Neurology

Choosing Your Treatment: DMTs in the SPMS Phase

At a Glance

In secondary progressive multiple sclerosis, treatment depends on whether relapses or new MRI lesions show active disease. Siponimod may help some people with active SPMS after safety testing, while medication changes and rehabilitation should be planned with a neurologist.

When you transition to Secondary Progressive Multiple Sclerosis (SPMS), the goals of treatment shift. While the focus in earlier stages was on stopping “attacks” (relapses), the focus now is on slowing the steady accumulation of disability ^[1]. Choosing a Disease-Modifying Therapy (DMT) for SPMS involves evaluating whether your disease is classified as “active” or “non-active”, along with your age, prior treatment, and other health factors ^[2]^[3].

The Treatment Decision Tree

The first question your neurologist will ask is: Is there still active inflammation?

1. For Active SPMS

If you have had a clinical relapse or new lesions on an MRI in a defined recent window, your disease is “active” ^[2]. In this stage, DMTs are generally used because they target the inflammatory “engine” that is still active.

Siponimod: This is currently an approved option specifically indicated for active SPMS in many jurisdictions ^[4]^[5]. In the large EXPAND clinical trial, siponimod reduced the relative risk of 6-month confirmed disability progression by 37% in people with active disease compared to placebo ^[6]. It has also shown secondary evidence of protecting cognitive processing speed ^[7].
Other Options: Your doctor may also consider other therapies like cladribine, ocrelizumab, or ozanimod, which are approved for relapsing forms of MS, which can include active SPMS depending on local regulations ^[3]^[4].

2. For Non-Active SPMS

If you have not had relapses or new MRI activity, your disease is “non-active”. This is a more challenging stage because current DMTs have not yet proven highly effective at stopping progression that happens independently of relapses in non-active SPMS ^[8].

In studies of siponimod, the benefit for the non-active group was not statistically significant ^[8]^[9].
If you fall into this group, you and your doctor will weigh the risks of continuing a DMT against the limited evidence for its benefit in non-active disease. Never stop a DMT on your own. Stopping a medication requires careful medical supervision ^[3]^[10].

Starting Siponimod: Individualized Safety Monitoring

Siponimod is a powerful drug that requires several checks to ensure it is safe for you. These are individualized based on your health profile:

Genetic Testing: You must have a CYP2C9 blood test. This gene determines how quickly your liver processes the drug. If you have a specific rare variant (*3/*3), you cannot take siponimod; for others, the results will dictate your daily dose ^[11]^[4].
Cardiac Check: Because siponimod can temporarily slow your heart rate (bradycardia), you will receive a baseline EKG and start with a “titration pack” that slowly increases your dose. Depending on your cardiac history, you may require first-dose observation in a clinic ^[1]^[12].
Immunity and Labs: Your doctor will check your complete blood count, liver function, and immunity to Varicella-Zoster (shingles); vaccination may be needed before starting ^[12]. You will also need an eye exam to check for macular edema, a known side effect, especially if you have diabetes or uveitis ^[1].

The Risks of Stopping or Switching

If you are transitioning to a new drug, how you stop your old one is critical. Abruptly stopping certain medications can lead to a rebound, where MS activity returns more aggressively than before.

Natalizumab: Stopping this drug can lead to significant disease reactivation within 3 to 4 months ^[13]^[14].
S1P Modulators (e.g., Fingolimod): Abruptly stopping these can cause a severe rebound of inflammatory activity, sometimes involving large “tumefactive” lesions ^[15]^[16].
The “Washout”: Your doctor will create a specific plan for your transition period between drugs. There is no single washout schedule; your neurologist will balance the risk of a disease rebound against the risk of overlapping immunosuppression and infection ^[13]^[17].

Beyond the Medication

In SPMS, medication is only one part of the standard of care. Because DMTs have limitations in the progressive phase, rehabilitation—including physical, occupational, and speech therapy—becomes a core pillar of treatment to maintain your current level of function and improve your quality of life ^[18]^[19].

