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Bortezomib is a first-line therapy for multiple myeloma and also recommended in many associations for relapsing disease. Hospital-at-Home (HaH) is an attractive alternative to Outpatient Hospital (OH) treatment. The purpose of the study is to compare costs and patient-reported outcomes of two different strategies: exclusive OH-based bortezomib administration or combined administration in both OH and HaH. A prospective non-randomized trial was conducted in Nancy University Hospital. QoL was measured using the EuroQol 5D (EQ-5D) and the European Organization for Research and Treatment of Cancer (EORTC) QoL Questionnaire Core 30 (QLQ-C30). The analysis was conducted from the National Health Insurance System (NHIS) perspective. A total of 42 patients were enrolled in the study. Twenty patients received all bortezomib injections in OH (median of 24 injections) and 22 patients received bortezomib in OH alternately with HaH (median of 28.5 injections, 10.5 in OH and 18.0 in HaH). The average cost per injection was 602.63 € in the OH group versus 479.52 € in the OH/HaH group. Combined administration of bortezomib in OH and HaH was associated with a substantial cost-saving of 20.4% for NHIS and no difference in QoL. This trial responds to chronic patients’ wish to assess innovative ways of care.