What are the treatment options for managing Multiple Sclerosis (MS) progression in adults?

Treatment Options for Managing MS Progression in Adults

For adults with relapsing-remitting MS that has failed high-efficacy disease-modifying therapy, autologous haematopoietic stem cell transplantation (AHSCT) should be considered as the most effective escalation therapy, demonstrating superior long-term outcomes with 87% progression-free survival at 10 years in optimal candidates. 1

Treatment Strategy Based on MS Subtype

Relapsing-Remitting MS (RRMS)

Initial Treatment Approach:

• Start with high-efficacy DMTs (ocrelizumab, ofatumumab, natalizumab, alemtuzumab, or cladribine) rather than moderate-efficacy options, as early aggressive treatment yields better long-term outcomes 1
• Oral dimethyl fumarate or teriflunomide can be considered for first-line therapy in less aggressive presentations 2, 3
• Injectable interferons (beta-1a, beta-1b) and glatiramer acetate remain FDA-approved options for relapsing forms including active secondary progressive disease 4, 5

Escalation Criteria: When patients demonstrate treatment failure—defined as new relapses, new/enlarging T2 lesions on MRI, gadolinium-enhancing lesions, or sustained EDSS progression—immediate escalation is warranted 6. The 2025 ECTRIMS-EBMT guidelines represent a paradigm shift, now endorsing AHSCT as standard of care for treatment-refractory disease rather than a last resort 1.

AHSCT: The Most Effective Option for Refractory Disease

Optimal Candidate Profile:

• Age <45 years 1
• Disease duration <10 years 1
• EDSS score <4.0 1
• High focal inflammation present 1
• Failed ≥1 high-efficacy DMT after meaningful treatment period 1

Outcomes Data: The most recent Swedish cohort studies demonstrate 87% progression-free survival at 10 years with zero transplant-related mortality in relapsing-remitting MS patients 1. This dramatically outperforms all available DMTs, which show 29-68% reduction in annualized relapse rates compared to placebo 7. The Italian BMT-MS Study Group reported 71% progression-free survival at 10 years for relapsing-remitting MS with only 1.4% transplant-related mortality 1.

When to Refer:

• Immediately after failure of first high-efficacy DMT in patients with aggressive disease markers (frequent relapses, incomplete recovery, high MRI lesion burden, rapid disability onset) 1
• Do not wait for multiple DMT failures—early referral (younger age, fewer prior DMTs) correlates with better outcomes 1

Progressive MS

Secondary Progressive MS (SPMS): AHSCT is indicated only for early inflammatory active disease 1. The critical distinction: patients must demonstrate clinical or MRI inflammatory activity within the past 12 months 1. Registry data shows AHSCT significantly slows disability progression in active SPMS compared to standard immunotherapy 1.

Primary Progressive MS (PPMS):

• Ocrelizumab is the only FDA-approved DMT specifically for PPMS 8
• AHSCT may be considered only in early inflammatory active disease with EDSS <6.0 1
• Outcomes in progressive MS are substantially worse than RRMS (33% vs 73% 5-year progression-free survival in older cohorts) 1

Critical Exclusion Criteria for AHSCT in Progressive MS:

• Age >55 years 1
• EDSS >6.0 1
• Absence of focal inflammation 1
• No inflammatory activity in past 12 months 1

Monitoring Protocol

MRI Surveillance:

• High-risk patients (highly active disease, recent treatment change): every 3-4 months 6
• Standard monitoring: every 6 months in first year, then annually if stable 6
• Include T2-weighted, T2-FLAIR, and gadolinium-enhanced T1-weighted sequences 6
• Maintain consistent protocols for serial comparison 6

Safety Monitoring:

• JC virus antibody testing every 6 months for natalizumab patients 6
• Brain MRI every 3-4 months if natalizumab duration ≥18 months 6
• Cognitive assessment (SDMT) every 6 months 6
• Liver function tests for interferon therapy 6

Critical Pitfalls to Avoid

Treatment Sequencing Errors:

• Do not unnecessarily prolong DMT withdrawal before AHSCT—increases relapse risk 6
• Do not underestimate carryover effects of alemtuzumab before AHSCT 6
• Do not delay escalation in aggressive disease waiting for "one more DMT trial" 1

Patient Selection Mistakes:

• Do not offer AHSCT to advanced progressive MS without inflammatory activity (futile and potentially harmful) 1
• Do not exclude younger patients with aggressive disease from early AHSCT consideration 1
• Do not rely on imaging alone—clinical assessment remains essential 6

Age-Related Considerations: For patients >55 years with stable disease, discontinuation of DMT may be appropriate as infection risks outweigh benefits 8. However, younger patients (<45 years) with short disease duration (<10 years) should continue therapy even if stable 8.

Treatment Algorithm Summary

1. New RRMS diagnosis → High-efficacy DMT (ocrelizumab, natalizumab, alemtuzumab) 1
2. Breakthrough disease on first high-efficacy DMT + aggressive features → Refer for AHSCT evaluation 1
3. Active SPMS with inflammatory activity → Consider AHSCT if EDSS <6.0 and age <45 1
4. PPMS → Ocrelizumab; consider AHSCT only if early inflammatory active disease 1, 8
5. Advanced progressive MS without inflammation → Symptomatic management, not AHSCT 1

The evidence strongly supports abandoning the traditional "try everything else first" approach to AHSCT. For appropriately selected patients with highly active or aggressive relapsing MS, AHSCT after failure of a single high-efficacy DMT offers the best chance of long-term disease control and should be pursued without delay 1.