Common questions in this guide

How is active SPMS different from non-active SPMS?

Active SPMS means you have had a recent clinical relapse or new activity on an MRI, such as a new lesion. Non-active SPMS means there is no recent relapse or new MRI activity. This distinction helps your neurologist decide whether a disease-modifying treatment is likely to help.

What does siponimod do for active SPMS?

Siponimod is an approved treatment option for active SPMS in many jurisdictions and is designed to reduce ongoing inflammatory activity. In a major clinical trial, it lowered the risk of confirmed disability progression in people with active disease. Its benefit has been less clear in non-active SPMS.

What tests are needed before starting siponimod?

Before siponimod, your clinician will use a CYP2C9 blood test to determine whether you can take it and which dose is appropriate. Checks may also include an EKG, blood counts, liver tests, immunity to chickenpox and shingles virus, and an eye exam. People with certain heart conditions or other risks may need extra monitoring when the dose is first started.

Should I stop my DMT if my SPMS is non-active?

Do not stop a disease-modifying treatment on your own, even if your SPMS is non-active. Your neurologist should weigh the possible risks of continuing it against the limited evidence of benefit and supervise any change.

Why does switching MS medication require a transition plan?

Stopping some MS medicines suddenly can cause a rebound, in which disease activity returns more aggressively. This risk is recognized with natalizumab and some S1P medicines such as fingolimod. Your neurologist will choose a transition or washout plan that balances rebound risk against infection and reduced immune defenses.

How can rehabilitation help with SPMS?

Physical, occupational, and speech therapy can help you maintain function, manage daily activities, and support quality of life as disability progresses. Rehabilitation is a core part of SPMS care alongside medication. Your care team can tailor therapy to the abilities and changes that matter most to you.

Get notified when new evidence is published on secondary progressive multiple sclerosis.

We monitor PubMed for new peer-reviewed studies on this topic and email a short summary when something meaningful changes.

References (19)

