Data on the impact of long term treatment with IMiDs on health-related quality of life is limited. The HOVON-87/NMSG18 study was a randomized, phase 3 study in newly diagnosed transplant ineligible patients with multiple myeloma, comparing melphalan-prednisolone in combination with thalidomide or lenalidomide, followed by maintenance therapy until progression (MPT-T or MPR-R). The EORTC QLQ-C30 and MY20 questionnaires were completed at baseline, after 3 and 9 induction cycles and 6 and 12 months of maintenance therapy. Linear mixed models and minimal important differences were used for evaluation. 596 patients participated in health-related quality of life reporting. Patients reported clinically relevant improvement in global quality of life, future perspective and role and emotional functioning, and less fatigue and pain in both arms. The latter being of large effect size. In general, improvement occurred after 6 to 12 months of maintenance only and was independent of WHO performance at baseline. Patients treated with MPR-R reported clinically relevant worsening of diarrhea, and patients treated with MPT-T reported a higher incidence of neuropathy. Patients who remained on lenalidomide maintenance therapy for at least 3 months reported clinically meaningful improvement in global QoL and role functioning at 6 months, remaining stable thereafter. There were no clinically meaningful deteriorations, but patients on thalidomide reported clinically relevant worsening in neuropathy. In general, health-related quality of life improves both during induction and maintenance therapy with IMiDs. Side effect profile of treatment did not negatively affect global quality of life, but it was, however, clinically relevant for the patients. (Clinicaltrials.gov identifier: NTR1630).