Mateos MV, et al. ASH 2017:LBA-4

A phase III randomized study of daratumumab with VMP versus VMP alone in newly diagnosed MM patients who are ineligible for transplant

Background

In the VISTA study, the addition of bortezomib to melphalan and prednisone (VMP) improved efficacy, but also increased toxicity in newly diagnosed multiple myeloma (NDMM) patients.1 Subsequent trials optimized VMP by reducing toxicity while maintaining efficacy.2,3 In a phase I study, the addition of daratumumab to VMP (D-VMP) was well tolerated in transplant-ineligible NDMM patients.4 Results from ALCYONE, the first phase III study to evaluate daratumumab in transplant-ineligible NDMM patients, were presented at ASH 2017.5

Study design

  • In the ALCYONE study, patients were randomized 1:1 between VMP and D-VMP.
  • Key eligibility criteria included:
    • Transplant-ineligible NDMM;
    • An Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2;
    • Creatinine clearance ≥40 mL/min; and
    • No peripheral neuropathy of grade ≥2.
  • Patients were stratified by International Staging System (ISS [I, II, III]), region (Europe vs. other), and age (<75 vs. ≥75 years).
  • The primary endpoint was progression-free survival (PFS).
  • Secondary endpoints included overall response rate (ORR), rate of very good partial response or better (≥VGPR), rate of complete response or better (≥CR), minimal residual disease (MRD) negativity, overall survival (OS), and safety.

Study design

Key findings

Baseline characteristics and disposition

  • The baseline characteristics were well balanced between the two arms.
  • The median age was 71 years, with the majority of patients being 65–74 years old.
  • Of the patients with available cytogenetic data, 15% in the VMP arm and 17% in the D-VMP arm had high-risk disease.
  • About half the patients in each arm had an ECOG PS of 1 (49% in VMP and 52% in D-VMP).
  • In the VMP and the D-VMP arms, respectively, 19% and 20% of patients were ISS stage I, 45% and 40% were ISS stage II, and 36% and 41% were ISS stage III.
  • The interim analysis was conducted after 231 PFS events.
  • Median follow-up was 16.5 months (range: 0.1–28.1).
  • At the clinical cut-off date, 17 patients (5%) in the VMP arm and 246 patients (71%) in the D-VMP arm were still on treatment.
  • Patient disposition is outlined on Table 1.

Table 1. Patient disposition

Efficacy

  • There was a 50% reduction in the risk of progression or death in patients receiving D-VMP when compared to those receiving VMP.
  • The median PFS was not reached in the D-VMP arm and was 18.1 months in the VMP arm (HR = 0.50, 95% CI: 0.38–0.65; p <0.0001). (Figure 1)
  • D-VMP prolonged PFS across all subgroups analyzed when compared with VMP, including age, region, and ISS staging.
  • The ORR was significantly improved with D-VMP when compared with VMP (91% vs. 74%; p <0.0001). (Figure 2)
  • D-VMP also led to significantly higher ≥VGPR and ≥CR rates as well as a >2-fold increase in rate of stringent CR when compared with VMP.
  • The median duration of response was not reached in the D-VMP arm and was 21.3 months in the VMP arm.
  • The MRD-negativity rate was significantly improved with D-VMP when compared with VMP (22% vs. 6%; p <0.0001).
  • There was a lower risk of progression or death in all MRD-negative patients.
  • The median OS was not reached in either treatment arm.

Figure 1. Progression-free survival

Figure 2. Overall response rate

Safety

  • The most common treatment-emergent adverse events (TEAEs) are presented in Table 2.
  • A total of 19 patients from each arm died due to TEAEs.
  • Serious adverse events (SAEs) were seen in 115 patients (33%) in the VMP arm and in 132 patients (38%) in the D-VMP arm.
  • The most common SAEs are presented in Table 3.
  • A total of 96 patients (28%) in the D-VMP arm experienced infusion-related reactions (IRRs).
  • Grade 3 and 4 IRRs occurred in 15 (4%) and 2 (1%) of patients, respectively, while no grade 5 IRRs were reported.
  • Most IRRs occurred during the first infusion.
  • Five patients (1.4%) discontinued daratumumab due to IRRs.
  • Montelukast was allowed as additional premedication and was used in <5% of patients.

Table 2. Most common treatment-emergent adverse events

Table 3. Most common severe adverse events

Key conclusions

  • In this first phase III randomized study with daratumumab in NDMM patients, D-VMP reduced the risk of progression or death by 50%.
  • D-VMP induced significantly deeper responses, including a >3-fold higher MRD-negative rate.
  • No new safety signals were observed except for higher infection events that eventually resolved.
  • ALCYONE strongly supports D-VMP as a standard of care in transplant-ineligible NDMM patients.

References 1. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Eng J Med 2008;359(9):906–17. 2. Mateos MV, Oriol A, Martínez-López J, et al. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol 2010;11(10):934–41. 3. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol 2010;28(34):5101–9. 4. Mateos MV, Moreau P, Comenzo R, et al. An open-label, multicenter, phase 1b study of daratumumab in combination with pomalidomide-dexamethasone and with backbone regimens in patients with multiple myeloma. EHA Congress Abstracts 2015:P275. 5. Mateos MV, Dimopoulos MA, 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). ASH Annual Meeting Abstracts 2017:LBA-4.