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Busulfan plus melphalan versus high-dose melphalan as a conditioning regimen for autologous stem cell transplantation in multiple myeloma with high-risk features (KMM 2015)

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Abstract

Despite the development of effective agents for multiple myeloma (MM), the management of patients with high-risk MM (HRMM) is challenging. High-dose treatment followed by autologous stem cell transplantation (ASCT) is regarded as upfront treatment for transplant-eligible patients with HRMM. In the present study, we retrospectively investigated the efficacies of two conditioning regimens for upfront ASCT in newly diagnosed patients with MM and high-risk features: high-dose melphalan (HDMEL; 200 mg/m2) and busulfan plus melphalan (BUMEL). In total, 221 patients underwent ASCT between May 2005 and June 2021; among these 221 patients, 79 had high-risk cytogenetic abnormalities. In patients with high-risk cytogenetics, BUMEL showed a tendency toward longer overall survival (OS) and progression-free survival (PFS) compared to HDMEL (median OS; not reached vs. 53.2 months; P = 0.091, median PFS; not reached vs. 31.7 months; P = 0.062). Additionally, multivariate analysis revealed that BUMEL was significantly associated with PFS (hazard ratio = 0.37, 95% confidence interval = 0.15–0.89, P = 0.026). We compared BUMEL with HDMEL in patients with other high-risk features, such as high lactate dehydrogenase level, extramedullary disease, and poor response to frontline therapy. Notably, among patients with less than very good partial response (VGPR) to frontline therapy, median PFS was significantly longer in the BUMEL group than in the HDMEL group (55.1 vs. 17.3 months, respectively; P = 0.011). These findings indicate that BUMEL may be an effective conditioning regimen for upfront ASCT in MM patients with high-risk cytogenetics; BUMEL may be more appropriate than HDMEL for patients with less than VGPR to frontline therapy.

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Data from this study can be obtained from the corresponding author on reasonable request.

References

  1. Raza S, Safyan RA, Rosenbaum E, Bowman AS, Lentzsch S (2017) Optimizing current and emerging therapies in multiple myeloma: a guide for the hematologist. Ther Adv Hematol 8(2):55–70

    Article  CAS  PubMed  Google Scholar 

  2. Brenner H, Gondos A, Pulte D (2008) Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood 111(5):2521–2526

    Article  CAS  PubMed  Google Scholar 

  3. Lahuerta JJ, Grande C, Blade J, Martínez-López J, de la Serna J, Alegre A, Garcia LJ, Caballero D, de la Rubia J, Marín J et al (2002) Myeloablative treatments for multiple myeloma: update of a comparative study of different regimens used in patients from the Spanish registry for transplantation in multiple myeloma. Leuk Lymphoma 43(1):67–74

    Article  PubMed  Google Scholar 

  4. Ria R, Falzetti F, Ballanti S, Minelli O, Di Ianni M, Cimminiello M, Vacca A, Dammacco F, Martelli MF, Tabilio A (2004) Melphalan versus melphalan plus busulphan in conditioning to autologous stem cell transplantation for low-risk multiple myeloma. Hematol J 5(2):118–122

    Article  CAS  PubMed  Google Scholar 

  5. Chanan-Khan AA, Giralt S (2010) Importance of achieving a complete response in multiple myeloma, and the impact of novel agents. J Clin Oncol 28(15):2612–2624

    Article  CAS  PubMed  Google Scholar 

  6. Nooka AK, Kaufman JL, Muppidi S, Langston A, Heffner LT, Gleason C, Casbourne D, Saxe D, Boise LH, Lonial S (2014) Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia 28(3):690–693

    Article  CAS  PubMed  Google Scholar 

  7. Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, Arnulf B, Macro M, Belhadj K, Garderet L et al (2017) Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N Engl J Med 376(14):1311–1320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Durie BGM, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, Thakuri M, Reu F, Reynolds CM, Sexton R et al (2017) Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet 389(10068):519–527

    Article  CAS  PubMed  Google Scholar 

  9. Rajkumar SV (2022) Multiple myeloma: 2022 update on diagnosis, risk stratification, and management. American Journal of Hematology 97(8):1086–1107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Roussel M, Moreau P, Huynh A, Mary JY, Danho C, Caillot D, Hulin C, Fruchart C, Marit G, Pégourié B 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

