The European Commission has approved daratumumab for use in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.
Jan van de Winkel, PhD
The European Commission has approved daratumumab (Darzalex) for use in combination with bortezomib (Velcade), melphalan, and prednisone (VMP) for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.
The approval was based on the pivotal, open-label phase III ALCYONE study, in which daratumumab plus VMP demonstrated a 50% reduction in the risk of progression or death compared with VMP alone (HR, 0.50; 95% CI, 0.38-0.65; P <.001). The median progression-free survival (PFS) was 18.1 months in the VMP arm and was not yet reached for those treated with the daratumumab regimen. Follow-up remained ongoing for overall survival at the 16.5-month assessment.
“Approved in this indication in the United States since early May, Darzalex in combination with bortezomib, melphalan and prednisone will now become an option for newly diagnosed multiple myeloma patients in Europe,” Jan van de Winkel, PhD, chief executive officer of Genmab, which codevelops daratumumab with Janssen, said in a statement. “We are very pleased that many more patients in need will have the opportunity for treatment with this regimen and we look forward to seeing this combination launched in Europe,” added van de Winkel.
Data from the ALCYONE study were published in the New England Journal of Medicine and presented at the 2017 ASH Annual Meeting.1,2 In the trial, 706 with newly diagnosed multiple myeloma were randomized to receive VMP alone (n = 356) or in combination with daratumumab (n = 350). VMP was administered at standard doses and daratumumab was added at 16 mg/kg once weekly in cycle 1 and every 3 weeks in cycles 2 through 9. Beyond month 9 in the investigational arm, daratumumab was continued every 4 weeks until disease progression.
Baseline characteristics were similar between the two groups of patients. In the daratumumab arm, the median age was 71 years and 30% were ≥75 years of age. The ECOG performance status was 0 (22%), 1 (52%), and 2 (26%). Ten percent of patients had light chain myeloma, with the remainder being IgG (64%) and IgA (21%). The most common ISS stages were III (41%) and II (40%). Seventeen percent of patients were high-risk by cytogenetic profile.
At the 12-month assessment, 87% of patients remained alive and progression-free in the daratumumab group versus 76% for VMP. The 18-month PFS rate was 71.6% (95% CI, 65.5%-76.8%) with daratumumab plus VMP compared with 50.2% (95% CI, 43.2%-56.7%) for VMP alone. PFS was improved with the addition of daratumumab across subgroups.
The objective response rate (ORR) with the daratumumab regimen was 90.9% compared with 73.9% in the control arm (P<.001), this included a complete response (CR) or better for 42.6% of patients in the daratumumab arm compared with 24.4% in the VMP alone group (P <.001). The very good partial response or better rate was 71% for daratumumab versus 50% for VMP alone. The median duration of response was 21.3 months for VMP and was not yet reached in the daratumumab group.
Significantly more patients tested negative for minimal residual disease (MRD) in the daratumumab group versus VMP alone. In the investigational arm, 22.3% were negative for MRD versus 6.2% in the VMP group (P <.001).
The most common hematologic adverse events (AEs) of grade 3/4 severity with the daratumumab combination versus VMP alone, respectively, were neutropenia (39.9% vs 38.7%), thrombocytopenia (37.6% vs 34.4%), and anemia (19.8% vs 15.9%). The most common grade 3/4 nonhematologic AEs for daratumumab versus VMP, respectively, were peripheral sensory neuropathy (1% vs 4%), diarrhea (3% each), and pneumonia (11% vs 4%). Infusion-related reactions occurred in 27.7% of patients in the daratumumab group.
The rate of grade 3/4 infection was 23.1% for daratumumab compared with 14.7% for VMP alone. Infections led to treatment discontinuation for 1.4% of patients in the VMP group and 0.9% in the daratumumab group. Serious AEs occurred in 41.6% of patients in the daratumumab arm and for 32.5% of patients in the VMP group. AEs led to discontinuation for 4.9% of patients in the daratumumab group versus 9.0% for the control arm.