Very recent data from cohorts, such as that of the French Observatory of Multiple Sclerosis (OFSEP) and the MSBase cohort, are the subject of new statistical analyses using propensity scores that enable the matching of relapses frequency, EDSS, age, and sex ratio in patient populations for comparisons with each other, which reduces selection biases. The first data from these cohorts revealed a decline in transition to secondary progressive MS with the most effective disease-modifying drugs currently available, especially when these drugs were used early in the disease. However, these studies remain limited regarding the number of patients, the duration of follow-up, the use of imperfect methodologies, and the level of evidence remains low. The Gothenburg cohort in Sweden, which has been followed since the 1950s, found that 14% of benign non-progressive multiple sclerosis (MS) never evolved to secondary progression after more than 45 years of evolution. EDSS 7 was reached after 48 years of disease (median), and 50% evolved to secondary progressive MS after 15 years (consistent with data from the historic London, Ontario cohort). These data demonstrate that most people living with MS evolve without treatment to a significant long-term disability and that this evolution is closely linked to secondary progression (more than the relapse frequency). Benign forms appear as MS that never passes into secondary progressive MS. Recent data demonstrate that the delay until transition to secondary progression (more than 30 years in the MSBase cohort) and the delay in reaching EDSS 6 decreased since the introduction of disease-modifying drugs 20 years ago. However, randomized placebo-controlled trials do not last more than 2 or 3 years, and many biases may be involved in long-term follow-up studies: worsening patients who are lost to follow-up (“informative censoring” bias: only good responders to treatment remain primarily under the same long-term treatment and are followed); changes in the populations in the most recent studies with a lower rate of relapse and lower progression of disability at the beginning of the disease prior to initiating treatments; and environmental changes that remain largely misunderstood and may contribute to a natural evolution towards less severe disease.