Treatment switches of disease-modifying therapies in people with multiple sclerosis: long-term experience from the German MS Registry

Abstract

Background: The spectrum of disease-modifying therapies (DMTs) for people with multiple sclerosis (PwMS) has expanded over years, but data on treatment strategies is largely lacking. DMT switches are common clinical practice.

Objective: To compare switchers and non-switchers, characterize the first DMT switch and identify reasons and predictors for switching the first DMT.

Methods: Data on 2722 PwMS from the German MS Registry were retrospectively analyzed regarding sociodemographic/clinical differences between 1361 switchers (PwMS discontinuing the first DMT) and non-switchers matched according to age, sex, and observation period. Frequencies of first and second DMTs were calculated and switch reasons identified. Predictors for DMT switches were revealed using univariable and multivariable regression models.

Results: Switchers and non-switchers differed significantly regarding time to first DMT, education, calendar period of the first DMT start (2014-2017 versus 2018-2021), first DMT class used [mild-to-moderate efficacy (MME) versus high-efficacy (HE) DMT], time on first DMT, and disease activity at first DMT start or cessation/last follow-up. The majority of PwMS started with MME DMTs (77.1%), with the most common being glatiramer acetate, dimethyl/diroximel fumarate, and beta-interferon variants. Switchers changed treatment more often to HE DMTs (39.6%), most commonly sphingosine-1-phosphate receptor modulators, anti-CD20 monoclonal antibodies, and natalizumab. Fewer PwMS switched to MME DMTs (35.9%), with the most common being dimethyl/diroximel fumarate, teriflunomide, or beta-interferon. Among 1045 PwMS with sufficient data (76.8% of 1361 switchers), the most frequent reasons for discontinuing the first DMT were disease activity despite DMT (63.1%), adverse events (17.1%), and patient request (8.3%). Predictors for the first DMT switch were MME DMT as initial treatment [odds ratio (OR) = 2.83 (1.76-4.61), p < 0.001; reference: HE DMT], first DMT initiation between 2014 and 2017 [OR = 11.55 (6.93-19.94), p < 0.001; reference: 2018-2021], and shorter time on first DMT [OR = 0.22 (0.18-0.27), p < 0.001].

Conclusion: The initial use of MME DMTs was among the strongest predictors of DMT discontinuation in a large German retrospective MS cohort, arguing for the need for prospective treatment strategy trials, not only but also on the initial broad use of HE DMTs in PwMS.

Keywords: discontinuation; disease-modifying therapy; multiple sclerosis; switch.

Figure 1.

Selection of people with MS. At the date of patient selection (1 December 2022), the GMSR contained data on 39,703 PwMS. In total, 3409 patients met the following inclusion criteria: complete basic demographic data, sufficient data on DMTs used, relapsing MS onset, first DMT start between 2014 and 2021, minimum age of 18 years, date of MS diagnosis from 2010, minimum follow-up of 1.5 years following the first DMT start and at least one follow-up visit after 2019. Matching patients with and without DMT switches by age at first DMT start, sex, and observation period revealed a study cohort of 2722 PwMS. Of those patients, 1361 stopped DMT at least once and 1361 persisted using one DMT without a break or cessation until the end of observation period. DMT, disease-modifying therapy; GMSR, German Multiple Sclerosis Registry; MS, multiple sclerosis; PwMS, people with multiple sclerosis.

Figure 2.

Characterization of the first DMT switch considering (a, c) all MS patients (N = 2722) and specifically (b, d) DMT-switching patients (N = 1361). The boxes on the left side represent the proportion of patients stratified by the first DMT used. Complementary to this, the immediately subsequent DMTs are shown on the right side (second DMTs). Boxes (a) and (b) show specific DMTs or DMT groups and boxes (c) and (d) visualize DMT efficacy categories. The color line sizes correspond to the proportions of patients using the respective DMTs. PwMS using mild-to-moderate efficacy DMTs more often switched to high-efficacy DMTs or stopped the therapy than patients initially treated with high-efficacy DMTs. ^†Median time of DMT break (25% quantile, 75% quantile): 3.1 (0.9, 10.7) months. *Median time from DMT cessation until the end of observation period (25% quantile, 75% quantile): 0.8 (0.3, 1.8) years. Anti-CD20 MAB, anti-CD 20 monoclonal antibodies: ocrelizumab/ofatumumab/rituximab; DMF, dimethyl fumarate; DMT, disease-modifying therapy; DRF, diroximel fumarate; MS, multiple sclerosis; N, number of patients; PwMS, people with multiple sclerosis; S1P RM, sphingosine-1-phosphate receptor modulators: fingolimod/ozanimod/ponesimod/siponimod.

Figure 3.

Frequencies of DMTs used across subsequent switches. Colored bars show the frequencies of DMTs used among treatment-switching PwMS (N = 1361), stratified by the sequence of DMT switches (from the first to the sixth DMT, respectively). Across the subsequent DMT switches, a decrease in the use of glatiramer acetate and DMF/DRF was observed, while the treatment with alemtuzumab, anti-CD20 MAB, cladribine, and teriflunomide increased. *Market removal in March 2018. Anti-CD20 MAB, anti-CD 20 monoclonal antibodies: ocrelizumab/ofatumumab/rituximab; DMF, dimethyl fumarate; DMT, disease-modifying therapy; DRF, diroximel fumarate; N, number of patients; PwMS, people with multiple sclerosis; S1P RM, sphingosine-1-phosphate receptor modulators: fingolimod/ozanimod/ponesimod/siponimod.

Figure 4.

Predictors of the first DMT switch among MS patients. A multivariable logistic regression model was used to identify variables associated with the first DMT switch among 2722 PwMS. The forest plot contains colored boxes indicating the ORs of the variables analyzed for discontinuing the first DMT. Box sizes represent the number of patients included. Whiskers symbolize the 95% CIs of ORs. Initiating the first DMT between 2014 and 2017, shorter time on the first DMT and mild-to-moderate efficacy drugs as first DMT have been identified to favor switching or stopping the first DMT. ARR, annualized relapse rate; CI, confidence interval; CSE/GCSE, certificate of secondary education/general CSE; DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; MS, multiple sclerosis; NSCE, no school-leaving certificate; OR, odds ratio; p, p-value; Ref, reference.

Figure 5.

Treatment duration with regard to the number of DMT switches (a, b), the period of the first DMT (c, d), and the efficacy category of the first DMT (e, f). Graphs show proportions (upper graph parts, respectively) and numbers (lower graph parts, respectively) of patients (left: total study population of 2722 PwMS; right: 1361 switchers) being on DMT (y-axis) across time following DMT initiation (x-axis), visualized as survival curves. The treatment duration mainly varies, particularly for the initial switch (total study population: p = 0.049; switchers only: p < 0.0001), while the retention time for subsequent DMTs is comparable. Furthermore, survival curves revealed a discontinuation of DMT after shorter treatment duration in patients who initiated their first DMT between 2018 and 2021 (total study population: p < 0.0001) and in those who received a mild-to-moderate efficacy DMT as first treatment (total study population: p < 0.0001; switchers only: p = 0.0092). The date of the last neurological consultation was chosen as censoring. DMT, disease-modifying therapy; HE, high efficacy; MME, mild-to-moderate efficacy; MS, multiple sclerosis; N, number of patients; p, log-rank p-value; PwMS, people with MS.