Progression independent of relapse activity (PIRA) implies disability progression in people with relapsing-remitting multiple sclerosis (RRMS) secondary to neurodegeneration. Mechanistically and biologically PIRA could impact the traditional distinction between progressive and relapsing-MS. Herein, we estimated progression independent of relapsing biology (PIRB) in a cohort of 823 participants with clinically-isolated syndrome/RRMS in Calgary, Canada using a modified criterion [excluding relapses, inflammatory MRI activity, interim disability worsening/improvement over the observation period, and progression secondary to alternative causes including formal conversion to secondary-progressive MS]. PIRB was rare and rates remained consistent across disease-modifying therapies (3.75% dimethyl fumarate, 3.67% fingolimod, 3.72% ocrelizumab, 3.52% minocycline) despite varied rates of disability progression. PIRB may offer a practical alternative to the concept of PIRA.