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The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended approval of daratumumab in combination with bortezomib, melphalan, and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.
Maria-Victoria Mateos, MD, PhD
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of daratumumab (Darzalex) in combination with bortezomib (Velcade), melphalan, and prednisone (VMP) for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT).
The recommendation is 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.
The European Commission will now review the CHMP recommendation and make a final decision on whether to approve daratumumab for this indication in the European Union.
“Multiple myeloma becomes harder to treat each time it returns, so the goal of initial therapy is to prevent the cancer from progressing for as long as possible,” lead ALCYONE investigator Maria-Victoria Mateos, MD, PhD, director of the Myeloma Unit at University Hospital of Salamanca-IBSAL Salamanca, Spain, said in a statement.
“Selecting the right treatment regimen for newly diagnosed patients is critical to their long-term survival, especially those who are transplant ineligible, so daratumumab could offer an important new standard of care in this indication,” added Mateos.
Data from the study were published in the New England Journal of Medicine and presented at the 2017 ASH Annual Meeting.1,2 In the ALCYONE 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.