FOR NEWLY DIAGNOSED multiple myeloma patients not eligible for transplant, the addition of the anti-CD38 monoclonal antibody daratumumab (Darzalex) to subcutaneous bortezomib (Velcade), melphalan, and prednisone (VMP) reduced the risk of disease progression or death by 50%, the phase III ALCYONE trial has shown.
Maria-Victoria Mateos, MD, PhD
Jesus San Miguel, MD, PhD
The results were presented at the 59th American Society of Hematology (ASH) Annual Meeting & Exposition by Maria- Victoria Mateos, MD, PhD, Director of the Myeloma Unit at the University Hospital of Salamanca–IBSAL in Spain, and at a press briefing by senior investigator Jesus San Miguel, MD, PhD, Medical Director of the Clínica Universidad de Navarra–CIMA, IDISNA, Pamplona, Spain.1 They were also simultaneously published in The New England Journal of Medicine.2
Median progression-free survival had not been reached in the daratumumab arm, after 16.5 months of follow-up, and was 18.1 months with VMP. At 18 months, 71.6% of patients in the daratumumab-plus-VMP (D-VMP) arm were progression-free, compared with 50.2% of the VMP-alone arm—a 50% reduction in risk (hazard ratio [HR] = 0.50; P < .001), Dr. Mateos reported from this late-breaking trial.
“ALCYONE strongly supports D-VMP as a standard of care in transplant-ineligible newly diagnosed multiple myeloma,” Dr. Mateos said. “Daratumumab plus VMP reduced the risk of disease progression or death and induced significantly deeper responses. There were no new safety signals observed except for [a higher incidence of] infection events that resolved.”
“Monoclonal antibodies like daratumumab have already been approved for use in relapsed patients. Here, we are showing that the benefits extend to newly diagnosed patients as well,” Dr. San-Miguel said at the press briefing.
The VMP regimen is used primarily outside of the United States, whereas more regimens including both proteasome inhibitors and immunomodulatory drugs have taken their place in this country. It is possible, that the outcomes would be even better when adding this drug to bortezomib, lenalidomide (Revlimid), and dexamethasone (VRd) or carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd), myeloma experts said.
ALCYONE Details
ALCYONE ENROLLED 706 patients with newly diagnosed multiple myeloma, randomizing them to VMP alone or in combination with daratumumab, 16 mg/kg once weekly in cycle 1 and every 3 weeks in cycles 2 through 9. Beyond 9 months, the investigational arm continued daratumumab administration every 4 weeks until disease progression.
Baseline characteristics were similar between the two groups of patients, with their median age being 71 years and with 30% aged 75 and older. By the International Staging System, approximately 40% of patients had stage III disease, 40% had stage II, and 20% had stage I. High-risk cytogenetic profiles were observed in 17%.
Deeper Responses, More MRD Negativity
IN ADDITION TO the 50% reduced risk of disease progression at 18 months, at the 12-month assessment, 87% of patients remained alive and progression-free in the daratumumab group vs 76% for the VMP group. The risk of disease progression was reduced across all subgroups with daratumumab on board, Dr. Mateos said.
Objective response rates were also significantly increased with daratumumab, reaching 91% compared with 74% for standard treatment (P < .001). This included complete responses or better (ie, stringent complete response) in 43% vs 24% (P < .001) and very good partial responses or better in 71% vs 50%, respectively. The median duration of response was 21.3 months for VMP and was not yet reached in the daratumumab group, Dr. Mateos reported.
“Monoclonal antibodies like daratumumab have already been approved for use in relapsed patients. Here, we are showing that the benefits extend to newly diagnosed patients as well.”— Jesus San Miguel, MD, PhD
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Dr. San Miguel commented that the improved depth of response achieved with daratumumab led to the 50% reduction in the risk of disease progression or death, “and even more relevant is the fact that minimal residual disease (MRD)-negative rates were more than threefold higher in the daratumumab arm. We know MRD negativity is the most relevant marker for prognosis in multiple myeloma,” he said.
In the investigational arm, 22.3% were negative for MRD vs 6.2% in the VMP group (P < .001). Regardless of the treatment used, those with MRD-negative status had a lower risk of disease progression or death compared with MRD-positive patients, the investigators noted.
At the time of the analysis, there had been 45 deaths in the daratumumab group and 48 in the VMP arm. Eighty-seven percent of patients remained alive in both groups. Follow-up for long-term survival remains ongoing.
No New Safety Signals
THE MOST COMMON hematologic adverse events of grade 3/4 severity with the daratumumab combination vs VMP alone, respectively, were neutropenia (40% vs 39%), thrombocytopenia (38% vs 34%), and anemia (20% vs 16%). The most common grade 3/4 nonhematologic toxicities for daratumumab vs VMP, respectively, were peripheral sensory neuropathy (1% vs 4%), diarrhea (3% each), and pneumonia (11% vs 4%). Infusion-related reactions occurred in 28% of patients in the daratumumab group.
The rate of grade 3/4 infection was 23% for daratumumab compared with 15% for VMP alone, but infections leading to treatment discontinuation were limited to about 1% per arm.
“The treatment was very well tolerated. Infusion reactions occur during the first course and are usually grade 1 or 2,” Dr. San Miguel said. “A slightly higher incidence of infections and pneumonia was observed in the daratumumab arm, but few patients discontinued treatment, and only one patient per arm discontinued treatment due to pneumonia.”
Based on the ALCYONE data, a supplemental biologics license application was submitted to the U.S. Food and Drug Administration in November for daratumumab plus VMP in transplant-ineligible patients with newly diagnosed multiple myeloma. Daratumumab is also being studied as an add-on to more contemporary regimens.
Ongoing front-line studies based on daratumumab combinations with newer agents will help “establish, different standards of care with a monoclonal antibody up front, in order to facilitate treatment individualization,” Dr. San Miguel said. ■
DISCLOSURE: Dr. Mateos reported no conflicts of interest. Dr. San Miguel disclosed relevant relationships with Novartis, Takeda, Roche, Sanofi, Amgen, MSD, Bristol-Myers Squibb, Celgene, and Janssen.
REFERENCES
1. Mateos M-V, Meletios DA, Cavo M, et al: Phase 3 randomized study of daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) in newly diagnosed multiple myeloma patients ineligible for transplant (ALCYONE). 2017 ASH Annual Meeting. Abstract LBA-4. Presented December 12, 2017.
2. Mateos M-V, Meletios DA, Cavo M, et al: Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. December 12, 2017 (early release online).
