ASH 2018 | Update on the Forte trial: a phase III clinical trial for newly diagnosed multiple myeloma

The 60th American Society of Hematology (ASH) Annual Meeting was held in San Diego, California, from 1–4 December 2018. On Saturday 1 December 2018, an oral abstract session was held entitled: Clinical Autologous Transplantation: Results: Multiple Myeloma: Upfront Autologous Transplantation, which focused on updates of advanced clinical trials for newly diagnosed multiple myeloma (NDMM).

Francesca Gay from the GIMEMA, European Myeloma Network, Italy, presented an update of the FORTE trial. This trial was designed for patients with NDMM, eligible for an autologous stem cell transplant (ASCT).

The primary endpoint of the trial was to examine the safety and efficacy of induction with carfilzomib (K) combined with cyclophosphamide (C) and dexamethasone (d) (KCd) followed by ASCT and consolidation with KCd (KCd-ASCT-KCd) versus (vs) induction with carfilzomib (K) combined with lenalidomide (R) and dexamethasone (d) (KRd) followed by ASCT and consolidation with KRd (KRd-ASCT-KRd) or only 12 cycles of KRd (KRd12) without ASCT. Prior to ASCT, patients received 200 mg/m² melphalan treatment (MEL200-ASCT).

Results from this presentation focused on secondary outcomes that were the rate of pre-maintenance response (stringent complete response [sCR]) and minimal residual disease (MRD) negativity, as well as safety (incidence of grade 3/4 adverse events [AEs]).

Study Design:

• Number of NDMM patients = 474
• Age = ≤ 65 years
• Randomization = 1:1:1
• Treatment arms:
  • KRd-ASCT-KRd (n = 158 patients): four 28-day cycles with KRd induction (carfilzomib: 20/36 mg/m²intravenous (IV), days 1,2,8,9,15,16; lenalidomide: 25 mg orally, days 1–21; dexamethasone: 20 mg orally, days 1,2,8,9,15,16), followed by MEL200-ASCT and four KRd consolidation cycles
  • KRd12 (n = 157 patients)
  • KCd-ASCT-KCd (n = 159 patients): four 28-day induction cycles with KCd (carfilzomib: 20/36 mg/m²IV, days 1,2,8,9,15,16; cyclophosphamide: 300 mg/m², days 1,8,15; dexamethasone: 20 mg, days 1,2,8,9,15,16) followed by MEL200-ASCT and four KCd consolidation cycles
• After each treatment, patients were randomized to maintenance with lenalidomide (R) alone or lenalidomide plus carfilzomib (KR) until appearance of any sign of disease progression or intolerance
• Centralized MRD (8-color second generation flow cytometry, sensitivity 10^-5) was performed in patients achieving ≥very good partial response (VGPR)

Key Data:

Results are presented as KRd-ASCT-KRd vs KRd12 vs KCd-ASCT-KCd

• Median follow-up = 20 months
• During treatment depth of response improved in all three arms
• Rates of pre-maintenance response:
  • sCR: 44% vs 43% vs 32% (KRd-ASCT-KRd vs KCd-ASCT-KCd, P = 0.047; KRd12 vs KCd-ASCT-KCd, P = 0.028)
  • ≥ CR + unconfirmed CR (missing immunofixation confirmation): 60% vs 61% vs 47%
  • ≥ VGPR: 89% vs 87% vs 76% (KRd-ASCT-KRd vs KCd-ASCT-KCd, P = 0.002; KRd12 vs KCd-ASCT-KCd, P = 0.008)
• Rates of pre-maintenance MRD negativity: 58% vs 54% vs 42% (KRd-ASCT-KRd vs KCd-ASCT-KCd, P = 0.009, odds ratio [OR] = 2.02; KRd12 vs KCd-ASCT-KCd, P = 0.042, OR = 1.73)
• Patients achieving extended (obtained ≥ 6 months apart) MRD negative status: 82% vs 78% vs 88%
• Treatment-related grade 3–4 adverse events (AEs) (without considering those related to ASCT):
  • Neutropenia: 17% vs 11% vs 11%
  • Thrombocytopenia: 8% vs 8% vs 6%
  • Infections: 10% vs 13% vs 9%
  • Dermatologic AEs: 6% vs 13% vs 1%
  • Increase in liver enzymes: 8% vs 10% vs 1%
  • Hypertension: 3% vs 8% vs 3%
• Discontinuation due to AEs: 8% vs 8% vs 7%

Conclusions

The updated results of the FORTE trial show that the treatment was well tolerated. KRd-ASCT-KRd and KRd12 significantly improved rates of sCR, VGPR and MRD negativity compared to KCd-ACST-KCd. These rates were similar between the KRd-ASCT-KRd and KRd12 arms. Longer follow-up of participants will allow to evaluate progression-free survival and overall survival rates.