Stem Cell Transplant Outperforms DMTs in Drug-Resistant Relapsing MS

When high-efficacy drugs stop holding relapsing-remitting multiple sclerosis (RRMS) in check, neurologists increasingly weigh an intensive option that aims to reset the immune system rather than suppress it indefinitely.

A review synthesizing more than 3 decades of transplant data concluded that autologous hematopoietic stem cell transplantation (AHSCT) produced higher rates of no evidence of disease activity (NEDA), a lower annualized relapse rate, and sustained functional gains compared with disease-modifying therapies (DMTs), all with very low treatment-related mortality.¹

Where Transplant Fits After High-Efficacy DMTs Fail

The clinical rationale for AHSCT rested on a persistent treatment gap, as many people with RRMS continued to relapse or accumulate disability despite potent immunomodulators. International guidance has increasingly formalized the procedure's place in that pathway. In a 2025 consensus statement, 2 European societies recommended AHSCT as an escalation option for highly active relapsing MS after failure of at least one high-efficacy DMT and before irreversible disability develops, while noting that its optimal position in the treatment algorithm remained uncertain.² That framing set up the review's central question of when and in which patients transplantation will deliver the most benefit.

MS is an autoimmune, inflammatory, and neurodegenerative disorder of the central nervous system now widely linked to Epstein-Barr virus infection and molecular mimicry, in which autoreactive lymphocytes attack myelin.¹ AHSCT, used in MS since the 1990s, worked by collecting a patient's own stem cells, delivering conditioning chemotherapy to eradicate the autoreactive immune repertoire, and reinfusing the graft to rebuild a more tolerant immune system. That mechanism helped explain why the procedure produced longer-lasting responses than agents that suppress disease only while being taken.

The pivotal comparison came from a randomized phase 3 trial that enrolled 110 participants with highly active RRMS, evenly assigned to AHSCT or DMTs (NCT00273364). Disease progression occurred in 6% of transplant recipients versus 67% of those on DMTs, and 85% of transplant recipients remained relapse-free at 5 years compared with 3% of those on DMTs. Transplant recipients also gained walking speed and arm function while accumulating fewer new MRI lesions. Subsequent cohorts reinforced the pattern, with more than 70% of people with RRMS showing disease-worsening-free survival at 10 years post-transplant. European guidelines recommended AHSCT for younger patients (under 45 years) with an Expanded Disability Status Scale score of 5.5 or lower and high clinical and MRI activity despite DMTs.

Conditioning Intensity and Transplant Timing Shaping Outcomes

The optimal conditioning regimen remained unsettled. High-intensity regimens using busulfan or total body irradiation fell out of favor because of transplant-related mortality and toxicities, including secondary autoimmune disease and hepatic veno-occlusive disease.

Across studies, intermediate-intensity BEAM (carmustine, etoposide, cytarabine, melphalan) plus antithymocyte globulin (ATG) and low-intensity cyclophosphamide plus ATG emerged as the preferred approaches, balancing relapse control against adverse effects. Timing also mattered, as the authors reported that transplantation delivered the most benefit soon after documented DMT failure in active RRMS or early active secondary progressive disease, while offering little to people with nonactive progressive disease dominated by neurodegeneration. Ongoing phase 3 trials, including BEAT-MS (NCT04047628) and RAM-MS (NCT03477500), were positioned to clarify how transplant compares with the most effective DMTs.

As a narrative review, the analysis pooled findings across heterogeneous designs, sample sizes, and conditioning protocols rather than a single harmonized dataset. Results for progressive MS remained mixed, with reported 5-year progression-free survival ranging from 0% to 78% across cohorts, and the pivotal randomized trial was constrained by a small sample and open-label design. The authors also noted that no consensus conditioning regimen had been established and that the role of AHSCT as a first-line option in treatment-naive patients was undefined.

The authors wrote that "Studies indicate that AHSCT can achieve higher rates of no evidence of disease activity compared with DMTs, a lower annualized relapse rate, and potential slowing of progressive disease with very low treatment-related mortality."

References

1. Condamoor S, Vittayawacharin P, Sy M, Kongtim P, Ciurea SO. Autologous stem cell transplantation for multiple sclerosis. Transplant Cell Ther. 2026;32:535-547. doi:10.1016/j.jtct.2025.12.1001
2. Muraro PA, Mariottini A, Greco R, et al. Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis and neuromyelitis optica spectrum disorder: recommendations from ECTRIMS and the EBMT. Nat Rev Neurol. 2025;21(3):140-158. doi:10.1038/s41582-024-01050-x