Maria-Victoria Mateos, MD, PhD, discusses updated findings from the ALCYONE trial in patients with newly diagnosed multiple myeloma.
Maria-Victoria Mateos, MD, PhD
Updated findings from the pivotal phase III ALCYONE study confirmed the significant progression-free survival (PFS) benefit with daratumumab plus bortezomib, melphalan, and prednisone(VMP) in patients with newly diagnosed multiple myeloma.
In initial findings from the open-label study, daratumumab (Darzalex) 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 PFS was 18.1 months in the VMP arm and was not yet reached for those treated with the daratumumab regimen.
Lead study author Maria-Victoria Mateos, MD, PhD, director of the Myeloma Unit at University Hospital of Salamanca-IBSAL Salamanca, Spain, presented the one-year follow-up findings during the 2018 ASH Annual Meeting, noting the median PFS for patients receiving daratumumab plus VMP had not been reached. In addition, the combination demonstrated a complete response rate of 45% and a manageable safety profile.
“The ALCYONE trial has right now a median follow-up of 28 months and we can confirm that daratumumab added to VMP is significantly superior to VMP, not only in terms of overall response rate and complete response rate, but also in terms of PFS,” said Mateos.
In an interview withTargeted Oncologyduring the 2018 ASH Annual Meeting, Mateos discussed the updated findings from the ALCYONE trial in patients with newly diagnosed multiple myeloma.
TARGETED ONCOLOGY:Can you give some background on this study?
Mateos:Multiple myeloma usually affects the elderly population. In fact, it's the second most frequent hematologic malignancy. Most patients with multiple myeloma are not eligible for autologous stem cell transplantation. Bortezomib plus melphalan and prednisone has been a standard of care that we have used for this population for many years. Daratumumab is an anti-CD38 monoclonal antibody that has shown to be very effective as a single agent and in combination with either bortezomib or lenalidomide in relapsed and refractory myeloma patients.
The rationale of this study was to combine VMP, a standard of care for elderly patients with newly diagnosed multiple myeloma, plus daratumumab. The Alcyone trial is a randomized phase III trial in which daratumumab plus VMP was compared with the standard of care, VMP, in a series of 706 newly diagnosed myeloma patients.
Patients in both arms received VMP or VMP plus daratumumab for 9 cycles. Beyond cycle 9, VMP therapy was stopped while the experimental arm continued receiving single-agent daratumumab once per month until disease progression. The primary endpoint of the study was progression-free survival (PFS). One year ago, the results were presented at the ASH meeting and published in theNew England Journal of Medicine. We had the opportunity to see how the addition of daratumumab to VMP significantly prolonged the median PFS. In fact, the median PFS was 18 months in the control arm and it was not reached in the experimental arm.
During this congress, what we have done is to update this series of patients with 1-year additional follow-up. We have confirmed the significant benefit in terms of PFS. The hazard ratio right now is at 0.45 and the median PFS for patients receiving daratumumab plus VMP has not been reached. In addition, we had the opportunity to see a plateau phase in the patients who continued on therapy receiving single-agent daratumumab. This is relevant because it confirms the robust data of maintenance with daratumumab single agent beyond daratumumab plus VMP.
In addition, the efficacy in terms of overall response rate and complete response rate are also very solid. In fact, when we add daratumumab to VMP, the complete response rate is approximately 45%, but also what is important is to evaluate the quality of the responses. Minimal residual disease (MRD) was evaluated in this study. MRD is an important marker predicting PFS and 1 year ago we had the opportunity to see how 22% of patients who receive daratumumab plus VMP achieved MRD-negativity. During this congress, and due to the effect of daratumumab as a single agent as part of maintenance, the MRD-negative rate increased to 27%, confirming the activity of single-agent daratmumab as maintenance after daratumumab/VMP.
The safety profile was acceptable 1 year ago, and 1 year later we have focused on the safety profile of daratumumab single agent, and really few patients had any hematologic or non-hematologic adverse events. In addition, overall survival (OS) data have not matured yet, but we have evaluated the PFS too as a surrogate marker for OS and there is a significant benefit for daratumumab VMP over VMP. Finally, I would include that these updated results that I presented during this congress clearly confirm the role of daratumumab plus VMP to be used in newly diagnosed myeloma patients not eligible for autologous stem cell transplantation and together with other trials that are also going to be presented during this congress, based on daratumumab plus VRD, cyclophosphamide, bortezomib, and dexamethasone, or lenalidomide and dexamethasone, I would say that the data is going to be a backbone that we are going to use in almost all newly diagnosed myeloma patients.
TARGETED ONCOLOGY:What other questions still need to be answered with this combination?
Mateos:I think we need maybe longer follow-up in order to confirm the benefit in OS, because the primary endpoint of the trial was PFS, but the benefit in OS is relevant. During this congress we have analyzed the PFS too and as a surrogate marker we have seen a significant benefit, so we can envision also a benefit in OS.
Another question that we can potentially also answer is as patients continue receiving daratumumab single agent as maintenance, we have to evaluate if additional patients can achieve MRD-negativity and how many patients are able to achieve sustained MRD-negativity and how this can translate into significant benefit, not only in terms of PFS, but also OS.
TARGETED ONCOLOGY:What are the key takeaway points?