Treatment with DMTs Associated with Lower Risk of Conversion to SPMS from RMS

Tomas Kalincik, PhD

Use of disease-modifying therapy (DMT) for patients with multiple sclerosis (MS) can lower their risk of conversion from relapsing MS to secondary progressive MS, according to new research.¹

In a cohort of 1555 patients with relapsing MS, the use of 3 DMTs—fingolimod (Gilenya, Novartis), natalizumab (Tysabri, Biogen), and alemtuzumab (Lemtrada, Sanofi Genzyme)—was also associated with an overall lower risk of conversion to secondary progressive MS even when compared to interferon ß (IFN-ß) or glatiramer acetate (hazard ratio [HR], 0.66; 95% CI, 0.44 to 0.99; P = .046). The 5-year absolute risk of conversion was 7% for those initially treated with one of the 3 DMTs.

A research team, including Tomas Kalincik, PhD, the research group leader of the University of Melbourne’s Clinical Outcomes Research Unit, wrote that these data, “considered along with the risks associated with these therapies, may help inform decisions regarding disease-modifying treatment selection for patients with relapsing-remitting MS.”

After 5 years, 7% of those initially treated with 1 of the DMTs (n = 235) converted to progressive MS compared to 12% of the match group that initially received glatiramer acetate or IFN-ß (n = 380). By 9 years, the conversion rate was 16% compared to 27%, respectively.

These findings were persevered after sensitivity analyses when the 7-year alternative definition of alemtuzumab treatment duration was used (HR, 0.60; 95% CI, 0.39 to 0.90; P = .01). As well, when considering patients in the glatiramer acetate/IFN-ß group who were escalated to mitoxantrone in the analysis, the significance remained (HR, 0.88; 95% CI, 0.84 to 0.91; P <.001).

Kalincik and colleagues used data from the massive MSBase data set, which Ari Green, MD, MCR, the medical director of the UCSF Multiple Sclerosis Center and director of the UCSF Neurodiagnostics Center, pointed out has “a major advantage” in that it utilizes “a standardized definition of what constitutes secondary progressive disease to compare time to secondary progression for patients taking different MS therapies,” in an accompanying editorial.²

“Within 2 decades of onset, 80% of untreated patients with relapsing-remitting MS convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between DMTs and this conversion has rarely been studied and never using a validated definition,” Kalincik and colleagues wrote.

As expected, 5-year absolute risk for patients initially treated with glatiramer acetate/IFN-ß (n = 407) was 12% compared to 27% for matched untreated patients (n = 213; HR, 0.71; 95% CI, 0.61 to 0.81; P <.001). The same was the case for those initially treated with all 3 DMTs. For patients initially treated with fingolimod (n = 85), their risk was 7%, compared to matched untreated patients (n = 174), whose risk was 32% (HR, 0.37; 95% CI, 0.22 to 0.62; P <.001). For those on natalizumab (n = 82), the 5-year absolute risk was 19% compared 38% for matched controls (n = 164; HR, 0.61; 95% CI, 0.43 to 0.86; P = .005). For those initially treated with alemtuzumab (n = 44) the 5-year absolute risk was 10% compared to 25% of the matched group (n = 92; HR, 0.52; 95% CI, 0.32 to 0.85; P = .009).

The probability of conversion was lower for patients for whom glatiramer acetate or IFN-ß was started within 5 years of disease onset (n = 120) compared to patients treated with them later (n = 38) on (HR, 0.77; 95% CI, 0.61 to 0.98; P = .03), with a 5-year absolute risk of 3% compared to 6%.

Additionally, escalation of glatiramer acetate or IFN-ß to fingolimod, alemtuzumab, or natalizumab within 5 years (n = 307) was associated with a lower risk of conversion (HR, .076; 95% CI, 0.66-0.88; P < .001) compared to post-5 years (n = 331). The 5-year absolute risks were 8% and 14%, respectively.

“The results were clear,” Green wrote in his editorial. “Nearly all agents appeared to have a measurable, favorable effect on disease progression. Moreover, the group of therapies that was most effective at decreasing relapse rates also had the greatest benefit on disease progression.”

He added that, in addition, these results show that an earlier initiation of these therapies “uniformly appeared to have a more significant effect on disease course” than the comparators. And while Green acknowledged that the study was not without its weaknesses and limitations, “the message is clear. As our stroke colleagues have been saying for more than 20 years: ‘Time is Brain.’”

As both Green and the original investigators pointed out, the use of propensity matching—the treated patients were from the MSBase cohort which draws patients from around the world, while the untreated patient data came from a single clinic in Wales&mdash;is not enough to guarantee that other differences between the populations did not influence the study outcomes. A number of additional limitations were also acknowledged.

Kalincik and colleagues concluded that “these findings, considered along with these therapies’ risks, may help inform decisions about DMT selection.”

REFERENCES

1. Brown JWL, Alasdair Coles A, Horakova D, et al. Association of initial disease-modifying therapy with later conversion to secondary progressive multiple sclerosis. JAMA. 2019;321(2):175-187. doi:10.1001/jama.2018.20588

2. Green AJ. Potential benefits of early aggressive treatment in multiple sclerosis. JAMA Neurol. Published online January 15, 2019. doi:10.1001/jamaneurol.2018.4932. Accessed January 15, 2019.