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Tandem autologous hematopoietic cell transplantation with sequential use of total marrow irradiation and high-dose melphalan in multiple myeloma

Bone Marrow Transplantation volume 56, pages 1297–1304 (2021)Cite this article

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Abstract

The goal of this phase II trial was to evaluate safety and efficacy of a tandem autologous hematopoietic cell transplantation (auto-HCT) using sequentially total marrow irradiation (TMI) at the dose of 12 Gy (4 Gy on days −3, −2, and −1) and melphalan 200 mg/m2 for patients with multiple myeloma (MM). TMI was performed using helical tomotherapy. Additional “boosts” (total 24 Gy) were applied for patients with active lesions as revealed by PET-FDG. Fifty patients with median age 58 years (41–64 years) were included and received tandem auto-HCT. TMI resulted in absolute neutropenia in all patients. Grade 3 infections were reported in 30% patients. Other toxicities were rare. Proportion of patients who achieved at least very good partial response increased from 46% before the first auto-HCT to 82% after tandem transplantation. Complete remission rates changed from 10% to 42%, respectively. The probabilities of overall and progression-free survival at 5 years were 74% and 55%, respectively. No patient died without progression. We conclude that conditioning with TMI ± PET-guided “boosts” represents personalized treatment approach in MM and is characterized by very good toxicity profile. Tandem auto-HCT using TMI in sequence with high-dose melphalan appears safe with encouraging early efficacy.

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Fig. 1: Total marrow irradiation technique.
Fig. 2: Long-term results of patients enrolled in the study.

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References

  1. 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;335:91–97.

    Article  CAS  Google Scholar 

  2. 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.

    Article  CAS  Google Scholar 

  3. Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben, Yehuda D, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371:895–905.

    Article  Google Scholar 

  4. Cavo M, Hájek R, Pantani L, Beksac M, Oliva S, Dozza L, et al. Autologous stem-cell transplantation versus bortezomib-melphalan-prednisone for newly diagnosed multiple myeloma: second interim analysis of the phase 3 EMN02/HO95 study. Blood. 2017;130:397.

    Article  Google Scholar 

  5. 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.

    Article  CAS  Google Scholar 

  6. Nieto Y, Valdez BC, Pingali SR, Bassett R, Delgado R, Nguyen J, et al. High-dose gemcitabine, busulfan, and melphalan for autologous stem-cell transplant in patients with relapsed or refractory myeloma: a phase 2 trial and matched-pair comparison with melphalan. Lancet Haematol. 2017;4:e283–92.

    Article  Google Scholar 

  7. 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 

  8. Wong JY, Liu A, Schultheiss T, Popplewell L, Stein A, Rosenthal J, et al. Targeted total marrow irradiation using three-dimensional image-guided tomographic intensity-modulated radiation therapy: an alternative to standard total body irradiation. Biol Blood Marrow Transpl. 2006;12:306–15.

    Article  Google Scholar 

  9. Wong JY, Rosenthal J, Liu A, Schultheiss T, Forman S, Somlo G. Image-guided total-marrow irradiation using helical tomotherapy in patients with multiple myeloma and acute leukemia undergoing hematopoietic cell transplantation. Int J Radiat Oncol Biol Phys. 2009;73:273–9.

    Article  Google Scholar 

  10. Somlo G, Spielberger R, Frankel P, Karanes C, Krishnan C, Parker P, et al. Total marrow irradiation: a new ablative regimen as part of tandem autologous stem cell transplantation for patients with multiple myeloma. Clin Cancer Res. 2011;17:174–82.

    Article  CAS  Google Scholar 

  11. Giebel S, Kruzel T, Czerw T, Sadus-Wojciechowska M, Najda J, Chmielowska E, et al. Intermediate-dose Ara-C plus G-CSF for stem cell mobilization in patients with lymphoid malignancies, including predicted poor mobilizers. Bone Marrow Transpl. 2013;48:915–21.

    Article  CAS  Google Scholar 

  12. Czerw T, Sadus-Wojciechowska M, Michalak K, Najda J, Mendrek W, Sobczyk-Kruszelnicka M, et al. Increased efficacy of stem-cell chemomobilization with intermediate-dose cytarabine plus granulocyte colony-stimulating factor (G-CSF) compared with G-CSF alone in patients with multiple myeloma: results of a randomized trial. Biol Blood Marrow Transpl. 2019;25:248–55.

    Article  CAS  Google Scholar 

  13. Mitrus I, Smagur A, Fidyk W, Czech M, Prokop M, Chwieduk A, et al. Reduction of DMSO concentration in cryopreservation mixture from 10% to 7.5 and 5% has no impact on engraftment after autologous peripheral blood stem cell transplantation: results of a prospective, randomized study. Bone Marrow Transpl. 2018;53:274–80.

    Article  CAS  Google Scholar 

  14. Mitrus I, Smagur A, Giebel S, Gliwinska J, Prokop M, Glowala-Kosinska M, et al. A faster reconstitution of hematopoiesis after autologous transplantation of hematopoietic cells cryopreserved in 7.5% dimethyl sulfoxide if compared to 10% dimethyl sulfoxide containing medium. Cryobiology. 2013;63:327–31.

