Introduction <p>Three patient-reported outcome (PRO) measures specific to lymphoma symptoms were previously defined using mixed-methods research, comprising questions from the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30) and Item Library (IL): measures of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Symptoms, Mantle Cell Lymphoma (MCL) Symptoms, and an Expanded Fatigue measure. The objective of this study was to assess psychometric properties of the measures and provide guidance for interpretation by identifying thresholds for determining meaningful within-patient change (MWPC).</p> Methods <p>Psychometric properties of the CLL/SLL-related Symptoms, MCL-related Symptoms, and Expanded Fatigue measures were assessed using classical test theory (CTT) and Rasch measurement theory (RMT) using blinded data collected from two phase 3 trials in participants with CLL/SLL (BRUIN-CLL-321, <i>N</i> = 211) and MCL (BRUIN-MCL-321, <i>N</i> = 523). CTT analyses assessed reliability, construct validity and ability to detect change, while RMT analyses explored adequacy of summing items to generate summary scores. MWPC for each score was estimated using anchor-based and distribution-based methods.</p> Results <p>The three measures demonstrated adequate internal consistency and test-retest reliability, and strong evidence of construct validity. Each showed a good ability to detect worsening and, to a lesser degree, improvement. RMT analyses confirmed adequacy of the response scales but suggested suboptimal targeting for participants with the lowest symptoms severity. For the two symptoms-related measures, items related to fatigue were over-discriminating, suggesting that they are driving the measures. Analyses of MWPC resulted in the following estimates: for the CLL/SLL-related Symptoms score, an improvement of -15.38 points (worsening unable to be estimated); for the MCL-related Symptoms score, an improvement of -10.25 points and a worsening of 5.12 points; and for the Expanded Fatigue score, an improvement -16.66 points in both CLL/SLL and MCL populations and a worsening of 11.11 points in participants with MCL (unable to be estimated in CLL/SLL).</p> Conclusion <p>The CLL/SLL-related Symptoms, MCL-related Symptoms, and Expanded Fatigue measures showed strong psychometric properties in both CTT and RMT frameworks. Combined with previously published qualitative data, this research showed that the measures are appropriate for use in clinical trials of participants with CLL/SLL and MCL.</p> Trial registrations <p>BRUIN-CLL-321, NCT04666038. Registered 07 December 2020, <a href="https://www.clinicaltrials.gov/study/NCT04666038">https://www.clinicaltrials.gov/study/NCT04666038</a>; BRUIN-MCL-321, NCT04662255, Registered 04 December 2020, <a href="https://clinicaltrials.gov/study/NCT04662255">https://clinicaltrials.gov/study/NCT04662255</a>.</p>