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Prognostic value and kinetic patterns of measurable residual disease following tandem autologous/allogeneic transplant in newly diagnosed myeloma patients

Bone Marrow Transplantation (2025)Cite this article

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Few trials have explored the clinical value of high-sensitivity measurable residual disease (MRD) following allogeneic (allo) hematopoietic cell transplant (HCT) [1,2,3]. In a prospective phase II study previously published in this journal, we included 39 young (≤50 years) and high-risk multiple myeloma (MM) patients who underwent upfront tandem autologous (auto)-allo HCT followed by bortezomib (BTZ) maintenance [4]. Both sibling and matched unrelated donor transplant recipients were conditioned respectively with fludarabine and cyclophosphamide or fludarabine and total body irradiation 200 cGy, with GVHD prophylaxis consisting of tacrolimus and mycophenolate mofetil as previously reported [4]. High-risk cytogenetics was defined as t(4;14) with ISS II or III, or del(17p13), t(14;16), t(14;20) and chromosome 1 abnormalities regardless of ISS. Those abnormalities were considered positive by FISH if present in ≥10% of bone marrow (BM) CD138 selected plasma cells. In addition, patients aged ≤50 years regardless of other factors were eligible [4]. Patients had BM MRD evaluations using next-generation flow cytometry [minimum sensitivity of 1 in 105 nucleated cells with a limit of detection (LOD) of 30 cells (0.0003%) and a limit of quantification (LOQ) of 50 cells (0.0005%)] prior to allo HCT, prior BTZ (4 months post allo HCT), then every 3 months for 2 years and at relapse However, MRD was neither used to modify nor to guide treatment before or after transplantation, and no patient was discontinued based on a positive MRD result. After a median follow-up of 48 months, our primary endpoint demonstrated a median progression-free survival (PFS) of 49 months with a 2-year PFS of 69% (95% CI: 52–81). In a multivariate analysis model including cytogenetics, ISS and MRD status, we demonstrated that MRD positivity prior to allo HCT (HR 3.75, p = 0.037) and 4 months after (prior BTZ) (HR 11.3, p = 0.018) were highly predictive of progressive disease (PD).

The incidence of PD at 5 years was 52% (95% CI: 35–66). In a multivariate analysis model which included cytogenetics, ISS and MRD status (defined negative as <30 myeloma cells out of 10 million bone marrow nucleated cell or <0.0003% myeloma events), MRD positivity prior to allo HCT (HR 3.20, p = 0.036) and 4 months post allo HCT (HR 5.56, p = 0.0005) remained highly predictive of PD (Fig. 1b), confirming our previous results. In a multivariate analysis model including moderate to severe chronic graft-versus-host disease (cGVHD), ≥grade 3 infection and MRD status, MRD positivity prior to allo HCT (HR 3.40, p = 0.029) and 4 months post allo HCT (HR 3.64, p = 0.014) remained the only factor predictive of PD (Fig. 1c). The number of clonal plasma cells prior to and 4 months after allo HCT was also inversely correlated to the best response achieved according to IMWG criteria [5] (Spearman r = −0.4793, p = 0.0020 and Spearman r = −0.4564, p = 0.0045 respectively).

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Fig. 1: Outcome and risk of progression.

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Acknowledgements

We wish to thank Mrs. Pascale Dubé and Mr. Sofiane Benhamou for their technical support for the flow cytometry analysis.

Funding

This work was supported by the Myeloma Canada Chair of Université de Montréal and the Maryse and William Brock Chair in Applied Research into Stem Cell Transplantation.

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Author notes

  1. These authors contributed equally: Rafik Terra, Stéphanie Thiant.

Authors and Affiliations

  1. Faculty of Medicine, Université de Montréal, Montréal, QC, Canada

    Rafik Terra, Jean-Sébastien Claveau, Jean Roy, Imran Ahmad & Richard LeBlanc

  2. Hematology-Oncology and Cell Therapy Institute, Hôpital Maisonneuve-Rosemont Research Center, Université de Montréal, Montréal, QC, Canada

    Rafik Terra, Stéphanie Thiant, Jean-Sébastien Claveau, Jean Roy, Imran Ahmad & Richard LeBlanc

  3. Centre de Recherche de l’Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada

    Stéphanie Thiant, Jean-Sébastien Claveau, Jean Roy, Imran Ahmad & Richard LeBlanc

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  1. Rafik Terra
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Contributions

RL, IA and JR conceived and planned the clinical trial, wrote the protocol, acquired data, analyzed the data, revised this manuscript. RT performed the analysis and interpretation on minimal residual disease assessment and revised the manuscript. ST analyzed the data, performed the statistics, wrote the manuscript (including first version). JSC revised the statistics and the manuscript.

Corresponding author

Correspondence to Richard LeBlanc.

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Competing interests

RL: consultancy for J&J, Amgen, Sanofi, Pfizer, Forus Therapeutics and GSK; honoraria from Janssen and Pfizer; research grants from Sanofi and Amgen; educational grant from Pfizer. IA: consultancy for AbbVie, Jazz Pharmaceuticals, Medexus, Sanofi, Vertex Pharmaceuticals. JR.: consultancy for Amgen, Sanofi, Janssen, and Forus Therapeutics. RT, ST and JSC: no conflict of interests.

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Terra, R., Thiant, S., Claveau, JS. et al. Prognostic value and kinetic patterns of measurable residual disease following tandem autologous/allogeneic transplant in newly diagnosed myeloma patients. Bone Marrow Transplant (2025). https://doi.org/10.1038/s41409-025-02626-x

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