Bortezomib Plus Dexamethasone Followed by Escalating Donor Lymphocyte Infusions for Patients with Multiple Myeloma Relapsing or Progressing after Allogeneic Stem Cell Transplantation

Abstract

Multiple myeloma relapsing after allogeneic stem cell transplantation (alloSCT) has a poor outcome. To assess the safety and efficacy of bortezomib and dexamethasone (VD) combination followed by donor lymphocyte infusions (DLIs) in myeloma patients relapsing or progressing after alloSCT, a prospective phase II study was designed. The treatment plan consisted of three VD courses followed by escalated doses of DLIs in case of response or at least stable disease. Nineteen patients were enrolled with a median age of 57 years (range, 33 to 67); 14 patients were allografted from human leukocyte antigen-identical siblings and 5 from alternative donors. Sixteen of 19 patients received the planned treatment, but 3 patients did not: 2 patients because of disease progression and 1 refused. After the VD phase the response rate was 62%, with 1 complete remission, 6 very good partial remissions, 5 partial remissions, 2 patients with stable disease, and 5 with progressive disease. After the DLI phase, the response rate was 68%, but a significant upgrade of response was observed: 3 stringent complete remissions, 2 complete remissions, 5 very good partial remissions, 1 partial remission, 4 with stable disease, and 1 with progressive disease. With a median follow-up of 40 months (range, 29 to 68), the 3-year progression-free survival and overall survival rates were 31% and 73%, respectively. Neither unexpected organ toxicities, in particular severe neuropathy, nor severe acute graft-versus-host disease flares were observed. VD-DLIs is a safe treatment for multiple myeloma patients relapsing or progressing after alloSCT and may be effective.

Allogeneic Blood or Marrow Transplantation with Post-Transplantation Cyclophosphamide as Graft-versus-Host Disease Prophylaxis in Multiple Myeloma

“…In MM, maintenance therapy with lenalidomide following alloBMT has been associated with high rates of GVHD [59], but this may be associated with improved outcomes [60]. The use of bortezomib following alloBMT appears to be relatively safe [61], and high response rates following DLI suggest that proteasome inhibitors may be effective post alloBMT [62, 63]. Recent approvals for several novel agents, including monoclonal antibodies, may provide additional maintenance strategies to improve disease control rates.…”

Safe and effective use of outpatient non-myeloablative allogeneic stem cell transplantation for myeloma

“…Novel agents, in particular bortezomib and lenalidomide, have well documented potent synergistic activity with alloreactive T cells post allograft and may provide a platform for enhancing tumor control post allograft, particularly in those patients with high-risk disease in CR or with minimal residual disease on flow cytometry or PCR. 7, 8 The feasibility of this approach in post allo SCT relapse patients has been explored recently by two groups, where the introduction of lenalidomide following NMA allo SCT resulted in responses in over a third of patients, often however at the expense of acute GVHD. 9, 10 Balancing the potential to achieve disease control with lenalidomide in this setting against the risk of inducing or exacerbating acute GVHD remains a challenge.…”

Allogeneic transplantation in multiple myeloma – How, when or at all?

“…Bortezomib appears to be effective in association with allo, due to a GVHD preventive effect, while presumably still preserving the GVM effect [42][43][44]. Its additional antimyeloma effect makes the rationale apparent for using it upfront in the conditioning regimen and/or for consolidation and maintenance.…”

“…Eight of these patients obtained hematologic CR and 7 of them a molecular remission. DLI associated with chronic GVHD seemed in one study to improve PFS and OS [43]. Thus, DLI is effective in treatment of relapse and progression, but the risk of inducing severe GVHD has to be considered.…”

“…Its additional antimyeloma effect makes the rationale apparent for using it upfront in the conditioning regimen and/or for consolidation and maintenance. In one study [43] 19 patients who had relapsed following RICallo were treated with bortezomib plus dexamethasone followed by DLI. Sixty eight % responded, including 10 of them with CR.…”