ASH 2018 | Long-term follow-up of the GEM05menos65 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).

Laura Rosiñol from the Hospital Clinic, Barcelona, Spain, presented the final results of the GEM05menos65 phase III trial for 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 trial led to the approval of the VTd triplet as an induction treatment prior to an ASCT by the European Medicines Agency in August 2013.

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

Study Design:

• Time period = April 6 2006–August 5 2009
• Number of patients = 386
• Age (median) = 56 vs 56 vs 57
• Gender (male) = 55% vs 54% vs 52%
• International Staging System (ISS) stage III = 20% vs 20% vs 18%
• High-risk cytogenetics [t(4;14); t(4;16); del17p] = 18 vs 17 vs 18
• Minimal residual disease (MRD) negative threshold = 10^-4
• Induction treatment arms:
  • Six 4-week cycles of VTD (bortezomib: 1.3 mg/m² intravenous [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/m² IV 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/m²)
• 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 vs 28 vs 32 months, P = 0.01
• Overall survival (OS) (median) = 128 vs 99 vs 93 months, P > 0.05
• PFS for high-risk patients significantly shorter than that of standard risk in the overall series = 15 vs 42 months, P = 0.001
• PFS comparison between high-risk vs standard risk patients per arm:
  • VTD arm = 23 vs 52 months: no significant difference, P = 0.125
  • TD arm = 7 vs 32 months: significant difference, P = 0.029
  • VBMCP/VBAD/B arm = 13 vs 38 months: significant difference, P = 0.027
• OS for high-risk patients significantly shorter than that of standard risk in the overall series = 38 vs 114 months, P = 0.0001
• OS comparison between high-risk vs standard risk patients per arm revealed a significant difference in all three groups:
  • VTD arm = 36 months vs not reached (NR), P = 0.0001
  • TD arm = 52 vs 113 months, P = 0.01
  • VBMCP/VBAD/B arm = 29 vs 93 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 vs TD, P = 0.03; VTD vs CT+V, P = 0.04; TD vs CT+V, P = 0.9
• MRD negativity after ASCT was associated with a longer PFS and OS compared to positive MRD
  • PFS = 55 vs 31 months, P < 0.0001
  • Median OS = NR vs 93 months, P = 0.001
• MRD negative patients after ASCT had similar PFS or OS independently of cytogenetic status -high-risk vs standard risk:
  • PFS = 33 vs 54 months, P = 0.335
  • OS = 105 months vs NR, 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 vs 31 months, P = 0.015
  • OS = 22 vs 105 months, P < 0.001
• Toxicities (grade 3–4):
  • Neutropenia = 10% vs 14% vs 22%
  • Thrombocytopenia = 8% vs 5% vs 6%
  • Infection = 21% vs 16% vs 15%
  • Gastrointestinal = 8% vs 25% vs 8%
• Peripheral neuropathy:
  • Grade 2 = 46% vs 8% vs 15%
  • Grade 3 = 12% vs 5% vs 7%
  • Grade 4 = 2% vs 0% vs 2%

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.