EHA 2019 | Results of the phase II CARFI trial: Carfilzomib for ASCT induction & maintenance in RRMM

On Sunday 16  June at the 24^th Congress of the European Hematology Association (EHA), Henrik Gregersen from Aalborg University Hospital, Aalborg, DK, presented the results of the CARFI phase II trial on behalf of the Nordic Myeloma Study Group (NMSG).¹

The current standard of care following autologous stem cell transplant (ASCT) for patients with relapsed or refractory multiple myeloma (RRMM) is lenalidomide maintenance. Preliminary results from a small phase I/II trial revealed that carfilzomib maintenance led to a 12-month progression-free survival (PFS) rate of 66.7% and a 12-month overall survival (OS) of 88.1%, indicating the potential benefit of carfilzomib in this setting.²

The open-label, randomized study (NCT025724921) investigated the efficacy and safety of carfilzomib as part of induction and maintenance therapy (with dexamethasone) for salvage ASCT, in patients with RRMM. There were dual primary endpoints of the trial. Firstly, the comparison of the time-to-progression (TTP) after salvage ASCT plus carfilzomib-based induction versus TTP after high-dose melphalan with ASCT. Secondly, comparison of TTP between RRMM patients receiving carfilzomib plus dexamethasone versus observation after salvage ASCT.

Study design & baseline characteristics

• N=200 patients with RRMM were enrolled. Patients with no previous carfilzomib exposure or relapse <1 year after ASCT were excluded from the study
• Dosing:
  • Induction: four 28-day cycles of carfilzomib (Car) + cyclophosphamide (Cy) + dexamethasone (Dex):
    • Car: intravenously 20mg/m² → 36mg/m² on Days 1, 2, 8, 9, 15, 16
    • Cy: orally 300mg/m² on Days 1, 8, 15
    • Dex: orally 20mg on Days 1, 2, 8, 9, 15, 16
  • Conditioning:
    • Car: 27mg/m² on Day -2, -1
    • Melphalan (mel): intravenously 200mg/m² on Day -2
  • Maintenance: two months after ASCT patients were 1:1 randomized to the following:
    • Observation (n=86)
    • Car+Dex (n=82):
      • Car: intravenously 27mg/m² → 56mg/m² every second week
      • Dex: orally 20mg every second week
    • Randomization was stratified according to:
      • Relapse 1–2 years or >2 years after ASCT
      • International Staging System (ISS) stage
      • Standard or high-risk cytogenetics
    • Table 1. Key baseline characteristics:

MM, multiple myeloma
Baseline characteristic	Total cohort (N=200)
Median age (range)	62 (56–66)
Time from MM diagnosis (range)	41.3 (30.0–58.4)
Bone disease	83%
Performance status I–II	91.5%
High-risk cytogenetics	19.5%

 Key findings

Induction/ASCT phase

• Median TTP (range):
  • After high-dose mel + ASCT: 33.2 (30.8–37.7) months
  • After Car+Cy+Dex plus salvage ASCT: 28.1 (25.1–31.5) months

Maintenance/Observation phase

• Median TTP (range):
  • With observation: 18.9 (14.3–23.3) months
  • With Car+Dex maintenance: 25.1 (24.4–not reached)
  • Comparison: log-rank p=0.006

Safety

Induction/ASCT phase (n=200)

• Patients discontinuing treatment at this stage: 16%
• Main reasons for discontinuation:
  • Adverse events (AEs) of any kind: 4.5%
  • Disease progression: 4%
  • Consent withdrawal: 3.5%

Maintenance phase (Car+Dex; n=82)

• Patients discontinuing treatment at this stage: 34.1%
• Main reasons for discontinuation:
  • Disease progression: 24.4%
  • AEs: 6.1%
  • Consent withdrawal: 3.7%
• 47 serious AEs (SAEs) occurred in 24 patients:
  • Infections: 35 events
  • Miscellaneous: 9 events
  • Cardiac & pulmonary: 3 events

Observation phase (n=86)

• Patients discontinuing treatment at this stage: 36%
• Main reasons for discontinuation:
  • Disease progression: 34.9%
  • Consent withdrawal: 1.2%
• 26 SAEs occurred in 18 patients:
  • Infections: 21 events
  • Miscellaneous: 1 event
  • Cardiac & pulmonary: 4 events

 Conclusions

The results of the phase II CARFI trial indicate that maintenance therapy with Car+Dex following salvage ASCT, prolongs TTP for patients with RRMM but also is associated with a higher infection risk. No difference was observed in TTP between patients who received salvage ASCT with Car+Cy+Dex induction versus the ones receiving high-dose melphalan with ASCT.