    Article  CAS  PubMed  Google Scholar 

  11. Bashir Q, Thall PF, Milton DR, Fox PS, Kawedia JD, Kebriaei P, Shah N, Patel K, Andersson BS, Nieto YL et al (2019) Conditioning with busulfan plus melphalan versus melphalan alone before autologous haemopoietic cell transplantation for multiple myeloma: an open-label, randomised, phase 3 trial. Lancet Haematol 6(5):e266–e275

    Article  PubMed  PubMed Central  Google Scholar 

  12. Roussel M, Lauwers-Cances V, Macro M, Leleu X, Royer B, Hulin C, Karlin L, Perrot A, Touzeau C, Chrétien ML et al (2022) Bortezomib and high-dose melphalan conditioning regimen in frontline multiple myeloma: an IFM randomized phase 3 study. Blood 139(18):2747–2757

    Article  CAS  PubMed  Google Scholar 

  13. Saini N, Bashir Q, Milton DR, Tang G, Delgado R, Rondon G, Popat UR, Hosing CM, Nieto Y, Kebriaei P et al (2020) Busulfan and melphalan conditioning is superior to melphalan alone in autologous stem cell transplantation for high-risk MM. Blood Adv 4(19):4834–4837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Haas PS, Bauchmüller K, Kühnemund A, Finke J, Ihorst G, Engelhardt M (2006) Efficacy of diverse high-dose regimens followed by autologous peripheral blood stem cell transplantation in consecutive multiple myeloma patients: a single-centre analysis over a 12-year period. Ann Hematol 85(3):191–193

    Article  CAS  PubMed  Google Scholar 

  15. Song GY, Jung SH, Kim JS, Eom HS, Moon JH, Yhim HY, Kim K, Min CK, Lee JJ (2022) Busulfan and thiotepa as a conditioning regimen for autologous stem cell transplantation in patients with multiple myeloma: A study of the Korean Multiple Myeloma Working Party (KMMWP-1801 study). Front Oncol 12:959949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Park SS, Kim K, Kim SJ, Lee JH, Yoon SS, Mun YC, Lee JJ, Eom HS, Kim JS, Min CK (2019) A Phase I/II, Open-Label, Prospective, Multicenter Study to Evaluate the Efficacy and Safety of Lower Doses of Bortezomib Plus Busulfan and Melphalan as a Conditioning Regimen in Patients with Multiple Myeloma Undergoing Autologous Peripheral Blood Stem Cell Transplantation: The KMM103 Study. Biol Blood Marrow Transplant 25(7):1312–1319

    Article  CAS  PubMed  Google Scholar 

  17. Nieto Y, Valdez BC, Pingali SR, Bassett R, Delgado R, Nguyen J, Shah N, Popat U, Jones RB, Andersson BS et al (2017) 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 4(6):e283–e292

    Article  PubMed  PubMed Central  Google Scholar 

  18. Talamo G, Claxton DF, Dougherty DW, Ehmann CW, Sivik J, Drabick JJ, Rybka W (2009) BU and CY as conditioning regimen for autologous transplant in patients with multiple myeloma. Bone Marrow Transplant 44(3):157–161

    Article  CAS  PubMed  Google Scholar 

  19. Abidi MH, Agarwal R, Ayash L, Deol A, Al-Kadhimi Z, Abrams J, Cronin S, Ventimiglia M, Lum L, Zonder J et al (2012) Melphalan 180 mg/m2 can be safely administered as conditioning regimen before an autologous stem cell transplantation (ASCT) in multiple myeloma patients with creatinine clearance 60 mL/min/1.73 m2 or lower with use of palifermin for cytoprotection: results of a phase I trial. Biol Blood Marrow Transplant 18(9):1455–1461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Blanes M, Lahuerta JJ, González JD, Ribas P, Solano C, Alegre A, Bladé J, San Miguel JF, Sanz MA, de la Rubia J (2013) 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 Transplant 19(1):69–74

    Article  CAS  PubMed  Google Scholar 

  21. Moreau P, Facon T, Attal M, Hulin C, Michallet M, Maloisel F, Sotto JJ, Guilhot F, Marit G, Doyen C et al (2002) 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 Myélome 9502 randomized trial. Blood 99(3):731–735

    Article  CAS  PubMed  Google Scholar 

  22. Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, Blade J, Richardson P, Orlowski R, Siegel D et al (2011) Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood 117(18):4691–4695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sevcikova S, Minarik J, Stork M, Jelinek T, Pour L, Hajek R (2019) Extramedullary disease in multiple myeloma - controversies and future directions. Blood Rev 36:32–39

