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Adding daratumumab to VMP doubles the progression-free survival in patients with newly diagnosed, transplant ineligible multiple myeloma

Results of the phase III ALCYONE study demonstrate that adding the human IgGκ anti-CD38 monoclonal antibody daratumumab to VMP (bortezomib, melphalan, prednisone) leads to a doubling in the progression-free survival (PFS) in patients with transplant ineligible newly diagnosed multiple myeloma (NDMM). This PFS benefit was mainly driven by a significantly higher rate of complete responses (CR) and a tripling in the rate of patients achieving minimal residual disease (MRD) negativity. Daratumumab is a human IgGκ anti-CD38 monoclonal antibody with a direct on-tumour and multifaceted immunomodulatory mechanism of action.

VMP is one of the current standard treatment regimens for patients with NDMM. In patients with relapsed/refractory MM, combining daratumumab with lenalidomide and dexamethasone was shown to significantly prolong the PFS and increase the depth of response.1 The good results with daratumumab in the relapsed/refractory setting formed the basis to also evaluate this agent in treatment-naïve patients.

In the phase III, randomised ALCYONE study, 706 NDMM patients who were ineligible for high-dose chemotherapy followed by an autologous stem cell transplantation (ASCT), were randomised (1:1) to receive VMP with or without daratumumab. Patients in the study received up to a maximum of nine 6-week cycles of VMP (V: 1.3 mg/m2 SC on Days 1, 4, 8, 11, 22, 25, 29, 32 of cycle 1 and on Days 1, 8, 22, and 29 of cycles 2-9; M: 9 mg/m2 PO and P: 60 mg/m2 PO on days 1-4 of cycles 1-9). Patients in the experimental arm also received daratumumab until disease progression (16 mg/kg IV QW for cycle 1, Q3W for cycles 2-9 and Q4W for the cycles thereafter). The primary endpoint of the trial was PFS, with overall response rate (ORR), the rate of a very good partial response (VGPR) or better, the rate of patients with a CR or better, the rate of MRD-negativity, overall survival (OS), and safety as secondary study objectives.

The median age of patients in the study was 71 years, with 30% of patients being older than 75 years. The patient population was mainly white (85%) and a quarter of patients had an ECOG performance status of 2 (rest 0-1). One fifth of patients was classified as having an ISS stage I, 40% was ISS stage II and the remainder had ISS stage I disease. With respect to cytogenetics, 84% had standard risk cytogenetics, while 16% had a high-risk cytogenetic profile.

At the time of the analysis, patients had received a median of 12 and 9 treatment cycles with daratumumab-VMP and VMP, respectively. In total, 80% of patients in the daratumumab-VMP arm completed 9 treatment cycles while this was the case for 62% of patients treated with VMP. The median cumulative bortezomib doses were 46.9 mg/m2 with daratumumab-VMP and 42.2 mg/m2 with VMP.

After a median follow-up of 16.5 months, the median PFS for patients treated with VMP was 18.1 months, while the median was not yet reached for patients in the daratumumab-VMP arm (HR[95%CI]: 0.50[0.30-0.65]; p< 0.0001). The PFS benefit of daratumumab-VMP over VMP was consistently seen across all pre-specified subgroups, including age ≥75 years, ISS stage III, and high-risk cytogenetics. The ORR was also significantly better with daratumumab-VMP compared to VMP: 91% vs. 74% (p< 0.0001). A complete response, or stringent CR was seen in 24% of patients in the VMP arm, while this was 43% in patients receiving daratumumab-VMP (p< 0.001). A VGPR or better was seen in 50% of patients treated with VMP, while this objective was reached in 71% of patients receiving daratumumab-VMP (p< 0.001). With daratumumab-VMP, MRD negativity was reached in 22% of patients, a rate that was more than 3-fold higher than what was seen with VMP (6%). An analysis of the PFS in function of the MRD status revealed that patients obtaining MRD negativity had a lower risk of progression than patients where MRD was still detectable. At the time of the analysis, the OS data were still immature.

The most common (≥20%) all-grade treatment emergent adverse events (AEs) (daratumumab-VMP/VMP) were neutropenia (49.7%/52.5%), thrombocytopenia (48.8%/53.7%), anaemia (28.0%/37.6%), peripheral sensory neuropathy (28.3%/34.2%), upper respiratory tract infection (26.3%/13.8%), diarrhoea (23.7%/24.6%), pyrexia (23.1%/20.9%), and nausea (20.8%/21.5%). The most common (≥10%) grade 3/4 treatment-emergent AEs were neutropenia (39.9%/38.7%), thrombocytopenia (34.4%/37.6%), anaemia (15.9%/19.8%), and pneumonia (11.3%/4.0%). Only 1 patient in each arm discontinued treatment due to pneumonia. The rate of grade 3/4 infections was 23.1% with daratumumab-VMP as compared to 14.7% with VMP. Treatment discontinuations due to infections were seen in 0.9% and 1.4% of daratumumab-VMP and VMP treated patients, respectively.

In summary, the results of this Phase III trial, conducted in transplant ineligible NDMM patients show that adding daratumumab to one of the current first-line therapies for these patients leads to a significantly longer PFS and higher rates, of deep responses. No new safety signals were observed when daratumumab was combined with VMP. As such, ALCYONE strongly supports daratumumab-VMP as a standard of care for transplant-ineligible NDMM.


1. Meletios A, Dimopoulos MD, Oriol A, Nahi H, et al. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 2016; 375:1319-1331.
2. Mateos M-V, Dimopoulos M, 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 (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE). Presented at ASH 2017; Abstract #LBA-4.

Speaker Maria-Victoria Mateos


Prof. Maria-Victoria Mateos, MD, PhD,University Hospital of Salamanca/IBSAL, Salamanca, Spain


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