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Final outcomes of escalated melphalan 280 mg/m2 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 Transplantation volume 54, pages 293–299 (2019)Cite this article

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Abstract

The most common preparative regimen for autologous transplantation (ASCT) in myeloma (MM) consists of melphalan 200 mg/m2 (MEL 200). Higher doses of melphalan 220–260 mg/m2, although relatively well tolerated, have not shown significant improvement in clinical outcomes. Several approaches have been pursued in the past to improve CR rates, including poly-chemotherapy preparative regimens, tandem ASCT, consolidation, and/or maintenance therapy. Since there is a steep dose–response effect for intravenous melphalan, we evaluated an alternative single ASCT strategy using higher-dose melphalan at 280 mg/m2 (MEL 280) with amifostine as a cytoprotectant as the maximum tolerated dose determined in an earlier phase I dose escalation trial. We report the final long-term outcomes of MM patients who underwent conditioning with MEL 280 with amifostine cytoprotection followed by ASCT. Although the complete response rate was quite high in the era pre-dating the routine use of novel therapies (proteasome inhibitors, immunomodulatory agents) (49%), the progression-free survival was a disappointing 22 months. The implications of this dichotomy between the excellent depth of ASCT response and progression-free survival are discussed.

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References

  1. Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348:1875–83. https://doi.org/10.1056/NEJMoa02234.

    Article  CAS  Google Scholar 

  2. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335:91–7. https://doi.org/10.1056/NEJM199607113350204.

    Article  CAS  Google Scholar 

  3. Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376:1311–20. https://doi.org/10.1056/NEJMoa1611750

    Article  CAS  Google Scholar 

  4. Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, et al. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015;16:1617–29. https://doi.org/10.1016/S1470-2045(15)00389-7

    Article  CAS  Google Scholar 

  5. Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371:895–905. https://doi.org/10.1056/NEJMoa1402888

    Article  Google Scholar 

  6. Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003;349:2495–502. https://doi.org/10.1056/NEJMoa032290.

    Article  CAS  Google Scholar 

  7. Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F, et al. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma:Bologna 96 clinical study. J Clin Oncol. 2007;25:2434–41. https://doi.org/10.1200/JCO.2006.10.2509.

    Article  Google Scholar 

  8. Goldschmidt H. Single vs double high-dose therapy in multiple myeloma: second analysis of the GMMG-HD-2 trial. Haematologica. 2005;90 Suppl 1:38.

    Google Scholar 

  9. JP Fermand,C Alberti,J-P Marolleau. Single versus tandem high dose therapy (HDT) supported with autologous stem cell transplantation using unselected or CD-34-enriched ABSC: results of a two by two designed randomized trial in 230 young patients with multiple myeloma [abstract]. Hematol J. 2003;4 Suppl 1:559–60.

    Google Scholar 

  10. Sonneveld PvdHB, Segeren C, et al. Intensive versus double intensive therapy in untreated multiple myeloma: updated analysis of the randomized phase III study HOVON 24 MM. Blood. 2004;104:943.

    Google Scholar 

  11. Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, et al. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010;28:1209–14. https://doi.org/10.1200/JCO.2009.25.6081

    Article  Google Scholar 

  12. Nath CE, Shaw PJ, Trotman J, Zeng L, Duffull SB, Hegarty G, et al. Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy. Br J Clin Pharmacol. 2010;69:484–97. https://doi.org/10.1111/j.1365-2125.2010.03638.x.

    Article  CAS  Google Scholar 

  13. Moreau P, Facon T, Attal M, Hulin C, Michallet M, Maloisel F, et al. Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood. 2002;99:731–5.

    Article  CAS  Google Scholar 

  14. Phillips GL, Meisenberg B, Reece DE, Adams VR, Badros A, Brunner J, et al. Amifostine and autologous hematopoietic stem cell support of escalating-dose melphalan: a phase I study. Biol Blood Marrow Transplant. 2004;10:473–83. https://doi.org/10.1016/j.bbmt.2004.03.001.