    Article  PubMed  Google Scholar 

  24. Kanda Y (2013) Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 48(3):452–458

    Article  CAS  PubMed  Google Scholar 

  25. Mateos MV, Martínez BP, González-Calle V (2021) High-risk multiple myeloma: how to treat at diagnosis and relapse? Hematology Am Soc Hematol Educ Program 2021(1):30–36

    Article  PubMed  PubMed Central  Google Scholar 

  26. Sonneveld P, Avet-Loiseau H, Lonial S, Usmani S, Siegel D, Anderson KC, Chng WJ, Moreau P, Attal M, Kyle RA et al (2016) Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood 127(24):2955–2962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. D'Agostino M, Cairns DA, Lahuerta JJ, Wester R, Bertsch U, Waage A, Zamagni E, Mateos M-V, Dall'Olio D, Van De Donk NW et al (2022) Second Revision of the International Staging System (R2-ISS) for Overall Survival in Multiple Myeloma: A European Myeloma Network (EMN) Report Within the HARMONY Project. J Clin Oncol 40(29):3406–3418

    Article  CAS  PubMed  Google Scholar 

  28. Mangiacavalli S, Pompa A, Ferretti V, Klersy C, Cocito F, Varettoni M, Cartia CS, Cazzola M, Corso A (2017) The possible role of burden of therapy on the risk of myeloma extramedullary spread. Ann Hematol 96(1):73–80

    Article  PubMed  Google Scholar 

  29. Vij R, Kumar S, Zhang MJ, Zhong X, Huang J, Dispenzieri A, Abidi MH, Bird JM, Freytes CO, Gale RP et al (2015) Impact of pretransplant therapy and depth of disease response before autologous transplantation for multiple myeloma. Biol Blood Marrow Transplant 21(2):335–341

    Article  PubMed  Google Scholar 

  30. Lahuerta JJ, Martinez-Lopez J, Grande C, Bladé J, Serna JDL, Alegre A, García-Laraña J, Caballero D, Sureda A, Rubia JDL et al (2000) Conditioning regimens in autologous stem cell transplantation for multiple myeloma: a comparative study of efficacy and toxicity from the Spanish Registry for Transplantation in Multiple Myeloma. Br J Haematol 109(1):138–147

    Article  CAS  PubMed  Google Scholar 

  31. Park S, Shin DY, Hong J, Kim I, Koh Y, Byun JM, Yoon SS (2021) Busulfan plus melphalan versus melphalan alone conditioning regimen after bortezomib based triplet induction chemotherapy for patients with newly diagnosed multiple myeloma. Ther Adv Hematol 12:20406207211012985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hawsun, Jeollanam-do, Republic of Korea

    Mihee Kim, Je-Jung Lee & Sung-Hoon Jung

  2. Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea

    Chang-Ki Min

  3. Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea

    Ji Yun Lee

  4. Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea

    Jae-Cheol Jo

  5. Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea

    Sung-Soo Yoon

  6. Inje University College of Medicine, Haeundae Paik Hospital, Busan, Republic of Korea

    Sung-Nam Lim

  7. Keimyung University, Dongsan Medical Center, Daegu, Republic of Korea

    Young Rok Do

  8. Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea

    Kihyun Kim

  9. Gachon University Gil Medical Center, Incheon, Republic of Korea

    Jae Hoon Lee & Kwai Han Yoo

  10. Daegu Catholic University Hospital, Daegu, Korea

    Sung Hwa Bae

  11. Chung-ang University Hospital, Seoul, Republic of Korea

    Jun Ho Yi

  12. National Cancer Center, Goyang, Republic of Korea

    Jongheon Jung & Hyeon-Seok Eom

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Contributions

JSH and JJL designed the study; MK and SHJ prepared the manuscript; CKM, JYL, JCJ, SSY, SNL, YRD, KK, JHL, KHY, SHB, JHY, JJ, and HSE critically reviewed the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Hyeon-Seok Eom or Sung-Hoon Jung.

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This study was approved by the institutional ethics committees of participating institutions and was conducted in accordance with the Declaration of Helsinki. The institutional ethics committees waived the requirement for informed patient consent because of the retrospective study design.

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Kim, M., Lee, JJ., Min, CK. et al. Busulfan plus melphalan versus high-dose melphalan as a conditioning regimen for autologous stem cell transplantation in multiple myeloma with high-risk features (KMM 2015). Ann Hematol 102, 2233–2240 (2023). https://doi.org/10.1007/s00277-023-05308-0

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