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Allogeneic Hematopoietic Stem Cell Transplantation for Myeloma: Time for an Obituary or Not Just Yet!

  • Sarita Rani Jaiswal
  • Suparno ChakrabartiEmail author
Review Article
  • 6 Downloads

Abstract

The management of myeloma has evolved dramatically in the last two decades. High dose melphalan and autologous hematopoietic stem cell transplantation (HSCT) marked the beginning of this journey. This was followed by an explosion of novel agents which were approved for management of myeloma. Allogeneic HSCT which was deemed as the only curative option was largely abhorred due to high transplant-related mortality (TRM) until the advent of reduced intensity conditioning (RIC). An approach of tandem autologous and RIC-allogeneic transplantations has showed the best promise for cure for this condition, particularly for those with high-risk cytogenetics. Yet, allogeneic HSCT seems to have fallen out of favor due to the projected high TRM and late relapses, even though the alternatives do not offer a cure, but merely prolong survival. Offering an allogeneic HSCT as a final resort in unlikely to yield gratifying results. At the same time, allogeneic HSCT needs to evolve in a disease-specific manner to address the relevant concerns regarding TRM and relapse. With the introduction of effective GVHD prophylaxis in the form of post-transplantation cyclophosphamide, transplantation from a haploidentical family donor has become a reality. The challenge lies in segregating graft-vs-myeloma effect from a graft-versus-host effect. We discuss the pro-survival and anti-apoptotic pathways via CD28-CD86 interactions which confer survival advantages to myeloma cells and the possibility of disruption of this pathway in the context of haploidentical transplantation through the use of CTLA4Ig without incurring T cell alloreactivity.

