Multiple myeloma (MM) is a disease characterised by the neoplastic proliferation of plasma cells in the bone marrow, often resulting in extensive skeletal destruction with osteolytic lesions, osteopenia and/or pathologic fractures. Daratumumab (Darzalex®) is a human monoclonal IgG1κ antibody directed against CD38. In May 2018, the US Food and Drug Administration (FDA) approved daratumumab in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed MM who are ineligible for autologous stem-cell transplantation (ASCT), whereas daratumumab is not approved by the EMA for the assessed indication.

The ALCYONE trial assessed the efficacy and safety of the addition of daratumumab to bortezomib, melphalan and prednisone 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with stem-cell transplantation (SCT). The patients received either nine cycles of bortezomib, melphalan and prednisone alone or in combination with daratumumab until disease progression. Analyses showed that daratumumab group patients had a lower risk of disease progression or death than patients of the control group: hazard ratio was 0.50 (95% CI, 0.38–0.65; p < 0.001). The 12-month rate and the 18-month rate of progression-free survival (PFS) were prolonged in patients receiving daratumumab (86.7% and 71.6% respectively) compared to control group patients (76.0% and 50.2% respectively). The overall response rate (ORR) was higher in the daratumumab group (90.9%) than in the control group (73.9%); the rates of very good partial response (PR) or better and the rate of complete response (CR) or better were statistically significantly higher in patients receiving daratumumab than in control group patients: 71.1% vs. 49.7% and 42.6% vs. 24.4% respectively. Also, the rate of negative status for minimal residual disease (MRD) was more than three times as high in the patients of the daratumumab group (22.3%) as in the patients of the control group (6.2%). The median duration of response was 21.3 months in the control group, whereas it was not reached in the daratumumab group. The median OS was not reached in either group. At a median follow-up of 16.5 months, death had occurred in 45 of 350 patients in the daratumumab group and in 48 of 356 patients in the control group. The most frequent adverse events (AEs) of grade 3 or 4 were neutropenia, thrombocytopenia and anaemia, occurring in 39.9%, 34.4% and 15.9% of daratumumab group patients and in 38.7%, 37.6% and 19.8% of control group patients respectively. The rate of grade 3 or 4 infections (most commonly pneumonia) was higher in patients receiving daratumumab (23.1%) than in patients of the control group (14.7%); however, the rate of discontinuation of trial treatment due to infection was similar in both groups (0.9% in the daratumumab group vs. 1.4% in the control group). The rate of serious AEs was higher in patients receiving daratumumab (41.6%) than in control group patients (32.5%). Of the patients receiving daratumumab, 27.7% experienced infusion-related reactions (IRRs), mostly during the first infusion. 4.3% and 0.6% of daratumumab group patients had grade 3 and grade 4 IRRs respectively.

The addition of daratumumab to the standard combination treatment of bortezomib, melphalan and prednisone in untreated MM patients resulted in a statistically significant benefit with a lower risk of disease progression or death, prolongation of PFS across all subgroups and a higher rate of negative status for MRD. These benefits need to be weighed against higher rates of infections and the occurrence of IRRs among patients receiving daratumumab. Furthermore, the costs for a four-drug regimen and the required concurrent medication have to be considered. Since no further valid OS data can be expected and quality of life data is lacking, the clinical benefit of the assessed intervention remains to be proven. Finally, more robust evidence, particularly for the use of daratumumab as front-line treatment of MM is needed, as well as the investigation of appropriate and feasible combination regimens.