BSH 2017: Plenary debate: Allogeneic transplantation should be considered for selected young patients

Even in the era of novel therapies for newly-diagnosed and relapsed/refractory MM, there is a group of patients for whom the myeloma biology significantly shortens life expectancy. Allogeneic stem cell transplantation (allo-SCT) may offer a treatment option that has the potential to cure MM…

Dr Roger Owen (Leeds General Infirmary) gives his opinion on the place of allogeneic transplant in myeloma following the debate.

Even in the era of novel therapies for newly-diagnosed and relapsed/refractory MM, there is a group of patients for whom the myeloma biology significantly shortens life expectancy. Allogeneic stem cell transplantation (allo-SCT) may offer a treatment option that has the potential to cure MM, although the risks involved are considerable. In the second plenary debate at BSH 2017, Dr Mark Cook from Birmingham stated that allo-SCT should not be considered a treatment of last resort, while Dr Martin Kaiser from London spoke argued that resources are better spent on optimising the use of new treatments.

For the motion

The efficacy of allo-SCT in MM relies on the transplanted immune system having an anti-tumour effect on the host bone marrow, the so-called graft-versus-myeloma (GvM) effect. In its early era allo-SCT was associated with transplant-related mortality (TRM) rates of around 40%,¹ and in Dr Cook’s opinion this has left a lingering perception in many MM clinicians’ minds that allo-SCT outcomes are poor. However, more recent clinical trials using reduced-intensity conditioning regimens have demonstrated event-free survival rates of up to 39 months and median overall survival not reached over a follow-up period of 7 years.² The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 study showed that patients receiving an autologous SCT (ASCT) followed by an allo-SCT had significantly higher CR rates that patients receiving double ASCTs.³ Although the higher CR rates did not translate into a survival benefit in this study, longer follow-up periods of up to 9 years show a significant OS and PFS benefit in favour of allo-SCT over double ASCT including in patients with high-risk cytogenetics.⁴ That allo-SCT may be beneficial for patients with high cytogenetic risk is confirmed by the results of a French retrospective analysis of 143 MM patients which showed no significant difference in PFS and OS rates following allo-SCT when stratifying patients according to del(13q), t(4;14), del(17p) and t(14;16) cytogenetics.⁵

Recurrent disease after allo-SCT can be treated with donor lymphocyte infusions (DLI) to achieve a deeper and more prolonged response.⁶ However, rather than wait for a relapse to happen, pre-emptive DLI could be used to upgrade the allo-SCT response and prevent relapse.⁷ In the recently completed LenaRIC study patients undergoing allo-SCT with reduced-intensity conditioning received lenalidomide for 12 months from day 35 post-transplantation, with DLI for mixed chimerism or persistent disease. The one-year TRM in this study was 10%; two-year PFS results are expected in June 2017. Other promising developments to improve outcomes in allo-SCT include conditioning with radiolabelled anti-CD66, as well as salvage therapy with daratumumab⁸ or newer imids which suggest that allo-SCT has the potential to enhance the efficacy of other therapies that may have been less effective pre-transplantation.

 

Against the motion

Novel therapies introduced in recent decades have quadrupled the life expectancy in patients diagnosed with MM.⁹ The biggest improvements in outcome are seen in younger, fitter patients – that is, those most likely to be candidates for allo-SCT.⁹ Allo-SCT may have the potential to be curative in MM, but allo-SCT studies are likely to be biased in terms of patient age and fitness and mortality and long-term toxicity from conditioning regimens remain high.¹⁰ Data from the European Society for Blood and Marrow Transplantation (EBMT) megafile database indicates that the graft-versus-tumour effect achieved with allo-SCT is weaker and PFS rates lower in MM than in other types of haematological cancers.¹¹ There is clinical study data to show that outcomes with allo-SCT can be improved by adding adjunct therapy with lenalidomide post-transplantation;¹² however, the finding in the Myeloma XI study that lenalidomide maintenance therapy was associated with a significant improvement in PFS but with little further improvement in depth of response¹³ suggests that the graft is providing an adjunct to highly effective maintenance therapy rather than the other way around. Myeloma XI also showed that lenalidomide maintenance therapy was superior to observation in patients with high-risk cytogenetics in all age groups.

With ageing populations and large numbers of innovative treatments in the MM pipeline, clinicians will need to consider very carefully the affordability of new therapies and how these can translate into  improved outcomes for patients.¹⁴ The risks associated with allo-SCT and the burden to the individual patient and society as a whole makes it unsustainable and clinicians should instead focus their efforts on giving patients access to new effective treatments, including maintenance therapy and especially for patients with high-risk MM.

References

1. Gahrton G, Tura S, Ljungman P, et al. Allogeneic bone marrow transplantation in multiple myeloma. European Group for Bone Marrow Transplantation. N Engl J Med 1991;325:1267-73.
2. Giaccone L, Storer B, Patriarca F, et al. Long-term follow-up of a comparison of nonmyeloablative allografting with autografting for newly diagnosed myeloma. Blood 2011;117:6721-7.
3. Krishnan A, Pasquini MC, Logan B, et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol 2011;12:1195-203.
4. Gahrton G, Iacobelli S, Bjorkstrand B, et al. Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study. Blood 2013;121:5055-63.
5. Roos-Weil D, Moreau P, Avet-Loiseau H, et al. Impact of genetic abnormalities after allogeneic stem cell transplantation in multiple myeloma: a report of the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. Haematologica 2011;96:1504-11.
6. Lokhorst HM, Schattenberg A, Cornelissen JJ, et al. Donor leukocyte infusions are effective in relapsed multiple myeloma after allogeneic bone marrow transplantation. Blood 1997;90:4206-11.
7. Levenga H, Levison-Keating S, Schattenberg AV, et al. Multiple myeloma patients receiving pre-emptive donor lymphocyte infusion after partial T-cell-depleted allogeneic stem cell transplantation show a long progression-free survival. Bone Marrow Transplant 2007;40:355-9.
8. Klyuchnikov E, von Pein U-M, Ayuk FA, et al. Daratumumab Is an Effective and Safe Salvage Therapy in Relapsed/Refractory Patients with Multiple Myeloma after Allogeneic Stem Cell Transplantation. Blood 2016;128:3437-3437.
9. Cancer Research UK.http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/myeloma/survival, 2014.
10. Sobh M, Michallet M, Gahrton G, et al. Allogeneic hematopoietic cell transplantation for multiple myeloma in Europe: trends and outcomes over 25 years. A study by the EBMT Chronic Malignancies Working Party. Leukemia 2016;30:2047-2054.
11. Stern M, de Wreede LC, Brand R, et al. Sensitivity of hematological malignancies to graft-versus-host effects: an EBMT megafile analysis. Leukemia 2014;28:2235-40.
12. Alsina M, Becker PS, Zhong X, et al. Lenalidomide maintenance for high-risk multiple myeloma after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2014;20:1183-9.
13. Jackson GH, Davies FE, Pawlyn C, et al. Lenalidomide Is a Highly Effective Maintenance Therapy in Myeloma Patients of All Ages; Results of the Phase III Myeloma XI Study. Blood 2016;128:1143-1143.
14. Sonneveld P, De Wit E, Moreau P. How have evolutions in strategies for the treatment of relapsed/refractory multiple myeloma translated into improved outcomes for patients? Crit Rev Oncol Hematol 2017;112:153-170.