    Article  Google Scholar 

  15. Hui SK, Kapatoes J, Fowler J, Henderson D, Olivera G, Manon RR, et al. Feasibility study of helical tomotherapy for total body or total marrow irradiation. Med Phys. 2005;32:3214–24.

    Article  Google Scholar 

  16. Głowacki G, Miszczyk L, Ślosarek K, Jochymek B, Woźniak G, Matulewicz Ł, et al. Method of total marrow irradiation (TMI). Nowotw J Oncol. 2014;64:314–20.

    Article  Google Scholar 

  17. Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467–73.

    Article  CAS  Google Scholar 

  18. Palumbo A, Bringhen S, Bruno B, Falcone AP, Liberati AM, Grasso M, et al. Melphalan 200 mg/m2 versus melphalan 100 mg/m2 in newly diagnosed myeloma patients: a prospective, multicenter phase 3 study. Blood. 2010;115:1873–9.

    Article  CAS  Google Scholar 

  19. Auner HW, Iacobelli S, Sbianchi G, Knol-Bout C, Blaise D, Russell NH, et al. Melphalan 140 mg/m(2) or 200 mg/m(2) for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party. Haematologica. 2018;103:514–21.

    Article  CAS  Google Scholar 

  20. Hari P, Reece DE, Randhawa J, Knol-Bout C, Blaise D, Russell NH, 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. 2019;54:293–9.

    Article  CAS  Google Scholar 

  21. Belkacemi Y, Labopin M, Giebel S, Loganadane G, Miszczyk L, Michallet M, et al. Single-dose daily fractionation is not inferior to twice-a-day fractionated total-body irradiation before allogeneic stem cell transplantation for acute leukemia: a useful practice simplification resulting from the SARASIN study. Int J Radiat Oncol Biol Phys. 2018;102:515–26.

    Article  Google Scholar 

  22. Chaudhry HM, Bruce AJ, Wolf RC, Litzow MR, Hogan WJ, Patnaik MS, et al. The incidence and severity of oral mucositis among allogeneic hematopoietic stem cell transplantation patients: a systematic review. Biol Blood Marrow Transpl. 2016;22:605–16.

    Article  Google Scholar 

  23. Lahuerta JJ, Mateos MV, Martínez-López J, Grande C, de la Rubia J, Rosiñol L, et al. Busulfan 12 mg/kg plus melphalan 140 mg/m2 versus melphalan 200 mg/m2 as conditioning regimens for autologous transplantation in newly diagnosed multiple myeloma patients included in the PETHEMA/GEM2000 study. Haematologica. 2010;95:1913–20.

    Article  CAS  Google Scholar 

  24. Blanes M, Lahuerta JJ, González JD, Ribas P, Solano C, Alegre A, et al. Intravenous busulfan and melphalan as a conditioning regimen for autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: a matched comparison to a melphalan-only approach. Biol Blood Marrow Transpl. 2013;19:69–74.

    Article  CAS  Google Scholar 

  25. Palumbo A, Bringhen S, Bruno B, Falcone AP, Liberati AM, Grasso M, et al. Melphalan 200 mg/m(2) versus melphalan 100 mg/m(2) in newly diagnosed myeloma patients: a prospective, multicenter phase 3 study. Blood. 2010;115:1873–9.

    Article  CAS  Google Scholar 

  26. 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.

    Article  Google Scholar 

  27. 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.

    Article  CAS  Google Scholar 

  28. Martino M, Tripepi G, Messina G, Vincelli ID, Console G, Recchia AG, et al. A phase II, single-arm, prospective study of bendamustine plus melphalan conditioning for second autologous stem cell transplantation in de novo multiple myeloma patients through a tandem transplant strategy. Bone Marrow Transpl. 2016;51:1197–203.

    Article  CAS  Google Scholar 

  29. 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 Transpl. 2016;22:1391–6.

    Article  CAS  Google Scholar 

  30. Stadtmauer EA, Pasquini MC, Blackwell B, Hari P, Bashey A, Devine S, et al. Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma: results of the BMT CTN 0702 trial. J Clin Oncol. 2019;37:589–97.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Bone Marrow Transplantation and Onco-Hematology, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland

    Sebastian Giebel, Małgorzata Sobczyk-Kruszelnicka, Maria Saduś-Wojciechowska, Jacek Najda, Tomasz Czerw, Włodzimierz Mendrek & Jerzy Hołowiecki

  2. Department of Radiotherapy, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland

    Sławomir Blamek, Grzegorz Woźniak, Bożena Jochymek & Leszek Miszczyk

  3. Department of Radiotherapy Planning, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland

    Michał Radwan, Wojciech Leszczyński, Łukasz Dolla & Krzysztof Ślosarek

  4. Department of PET Diagnostics, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland

    Andrea D’Amico

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  1. Sebastian Giebel
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Correspondence to Sebastian Giebel.

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Giebel, S., Sobczyk-Kruszelnicka, M., Blamek, S. et al. Tandem autologous hematopoietic cell transplantation with sequential use of total marrow irradiation and high-dose melphalan in multiple myeloma. Bone Marrow Transplant 56, 1297–1304 (2021). https://doi.org/10.1038/s41409-020-01181-x

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