Allogeneic Hematopoietic Cell Transplantation Using Fludarabine, Melphalan and Bortezomib (Flu/Mel/Vel) Conditioning for Consolidation of VGPR or CR in Myeloma

Background:

The role of allogeneic hematopoietic cell transplantation (HCT) in multiple myeloma for consolidation of initial response in the era of novel agents has not been defined. Therefore, we conducted a phase 2 study of allogeneic HCT in MM patients achieving at least very good partial response (VGPR) after initial therapy.

Methods:

Seventeen MM patients with first VGPR or complete remission (CR) received allogeneic HCT between 01/2010 and 04/2013 at Moffitt Cancer Center (NCT 00948922). Eligible patients were age ≤ 60and have suitable HLA-matched donors. All patients received either bortezomib or lenalidomide (or both) based induction. Three patients (18%) underwent autologous HCT with melphalan plus bortezomib conditioning (MEL 200 plus bortezomib 1.3 mg/m²) after induction for cytoreduction. Conditioning regimen before allogeneic HCT consisted of fludarabine 30 mg/m² x 4 days and melphalan 70 mg/m² x 2 days followed by bortezomib 1.3 mg/m² (Flu/Mel/Vel). GVHD prophylaxis was tacrolimus plus either methotrexate (n=9), or mycophenolate mofetil (n=4), or sirolimus (n=4). No maintenance therapy was prescribed.

Results:

The median age at transplant was 51 (25 – 57) years. Seven patients (41%) have high-risk cytogenetics/FISH. Disease status at the time of allogeneic HCT was VGPR (n=8), CR (n=3), or stringent CR (n=6). All patients received unmanipulated peripheral blood stem cell grafts from HLA-matched sibling donors (n=7) or 8/8 HLA-matched unrelated donors (n=10). Neutrophil engraftment was achieved at a median of 14 (11 - 18) days and platelet engraftment with a median of 17 (13 - 21) days. Best responses after allogeneic HCT were CR (n=2), sCR (n=13), and disease progression (n=2). The 2-year progression-free survival estimate is 80% (95%CI: 51 – 98) for standard-risk and 51% (95%CI: 15 – 87) for high-risk, respectively. With a median follow up of 18 (3 - 43) months, the 2-year overall survival estimate is 88% (95%CI: 68 – 99). The cumulative incidence of non-relapse mortality was 6% (95%CI: 0.0 – 22) at 100 days and 13% (95%CI: 1 – 34) at 1 year, respectively. The cumulative incidence of grades 2-4 acute GVHD at day 100 was 41% (95% CI: 20 – 65) and the cumulative incidence of moderate to severe chronic GVHD at 1 year was 8.0% (95% CI: 0.0 – 29).

Conclusions:

These results indicate that allogeneic HCT for MM in VGPR or CR as consolidation achieves favorable disease control. The study is ongoing to assess long-term safety of this modality. A multicenter trial is planned to evaluate the utility of allogeneic HCT in high-risk MM.