OBJECTIVES: Multiple myeloma (MM) patients report high symptom burden and reduced health-related quality of life (HRQoL) compared to patients with other haematological malignancies. The aim of this review was to analyse published longitudinal studies including MM patients according to a change in HRQoL scores, which is perceived as beneficial to the patient according to two published guidelines. METHODS: A literature search was performed May 2016. Publications with longitudinal follow-up using the EORTC QLQ-C30 instrument for HRQoL measurement of physical functioning, global quality of life, fatigue and/or pain were included. An analysis of mean change from baseline was carried out according to minimal important difference (MID). RESULTS: Large and medium HRQoL improvements were reported during first-line treatments. No clinically beneficial change or deteriorations in scores of global QoL or fatigue were reported during relapse treatment. HRQoL data during maintenance therapy are sparse and inconclusive. CONCLUSIONS: Guidelines for interpreting changes in HRQoL including definitions of MID have been developed; however, consensus is missing. Improvements in HRQoL are far more likely to occur during first-line compared to relapsed treatment regimens. The background of these findings should be in focus in future studies, and HRQoL measurements should be integrated in maintenance studies.