Mini–Midi–Maxi? How to harness the graft-versus-myeloma effect and target molecular remission after allogeneic stem cell transplantation

Kröger, N

doi:10.1038/sj.leu.2404775

Cited by 26 publications

(20 citation statements)

References 73 publications

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“…53 There is limited data regarding the use of bortezomib in this setting. In a small study, two cycles of four doses were completed by 14 patients, 55 with neurotoxicity and thrombocytopenia being the most frequently reported adverse events and in four patients there might have been some stimulation of GVHD.…”

Section: Is Allosct the Penultimate Intervention? Post-allosct Therapymentioning

confidence: 99%

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

Cook

Bird

Marks

2008

Bone Marrow Transplant

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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.

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Section: Is Allosct the Penultimate Intervention? Post-allosct Therapymentioning

confidence: 99%

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

Cook

Bird

Marks

2008

Bone Marrow Transplant

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“…40,41 Kröger expresses the view that we should be targeting molecular remission and not settling for less rigorous assessments of disease. 42 The shortcomings of these data have been noted (heterogeneity and short follow-up), and disease-specific clinical trials are required.…”

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confidence: 99%

“…42 There are limited data concerning the use of bortezomib in this setting. In a small study, two cycles of four doses were completed by 14 patients, 44 with neurotoxicity and thrombocytopenia being the most frequent reported adverse events, and in four patients there may have been some stimulation of GvHD.…”

mentioning

confidence: 99%

“…Nonetheless, with all other therapy MM is a universally fatal malignancy, and while improvements have been made in OS with the introduction of new drugs, the median survival is still unacceptably short. With the introduction of novel agents, the potential to take patients to alloSCT with considerably reduced tumor burdens represents the way forward, while permitting a more intensive conditioning regimen (Mini, Midi, Maxi) 42 resulting from reduced pretransplant end-organ therapy-related damage. Furthermore, the alloSCT should be viewed as the platform from which to launch a pre-emptive consolidative strategy to minimise the risk for disease relapse.…”

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confidence: 99%

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Capturing Alloreactivity in Multiple Myeloma

Cook¹

2009

Oncology &Amp; Hematology Review (US)

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Allogeneic stem cell transplantation (alloSCT) has been utilised in the management of leukemia 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 treatmentrelated 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 immunesuppression-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 leukemia, 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 decade 9 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, with the result that only a minority of patients are eligible for consideration for alloSCT, even when reduced- KeywordsAllogeneic stem cell transplantation, multiple myeloma, adoptive immunotherapy, immunomodulatory agentsThe author has no conficts of interest to declare. 1983-1993 and 1994-1998 showed that TRM decreased from 46 to 30% 4 due to better patient selection, particularly transplantation earlier in the course of the disease. Subsequently, there were several reports from single centres indicating that with stringen...

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confidence: 99%

Capturing Alloreactivity in Multiple Myeloma

Cook¹

2009

European Oncology &Amp; Haematology

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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

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Mini–Midi–Maxi? How to harness the graft-versus-myeloma effect and target molecular remission after allogeneic stem cell transplantation

Cited by 26 publications

References 73 publications

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

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

Capturing Alloreactivity in Multiple Myeloma

Capturing Alloreactivity in Multiple Myeloma

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