Patients non-eligible for transplant

Updated results from the ALCYONE study demonstrate overall survival benefit with D-VMP versus VMP in patients with transplant-ineligible newly diagnosed MM

The Multiple Myeloma (MM) Hub was delighted to be present at the 61st American Society of Hematology (ASH) Annual Meeting & Exposition held in Orlando, FL, US, from 7–10 December 2019. On Monday 9th December, an oral abstract was presented by Maria-Victoria Mateos from the University Hospital of Salamanca/IBSAL, Salamanca, ES, entitled (Abstract #859): daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) in patients with transplant-ineligible newly diagnosed MM (NDMM): overall survival in Alcyone.1 This article is based on data presented at ASH and may supersede the data in the published abstract.

The primary analysis of the phase III ALCYONE study (median follow-up 16.5 months) has previously been published and a significant progression-free survival (PFS) benefit was observed with D-VMP versus VMP (hazard ratio [HR] for disease progression or death, 0.50; 95% confidence interval [CI], 0.38–0.65; p< 0.001) in patients with transplant-ineligible NDMM.2

ALCYONE study design
  • Patients: NDMM ineligible for high-dose chemotherapy and autologous stem cell transplantation due to age (≥ 65 years) or comorbidities
  • Treatment:
    • Randomization 1:1
    • Up to nine 6-week cycles of VMP (bortezomib 1.3mg/m2 subcutaneously on Days one, four eight, 11, 22, 25, 29, and 32 of Cycle one and Days one, 8, 22, and 29 of Cycles 2–9; melphalan 9mg/m2 orally and prednisone 60mg/m2 orally on Days 1–4 of Cycles 1–9) with or without daratumumab (16mg/kg intravenously once weekly for Cycle one, once every three weeks for Cycles 2–9, and once every four weeks for Cycles 10+ until disease progression)
  • Primary endpoint: PFS
  • Secondary endpoints: overall response rate (ORR), rate of complete response (CR) or better, rate of very good partial response or better, MRD-negativity rate (10–5 threshold), PFS on subsequent line of therapy (PFS2), overall survival (OS), and safety
Baseline characteristics
  • A total of 706 patients were enrolled:
    • D-VMP: n= 350
    • VMP: n= 356
  • Patient baseline characteristics were well balanced between treatment arms
  • Median age was 71 (range 40–93) years, and 29.9% of patients were ≥ 75 years of age
  • Out of 616 patients evaluated, 518 patients (84.1%) had standard cytogenetic risk and 98 patients (15.9%) had high cytogenetic risk (del17p, t[14;16], and/or t[4;14] positive)
Key results at a median follow-up of 40.1 months1
  • At the cutoff date of 24th June 2019:
    • All patients either discontinued or completed nine treatment cycles of VMP
    • Patients in the D-VMP arm continuing to receive daratumumab monotherapy: 146 patients (42%)
  • Median PFS was 36.4 months with D-VMP versus 19.3 months with VMP (HR, 0.42; 95% CI, 0.34–0.51; p< 0.0001)
  • Estimated 42-month PFS rate was 48% with D-VMP versus 14% with VMP
  • ORR: 91% with D-VMP (46% ≥ CR) versus 74% with VMP (25% ≥ CR)
  • MRD-negativity: 28% with D-VMP versus 7% with VMP
    • In the D-VMP arm, MRD-negativity rate increased with longer follow-up (22% at 16.5 months and 28% at 40.1 months)
    • Patients who achieved MRD-negativity had improved PFS, regardless of treatment arm
  • Median PFS2 was not reached with D-VMP versus 42.3 months with VMP (HR, 0.55; 95% CI, 0.43–0.71; p< 0.0001)
  • The median OS was not reached in either treatment arm. The estimated 42-month OS rate was 75% with D-VMP versus 62% with VMP (HR, 0.60; 95% CI, 0.46–0.80; p= 0.0003)
  • Median time to subsequent therapy: not reached in the D-VMP arm and 25.9 months in the VMP arm (HR, 0.41; 95% CI, 0.33–0.52; p< 0.0001)
  • No new safety concerns were identified with longer follow-up
  • Rate of discontinuation due to treatment-emergent adverse events (TEAEs):
    • D-VMP: 6.9%
    • VMP: 9.3%
  • Grade 5 TEAEs:
    • D-VMP: 6.9%
    • VMP: 5.6%
  • Most frequent AEs during maintenance with daratumumab monotherapy in patients in the D-VMP group were:
    • Upper respiratory tract infection: 19%
    • Bronchitis: 15%
    • Viral upper respiratory tract infection: 12%
    • Cough: 12%
    • Diarrhea: 10%
Conclusions
  • D-VMP continued to demonstrate a significant PFS benefit versus VMP, which was also maintained during the subsequent line of therapy
  • Responses with D-VMP continued to deepen over time from the primary analysis, with improvement in rates of ≥ CR and MRD-negativity
  • D-VMP significantly prolonged OS in patients with transplant-ineligible NDMM, with a 40% reduction in the risk of death versus VMP after a median follow-up of 40.1 months
  • The updated results of the ALCYONE study continue to support the addition of daratumumab to frontline treatment regimens in patients with transplant-ineligible NDMM
References
  1. Mateos M-V. et al., Daratumumab plus bortezomib, melphalan, and prednisone versus bortezomib, melphalan, and prednisone in patients with transplant-ineligible newly diagnosed multiple myeloma: overall survival in Alcyone; 2019 Dec 9; Abstract 859: ASH 61st Annual Meeting & Exposition, Orlando, FL
  2. Mateos M-V. et al., Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378:518–28. DOI: 10.1056/NEJMoa1714678
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