Purpose: We 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). Methods: Data 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. Results: Records 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. Conclusion: HRQoL 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. [ABSTRACT FROM AUTHOR]