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 61^st American Society of Hematology (ASH) Annual Meeting & Exposition held in Orlando, FL, US, from 7–10 December 2019. On Monday 9^th 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 24^th 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