    Article  CAS  Google Scholar 

  15. Hensley ML, Schuchter L, Lindley C, et al. American Society of Clinical Oncology clinical practice guideline for the use of chemotherapy and radiotherapy protectants. J Clin Oncol. 1999;17:3333–55.

    Article  CAS  Google Scholar 

  16. Koukourakis MI. Amifostine: is there evidence of tumor protection. Semin Oncol Suppl. 2003;30 Suppl 18:18–30.

    Article  CAS  Google Scholar 

  17. Kapoor P, Kumar SK, Dispenzieri A, Lacy MQ, Buadi F, Dingli D, et al. Importance of achieving stringent complete response after autologous stem-cell transplantation in multiple myeloma. J Clin Oncol. 2013;31:4529–35. https://doi.org/10.1200/JCO.2013.49.0086.

    Article  Google Scholar 

  18. Iacobelli S, de Wreede LC, Schonland S, Bjorkstrand B, Hegenbart U, Gruber A, et al. Impact of CR before and after allogeneic and autologous transplantation in multiple myeloma: results from the EBMT NMAM2000 prospective trial. Bone Marrow Transplant. 2015;50:505–10. https://doi.org/10.1038/bmt.2014.310

    Article  CAS  Google Scholar 

  19. Lee CK, Barlogie B, Munshi N, Zangari M, Fassas A, Jacobson J, et al. DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma. J Clin Oncol. 2003;21:2732–9. https://doi.org/10.1200/JCO.2003.01.055.

    Article  CAS  Google Scholar 

  20. Bearman SI, Appelbaum FR, Buckner CD, Petersen FB, Fisher LD, Clift RA, et al. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol. 1988;6:1562–8.

    Article  CAS  Google Scholar 

  21. Blade JSD, Reece D, Apperley J, Bjorlestrand B, Gahrton G, Gertz M, Giralt S, Jagannath, Vesole D. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and hematopoietic stem cell transplantation. Bone Marrow Transplant. 1998;21:337–43.

    Article  Google Scholar 

  22. Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467–73. https://doi.org/10.1038/sj.leu.2404284.

    Article  CAS  Google Scholar 

  23. Higman MA, Port JD, Beauchamp NJ Jr., Chen AR. Reversible leukoencephalopathy associated with re-infusion of DMSO preserved stem cells. Bone Marrow Transplant. 2000;26:797–800. https://doi.org/10.1038/sj.bmt.1702589.

    Article  CAS  Google Scholar 

  24. Memon M, deMagalhaes-Silverman M, Bloom EJ, Lister J, Myers DJ, Pincus SM, et al. Reversible cyclosporine-induced cortical blindness in allogeneic bone marrow transplant recipients. Bone Marrow Transplant. 1995;15:283–6.

    CAS  PubMed  Google Scholar 

  25. Blijlevens N, Schwenkglenks M, Bacon P, D’Addio A, Einsele H, Maertens J, et al. Prospective oral mucositis audit: oral mucositis in patients receiving high-dose melphalan or BEAM conditioning chemotherapy--European Blood and Marrow Transplantation Mucositis Advisory Group. J Clin Oncol. 2008;26:1519–25. https://doi.org/10.1200/JCO.2007.13.6028.

    Article  CAS  Google Scholar 

  26. Spencer A, Horvath N, Gibson J, Prince HM, Herrmann R, Bashford J, et al. Prospective randomised trial of amifostine cytoprotection in myeloma patients undergoing high-dose melphalan conditioned autologous stem cell transplantation. Bone Marrow Transplant. 2005;35:971–7. https://doi.org/10.1038/sj.bmt.1704946.

    Article  CAS  Google Scholar 

  27. Bensinger WI, Becker PS, Gooley TA, Chauncey TR, Maloney DG, Gopal AK, et al. A randomized study of melphalan 200 mg/m2 vs 280 mg/m2 as a preparative regimen for patients with multiple myeloma undergoing auto-SCT. Bone Marrow Transplant. 2016 Jan;51(1):67-71. https://doi.org/10.1038/bmt.2015.211. Epub 2015 Sep 14.PMID:26367217.

