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. 2025 Oct;60(10):1361-1368.
doi: 10.1038/s41409-025-02675-2. Epub 2025 Jul 30.

Outcomes following different upfront stem cell transplantation strategies for multiple myeloma: a statistical perspective on behalf of the Chronic Malignancies Working Party of the EBMT

Simona Iacobelli #  1 , Stefan Schönland #  2 , Linda Koster  3 , Didier Blaise  4 , Emma Nicholson  5 , A E C Broers  6 , Patrice Chevallier  7 , Péter Reményi  8 , František Folber  9 , John G Gribben  10 , Erfan Nur  11 , Neil Rabin  12 , Matthew Collin  13 , Tobias Gedde-Dahl  14 , Katharine Bailey  15 , Paul Ferguson  16 , Matthias Stelljes  17 , Adrian Bloor  18 , Meral Beksac  19 , Joanna Drozd-Sokolowska  20 , Kavita Raj  12 , Patrick J Hayden  21 , Ibrahim Yakoub-Agha  22 , Donal P McLornan  12 , Nicolaus Kröger  23
Affiliations

Outcomes following different upfront stem cell transplantation strategies for multiple myeloma: a statistical perspective on behalf of the Chronic Malignancies Working Party of the EBMT

Simona Iacobelli et al. Bone Marrow Transplant. 2025 Oct.

Abstract

Multiple myeloma (MM) is a heterogenous malignant disease. Novel agents including bispecific antibodies and chimeric antigen receptor (CAR) T cells have improved response rates and patient outcome, but the majority of patients ultimately still relapse. High dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HCT) remains standard care of treatment for transplant-eligible patients. While single auto-HCT is commonly used, a planned tandem auto-HCT or auto-allo approach remains controversial, based on conflicting results from clinical trials. Here we compared the outcome of 24,936 MM patients aged between 20 and 65 years who underwent first auto-HCT during 2002-2015, reported to the EBMT registry, of whom 3683 and 878 got tandem auto-HCT and auto-allo-HCT respectively. We used non-standard statistical approaches to account for time-dependence of treatments and of their effects, including models with multiple timescales and dynamic prediction. Differences were reported by graphs of hazard functions, hazard ratios and conditional probabilities over time. For both OS and PFS, there was a limited but persistent advantage for the tandem auto-HCT group compared to single auto-HCT, and a clear advantage for the auto-allo-HCT group over both other strategies in the longer term, albeit at the cost of higher early mortality.

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Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: This manuscript follows the relevant guidelines and regulations as appropriate. The study is based on the EBMT registry data. EBMT centers commit to obtain informed consent according to the local regulations applicable at the time of transplantation in order to report pseudonymized data to the EBMT. All EBMT Registry studies are performed under the supervision of the EBMT Working Parties. This study was approved by the Chronic Malignancies Working Party of the EBMT.

Figures

Fig. 1
Fig. 1. Schemas representing the disease histories of interest as a Multi-State Models with 4 states, of which 1 absorbing, and 5 transitions.
Left: Overall Survival (OS). Right: Progression-Free Survival (PFS) (see Supplementary Material).
Fig. 2
Fig. 2. Overall survival and progression-free survival.
Overall survival (OS, solid line) and progression-free survival (PFS, dashed line) Kaplan–Meier estimates, with bands for the 95% CI at each time point, for the whole study population (n = 24,936).
Fig. 3
Fig. 3. Landmark Kaplan–Meier curves, from 9 months after first auto-HCT.
Left: Conditional overall survival. Right: Conditional progression-free survival. The landmark time was set at 9 months, being the maximum time of administration of a tandem transplantation approach.
Fig. 4
Fig. 4. Cox models, estimated Hazard Ratios (HR) with 95% CI.
Forest plots; the corresponding estimates are displayed in Supplementary Table S1. Effects of tandem transplants split in time periods since their administration. These are also shown in Supplementary Fig. S3 for comparison with the Poisson models. Adjustment for characteristics measured at first auto-HCT; Age and Calendar Year as continuous variables, HRs quantifying the effect of +10 years of age and of +1 calendar year respectively; Disease Status dichotomized as not being in Complete Remission (CR) versus being in CR. 95% CI not including the value 1 indicates significance at 5% level.
Fig. 5
Fig. 5. Hazard functions for Single auto-HCT, tandem auto-HCT and tandem auto-allo-HCT estimated using the Poisson model with two time scales.
The bands correspond to the limits of 95% CI. Pattern of characteristics at first auto: Age = 55, Calendar year = 2008, Disease Status = no Complete Remission. Timing of tandem transplant: 3 months after first auto-HCT.
Fig. 6
Fig. 6. Dynamic prediction curves.
Left: Conditional 8-years overall survival. Right: Conditional 3-years progression-free survival. Pattern of characteristics at first auto-HCT: Age = 55, Calendar year = 2008, Disease status = no complete remission. Timing of tandem transplant: 3-months after first auto-HCT. For example: For patients alive 36-months after first auto-HCT, the probability of being still alive 8-years later was 43.2% for single auto-HCT, 47.5% for tandem auto-HCT, and 56.4% for tandem auto-allo-HCT. For patients’ alive relapse/progression-free 36-months after first auto-HCT, the probability of being still alive relapse/progression-free after additional 3-years was 46.8% for single auto-HCT, 52.7% for tandem auto-HCT, and 71.5% for tandem auto-allo-HCT.
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