ATLANTA — The novel monoclonal antibody product daratumumab (Darzalex, Janssen) is already used for multiple myeloma in patients who have progressed on other therapies, but now it has been propelled to the front line.
New results show that it also improves outcomes in patients with newly diagnosed multiple myeloma who are ineligible for transplant, when used in combination with triple therapy.
The findings, from the phase 3 ALCYONE trial, show that when daratumumab was added to a regimen of bortezomib (Velcade, Millennium), melphalan, and prednisone (D-VMP), there was a 50% lower risk for disease progression or death compared with triple therapy without the antibody.
"In this first phase 3 randomized study with a monoclonal antibody in newly diagnosed multiple myeloma, D-VMP also induced significantly deeper responses, including a more than threefold higher minimal residual disease negative rate," said study author Jesus F. San-Miguel, MD, from the Clínica Universidad de Navarra-CIMA, IDISNA, Pamplona, Spain.
"There were also no new safety signals except for higher infection events that resolved," he said.
The findings were presented here at the American Society of Hematology (ASH) 2017 Annual Meeting and published simultaneously in the New England Journal of Medicine to coincide with the meeting.
Looking at Front Line
Daratumumab was first approved by the US Food and Drug Administration in 2015 for patients with multiple myeloma who have tried at least three other drug therapies, and it was the first monoclonal antibody for use in this disease.
A year later, in 2016, the FDA expanded the indication and approved daratumumab to be used in combination with lenalidomide (Revlimid, Celgene) and dexamethasone or with bortezomib and dexamethasone for patients with myeloma who have received at least one prior therapy.
"What is important about this study is that while daratumumab has been studied and approved for use in patients with relapsed/refractory multiple myeloma, this is the first study to look at it as a front-line agent in newly diagnosed patients," said Ajai Chari, MD, PhD, associate professor of medicine and director of clinical research in the Multiple Myeloma Program at Mt Sinai Health System, New York, City, who was approached by Medscape Medical News for an independent comment.
"We may be now looking at an alternative therapy for front-line treatment, in those who are ineligible for transplantation," Dr. Chari added.
Study Met All Endpoints
The ALCYONE study is multicenter trial conducted at 25 centers globally in 706 patients with newly diagnosed myeloma who were not considered to be candidates for transplant because of coexisting conditions or because they were 65 years of age or older.
Dr San-Miguel and colleagues randomly assigned the patients to VMP or D-VMP.
All patients received nine cycles of VMP: bortezomib 1.3 mg/m2 subcutaneously twice a week for the first cycle and then once weekly for eight cycles; 9 mg/m2 melphalan orally on days 1 to 4; and prednisone 60 mg/m2 on days 1 to 4.
Patients randomly assigned to D-VMP also received daratumumab 16 mg/kg intravenously once for cycle 1, then every 3 weeks for cycles 2 to 9, and every 4 weeks for cycles 10 and beyond (post–VMP treatment phase) until disease progression.
The primary endpoint was progression-free survival, and secondary endpoints included overall response rate (ORR), rate of very good partial response (VGPR) or better, rate of complete response, rate of minimal residual disease negativity (10-5 threshold, Adaptive clonoSEQ Assay), overall survival, and safety.
At a median follow-up of 16.5 months, the hazard ratio for PFS (D-VMP vs VMP) was 0.50 (P < .0001), which represented a 50% reduction in the risk for progression or death for the D-VMP cohort, explained Dr San-Miguel.
Median PFS was not reached in the D-VMP group (with up to 27 months of follow-up) vs 18.1 months for the VMP group. These findings were consistent across all prespecified subgroups, including age 75 years or older and patients with high-risk cytogenetics.
All secondary endpoints were also significantly higher for D-VMP than for VMP. ORR was 90.9% vs 73.9%, the rate of VGPR or better was 71.1% vs 49.7%, complete response rate was 42.6% vs 24.4%, and rate of minimal residual disease negativity was 22.3% vs 6.2% (all P < .0001).
The overall survival data remain immature, but to date 93 patients have died (45 in the D-VMP group and 48 in the VMP group).
The most common grade 3/4 treatment emergent adverse events for D-VMP vs VMP were neutropenia (39.9% vs 38.7%), thrombocytopenia (34.4% vs 37.6%), anemia (15.9% vs 9.8%), and pneumonia (11.3% vs 4.0%; one patient in each group stopped treatment because of pneumonia).
Dr San-Miguel pointed out that other ongoing studies are looking at front-line daratumumab in combination with other agents, including the phase 3 MAIA and CASSIOPEIA trials and the phase 2 GRIFFIN study.
While some patients may prefer drug therapy over a transplant, Dr Chari cautioned that these results do not speak to that issue. "This study will not answer the question of whether quadruple therapy will replace transplant because the population in this study is transplant ineligible," he said. "That study will have to be done, to address the question of quadruple therapy as an alternative to transplant."
The study was supported by Janssen Research & Development. Dr. San-Miguel reports consultancy/advisory roles for Novartis, Takeda, Roche, Sanofi, Amgen, Cilag, Bristol-Myers Squibb, Celgene, and Janssen. Several coauthors also report relationships with industry, including Janssen, the manufacturer.
American Society of Hematology (ASH) 2017 Annual Meeting. Abstract LBA-4. Presented December 12, 2017.
N Engl J Med. Published online December 12, 2017. Full text
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Cite this: Daratumumab Ready to Move to Front Line in Multiple Myeloma - Medscape - Dec 13, 2017.