What are the newest management approaches for a patient with multiple sclerosis (MS)?

Newest Management Approaches for Multiple Sclerosis

Autologous Hematopoietic Stem Cell Transplantation (AHSCT) as Emerging Standard of Care

AHSCT is now recommended as an appropriate escalation therapy for highly active relapsing-remitting MS that has failed high-efficacy disease-modifying therapy (DMT), representing the most significant advancement in MS management with 87% progression-free survival at 10 years. 1

Optimal Candidate Selection for AHSCT

The 2025 ECTRIMS-EBMT consensus guidelines establish specific criteria for AHSCT candidacy:

• Age <45 years with disease duration <10 years 1, 2
• EDSS score <4.0 (ideally 0.0-6.0 depending on protocol) 1
• High focal inflammation documented on MRI (≥1 gadolinium-enhancing lesion or ≥1 new T2 lesion in past 12 months) 1
• Failure of high-efficacy DMT after meaningful treatment period (≥6 months) 1

Critical caveat: For patients with rapidly evolving severe MS with poor prognosis, AHSCT may be considered as first-line therapy, though this should ideally occur within clinical trials. 1, 2

AHSCT Conditioning Protocols

Four major ongoing randomized controlled trials (RAM-MS, BEAT-MS, STAR-MS, NET-MS) are comparing AHSCT against high-efficacy DMTs using two primary conditioning regimens:

• Cyclophosphamide + anti-thymocyte globulin (Cy+ATG) 1
• BEAM protocol (carmustine, etoposide, cytarabine, melphalan) + ATG 1

Pre-AHSCT Washout Considerations

A critical pitfall: Carryover effects from previous DMTs—particularly long-acting lymphodepleting agents like alemtuzumab—can complicate mobilization, conditioning, and immune reconstitution. 1 The washout period must balance MS relapse risk against treatment sequence complications, keeping withdrawal as short as possible. 1

Early Aggressive Treatment Strategy Paradigm Shift

The European Academy of Neurology-ECTRIMS guidelines now recommend early escalation and induction strategies over traditional stepped approaches for relapsing-remitting MS. 1, 2, 3

High-Efficacy DMTs as First-Line Therapy

For patients with markers of aggressive disease (frequent relapses, incomplete recovery, high MRI lesion frequency, rapid disability onset):

• Alemtuzumab, natalizumab, ocrelizumab, ofatumumab should be initiated early in disease course 1, 2
• Cladribine is included in some high-efficacy classifications 1

Evidence supporting early initiation: High-efficacy DMTs are more effective when started early, with real-world data demonstrating that delayed initiation results in worse long-term disability outcomes. 1, 3

Treatment Failure Criteria Triggering Escalation

Escalation to AHSCT or alternative high-efficacy DMT should occur when:

• ≥1 clinical relapse occurring ≥3 months after DMT initiation 2
• MRI activity defined as ≥1 gadolinium-enhancing or ≥1 new T2 lesion 2, 3
• Incomplete recovery from relapses 2

Progressive MS Management Updates

Secondary Progressive MS (SPMS)

AHSCT is only indicated for young patients (<45 years) with early SPMS of short duration and documented active inflammatory disease on both clinical and radiological grounds. 1, 2, 3

Critical distinction: AHSCT is not appropriate for advanced progressive MS without active inflammation. 1

Primary Progressive MS (PPMS)

Ocrelizumab remains the only specific treatment indicated for PPMS, though efficacy is limited primarily to slowing disability progression. 2, 3

Advanced MRI Monitoring Protocols

Baseline and Surveillance Imaging

Obtain baseline brain MRI before initiating therapy to differentiate subsequent MS symptoms from complications like progressive multifocal leukoencephalopathy (PML). 1, 4

Risk-Stratified Monitoring Frequency

• Every 3-4 months: Highly active disease, recent treatment changes, or natalizumab therapy (PML risk) 2, 5, 3, 4
• Every 6 months: First year of treatment 5
• Annually: Stable patients 1, 2

Essential sequences: T2/FLAIR for new or enlarging lesions, T1-weighted with gadolinium for active inflammation 1, 2

Prognostic Value of Early MRI

Infratentorial lesions (cerebellar and brainstem) have particularly high prognostic value: Presence of ≥2 infratentorial lesions in clinically isolated syndrome predicts long-term disability accumulation. 1

79% of CIS patients with normal baseline brain MRI did not convert to definite MS after 20 years. 1

Natalizumab-Specific PML Risk Management

Given natalizumab's continued use as high-efficacy DMT, updated PML surveillance is critical:

JC Virus Antibody Testing Protocol

• Wait ≥2 weeks after plasma exchange to avoid false-negative results 4
• Wait ≥6 months after IVIg to avoid false-positive results 4

Enhanced Monitoring for High-Risk Patients

Brain MRI every 3-4 months for patients at high PML risk, as MRI findings may precede clinical symptoms. 4 Asymptomatic PML cases diagnosed on MRI with JCV DNA in CSF have been reported, with better outcomes when detected early. 4

PML Diagnostic Evaluation

When PML is suspected:

• Gadolinium-enhanced brain MRI 4
• CSF analysis for JC viral DNA 4
• Continue withholding natalizumab if initial evaluation negative but suspicion remains 4

Plasma exchange (3 sessions over 5-8 days) accelerates natalizumab clearance, though α4-integrin receptor binding often remains high. 4 IRIS occurs in the majority of natalizumab-treated PML patients after discontinuation, typically within days to weeks post-PLEX. 4

Age-Based Treatment Discontinuation Guidance

Patients >55 Years with Stable Disease

Consider treatment discontinuation, as benefits of continuing immunosuppressive therapy may be outweighed by increased infection risk and other adverse effects. 2, 3

Patients <45 Years with Short Disease Duration

Continue current therapy even if stable, particularly those with disease duration <10 years or history of highly active disease before stabilization. 2, 3

Post-AHSCT Rehabilitation Protocol

Rehabilitation must begin immediately after AHSCT to exploit brain reorganization capacity during complete inflammatory suppression. 2

Phased Rehabilitation Approach

• Pre-habilitation: Before AHSCT 2
• Early mobilization: Immediately post-transplant 2
• Intensive outpatient rehabilitation: Following hospital discharge 2
• Maintenance rehabilitation: Long-term functional preservation 2

Common Pitfalls to Avoid

Do not mistake pseudoatrophy effect for disease progression: Excessive brain volume decrease within first 6-12 months of treatment reflects resolution of inflammation, not true atrophy. 2, 5

Do not delay high-efficacy DMT or AHSCT referral in patients with aggressive disease while pursuing sequential moderate-efficacy therapies—early intervention improves long-term outcomes. 1, 2

Ensure appropriate DMT washout periods to avoid mobilization complications and immune reconstitution issues, particularly after alemtuzumab or cytotoxic treatments. 1

Monitor for at least 6 months post-AHSCT discontinuation, as PML has been reported after stopping therapy in patients without findings suggestive of PML at discontinuation. 4