Keywords

Myeloma Allogeneic transplantation Haploidentical CD28-CD86 CTLA4Ig NK cell 

Notes

References

  1. 1.
    Harousseau JL, Attal M, Divine M, Marit G, Leblond V, Stoppa AM et al (1995) Autologous stem cell transplantation after first remission induction treatment in multiple myeloma: a report of the French Registry on autologous transplantation in multiple myeloma. Blood 85(11):3077–3085Google Scholar
  2. 2.
    Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P et al (1999) Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341(21):1565–1571.  https://doi.org/10.1056/NEJM199911183412102 CrossRefGoogle Scholar
  3. 3.
    Kumar S (2017) Emerging options in multiple myeloma: targeted, immune, and epigenetic therapies. Hematol Am Soc Hematol Edu Program 2017(1):518–524.  https://doi.org/10.1182/asheducation-2017.1.518 Google Scholar
  4. 4.
    Harousseau JL, Attal M (2017) How I treat first relapse of myeloma. Blood 130(8):963–973.  https://doi.org/10.1182/blood-2017-03-726703 CrossRefGoogle Scholar
  5. 5.
    Bjorkstrand BB, Ljungman P, Svensson H, Hermans J, Alegre A, Apperley J et al (1996) Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: a retrospective case-matched study from the European Group for Blood and Marrow Transplantation. Blood 88(12):4711–4718Google Scholar
  6. 6.
    Gahrton G, Tura S, Ljungman P, Blade J, Brandt L, Cavo M et al (1995) Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma. J Clin Oncol 13(6):1312–1322.  https://doi.org/10.1200/JCO.1995.13.6.1312 CrossRefGoogle Scholar
  7. 7.
    Hari P (2017) Recent advances in understanding multiple myeloma. Hematol Oncol Stem Cell Ther 10(4):267–271.  https://doi.org/10.1016/j.hemonc.2017.05.005 CrossRefGoogle Scholar
  8. 8.
    Chakrabarti S, Buyck HC (2007) Reduced-intensity transplantation in the treatment of haematological malignancies: current status and future-prospects. Curr Stem Cell Res Ther 2(2):163–188CrossRefGoogle Scholar
  9. 9.
    Karlin L, Arnulf B, Chevret S, Ades L, Robin M, De Latour RP et al (2011) Tandem autologous non-myeloablative allogeneic transplantation in patients with multiple myeloma relapsing after a first high dose therapy. Bone Marrow Transplant 46(2):250–256.  https://doi.org/10.1038/bmt.2010.90 CrossRefGoogle Scholar
  10. 10.
    Bjorkstrand B, Iacobelli S, Hegenbart U, Gruber A, Greinix H, Volin L et al (2011) Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up. J Clin Oncol 29(22):3016–3022.  https://doi.org/10.1200/JCO.2010.32.7312 CrossRefGoogle Scholar
  11. 11.
    Palumbo A, Attal M, Roussel M (2011) Shifts in the therapeutic paradigm for patients newly diagnosed with multiple myeloma: maintenance therapy and overall survival. Clin Cancer Res 17(6):1253–1263.  https://doi.org/10.1158/1078-0432.CCR-10-1925 CrossRefGoogle Scholar
  12. 12.
    Rajkumar SV (2011) Multiple myeloma: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol 86(1):57–65.  https://doi.org/10.1002/ajh.21913 CrossRefGoogle Scholar
  13. 13.
    Rajkumar SV (2016) Myeloma today: Disease definitions and treatment advances. Am J Hematol. 91(1):90–100.  https://doi.org/10.1002/ajh.24236 CrossRefGoogle Scholar
  14. 14.
    Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT et al (2014) Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med 371(10):895–905.  https://doi.org/10.1056/NEJMoa1402888 CrossRefGoogle Scholar
  15. 15.
    Hari P, Pasquini MC, Vesole DH (2006) Cure of multiple myeloma – more hype, less reality. Bone Marrow Transplant 37(1):1–18.  https://doi.org/10.1038/sj.bmt.1705194 CrossRefGoogle Scholar
  16. 16.
    Hari P, Reece DE, Randhawa J, Flomenberg N, Howard DS, Badros AZ et al (2018) Final outcomes of escalated melphalan 280 mg/m(2) with amifostine cytoprotection followed autologous hematopoietic stem cell transplantation for multiple myeloma: high CR and VGPR rates do not translate into improved survival. Bone Marrow Transplant.  https://doi.org/10.1038/s41409-018-0261-y Google Scholar
  17. 17.
    Breitkreutz I, Becker N, Benner A, Kosely F, Heining C, Hillengass J et al (2016) Dose-intensified bendamustine followed by autologous peripheral blood stem cell support in relapsed and refractory multiple myeloma with impaired bone marrow function. Hematol Oncol 34(4):200–207.  https://doi.org/10.1002/hon.2199 CrossRefGoogle Scholar
  18. 18.
    Roussel M, Moreau P, Huynh A, Mary JY, Danho C, Caillot D et al (2010) Bortezomib and high-dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: a phase 2 study of the Intergroupe Francophone du Myelome (IFM). Blood 115(1):32–37.  https://doi.org/10.1182/blood-2009-06-229658 CrossRefGoogle Scholar
  19. 19.
