Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

Impact of minimal residual disease (MRD) in salvage autologous stem cell transplantation for relapsed myeloma: results from the NCRI Myeloma X (intensive) trial

Bone Marrow Transplantation volume 59, pages 431–434 (2024)Cite this article

Subjects

Minimal residual disease (MRD) is a reproducible and independent predictor of both progression-free (PFS) and overall (OS) survival in multiple myeloma [1]. These data along with ever improving survival outcomes has led to consideration of MRD as a potential surrogate end point for regulatory purposes and an appropriate endpoint in academic studies which could accelerate evaluation of novel agents [2]. The value of MRD in myeloma has primarily been demonstrated in the upfront setting and following autologous stem cell transplantation (ASCT) in particular [3]. Improving survival is increasingly reported in the relapse setting and here we examine the role of MRD (assessed by multi parameter flow cytometry) in first relapse following prior autologous stem cell transplantation (ASCT) in the context of the NCRI Myeloma X (intensive) trial.

The NCRI Myeloma X (intensive) trial was a randomized, multicenter, phase III trial for which the study protocol and clinical results have been previously described [4, 5]. The protocol was approved by the relevant institutional review boards and all patients provided written informed consent. Eligible patients with progressive or relapsed disease requiring treatment after a first ASCT with durable response (>12 months) who completed re-induction chemotherapy with bortezomib, adriamycin and dexamethasone (PAD) were randomized to receive either salvage ASCT or non-transplant consolidation (NTC: oral cyclophosphamide in 12 weekly cycles). Bone marrow aspirates were obtained after re-induction and at day 100 after salvage ASCT or 30 days after completion of NTC for comparability. Flow cytometric analysis was performed by a single laboratory using a previously published methodology with a lower limit of detection (LOD) of 0.004% [6]. Statistical analysis was also performed as reported previously, with time to progression (TTP) and OS data landmarked to the date of the MRD assessment rather than the date of randomisation. In exploratory multivariable analysis, the prognostic potential of MRD for these end points was assessed adjusting for patient age at trial entry, sex, international staging system (ISS; I vs II vs III), durability of response after first ASCT (<18 vs ≥ 18 months) and whether or not stem cell mobilization was performed on trial (yes vs no).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Outcome according to minimal residual disease (MRD).
Fig. 2: Prognostic significance of MRD is independent of treatment received.

References

  1. Munshi NC, Avet-Loiseau H, Rawstron AC, Owen RG, Child JA, Thakurta A, et al. Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: a meta-analysis. JAMA Oncol. 2017;3:28–35.

    Article  PubMed  PubMed Central  Google Scholar 

  2. European Medicines Agency Oncology Working Party. Guideline on the use of minimal residual disease as a clinical endpoint in multiple myeloma studies. 1st ed. London, UK: European Medicines Agency Press; 2018.

  3. Paiva B, Vidriales M-B, Cervero J, Mateo G, Perez JJ, Sureda A, et al. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood. 2008;112:4017–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cook G, Williams C, Brown JM, Cairns DA, Cavenagh J, Snowden J. et al. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:874–85.

    Article  CAS  PubMed  Google Scholar 

  5. Cook G, Ashcroft AJ, Cairns DA, Williams C, Hockaday A, Cavenagh J, et al. The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Lancet Haematol. 2016;3:e340–351.

    Article  PubMed  Google Scholar 

  6. Rawstron AC, Child JA, de Tute RM, Davies FE, Gregory W, Bell SE, et al. Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study. J Clin Oncol J Am Soc Clin Oncol 2013;31:2540–7.

    Article  Google Scholar 

  7. Ferrero S, Ladetto M, Drandi D, Cavallo F, Genuardi E, Urbano M, et al. Long-term results of the GIMEMA VEL-03-096 trial in MM patients receiving VTD consolidation after ASCT: MRD kinetics’ impact on survival. Leukemia. 2015;29:689–95.

    Article  CAS  PubMed  Google Scholar 

  8. Siegel DS, Dimopoulos MA, Ludwig H, Facon T, Goldschmidt H, Jakubowiak A, et al. Improvement in overall survival with carfilzomib, lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol J Am Soc Clin Oncol 2018;36:728–34.

    Article  CAS  Google Scholar 

  9. Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, et al. Oral ixazomib, lenalidomide and dexamethasone for multiple myeloma. N Engl J Med 2016;374:1621–34.

    Article  CAS  PubMed  Google Scholar 

  10. Chari A, Suvannasankha A, Fay JW, Arnulf B, Kaufman JL, Ifthikharuddin JJ. et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130:974–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Paiva B, Chandia M, Puig N, Vidriales MB, Perez JJ, Lopez-Corral L, et al. The prognostic value of multiparameter flow cytometry minimal residual disease assessment in relapsed multiple myeloma. Haematologica. 2015;100:e53–55.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Mateos M-V, Sonneveld P, Hungria V, Nooka AK, Estell JA, Barreto W, et al. Daratumumab, bortezomib, and dexamethasone versus bortezomib and dexamethasone in patients with previously treated multiple myeloma: three-year follow-up of CASTOR. Clin Lymphoma Myeloma Leuk. 2020;20:509–18.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This trial was registered with ClinicalTrials.gov, number NCT00747877, and the European Clinical Trials Database, number 2006-005890-24. The study was funded by Cancer Research UK [CRUK/06/018] with further support from Janssen-Cilag and Chugai Pharma UK. Data collection and the final analysis were performed by the Clinical Trials Research Unit, University of Leeds. We thank the study investigators, coordinators, nurses, research staff, and patients and families for their contributions to this study. The study was approved by the national ethics review board (Multicentre Research Ethics Committee, UK), institutional review boards of the participating centers, approved by the competent regulatory authority (Medicines and Healthcare Products Regulatory Agency, UK) and was conducted according to the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice.

