What is the initial treatment for secondary progressive multiple sclerosis?

Initial Treatment for Secondary Progressive Multiple Sclerosis

Siponimod 2 mg daily (after dose titration) is the recommended first-line treatment for active secondary progressive multiple sclerosis (SPMS), defined by the presence of relapses or MRI evidence of ongoing inflammatory activity. 1, 2, 3

Patient Selection and Eligibility

Active SPMS is the critical determinant for treatment initiation. The following characteristics define appropriate candidates:

• Presence of relapses or focal inflammatory MRI activity (new/enlarging T2 lesions or gadolinium-enhancing lesions) within the past 1-2 years 1, 4
• Age <45 years with disease duration <10 years represents the optimal treatment window, though siponimod can be used in older patients with active disease 5, 1
• EDSS score <6.5 at baseline, as patients with more severe disability were excluded from pivotal trials 3
• Younger patients with early SPMS of short duration and documented inflammatory disease on clinical and radiological grounds are most likely to benefit 5, 1

Pre-Treatment Assessment Requirements

Before initiating siponimod, the following mandatory evaluations must be completed 2:

• CYP2C9 genotype testing to determine appropriate maintenance dose (contraindicated in *3/*3 genotype) 2
• Electrocardiogram to identify preexisting conduction abnormalities; first-dose cardiac monitoring required for patients with cardiac history, conduction abnormalities, or concurrent use of heart rate-lowering medications 2
• Complete blood count within the past 6 months 2
• Liver function tests (transaminases and bilirubin) within the past 6 months 2
• Ophthalmologic examination including fundus and macula evaluation 2
• Varicella zoster virus antibody testing; vaccinate antibody-negative patients before treatment initiation 2

Dosing Protocol

Siponimod requires a 5-day dose titration to minimize cardiac effects 2, 3:

• Day 1-2: 0.25 mg once daily
• Day 3: 0.5 mg once daily (2 × 0.25 mg tablets)
• Day 4: 0.75 mg once daily (3 × 0.25 mg tablets)
• Day 5: 1.25 mg once daily (5 × 0.25 mg tablets)
• Day 6 onward: 2 mg once daily maintenance dose for CYP2C9 genotypes *1/*1, *1/*2, or *2/*2 2

**For CYP2C9 genotypes *1/*3 or 2/3, the maintenance dose is 1 mg daily (not 2 mg) 2

If a titration dose is missed for >24 hours, restart from Day 1 2

Evidence Supporting Siponimod as First-Line

The EXPAND trial demonstrated that siponimod significantly reduced 3-month confirmed disability progression by 21% compared to placebo (HR 0.79,95% CI 0.65-0.95; p=0.013) 3. This represents the only positive phase 3 trial specifically designed for SPMS that met its primary endpoint 4, 6.

Subgroup analyses reveal that efficacy is highest in:

• Patients with recent inflammatory activity (relapses or MRI lesions) 4, 3
• Younger patients with shorter disease duration 4
• Patients without severe baseline disability 3

Alternative Treatment Considerations

For inactive SPMS (no relapses or MRI activity), siponimod is not indicated 1, 4. In such cases:

• No disease-modifying therapy may be appropriate, as there is limited evidence for treatment benefit in non-inflammatory progressive disease 5, 1
• Autologous hematopoietic stem cell transplantation (AHSCT) should only be considered in young patients (<45 years) with early SPMS and documented active inflammatory disease, not for advanced or inactive SPMS 5, 1

Other DMTs have shown inconsistent or negative results in SPMS:

• Beta interferons showed inconsistent results across trials 4
• Natalizumab showed negative results in the ASCEND trial 4
• Ocrelizumab reduced disability progression in relapsing MS but has not been specifically studied in an SPMS population 4

Monitoring During Treatment

MRI surveillance should occur at least annually, with more frequent imaging (every 3-4 months) for patients with highly active disease or recent treatment changes 1, 7. Use T2/FLAIR sequences to detect new or enlarging lesions 1.

Clinical monitoring includes:

• EDSS assessments every 3-6 months to detect confirmed disability progression 3
• Symbol Digit Modalities Test to assess cognitive function 8
• Liver function tests periodically during treatment 2
• Complete blood count monitoring for lymphopenia 2, 3
• Blood pressure monitoring for hypertension 3

Common Pitfalls to Avoid

Do not delay treatment in patients with active SPMS while waiting for further disease progression—early intervention with siponimod provides better outcomes 1, 4. The therapeutic window narrows as disability accumulates and inflammatory activity decreases 5, 1.

Do not use siponimod in patients without evidence of inflammatory activity, as the drug targets inflammatory mechanisms rather than neurodegenerative processes 4. Inactive SPMS patients were less likely to benefit in EXPAND trial subgroup analyses 4, 3.

Do not skip CYP2C9 genotyping—patients with *3/*3 genotype have contraindication to siponimod due to significantly increased drug exposure 2.

Do not restart siponimod at maintenance dose after treatment interruption >4 days—reinitiate with the 5-day titration regimen to avoid cardiac effects 2.