    Byun JM, Lee J, Shin SJ, Kang M, Yoon SS, Koh Y (2018) Busulfan plus melphalan versus high-dose melphalan as conditioning regimens in autologous stem cell transplantation for newly diagnosed multiple myeloma. Blood Res 53(2):105–109.  https://doi.org/10.5045/br.2018.53.2.105 CrossRefGoogle Scholar
  20. 20.
    Moreau P (2017) How I treat myeloma with new agents. Blood 130(13):1507–1513.  https://doi.org/10.1182/blood-2017-05-743203 CrossRefGoogle Scholar
  21. 21.
    Auner HW, Szydlo R, van Biezen A, Iacobelli S, Gahrton G, Milpied N et al (2013) Reduced intensity-conditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after autologous transplantation: a study by the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 48(11):1395–1400.  https://doi.org/10.1038/bmt.2013.73 CrossRefGoogle Scholar
  22. 22.
    Kane RC, Farrell AT, Sridhara R, Pazdur R (2006) United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy. Clin Cancer Res 12(10):2955–2960.  https://doi.org/10.1158/1078-0432.CCR-06-0170 CrossRefGoogle Scholar
  23. 23.
    Pulte ED, Dmytrijuk A, Nie L, Goldberg KB, McKee AE, Farrell AT et al (2018) FDA Approval Summary: Lenalidomide as Maintenance Therapy After Autologous Stem Cell Transplant in Newly Diagnosed Multiple Myeloma. Oncologist 23(6):734–739.  https://doi.org/10.1634/theoncologist.2017-0440 CrossRefGoogle Scholar
  24. 24.
    Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ et al (2016) Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood 127(21):2561–2568.  https://doi.org/10.1182/blood-2015-11-682518 CrossRefGoogle Scholar
  25. 25.
    Yin X, Tang L, Fan F, Jiang Q, Sun C, Hu Y (2018) Allogeneic stem-cell transplantation for multiple myeloma: a systematic review and meta-analysis from 2007 to 2017. Cancer Cell Int 18:62.  https://doi.org/10.1186/s12935-018-0553-8 CrossRefGoogle Scholar
  26. 26.
    Collins RH Jr, Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R et al (1997) Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 15(2):433–444CrossRefGoogle Scholar
  27. 27.
    Zeidan AM, Forde PM, Symons H, Chen A, Smith BD, Pratz K et al (2014) HLA-haploidentical donor lymphocyte infusions for patients with relapsed hematologic malignancies after related HLA-haploidentical bone marrow transplantation. Biol Blood Marrow Transplant 20(3):314–318.  https://doi.org/10.1016/j.bbmt.2013.11.020 CrossRefGoogle Scholar
  28. 28.
    Yanamandra U, Khattry N, Kumar S, Raje N, Jain A, Jagannath S et al (2017) Consensus in the Management of Multiple Myeloma in India at Myeloma State of the Art 2016 Conference. Indian J Hematol Blood Transfus 33(1):15–21.  https://doi.org/10.1007/s12288-016-0773-9 CrossRefGoogle Scholar
  29. 29.
    Chakrabarti S (2002) Critical factors in optimizing graft-versus-leukemia effect for relapsed leukemias. J Clin Oncol 20(11):2756.  https://doi.org/10.1200/JCO.2002.20.11.2756 CrossRefGoogle Scholar
  30. 30.
    Malek E, El-Jurdi N, Kroger N, de Lima M (2017) Allograft for Myeloma: Examining Pieces of the Jigsaw Puzzle. Front Oncol 7:287.  https://doi.org/10.3389/fonc.2017.00287 CrossRefGoogle Scholar
  31. 31.
    Kolb HJ (2008) Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 112(12):4371–4383.  https://doi.org/10.1182/blood-2008-03-077974 CrossRefGoogle Scholar
  32. 32.
    Schmid C, Labopin M, Nagler A, Bornhauser M, Finke J, Fassas A et al (2007) Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol 25(31):4938–4945.  https://doi.org/10.1200/JCO.2007.11.6053 CrossRefGoogle Scholar
  33. 33.
    Soiffer RJ (2008) Donor lymphocyte infusions for acute myeloid leukaemia. Best Pract Res Clin Haematol 21(3):455–466.  https://doi.org/10.1016/j.beha.2008.07.009 CrossRefGoogle Scholar
  34. 34.
    Bashey A, Solomon SR (2014) T-cell replete haploidentical donor transplantation using post-transplant CY: an emerging standard-of-care option for patients who lack an HLA-identical sibling donor. Bone Marrow Transplant 49(8):999–1008.  https://doi.org/10.1038/bmt.2014.62 CrossRefGoogle Scholar
  35. 35.
    Bashey A, Zhang X, Jackson K, Brown S, Ridgeway M, Solh M et al (2015) Comparison of Outcomes of Hematopoietic Cell Transplants from T-Replete Haploidentical Donors Using Post-Transplantation Cyclophosphamide with 10 of 10 HLA-A, -B, -C, -DRB1, and -DQB1 Allele-Matched Unrelated Donors and HLA-Identical Sibling Donors: A Multivariable Analysis Including Disease Risk Index. Biol Blood Marrow Transplant.  https://doi.org/10.1016/j.bbmt.2015.09.002 Google Scholar
  36. 36.
    Raiola AM, Dominietto A, Di GC, Lamparelli T, Gualandi F, Ibatici A et al (2014) Unmanipulated haploidentical transplants compared with other alternative donors and matched sibling grafts. Biol Blood Marrow Transplant 20(10):1573–1579.  https://doi.org/10.1016/j.bbmt.2014.05.029 CrossRefGoogle Scholar
  37. 37.
