OBJECTIVES:  Real world health-related quality of life (HRQoL) data for patients with MM is scarce, yet it is an important objective in the management of patients today. The objective of this study was to assess HRQoL of patients with MM in the real world setting. METHODS: This observational, cross-sectional, multi-center study was conducted in France among 41 physicians and 445 patients (February/March 2016). Physicians completed a case report form detailing patient and disease characteristics, current disease management, treatment status and most recently assessed treatment response for each patient. In parallel, HRQoL was assessed at baseline using 3 self-administered questionnaires (EORTC QLQ-C30, EORTC-MY20 and EQ-5D). Patients included were selected based on an assigned quota by current or most recently completed line of treatment (1L, 2L, 3L, 4L and supportive care). RESULTS:  A total of 445 patients were included, with median age ranging from 70 years in 1L to 77 for those on supportive care. 32% of patients had received a stem cell transplant in 1L and/or 2L. HRQoL, as assessed by the EORTC QLQ-C30 global status, decreased from 63.0 in 1L to 59.7 in 2L, 52.6 in 3L and 53.6 in 4L (p<0.01). Depth of response was associated with better HRQoL (61.8 for ≥VGPR, 56.8 for partial response and 48.0 for stable disease [p<0.01 overall test]). HRQoL worsened as the line of treatment advanced according to both the EORTC-MY20 and the EQ-5D. Patients aged above 70 and those who experienced any adverse event had worse HRQoL versus the overall group. CONCLUSIONS:  With lower HRQoL in more advanced stages of disease, these data demonstrate the importance of effective treatment options in MM that result in better levels of response and delayed disease progression in order to preserve HRQoL for MM patients.