Author information

Authors and Affiliations

  1. Haematological Malignancy Diagnostic Service, Leeds Teaching Hospitals Trust, Leeds, UK

    Ruth M. de Tute, Andy C. Rawstron & Roger G. Owen

  2. Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK

    Gordon Cook, David A. Cairns, Julia M. Brown & Anna Hockaday

  3. Department of Haematology, Barts & The London NHS Trust, London, UK

    Jamie Cavenagh

  4. Mid-Yorks NHS Trust, Wakefield, UK

    A. John Ashcroft

  5. Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust & Department of Endocrinology & Metabolism, University of Sheffield, Sheffield, UK

    John A. Snowden

  6. Department of Haematology, University College London, London, UK

    Kwee Yong

  7. Department of Clinical Haematology, Manchester Royal Infirmary, Manchester Foundation Trust, Manchester, UK

    Eleni Tholouli

  8. University Hospital Southampton NHS Foundation Trust, Southampton, UK

    Matthew Jenner

  9. Institute of Immunology and Immunotherapy University of Birmingham, Birmingham, UK

    Mark T. Drayson

  10. College of Myeloma, Belfast, UK

    Treen C. M. Morris

Authors
  1. Ruth M. de Tute
    View author publications

    Search author on:PubMed Google Scholar

  2. Gordon Cook
    View author publications

    Search author on:PubMed Google Scholar

  3. David A. Cairns
    View author publications

    Search author on:PubMed Google Scholar

  4. Julia M. Brown
    View author publications

    Search author on:PubMed Google Scholar

  5. Jamie Cavenagh
    View author publications

    Search author on:PubMed Google Scholar

  6. A. John Ashcroft
    View author publications

    Search author on:PubMed Google Scholar

  7. John A. Snowden
    View author publications

    Search author on:PubMed Google Scholar

  8. Kwee Yong
    View author publications

    Search author on:PubMed Google Scholar

  9. Eleni Tholouli
    View author publications

    Search author on:PubMed Google Scholar

  10. Matthew Jenner
    View author publications

    Search author on:PubMed Google Scholar

  11. Anna Hockaday
    View author publications

    Search author on:PubMed Google Scholar

  12. Mark T. Drayson
    View author publications

    Search author on:PubMed Google Scholar

  13. Treen C. M. Morris
    View author publications

    Search author on:PubMed Google Scholar

  14. Andy C. Rawstron
    View author publications

    Search author on:PubMed Google Scholar

  15. Roger G. Owen
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Research design: RM de T, GC, RGO. Provision of study materials or patients: GC, JC, JA, JAS, CW, KY, ET, MJ, TCMM, RGO. Collection and assembly of data: RM de T, DAC, AH, MTD, ACR, RGO. Data analysis and interpretation: RM de T, GC, DAC, JMB, MTD, ACR, RGO. Manuscript writing, final approval of manuscript: All authors.

Corresponding authors

Correspondence to Ruth M. de Tute or Gordon Cook.

Ethics declarations

Competing interests

GC has received grant/research support from Celgene/BMS, Janssen, and Takeda & Honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda, Roche, Oncopeptides and Sanofi. DAC has received research funding top institution from Celgene Corporation, Amgen, Millennium Pharmaceuticals, and Merck Sharp and Dohme. JMB is Deputy Chair of the NIHR HTA Funding Committee. AJA has received speaking/advisory boards fees from Janssen, Celgene and Amgen. JAS declares honoraria for speaking from Janssen and Gilead, an advisory board from Medac, and IDMC membership for a clinical trial supported by Kiadis. ET has received advisory board &/or speakers fees from Celgene, Gilead/Kite, Janssen, Jazz, Novartis and Pfizer. Also received consultancy for educational materials from Gilead/Kite MTD has shares in Abingdon Health (a biodiagnostics company). ACR AbbVie: Advisory Board, Research Funding &/or Honoraria from AbbVie, Beckman Coulter, Celgene, Gilead, Janssen and Pharmacyclics, Consultancy fees from Gilead and Pharmacyclics, Royalties, research funding and honararia from BD Bio-sciences and is director of Medical Education and Developments Services Ltd. RGO has received honoraria from Celgene, Janssen, Astra Zeneca, Beigene and advisory boards fees from Janssen and Beigene.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Tute, R.M., Cook, G., Cairns, D.A. et al. Impact of minimal residual disease (MRD) in salvage autologous stem cell transplantation for relapsed myeloma: results from the NCRI Myeloma X (intensive) trial. Bone Marrow Transplant 59, 431–434 (2024). https://doi.org/10.1038/s41409-023-02164-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41409-023-02164-4

Search

Advanced search

Quick links