    McCurdy SR, Kanakry JA, Showel MM, Tsai HL, Bolanos-Meade J, Rosner GL et al (2015) Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide. Blood 125(19):3024–3031.  https://doi.org/10.1182/blood-2015-01-623991 CrossRefGoogle Scholar
  38. 38.
    Jaiswal SR, Zaman S, Chakrabarti A, Sen S, Mukherjee S, Bhargava S et al (2016) Improved Outcome of Refractory/Relapsed Acute Myeloid Leukemia after Post-Transplantation Cyclophosphamide-Based Haploidentical Transplantation with Myeloablative Conditioning and Early Prophylactic Granulocyte Colony-Stimulating Factor-Mobilized Donor Lymphocyte Infusions. Biol Blood Marrow Transplant 22(10):1867–1873.  https://doi.org/10.1016/j.bbmt.2016.07.016 CrossRefGoogle Scholar
  39. 39.
    Kanakry CG, Ganguly S, Zahurak M, Bolanos-Meade J, Thoburn C, Perkins B et al (2013) Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide. Sci Transl Med 5(211):211.  https://doi.org/10.1126/scitranslmed.3006960 CrossRefGoogle Scholar
  40. 40.
    Jaiswal SR, Zaman S, Nedunchezhian M, Chakrabarti A, Bhakuni P, Ahmed M et al (2017) CD56-enriched donor cell infusion after post-transplantation cyclophosphamide for haploidentical transplantation of advanced myeloid malignancies is associated with prompt reconstitution of mature natural killer cells and regulatory T cells with reduced incidence of acute graft versus host disease: A pilot study. Cytotherapy 19(4):531–542.  https://doi.org/10.1016/j.jcyt.2016.12.006 CrossRefGoogle Scholar
  41. 41.
    Najafian N, Sayegh MH (2000) CTLA4-Ig: a novel immunosuppressive agent. Expert Opin Investig Drugs 9(9):2147–2157.  https://doi.org/10.1517/13543784.9.9.2147 CrossRefGoogle Scholar
  42. 42.
    Jaiswal SR, Bhakuni P, Zaman S, Bansal S, Bharadwaj P, Bhargava S et al (2017) T cell costimulation blockade promotes transplantation tolerance in combination with sirolimus and post-transplantation cyclophosphamide for haploidentical transplantation in children with severe aplastic anemia. Transpl Immunol.  https://doi.org/10.1016/j.trim.2017.07.004 Google Scholar
  43. 43.
    Chen Y, Fukuda T, Thakar MS, Kornblit BT, Storer BE, Santos EB et al (2011) Immunomodulatory effects induced by cytotoxic T lymphocyte antigen 4 immunoglobulin with donor peripheral blood mononuclear cell infusion in canine major histocompatibility complex-haplo-identical non-myeloablative hematopoietic cell transplantation. Cytotherapy 13(10):1269–1280.  https://doi.org/10.3109/14653249.2011.586997 CrossRefGoogle Scholar
  44. 44.
    Kean LS, Hamby K, Koehn B, Lee E, Coley S, Stempora L et al (2006) NK cells mediate costimulation blockade-resistant rejection of allogeneic stem cells during nonmyeloablative transplantation. Am J Transplant. 6(2):292–304.  https://doi.org/10.1111/j.1600-6143.2005.01172.x CrossRefGoogle Scholar
  45. 45.
    Peng Y, Luo G, Zhou J, Wang X, Hu J, Cui Y et al (2013) CD86 is an activation receptor for NK cell cytotoxicity against tumor cells. PLoS ONE 8(12):e83913.  https://doi.org/10.1371/journal.pone.0083913 CrossRefGoogle Scholar
  46. 46.
    Jaiswal SR, Bhakuni P, Zaman S, Chakrabarti S (2017) CTLA4Ig Primed Donor Lymphocyte Infusions (DLI): A Novel Approach to Natural Killer Cell Immunotherapy Following Haploidentical PBSC Transplantation for Advanced Hematological Malignancies. Blood 130(1):4468Google Scholar
  47. 47.
    Murray ME, Gavile CM, Nair JR, Koorella C, Carlson LM, Buac D et al (2014) CD28-mediated pro-survival signaling induces chemotherapeutic resistance in multiple myeloma. Blood 123(24):3770–3779.  https://doi.org/10.1182/blood-2013-10-530964 CrossRefGoogle Scholar
  48. 48.
    Nair JR, Carlson LM, Koorella C, Rozanski CH, Byrne GE, Bergsagel PL et al (2011) CD28 expressed on malignant plasma cells induces a prosurvival and immunosuppressive microenvironment. J Immunol 187(3):1243–1253.  https://doi.org/10.4049/jimmunol.1100016 CrossRefGoogle Scholar
  49. 49.
    Besson L, Charrier E, Karlin L, Allatif O, Marcais A, Rouzaire P et al (2018) One-Year Follow-Up of Natural Killer Cell Activity in Multiple Myeloma Patients Treated With Adjuvant Lenalidomide Therapy. Front Immunol 9:704.  https://doi.org/10.3389/fimmu.2018.00704 CrossRefGoogle Scholar
  50. 50.
    Hsu AK, Quach H, Tai T, Prince HM, Harrison SJ, Trapani JA et al (2011) The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy. Blood 117(5):1605–1613.  https://doi.org/10.1182/blood-2010-04-278432 CrossRefGoogle Scholar

Copyright information

© Indian Society of Hematology and Blood Transfusion 2019

Authors and Affiliations

  1. 1.Cellular Therapy and ImmunologyManashi Chakrabarti FoundationKolkataIndia
  2. 2.Department Of Blood and Marrow Transplantation and HematologyDharamshila Narayana Superspeciality Hospital and Research CentreNew DelhiIndia

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