Capturing Alloreactivity in Multiple Myeloma

Gordon Cook
US Hematology, 2009;2(1):45-8
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Abstract

Allogeneic stem cell transplantation (alloSCT) has been utilised in the management of both malignant and non-malignant haematological disorders for several decades and has established its role in producing long-term remissions. In the context of multiple myeloma (MM), compared with conventional therapies alloSCT induces the highest rate of remissions, resulting in long-term disease-free survival in over 30% of patients. However, it is associated with the highest rate of treatment-related mortality of all the interventions for MM. Following the introduction of new biological agents for the management of MM, the question of what role alloSCT has in MM is raised. This article aims to review where we are with alloSCT in MM, drawing from our experience thus far to plan the future role of alloSCT if we are to capitalise on a potential donor antimyeloma immune therapeutic effect.
Keywords
Allogeneic stem cell transplantation, multiple myeloma, adoptive immunotherapy, immunomodulatory agents
Disclosure The author has no conficts of interest to declare.
Received: March 27, 2009 Accepted June 23, 2009
Correspondence: Gordon Cook, MBChB, PhD, FRCP, FRCPath, FRCPI, Director, Blood and Marrow Transplantation, St James’s Institute of Oncology, Bexley Wing, St James’s University Hospital, Leeds, LS9 7TF, UK. E: Gordon.Cook@leedsth.nhs.uk

Allogeneic stem cell transplantation (alloSCT) has been utilised in the management of leukaemia for several decades and has established its role in producing long-term remission. In the context of multiple myeloma (MM), alloSCT induces the highest rate of remissions, including molecular remission, resulting in long-term disease-free survival (DFS) in <30% of patients.1–3 However, it is associated with the highest rate of treatment-related mortality (TRM) of all of the interventions for MM, resulting from conditioning-related end-organ damage and the unwanted immunological toxicity of graft-versus-host disease (GvHD), in addition to immune-suppression-related opportunistic infection.4

The effectiveness of alloSCT results from the combination of high-dose chemotherapy and the adoptive transfer of immune-competent donor immune-effector cells (graft-versus-myeloma [GvM] effect). The former aims to cytoreduce and is combined with autologous stem-cell rescue as first-line therapy in suitably fit patients;5,6 however, all patients ultimately relapse. The GvM immunological effect is best demonstrated by the use of donor lymphocyte infusions (DLIs) to re-induce disease responses following relapse post-alloSCT. Although less potent than that seen with chronic myeloid leukaemia, it significantly contributes to the DFS effect noted with alloSCT in MM.7,8 The published evidence surrounding these two main factors in alloSCT for MM suggests that they are not mutually exclusive in their contribution to long-term DFS in MM, although the relevant contribution of each to this effect remains to be clarified. There is evidence that both the method and degree of cytoreduction and the GvM effect contribute to long-term DFS in MM. As such, the challenge for transplant physicians is how to harness the GvM effect while maintaining acceptable toxicity and extending the spectrum of patients with MM who would and could benefit from alloSCT.

The survival of patients with MM ranges from a few weeks to >20 years, but there is good evidence that the median survival of patients has increased over the last decade9 to between three and four years. This improvement is probably due to improvements in supportive care, the introduction of novel therapies and the increased use of high-dose therapy, which has made decision-making for younger patients with a human leukocyte antigen (HLA)-matched sibling donor even more difficult. MM has a median age at presentation of approximately 70 years and only 15% of patients are <60 years of age, with the result that only a minority of patients are eligible for consideration for alloSCT, even when reduced-intensity conditioning (RIC) alloSCT is included. Myeloablative alloSCT is associated with a high TRM, most likely due to a combination of factors, including advanced age of patients, myeloma-related organ damage (particularly renal impairment), disease-associated immune dysfunction and infection risk with the effects of previous treatment.

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