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Peer-reviewedCC BYHematology, Transfusion and Cell Therapy

QUANTIFYING THE IMPACT OF TRANSPLANT-RELATED MORTALITY ON THE CLINICAL BENEFIT OF AUTOLOGOUS STEM CELL TRANSPLANTATION: A MATHEMATICAL MODEL OF TREATMENT TRANSPORTABILITY

  • Sebastião José ISMAEL1
  • Fernando CALLERA2
  1. 1Centro de Hematologia de Ribeirão Preto, Ribeirão Preto, SP, Brazil
  2. 2Faculdade de Ciencias Médicas de São José dos Campos, (Humanitas), São José dos Campos, SP, Brazil; Centro de Hematologia do Vale, São José dos Campos, SP, Brazil
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Abstract

Background: Autologous stem cell transplantation (ASCT) remains the standard consolidative therapy for transplant-eligible patients with multiple myeloma. However, the clinical benefit observed in randomized trials may not be fully reproduced in routine practice because transplant-related mortality (TRM) varies across transplant centers. We developed a mathematical model to quantify how center-specific TRM influences the effective benefit of ASCT. Aim: To develop and validate a mathematical model estimating the impact of excess transplant-related mortality on the expected clinical benefit of upfront ASCT in multiple myeloma. Methods: The Transportability-Based Risk-Adjusted Benefit Model (TRABM) was developed using a competing-risk approach in which early transplant-related death prevents patients from achieving the survival benefit of ASCT. The model incorporates three variables: absolute treatment benefit (Δ), baseline outcome in the control group (B₀), and excess transplant-related mortality (p), generating estimates of adjusted net benefit and treatment transportability. Model parameters were derived from pooled phase III trials (IFM 2009, DETERMINATION, EMN02/HO95, and FORTE), corresponding to an estimated progression-free survival gain of 16.5 months over a baseline of 32 months. Sensitivity analyses evaluated excess TRM from 0.5% to 10%. Results: Increasing excess TRM produced a progressive, nearly linear reduction in the net clinical benefit of ASCT. The estimated progression-free survival gain declined from 16.3 months at 0.5% excess mortality to 16.0 months at 1%, 15.5 months at 2%, 14.1 months at 5%, and 11.6 months at 10%. More than 95% of the benefit observed in randomized trials was preserved when excess TRM remained close to 1%, whereas clinically meaningful attenuation occurred with higher mortality rates. Simulations also demonstrated that patients with greater baseline treatment benefit maintained favorable outcomes despite modest increases in TRM, whereas lower-benefit scenarios lost clinical advantage earlier. Conclusion: The TRABM demonstrates that the effectiveness of ASCT depends not only on treatment efficacy but also on the quality and safety of transplant programs. Even modest increases in transplant-related mortality substantially reduce the benefit expected from clinical trials. This mathematical framework provides an objective tool for translating trial results into real-world practice and may support benchmarking of transplant centers, quality improvement initiatives, and individualized decision-making in hematopoietic stem cell transplantation.

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Cite

BibTeXRIS
BibTeX
@article{ismael2026quantifying,
  title = {{QUANTIFYING THE IMPACT OF TRANSPLANT-RELATED MORTALITY ON THE CLINICAL BENEFIT OF AUTOLOGOUS STEM CELL TRANSPLANTATION: A MATHEMATICAL MODEL OF TREATMENT TRANSPORTABILITY}},
  author = {Sebastião José ISMAEL and Fernando CALLERA},
  journal = {Hematology, Transfusion and Cell Therapy},
  year = {2026},
  month = oct,
  doi = {10.1016/j.htct.2026.107923},
  url = {https://doi.org/10.1016/j.htct.2026.107923},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - QUANTIFYING THE IMPACT OF TRANSPLANT-RELATED MORTALITY ON THE CLINICAL BENEFIT OF AUTOLOGOUS STEM CELL TRANSPLANTATION: A MATHEMATICAL MODEL OF TREATMENT TRANSPORTABILITY
AU  - Sebastião José ISMAEL
AU  - Fernando CALLERA
PY  - 2026
DA  - 2026/10/23
JO  - Hematology, Transfusion and Cell Therapy
DO  - 10.1016/j.htct.2026.107923
UR  - https://doi.org/10.1016/j.htct.2026.107923
AB  - Background: Autologous stem cell transplantation (ASCT) remains the standard consolidative therapy for transplant-eligible patients with multiple myeloma. However, the clinical benefit observed in randomized trials may not be fully reproduced in routine practice because transplant-related mortality (TRM) varies across transplant centers. We developed a mathematical model to quantify how center-specific TRM influences the effective benefit of ASCT. Aim: To develop and validate a mathematical model estimating the impact of excess transplant-related mortality on the expected clinical benefit of upfront ASCT in multiple myeloma. Methods: The Transportability-Based Risk-Adjusted Benefit Model (TRABM) was developed using a competing-risk approach in which early transplant-related death prevents patients from achieving the survival benefit of ASCT. The model incorporates three variables: absolute treatment benefit (Δ), baseline outcome in the control group (B₀), and excess transplant-related mortality (p), generating estimates of adjusted net benefit and treatment transportability. Model parameters were derived from pooled phase III trials (IFM 2009, DETERMINATION, EMN02/HO95, and FORTE), corresponding to an estimated progression-free survival gain of 16.5 months over a baseline of 32 months. Sensitivity analyses evaluated excess TRM from 0.5% to 10%. Results: Increasing excess TRM produced a progressive, nearly linear reduction in the net clinical benefit of ASCT. The estimated progression-free survival gain declined from 16.3 months at 0.5% excess mortality to 16.0 months at 1%, 15.5 months at 2%, 14.1 months at 5%, and 11.6 months at 10%. More than 95% of the benefit observed in randomized trials was preserved when excess TRM remained close to 1%, whereas clinically meaningful attenuation occurred with higher mortality rates. Simulations also demonstrated that patients with greater baseline treatment benefit maintained favorable outcomes despite modest increases in TRM, whereas lower-benefit scenarios lost clinical advantage earlier. Conclusion: The TRABM demonstrates that the effectiveness of ASCT depends not only on treatment efficacy but also on the quality and safety of transplant programs. Even modest increases in transplant-related mortality substantially reduce the benefit expected from clinical trials. This mathematical framework provides an objective tool for translating trial results into real-world practice and may support benchmarking of transplant centers, quality improvement initiatives, and individualized decision-making in hematopoietic stem cell transplantation.
SN  - 2531-1379
SN  - 2531-1387
ER  -