Multiple myeloma (MM) relapsing after allogeneic stem cell transplantation (alloSCT) has a poor outcome. To assess the safety and efficacy of bortezomib and dexamethasone (VD) combination followed by donor lymphocyte infusions (DLI) in myeloma patients relapsing or progressing after alloSCT, a prospective phase II study was designed. The treatment plan consisted of 3 VD courses followed by escalated doses of DLIs in case of response or at least stable disease. Nineteen patients were enrolled. Median age was 57 years (range 33-67); 14 patients were allografted from HLA-identical siblings, and 5 from alternative donors. Sixteen of 19 patients received the planned treatment, while 2 patients did not because of disease progression and one for refusal. After the VD phase the response rate (RR) was 62%, with one complete remission (CR), 6 very good partial remissions (VGPR), 5 partial remissions (PR), 2 patients with stable disease (SD), and 5 with progressive disease (PD). After the DLI phase the RR was 68%, but a significant upgrade of response was observed: 3 stringent CR, 2 CR, 5 VGPR, 1 PR, 4 SD, and 1 PD. With a median follow-up of 40 months (range, 29-68), the 3 year PFS and OS were 31%, and 73%, respectively. Neither unexpected organ toxicities, in particular severe neuropathy, nor severe acute GVHD flares were observed. VD-DLIs is a safe treatment for MM patients relapsing or progressing after alloSCT and may be effective.