Progressive multiple sclerosis poses a considerable challenge in the evaluation of disease progression and treatment response owing to its multifaceted pathophysiology. Traditional clinical measures such as the Expanded Disability Status Scale are limited in capturing the full scope of disease and treatment effects. Advanced imaging techniques, including MRI and PET scans, have emerged as valuable tools for the assessment of neurodegenerative processes, including the respective role of adaptive and innate immunity, detailed insights into brain and spinal cord atrophy, lesion dynamics and grey matter damage. The potential of cerebrospinal fluid and blood biomarkers is increasingly recognized, with neurofilament light chain levels being a notable indicator of neuro-axonal damage. Moreover, patient-reported outcomes are crucial for reflecting the subjective experience of disease progression and treatment efficacy, covering aspects such as fatigue, cognitive function and overall quality of life. The future incorporation of digital technologies and wearable devices in research and clinical practice promises to enhance our understanding of functional impairments and disease progression. This Review offers a comprehensive examination of these diverse evaluation tools, highlighting their combined use in accurately assessing disease progression and treatment efficacy in progressive multiple sclerosis, thereby guiding more effective therapeutic strategies.

• Effective treatment of progressive multiple sclerosis (MS) remains an urgent medical need.
• The recent approvals of treatments for progressive forms of MS highlight the importance of better disease monitoring measures in clinical trials and practice.
• Traditional MRI biomarkers do not adequately track progressive MS. Advances in MRI, such as brain atrophy and lesion volume analysis, show promise in assessing disease progression and response to treatment.
• Remyelination is key in MS neuroprotection. MRI techniques such as magnetization transfer and myelin water fraction imaging, alongside PET scans, provide deeper insights into myelin repair and inflammation.
• Changes in optical coherence tomography, a non-invasive imaging modality that measures retinal layer thickness, reflect brain atrophy and MS progression, offering a valuable window into neurodegeneration and treatment efficacy.
• Body fluid biomarkers, such as neurofilament light in blood, and immune activation and neuronal damage markers in cerebrospinal fluid are emerging as important tools for assessing disease activity and treatment response in progressive MS.
• Patient-reported outcomes capture the unique experience of individuals with MS, which is of particular importance in progressive forms of the disease. These assessments can help evaluate hidden symptoms such as fatigue and cognitive impairment and are becoming vital in clinical trials and routine practice.