  28. Olivieri A, Corvatta L, Montanari M, Brunori M, Offidani M, Ferretti GF, et al. Paroxysmal atrial fibrillation after high-dose melphalan in five patients autotransplanted with blood progenitor cells. Bone Marrow Transplant. 1998;21:1049–53. https://doi.org/10.1038/sj.bmt.1701217.

    Article  CAS  Google Scholar 

  29. Roussel M, Moreau P, Huynh A, Mary JY, Danho C, Caillot D, et al. 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. 2010;115:32–7. https://doi.org/10.1182/blood-2009-06-229658.

    Article  CAS  Google Scholar 

  30. Cavo M, Gay FM, Patriarca F, Zamagni E, Montefusco V, Dozza L, et al. Double autologous stem cell transplantation significantly prolongs progression-free survival and overall survival in comparison with single autotransplantation in newly diagnosed multiple myeloma: an analysis of phase 3 EMN02/HO95 study. Blood. 2017;130 Suppl 1:401–1.

    Google Scholar 

  31. Chakraborty R, Muchtar E, Kumar SK, Jevremovic D, Buadi FK, Dingli D, et al. Impact of post-transplant response and minimal residual disease on survival in myeloma with high-risk cytogenetics. Biol Blood Marrow Transplant. 2017;23:598–605. https://doi.org/10.1016/j.bbmt.2017.01.076

    Article  Google Scholar 

  32. Lahuerta JJ, Paiva B, Vidriales MB, Cordon L, Cedena MT, Puig N, et al. Depth of response in multiple myeloma: a pooled analysis of three PETHEMA/GEM clinical trials. J Clin Oncol. 2017;35:2900–10. https://doi.org/10.1200/JCO.2016.69.2517

    Article  CAS  Google Scholar 

  33. Hari P, Aljitawi OS, Arce-Lara C, Nath R, Callander N, Bhat G, et al. A phase IIb, multicenter, open-label, safety, and efficacy study of high-dose, propylene glycol-free melphalan hydrochloride for injection (EVOMELA) for myeloablative conditioning in multiple myeloma patients undergoing autologous transplantation. Biol Blood Marrow Transplant. 2015;21:2100–5. https://doi.org/10.1016/j.bbmt.2015.08.026

    Article  CAS  Google Scholar 

  34. Qazilbash MH, Bashir Q, Thall PF, Milton DR, Shah N, Patel KK, et al. A randomized phase III trial of busulfan+melphalan vs melphalan alone for multiple myeloma. Blood. 2017;130 Suppl 1:399–9.

    Google Scholar 

  35. Rodriguez TE, Hari P, Stiff PJ, Smith SE, Sterrenberg D, Vesole DH. Busulfan, melphalan, and bortezomib versus high-dose melphalan as a conditioning regimen for autologous hematopoietic stem cell transplantation in multiple myeloma. Biol Blood Marrow Transplant. 2016;22:1391–6. https://doi.org/10.1016/j.bbmt.2016.03.021

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Medical College of Wisconsin, Milwaukee, WI, USA

    Parameswaran Hari & Jasleen Randhawa

  2. Princess Margaret Hospital, Toronto, ON, Canada

    Donna E. Reece

  3. Thomas Jefferson University, Philadelphia, PA, USA

    Neal Flomenberg & Joanne Filicko-Ohara

  4. Wake Forest Baptist Medical Center Wake Forest, Winston-Salem, NC, USA

    Dianna S. Howard & Gordon L. Phillips

  5. University of Maryland, Baltimore, MD, USA

    Ashrof Z. Badros & Aaron P. Rapoport

  6. DeCesaris Cancer Institute, Anne Arundel Medical Center, Annapolis, MD, USA

    Barry R. Meisenberg

  7. John Theurer Cancer Center at Hackensack UMC, Hackensack, NJ, USA

    David H. Vesole

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Correspondence to David H. Vesole.

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Hari, P., Reece, D.E., Randhawa, J. et al. Final outcomes of escalated melphalan 280 mg/m2 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 54, 293–299 (2019). https://doi.org/10.1038/s41409-018-0261-y

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