Patients with multiple myeloma (MM) report high symptom burden and functional disabilities resulting in impaired health-related quality of life (HRQoL). Effective evidence-based rehabilitation guidelines are needed for patients with MM to improve HRQoL. The primary aim of this study was to investigate HRQoL in patients with rehabilitation needs living their everyday life. Patients with MM in remission attended a 12-week multidisciplinary rehabilitation program including a 5-day residential course, home-based exercise and a 2-day follow-up course. The patients were referred by the treating haematologist and completed a booklet of validated HRQoL questionnaires at baseline and before arriving for the 2-day follow-up course. The proportion of participants with moderate to severe symptoms and functional problems were assessed at the two time points and multivariate logistic regression was used to investigate explaining factors of impaired HRQoL at baseline. Ninety-two patients participated with a follow-up compliance rate of 90%. Median age was 67 years and median time since diagnosis was 26 months (ranged 5 months to 15.6 years). The most frequently reported symptoms were global quality of life, role functioning, fatigue, pain, peripheral neuropathy and physical functioning. Pain and fatigue were both highly coherent with impairment in physical functioning and those two symptoms explained most HRQoL impairments. Overall, the participants reported no change in HRQoL after the 12-week rehabilitation program. The study supports the need for an evidence-based guideline for rehabilitation and palliative care to patients with MM in remission living their everyday life.