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ASH 2018 | Long-term follow-up of the GEM05menos65 clinical trial for newly diagnosed multiple myeloma

Dec 14, 2018

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).

Laura Rosiñolfrom the Hospital Clinic , Barcelona, Spain, presented the final results of the GEM05menos65 phase III trialfor NDMM patients under 65, around ten years after the last patient was recruited. Patients were randomized (1:1:1) to three arms of induction treatment [combination chemotherapy (CT) (VBMCP-VBAD) and bortezomib (CT+V); thalidomide and dexamethasone (Td); bortezomib, thalidomide, and dexamethasone (VTd)] prior to receiving an autologous stem cell transplant (ASCT). The results of this trial along with those of the GIMEMA-MMY-3006 trialled to the approval of the VTd triplet as an induction treatment prior to an ASCT by the European Medicines Agencyin August 2013.

Data are presented as VTd versus( vs) Td vsCT+V

Study Design:

  • Time period = April 6 2006–August 5 2009
  • Number of patients = 386
  • Age (median) = 56 vs56 vs57
  • Gender (male) = 55% vs54% vs52%
  • International Staging System (ISS) stage III = 20% vs20% vs18%
  • High-risk cytogenetics [t(4;14); t(4;16); del17p] = 18 vs17 vs18
  • Minimal residual disease (MRD) negative threshold = 10 - 4
  • Induction treatment arms:
    • Six 4-week cycles of VTD (bortezomib: 1.3 mg/m 2intravenous [IV] on days 1, 4, 8, and 11; thalidomide: 200 mg daily; dexamethasone: 40 mg on days 1–4 and 9–12); N = 130 patients
    • Six 4-week cycles of Td (thalidomide: 200 mg daily; dexamethasone: 40 mg on days 1–4 and 9–12); N = 127 patients
    • CT+V (4 cycles of alternating VBMCP and VBAD followed by two cycles of bortezomib: 1.3 mg/m 2IV on days 1,4,8, and 11 every 3 weeks); N = 129 patients
  • Duration of induction therapy = 24 weeks in all arms
  • Induction therapy in all three arms was followed by autologous stem cell transplant (ASCT) with high dose melphalan (200 mg/m 2)
  • ASCT was followed by a three-year maintenance treatment randomly distributed in three arms:
    • thalidomide/bortezomib (TV)
    • thalidomide (T)
    • alfa-2b-interferon (alfa2-IFN)

Key Data:

  • Median follow-up = 115 months
  • Progression-free survival (PFS) (median) = 52 vs28 vs32 months, P= 0.01
  • Overall survival (OS) (median) = 128 vs99 vs93 months, P> 0.05
  • PFS for high-risk patients significantly shorter than that of standard risk in the overall series = 15 vs42 months, P= 0.001
  • PFS comparison between high-risk vsstandard risk patients per arm:
    • VTD arm = 23 vs52 months: no significant difference, P= 0.125
    • TD arm = 7 vs32 months: significant difference, P= 0.029
    • VBMCP/VBAD/B arm = 13 vs38 months: significant difference, P= 0.027
  • OS for high-risk patients significantly shorter than that of standard risk in the overall series = 38 vs114 months, P= 0.0001
  • OS comparison between high-risk vsstandard risk patients per arm revealed a significant difference in all three groups:
    • VTD arm = 36 months vsnot reached (NR), P= 0.0001
    • TD arm = 52 vs113 months, P= 0.01
    • VBMCP/VBAD/B arm = 29 vs93 months, P= 0.01
  • MRD negative rates after ASCT (MRD available in 226/284 transplanted patients):
    • Overall series = 135/226 patients (60%)
    • VTD = 60/83 patients (72%)
    • TD = 27/50 (46%)
    • CT+V = 48/85 (56%)
    • VTD vsTD, P= 0.03; VTD vsCT+V, P= 0.04; TD vsCT+V, P= 0.9
  • MRD negativity after ASCT was associated with a longer PFS and OS compared to positive MRD
    • PFS = 55 vs31 months, P< 0.0001
    • Median OS = NR vs93 months, P= 0.001
  • MRD negative patients after ASCT had similar PFS or OS independently of cytogenetic status -high-risk vsstandard risk:
    • PFS = 33 vs54 months, P= 0.335
    • OS = 105 months vsNR, P= 0.322
  • MRD positive patients after ASCT with high-risk cytogenetics had significantly shorter PFS or OS than MRD positive standard risk patients:
    • PFS = 15 vs31 months, P= 0.015
    • OS = 22 vs105 months, P< 0.001
  • Toxicities (grade 3–4):
    • Neutropenia = 10% vs14% vs22%
    • Thrombocytopenia = 8% vs5% vs6%
    • Infection = 21% vs16% vs15%
    • Gastrointestinal = 8% vs25% vs8%
  • Peripheral neuropathy:
    • Grade 2 = 46% vs8% vs15%
    • Grade 3 = 12% vs5% vs7%
    • Grade 4 = 2% vs0% vs2%

Conclusions

The long-term follow-up of the GEM05menos65 phase III trial confirms that induction with VTd is superior to that of Td or CT+V in terms of PFS and supports the use of VTd as the standard of care for pre-transplant induction in patients with NDMM. Patients who achieved MRD negativity after ASCT treatment had similar PFS and OS, independent of cytogenetic status. Patients with high-risk cytogenetics who remained MRD positive post-transplant had an unfavorable prognosis.

References

Rosiñol L. et al.VTD (Bortezomib/Thalidomide/Dexamethasone) As Pretransplant Induction Therapy for Multiple Myeloma: Definitive Results of a Randomized Phase 3 Pethema/GEM Study. 2018 Dec 1; Oral Abstract #126: ASH 60th Annual Meeting and Exposition, San Diego, CA.