EBMT 2018 | Efficacy and safety of bortezomib in allogeneic-transplant for high-risk relapsed MM

The MM Hub were delighted to attend the 44th Annual Meeting of the European Society for Blood and Marrow Transplantation held in Lisbon, Portugal, from 18–21 March 2018. On Monday 19 March 2018 the oral abstract session 4 was held. The session was moderated by Catarina Geraldes, from the University of Coimbra, Portugal and Tamás Masszi, from Semmelweis University, Budapest, Hungary.

The fourth talk of this session was presented by Jose Antonio Pérez-Simón, from the Department of Hematology, Hospital Universitario Virgen del Rocío (IBIS), Seville, Spain with the title: European myeloma network phase I trial on RIC allogeneic transplantation: an optimized program for high risk relapsed myeloma patients. The aim of this study was to evaluate the safety and efficacy of bortezomib used within the reduced intensity conditioning (RIC) regimen, as well as soon after allogeneic transplantation (allo trx) in high-risk and relapsed multiple myeloma (MM) patients. 

Bortezomib has been shown to specifically inhibit NFкβ, inducing a selective pro-apoptotic effect on allo-reactive T cells. Previous murine studies have shown that a combination of bortezomib and sirolimus (siro) has a synergistic effect, decreasing the production of pro-inflammatory cytokines, leading to an increased survival rate and could, therefore, be used for graft versus host disease (GvHD) prophylaxis.

Study design:

• Patients (pts) received:
  • Reduced intensity conditioning (RIC) at days -9 and -2 prior to transplantation (trx) – fludarabine and melphalan (FluMel) plus bortezomib (bort)
  • GvHD prophylaxis – Bort at 1.3mg/m² on days 1, 4 and 7 after trx, sirolimus (siro) from day 5 before trx and tacrolimus (TK) from day 3 prior to trx

Demographics:

• N = 25 patients (pts); 23 multiple myeloma (MM) pts and 2 plasma cell leukemia (PCL) pts
• Extramedullary (EMD) disease = 12/25 pts
• Median age = 53 years (40–69)
• Previous lines of treatment: Median (range) = 3 (1–5); 1 line = 3 pts; 2 lines = 2 pts; 3 lines = 8 pts; ≥ 4 lines = 12 pts; previous Bz = 25 pts; previous immunomodulatory drugs (IMiD) = 22 pts
• Previous autologous stem cell transplantation (ASCT) = 22 pts
• Cytogenetics: 17p = 6 pts; t(4;14) = 4 pts; 17p & t(4;14) = 1 pt; del 13q = 2 pts; t(11,14) = 1 pt; normal = 2 pts; others/unknown = 9 pts
• Disease status at transplant: Complete remission (CR) = 7 pts; Partial remission (PR) = 15 pts; Stable disease (SD) = 1 pt
• Progression/relapse = 2 pts
• Minimal residual disease (MRD) pre-Trx (positive) = 18 pts
• Donor status: matched related donor = 19 pts; matched unrelated donor (MURD) = 5 pts and mismatched unrelated donor (MMURD) = 1 pt
• Source of progenitor cells: bone marrow (BM) = 2 pts; peripheral blood (PB) = 23 pts
• Median age of donors (range) = 49 (19–77); male = 13 pts
• Median no of cells infused (range) = 5.8 (2.5–8.7)

Key Findings:

• N = 22 pts evaluable at day +100
• Clinical outcomes: Complete response (CR) = 15 pts (68%); Very good response rate (VGPR) = 1 pt (5%); Partial response (PR) = 6 pts (27%)
• Incidence of acute GvHD (aGvHD): grades 2-4 = 35%; grades 3-4 = 10%
• Non-relapse mortality (NRM) at 2 years = 16%
• Relapse-related mortality (RRM) = 13.5%
• Event-free survival = 30%
• OS at 2 years = 60%
• Pts maintained low levels of plasmocytoid dendritic cells (DCs)
• Pts displayed low levels of CD4⁺ naïve and central memory and high levels of CD4⁺ peripheral memory CD4⁺ T-cells
• Pts showed increased levels of CD56 bright fraction of natural killer (NK) cells compared to healthy controls
• All positive MRD pts relapsed (n = 7)

To conclude, the addition of bortezomib to a RIC based on fludarabine is safe, allowing good disease control after transplant. Additionally, the combination of bortezomib, sirolimus, and tacrolimus displayed a good toxicity profile with an incredible efficacy in terms of GvHD prevention. However, it is important to stress the need for maintenance therapy with the use of new drugs and transplant in earlier stages of the disease in order to improve outcome.