and 47.0% (n=132) of those in the Rd arm discontinued treatment.
The most common reasons for discontinuation were progression (14.1% in the DRd arm and 34.2% in the Rd arm) and adverse events (6.7% and 8.2%, respectively).
Response
The overall response rate among evaluable patients (281 in the DRd arm and 276 in the Rd arm) was 92.9% in DRd arm and 76.4% in the Rd arm (P<0.001).
The rates of complete response or better were 43.1% and 19.2%, respectively. And the rates of stringent complete response were 18.1% and 7.2%, respectively.
In the DRd arm, 22.4% of patients had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells). The same was true for 4.6% of patients in the Rd arm (P<0.001).
PFS and OS
At a median follow-up of 13.5 months, there were 169 events of disease progression or death. The incidence was 18.5% (53/286) in the DRd arm and 41% (116/283) in the Rd arm. The hazard ratio was 0.37 (P<0.001).
At 12 months, the rate of PFS was 83.2% in the DRd arm and 60.1% in the Rd arm. The median PFS has not been reached in the DRd arm but was 18.4 months for patients in the Rd arm.
The improvement in PFS for the DRd arm was seen across all patient subgroups, regardless of age, ISS stage, prior treatment, etc.
In addition, there was an overall survival (OS) advantage with DRd. The 12-month OS was 92.1% in the DRd arm and 86.8% in the Rd arm.
The median OS was not reached in the DRd arm and was 20.3 months in the Rd arm. The hazard ratio was 0.64 (P=0.0534). The researchers said follow-up for long-term survival is ongoing.
Safety
The most common hematologic adverse events (in the DRd and Rd arms, respectively) were neutropenia (59.4% and 43.1%), anemia (31.1% and 34.9%), thrombocytopenia (26.9% and 27.4%), lymphopenia (6.0% and 5.3%), and febrile neutropenia (5.7% and 2.5%). Deep vein thrombosis occurred in 1.8% and 3.9% of patients, respectively.
The most common non-hematologic adverse events (in the DRd and Rd arms, respectively) were diarrhea (42.8% and 24.6%), fatigue (35.3% and 27.8%), upper respiratory tract infection (31.8% and 20.6%), constipation (29.3% and 25.3%), cough (29.0% and 12.5%), muscle spasms (25.8% and 18.5%), and pneumonia (14.1% and 13.2%).
Patients in the DRd arm had a higher rate of several grade 3/4 events, including neutropenia (51.9% and 37.0%), diarrhea (5.3% and 3.2%), fatigue (6.4% and 2.5%), nausea (1.4% and 0%), dyspnea (3.2% and 0.7%), and infection (28.3% and 22.8%).
Serious adverse events occurred in 48.8% of patients in the DRd arm and 42.0% in the Rd arm. Pneumonia was the most common serious event, occurring in 8.1% and 8.5% of patients, respectively.
Daratumumab-infusion-related reactions occurred in 47.7% of patients, were mostly grade 1/2, and occurred predominantly during the first infusion.
The researchers also noted that daratumumab interferes with laboratory-based blood compatibility tests because the drug binds to CD38 on red cells.
Daratumumab development
Data from the phase 3 CASTOR trial—in which researchers compared daratumumab, bortezomib, and dexamethasone to bortezomib and dexamethasone alone—were also recently published in NEJM.
“Following the publication of the phase 3 CASTOR data, we are pleased that the positive data from the phase 3 POLLUX study has now also been published in the New England Journal of Medicine,” said Jan van de Winkel, PhD, chief executive officer of Genmab.
“The data from this study formed the basis, along with data from the CASTOR study, of 2 regulatory submissions in August—the supplemental Biologics License Application submitted to the US Food and Drug Administration and the submission of the variation to the Marketing Authorization to the European Medicines Agency.”
Both submissions seek to expand the current indication for daratumumab so the drug can be used in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone to treat MM patients who have received at least 1 prior therapy.
Daratumumab currently has conditional approval from the European Commission as monotherapy for adults with relapsed and refractory MM who progressed on their last therapy and have received treatment with a proteasome inhibitor and an immunomodulatory agent.
Daratumumab has accelerated approval in the US as monotherapy for MM patients who have received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.
Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license from Genmab to develop, manufacture, and commercialize daratumumab.