1
Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study.
Kappos L, Bar-Or A, Cree BAC, et al.
Lancet (London, England) 2018; (391(10127)):1263-1273 doi:10.1016/S0140-6736(18)30475-6.
PMID: 29576505
2
MRI versus relapse: optimal activity monitoring for management of progressive multiple sclerosis.
Giovannoni G, Hetherington S, Jones E, et al.
Brain communications 2025; (7(1)):fcaf010 doi:10.1093/braincomms/fcaf010.
PMID: 39906569
3
Disease-modifying therapies for relapsing/active secondary progressive multiple sclerosis - a review of population-specific evidence from randomized clinical trials.
Bayas A, Christ M, Faissner S, et al.
Therapeutic advances in neurological disorders 2023; (16()):17562864221146836 doi:10.1177/17562864221146836.
PMID: 36710720
4
Gaining First Insights on Secondary Progressive Multiple Sclerosis Patients Treated With Siponimod in Clinical Routine: Protocol of the Noninterventional Study AMASIA.
Ziemssen T, Hoffmann O, Klotz L, et al.
JMIR research protocols 2020; (9(7)):e19598 doi:10.2196/19598.
PMID: 32499214
5
The Two Sides of Siponimod: Evidence for Brain and Immune Mechanisms in Multiple Sclerosis.
Cohan SL, Benedict RHB, Cree BAC, et al.
CNS drugs 2022; (36(7)):703-719 doi:10.1007/s40263-022-00927-z.
PMID: 35725892
6
Siponimod vs placebo in active secondary progressive multiple sclerosis: a post hoc analysis from the phase 3 EXPAND study.
Gold R, Piani-Meier D, Kappos L, et al.
Journal of neurology 2022; (269(9)):5093-5104 doi:10.1007/s00415-022-11166-z.
PMID: 35639197
7
Siponimod and Cognition in Secondary Progressive Multiple Sclerosis: EXPAND Secondary Analyses.
Benedict RHB, Tomic D, Cree BA, et al.
Neurology 2021; (96(3)):e376-e386 doi:10.1212/WNL.0000000000011275.
PMID: 33328324
8
Anti-inflammatory disease-modifying treatment and short-term disability progression in SPMS.
Lorscheider J, Jokubaitis VG, Spelman T, et al.
Neurology 2017; (89(10)):1050-1059 doi:10.1212/WNL.0000000000004330.
PMID: 28794248
9
Progression to Wheelchair in Secondary Progressive Multiple Sclerosis and Impact of Siponimod: Post Hoc Analyses From the EXPAND Study.
Vermersch P, Arnould S, Gold R, et al.
European journal of neurology 2026; (33(6)):e70659 doi:10.1111/ene.70659.
PMID: 42257510
10
Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension.
Kapoor R, Ho PR, Campbell N, et al.
The Lancet. Neurology 2018; (17(5)):405-415 doi:10.1016/S1474-4422(18)30069-3.
PMID: 29545067
11
Pharmacogenetics of siponimod: A systematic review.
Díaz-Villamarín X, Piñar-Morales R, Barrero-Hernández FJ, et al.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2022; (153()):113536 doi:10.1016/j.biopha.2022.113536.
PMID: 36076616
12
[Siponimod (BAF312): General Characteristics and Clinical Implications of Pharmacogenomic Dosage in the Treatment of Active Secondary Progressive Multiple Sclerosis].
Calfunao S, Carrasco M, Gutierrez C, et al.
Revista medica de Chile 2023; (151(10)):1375-1384 doi:10.4067/s0034-98872023001001375.
PMID: 39093141
13
Switching from natalizumab to fingolimod: A randomized, placebo-controlled study in RRMS.
Kappos L, Radue EW, Comi G, et al.
Neurology 2015; (85(1)):29-39 doi:10.1212/WNL.0000000000001706.
PMID: 26024899
14
Long-term evaluation of NEDA-3 status in relapsing-remitting multiple sclerosis patients after switching from natalizumab to fingolimod.
Diem L, Nedeltchev K, Kahles T, et al.
Therapeutic advances in neurological disorders 2018; (11()):1756286418791103 doi:10.1177/1756286418791103.
PMID: 30116299
15
Tumefactive multiple sclerosis lesions associated with fingolimod treatment: Report of 5 cases.
Sánchez P, Meca-Lallana V, Vivancos J
Multiple sclerosis and related disorders 2018; (25()):95-98 doi:10.1016/j.msard.2018.07.001.
PMID: 30056362
16
Fingolimod for multiple sclerosis and emerging indications: appropriate patient selection, safety precautions, and special considerations.
Ayzenberg I, Hoepner R, Kleiter I
Therapeutics and clinical risk management 2016; (12()):261-72 doi:10.2147/TCRM.S65558.
PMID: 26929636
17
Switching natalizumab to fingolimod within 6 weeks reduces recurrence of disease activity in MS patients.
Leurs CE, van Kempen ZL, Dekker I, et al.
Multiple sclerosis (Houndmills, Basingstoke, England) 2018; (24(11)):1453-1460 doi:10.1177/1352458517726381.
PMID: 28823223
18
Charting a global research strategy for progressive MS-An international progressive MS Alliance proposal.
Thompson AJ, Carroll W, Ciccarelli O, et al.
Multiple sclerosis (Houndmills, Basingstoke, England) 2022; (28(1)):16-28 doi:10.1177/13524585211059766.
PMID: 34850641
19
Secondary Progressive Multiple Sclerosis: A Review of Clinical Characteristics, Definition, Prognostic Tools, and Disease-Modifying Therapies.
Ziemssen T, Bhan V, Chataway J, et al.
Neurology(R) neuroimmunology & neuroinflammation 2023; (10(1)) doi:10.1212/NXI.0000000000200064.
PMID: 36414428

This page is for informational purposes only and does not constitute medical advice. Talk with your neurologist before starting, stopping, or switching a DMT or interpreting monitoring results.