COPENHAGEN, Denmark — For the second time in the space of a week, results with the novel agent daratumumab (Darzalex, Janssen Biotech) show significant improvements in the risk for disease progression or death in relapsed or refractory multiple myeloma (RMM).
The latest news comes from the POLLUX trial, in which daratumumab was combined with lenalidomide (Revlimid, Celgene) and dexamethasone. The results were presented during a presidential symposium here at the European Hematology Association 2016 Congress.
This trial also showed the highest response rates ever seen this patient population, noted principal investigator Meletios A. Dimopoulos, MD, professor and chair of the Department of Clinical Therapeutics at the University Athens School of Medicine in Greece.
"The combination induces deep and durable responses and improves in a very dramatic way patients' progression-free survival," he reported.
The news comes hot on the heels of similar news released just over a week ago. Those results came from the CASTOR trial, in which daratumumab was combined with bortezomib (Velcade, Millennium) and dexamethasone. They also showed a significant progression-free survival benefit in RMM. Those findings were presented during a plenary session at the American Society of Clinical Oncology annual meeting.
At both meetings, investigators said that the results set a new milestone in the treatment of RMM.
"This combination with daratumumab potentially represents a new standard of care for myeloma patients after one or more previous treatments," Dr Dimopoulos said, echoing a similar statement made last week by researchers presenting data from the CASTOR study.
An expert not involved in either trial agrees that daratumumab combinations will become a new standard of care. Paul Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, in Boston, told Medscape Medical Newsthat daratumumab combinations will "become a new standard of care once approvals are through, and both CASTOR and the POLLUX study are game changers in my view."
At present, daratumumab is approved for use as a monotherapy in patients who have received at least three previous lines of therapy. Accelerated approval from the US Food and Drug Administration was granted in November 2015.
It is the first monoclonal antibody for myeloma, and has both direct and indirect antimyeloma activity, targeting the CD38 antigen, which is present on nearly all myeloma cells.
Results From the POLLUX Trial
The phase 3 POLLUX study was conducted in 569 patients with RMM who had received at least one previous line of therapy (19% had received three or more). Median age was 65 years.
All patients received oral lenalidomide 25 mg for 21 days of each 28-day cycle plus dexamethasone 40 mg weekly. In addition, 286 of the patients were randomized to a daratumumab injection 16 mg/kg once a week for 8 weeks, once every 2 weeks for 16 weeks, and then once every 4 weeks until progression. The other 283 patients served as the control group.
At a median follow-up of 13.5 months, the risk for progression or death was 63% lower in the daratumumab group than in the control group (hazard ratio [HR], 0.37; P < .0001).
This is similar to the 61% reduction in the risk for progression or death seen with the daratumumab combination in the CASTOR study (HR, 0.39; P < .001).
In addition to meeting the primary end point of progression-free survival, the POLLUX study showed significant delays in time to progression, which was not reached in the daratumumab group, but the estimated median in the control group was 18.4 months (P < .0001).
The overall response rate was significantly better in the daratumumab group than in the control group (93% vs 76%; P < .0001).
Rates of very good partial response or better were superior in the daratumumab group than in the control group (76% vs 44%, P < .0001), as were rates of complete response (43% vs 19%; P < .0001). The median duration of response was not reached in the daratumumab group, but was 17.4 months in the control group.
"It is particularly important that not only 93% of patients achieved at least a partial response, but as many as 43% of patients achieved complete response," Dr Dimopoulos said.
Further analysis of progression-free survival showed a consistent treatment effect of daratumumab in all prespecified subgroups.
The time to achieve response in the daratumumab group was rapid, with responses evident within a month.
"This is clinically important because symptoms and signs came into control," Dr Dimopoulos explained. And "with continued therapy, there was a continued improvement in response."
The most common treatment-emergent adverse events seen in the daratumumab and control groups were neutropenia (59% vs 43%), diarrhea (43% vs 25%), fatigue (35% vs 28%), upper respiratory tract infection (32% vs 21%), anemia (31% vs 35%), constipation (29% vs 25%), cough (29% vs 13%), thrombocytopenia (27% vs 27%), and muscle spasms (26% vs 19%). Grade 3 or 4 treatment-emergent adverse events included neutropenia (52% vs 37%), thrombocytopenia (13% vs 14%), and anemia (12% vs 20%).
Infusion-related reactions with daratumumab were relatively high, at about 48%. However, the events were nearly always after the first infusion and were also almost always grade 1 or grade 2, Dr Dimopoulos noted.
Results Herald "New Era" in Myeloma
Commenting on the results, Heinz Ludwig, MD, head of the Department of Medicine and Medical Oncology and director of the Myeloma Reference Center at the Wilhelminen Hospital in Vienna, agreed that daratumumab is a potential game-changer for RMM.
"Indeed, daratumumab will become 'the better rituximab' for multiple myeloma," he told Medscape"These findings pave the way to a new era of immunotherapies in multiple myeloma," he said.
Dr Ludwig predicted that, in the future, induction regimens in young and elderly patients with multiple myeloma will comprise at least one immune therapy (such as daratumumab) in addition to a proteasome inhibitor (such as bortezomib) or immune-modulating drug (such as lenalidomide) added to dexamethasone. "These regimens could even be expanded by adding alkylating agents," he said.
Dr Ludwig noted reassuring evidence in the POLLUX study regarding concerns about blood transfusions in patients treated with daratumumab.
"It was rewarding to hear that transfusions of either red blood cells or platelets, which were given to 17% of patients, were tolerated without problems," he added.
"This is important because daratumumab shows weak binding to red cells and may lead to a false- positive Coombs test," he said. "To circumvent problems with cross typing of blood products, the transfusion department should be become involved, even before the administration of daratumumab, to allow for correct compatibility testing."
Pieter Sonneveld, MD, PhD, head of the Department of Hematology at the Erasmus MC Cancer Institute at University Medical Center Rotterdam in the Netherlands, agrees that the results offer important insights into the potential of daratumumab for RMM patients.
Previously published results have been for daratumumab monotherapy and did not come from randomized comparisons, he told Medscape Medical News.
He underscored the unique challenges in the treatment of RMM, and the need for better therapies.
"It is important to rapidly reduce tumor burden in order to reduce symptoms and morbidity, followed by sustained tumor control," Dr Sonneveld said.
"The results of the triple combination are very significantly better [than the two agents alone] and represent the best option available today," he added.
The study received funding from Janssen Research & Development. Dr Dimopoulos reports relationships with Amgen, Celgene, Janssen, Novartis, and Takeda. Dr Ludwig reports relationships with Ortho Biotech, Amgen, and Roche. Dr Sonneveld reports relationships with SkylineDx, Karyopharm, Amgen, Celgene, and Janssen.
European Hematology Association (EHA) 2016 Congress: Abstract LB2238. Presented June 11, 2016.
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