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Daratumumab plus Standard of Care Improves Overall Survival in ALCYONE Trial

Conference Correspondent  - ASH 2019 MM

In the phase 3 ALCYONE trial of patients with transplant-ineligible, newly diagnosed multiple myeloma, the addition of daratumumab to bortezomib, melphalan, and prednisone (D-VMP) continues to demonstrate a significant progression-free survival (PFS) benefit, in addition to a prolonged overall survival (OS) benefit, when compared with bortezomib, melphalan, and prednisone (VMP) alone.

Now, after a median follow-up of 40.1 months, updated survival data reveal a median PFS of 36.4 months with D-VMP versus 19.3 months with VMP (P <.0001; hazard ratio, 0.42). The estimated 42-month OS rate was 75% with D-VMP versus 62% with VMP, with a significant benefit for OS observed for D-VMP versus VMP alone (P = .0003). Median OS was not reached in either group and follow-up is ongoing.

“For the first time, we demonstrate that the addition of daratumumab to bortezomib, melphalan, and prednisone prolongs overall survival in patients with transplant-ineligible newly diagnosed multiple myeloma, with a 40% reduction in the risk of death versus [bortezomib, melphalan, and prednisone] alone, after a median follow-up of 40 months,” said presenting author Maria-Victoria Mateos, from University Hospital of Salamanca/IBSAL, in Salamanca, Spain.

As previously reported, after a median follow-up of almost 30 months, D-VMP reduced the risk of disease progression or death by 57% versus VMP alone, with a 24-month PFS rate of 63% in the D-VMP group and 36% in the VMP group. This PFS benefit was observed regardless of patient age and was maintained during the subsequent line of therapy in these patients.

Together with the phase 3 MAIA study, which established the benefit of adding daratumumab to lenalidomide and dexamethasone, these findings continue to support the addition of daratumumab to frontline treatment regimens in patients with transplant-ineligible, newly diagnosed multiple myeloma.

Daratumumab is a human, CD38-targeting, IgG1κ monoclonal antibody with direct antitumor effects and an immunomodulatory component that has recently led to survival improvements in patients with multiple myeloma when added to standard-of-care regimens. These data confirm the OS benefit of adding daratumumab to standard of care in newly diagnosed, transplant-ineligible patients.

In the trial, 706 patients from 25 countries with newly diagnosed multiple myeloma who were ineligible for high-dose chemotherapy and autologous stem-cell transplantation due to age (≥65 years) or comorbidities were randomized 1:1 to either D-VMP (N = 350) or VMP (N = 356). The median age was 71 years, approximately 30% of patients were over 75 years of age, and the majority of patients had an Eastern Cooperative Oncology Group performance status of 0-1. Patients in the D-VMP and VMP arms, respectively, were International Staging System stage I (20%, 19%), stage II (40%, 45%), and stage III (41%, 36%), and classified as having high cytogenetic risk (17%, 15%).

Overall response rates at primary and updated analysis with D-VMP versus VMP did not change, and remained at 91% and 74%, respectively. However, the quality of responses deepened over time with longer follow-up, with 46% of patients achieving complete response at 40 months, compared with 43% at 16.5 months.

Patients who received D-VMP also had significantly higher rates of minimal residual disease (MRD)-negativity: 28% versus 7% at the time of updated analysis. Regardless of treatment arm, MRD-negative patients saw significantly improved PFS and OS. “However, when we evaluated the proportion of patients who achieved MRD-negativity, at the primary as well as at the updated analysis, D-VMP was always superior to VMP,” she said. MRD-negativity was also more sustained with D-VMP, with 14% of patients still MRD-negative at 1 year, compared with 3% in the VMP arm.

At the clinical cutoff date of June 24, 2019, all patients had either discontinued or completed 9 treatment cycles of VMP, but 146 (42%) patients in the D-VMP group continue to receive daratumumab monotherapy in cycle 10 and beyond (38% of D-VMP patients have discontinued study treatment, mainly due to progressive disease).

Median time to subsequent therapy was not reached for the D-VMP group, and was 25.9 months for the VMP group. No new safety concerns were identified, and rates of discontinuation due to treatment-related adverse events were 6.9% and 9.3% in the D-VMP and VMP arms, respectively.

“This first report of an OS benefit with daratumumab continues to support the use of daratumumab-containing regimens for the treatment of patients with multiple myeloma,” Dr Mateos concluded.


Mateos M, et al. ASH Abstract 859.

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Last modified: December 10, 2019