Daratumumab Boosts Outcomes in Newly Diagnosed Multiple Myeloma

Nancy A. Melville

June 17, 2019

Adding daratumumab (Darzalex, Janssen) to standard-of-care therapy for patients newly diagnosed with multiple myeloma who are eligible for autologous stem cell transplant (ASCT) significantly improves responses without compromising safety, according to new findings from the phase 3 CASSIOPEIA trial.

"The CASSIOPEIA study is the first to show that addition of a monoclonal antibody to an induction and consolidation regimen is effective and well tolerated in transplant-eligible patients," said first author Philippe Moreau, MD, head of the Department of Hematology, University Hospital Hôtel-Dieu, Nantes, France.

"These results support [the daratumumab regimen] as a new standard of care for newly diagnosed multiple myeloma patients who are eligible for ASCT," he said.

Moreau presented the new data here at the European Hematology Association (EHA) 2019 Annual Meeting. The study was simultaneously published online in the Lancet.

For patients newly diagnosed with multiple myeloma, the standard triplet of bortezomib (Velcade, Millennium), thalidomide (Thalomid, Celgene), and dexamethasone (VTd) (multiple brands) is widely used before and after stem cell transplant, he explained.

Although treatment with daratumumab, a CD38-targeting human monoclonal antibody, has been associated with reduced disease progression and improved complete response in patients with relapsed or refractory multiple myeloma who were not eligible for transplant, evidence of its role in transplant-eligible patients with newly diagnosed disease has been lacking.

"Currently, we have no data on the effect of daratumumab for the treatment of younger patients. Several trials are ongoing, and CASSIOPEIA is the first trial to look at daratumumab with VTd in transplantation-eligible patients," Moreau said.

In the study, 1085 transplant-eligible patients younger than 66 years were enrolled from 2015 to 2017 at 11 sites and were randomly allocated to receive either daratumumab plus VTd (D-VTd; n = 543) or VTd alone (n = 542).

Part one of the study investigated treatment with or without daratumumab in induction and consolidation therapy. The treatment regimens included VTd in four cycles of 28 days before and two cycles of 28 days after transplant. When daratumumab was included, the drug was infused at a dose of 16 mg/kg weekly in the first two cycles and subsequently every 2 weeks.

In part two of the study, patients who demonstrated a response after the consolidation phase were randomly assigned to receive either maintenance therapy with daratumumab as a single agent infused every 8 weeks with a fixed duration every 2 years or no maintenance.

The median age of the patients was 58 years. The two groups were well balanced; 15% of patients had a high-risk cytogenic profile.

In reporting the full results from part one of the study, Moreau said the rate of stringent complete response at 100 days post transplant was significantly higher in the daratumumab-treated group, which showed a post-consolidation stringent complete response rate of 28.9%, compared to 20.3% in the VTd-only arm (odds ratio, 1.60; P = .001).

The median follow-up period from the first randomization was 18.8 months. At that follow-up, the rate of progression-free survival also favored D-VTd (hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.33 – 0.67; P < .0001).

"This represents a 53% reduction in the risk of progression or death in the D-VTd arm," Moreau said.

Neither arm reached a median progression-free survival. The 18-month rates of progression-free survival were 92.7% for the D-VTd arm and 84.6% for the VTd-alone group.

Other measures that favored the daratumumab-treated group included complete response (38.9% vs 26.0%; P < .0001), very good partial response (83.4% vs 78%; P = .02), and minimal residual disease (MRD) negativity (63.7% vs 43.5%; P < .0001).

The median overall survival rate could not be determined in either arm. However, there was a trend for improved overall survival (HR = .43) in favor of the D-VTd arm, and the 24-month overall survival rate of 97% in the D-VTd group was "remarkable," Moreau commented.

"Those results are the best ever reported in the setting of stem cell transplantation," he said.

He also commented that although the stringent complete response rate of 28.9% may not appear to be high, this rate reflected a very strict definition, per International Myeloma Working Group criteria. These criteria include serum immunofixation and urine immunofixation negativity, defined as fewer than 5% plasma cells in bone marrow; four-color flow negativity; normal free light chain ratio; and disappearance of all plasmacytomas. Importantly, these criteria needed to be confirmed at the next visit.

Prespecified subgroup analysis of stringent complete response with respect to age, sex, disease stage, hepatic function, type of multiple myeloma, and other factors showed similar increased efficacy with D-VTd, with the exception of cytogenetic profile at trial entry and stage III disease, as determined per the International Staging System.

The most common grade 3/4 treatment-emergent adverse events (≥10%) were neutropenia (27.6% in the daratumumab-plus-triplet arm vs 14.7% in the triplet arm), lymphopenia (17.0% vs 9.7%), stomatitis (12.7% vs 16.4%), and thrombocytopenia (11.0% vs 7.4%).

In the daratumumab-plus-triplet arm, infusion-related reactions occurred in 35.4% of patients; of these reactions, 4% were of grade 3 or 4.

"The D-VTd combination was well tolerated and consistent with the known safety profiles of daratumumab and VTd," Moreau said.

He concluded that "treatment with D-VTd induces significant increases in proportions of patients achieving deep responses, including MRD, than bortezomib, thalidomide, and dexamethasone alone."

In commenting on the study, Anton Hagenbeek, MD, professor of hematology at the Academic Medical Center, the University of Amsterdam, the Netherlands, agreed that the findings offer important insights on how daratumumab can help boost outcomes relating to ASCT in patients newly diagnosed with multiple myeloma.

"We know daratumumab is very effective against malignant plasma cells," he told Medscape Medical News. "Hematologists have had a lot of experience in antibodies in recent years, and with this, there really was quite an increase in progression-free survival.

"The effect was very significant, so I would say it's a very impressive study," he said.

The US Food and Drug Administration announced this month that on the basis of the CASSIOPEIA trial findings, it was granting priority review of daratumumab in combination with VTd for the treatment of patients newly diagnosed with multiple myeloma who are eligible for ASCT.

The study received funding from the Intergroupe Francophone du Myélome and Dutch-Belgian Cooperative Trial Group for Hematology Oncology. Moreau is a consultant for and has received honoraria from Janssen, Celgene, Amgen, Takeda, and AbbVie. Hagenbeek is a consultant to Takeda USA.

European Hematology Association (EHA) 2019 Annual Meeting: Abstract S145. Presented June 14, 2019.

Lancet. Published June 3, 2019. Abstract

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