PurposeWe aimed to explore patient-reported outcomes (PROs) and patient and physician concordance of side effects perception across lines of therapy (LOT) in multiple myeloma (MM) within the United States of America (USA).MethodsData were drawn from the Adelphi Real World MM III Disease Specific Programme™, a point-in-time survey of hemato-oncologists/hematologists and their patients with MM conducted in the USA between August 2020 and July 2021. Physicians reported patient characteristics and side effects. Patients reported side-effect bother and health-related quality of life (HRQoL) using validated PRO tools (European Organisation for the Research and Treatment of Cancer Quality of Life Core Questionnaire/-MM Module [EORTC QLQ-C30/-MY20], EQ-5D-3L and Functional Assessment of Cancer Therapy—General Population physical item 5). Descriptive, linear regression and concordance analyses were performed.ResultsRecords from 63 physicians and 132 patients with MM were analyzed. EORTC QLQ-C30/-MY20 and EQ-5D-3L scores were consistent across LOTs. Scores tended to be worse with higher side-effect bother; patients “very much” bothered by side effects had lower median (interquartile range) global health status scores (33.3 [25.0–50.0]) than those “not at all” bothered (79.2 [66.7–83.3]). Patient and physician concordance on side-effect reporting was poor to fair. Patients frequently reported fatigue and nausea as bothersome side effects.ConclusionHRQoL of patients with MM was worse with greater side-effect bother. Discordant patient and physician reporting of side effects indicated a need for improved communication during management of MM.Supplementary informationThe online version contains supplementary material available at 10.1007/s00520-023-07836-x.