In pursuit of the allo-immune response in multiple myeloma: where do we go from here?

Abstract

AlloSCT is a potentially curative procedure for haematological malignancies and marrow failure syndromes. However, unlike leukaemia and lymphoproliferative disorders, AlloSCT has yet to find its place in the clinical management of patients with multiple myeloma. AlloSCT in multiple myeloma is associated with a high procedurerelated mortality (TRM up to 35%) when full-intensity conditioning is used and only up to 36% of cases show long-term disease-free survival. The introduction of reduced intensity conditioning AlloSCT, more recently following an autologous SCT, has reduced the TRM to o20%, but there is an associated increased relapse risk. The use of donor lymphocyte infusions and novel biological agents (thalidomide, bortezomib), alone or together, can be effective in relapsed and even persistent disease post-AlloSCT. Thus, in pursuit of the putative graft-versus-myeloma effect, we need to consider the whole patient management pathway both preceding (depth of response to novel agents) and post-AlloSCT, to minimize the toxicity while harnessing the adoptive immunotherapy effect. This review sets out what we have learned to date from the clinical research studies in this area, examines concepts for improving the outcomes of AlloSCT and proposes a potential direction of clinical investigation to maximize the effect of AlloSCT in multiple myeloma.

Downregulation of myeloma-induced ICOS-L and regulatory T cell generation by lenalidomide and dexamethasone therapy

“…In myeloma, a malignancy of mature B-cells, both dysfunctional effector responses and augmented regulatory cell compartments have been described [1,10,[29][30][31]. To date, attempts to overcome this have been largely limited to the adoptive immunotherapeutic effect of an allogeneic stem cell transplant, which though effective, entails inherent procedure-related toxicity which limits its suitability for the majority of myeloma patients [32]. As such, an alternative immunotherapeutic strategy is required and thus a re-examination of the defined immune defects is warranted.…”

Hematopoietic stem cell transplantation for multiple myeloma beyond 2010

“…With the current data, Allo-RIC from either related or unrelated donors seems the most promising allogeneic approach, but there may still be a role for myeloablative allografting in selected patients (ie, younger patients with poor cytogenetics). 101 Who are the patients most likely to benefit from Allo-RIC?…”

Evolution or revolution in multiple myeloma therapy and the role of the UK

“…14,15,16 Allogenic transplantation (allo-SCT) has been performed in a small proportion of patients throughout this period but the potential benefits were marred by regimen-related toxicity and graft-versus-host disease in the pursuit of the putative graft-versus-myeloma effect. 17,18 However a limited number of studies have now been reported showing that the benefits of allo-SCT may be obtained by combining a reduced-intensity allo-SCT with a prior ASCT (auto-allo) thus reducing the transplant-related mortality, although benefit for the auto-allo group only became obvious after five-year followup. 18,19 It is of interest that only now are we closer to harnessing a targeted immunotherapy-based therapeutic strategy in myeloma with the evolution of CAR T-cells and bi-specific T-cell engager (BiTE) technology in MM.…”