Abstract Background: Data from the literature have suggested that bortezomib is the only effective agent in the treatment of plasma cell leukemia (PCL), a type of plasma cell dyscrasia characterized by poor prognosis despite conventional chemotherapy including autologous and allogeneic transplantation. Objective: This case series examined the antineoplastic activity of the bortezomib-based regimens in a small cohort of patients with PCL. Case summaries: We describe a retrospective review of the 3 cases of PCL diagnosed at Antonio Perrino Hospital, Brindisi, Italy, between July 2004 and October 2006 (2 women and 1 man, all white, ages 71, 64, and 42 years; 2 with primary PCL and 1 with secondary PCL). These patients were treated with bortezomib variously combined with other drugs outside of clinical trials. Patients 1 and 2 received bortezomib-based regimens (bortezomib 1.3 mg/m2 IV once daily on days 1, 4, 8, and 11; dexamethasone 20 mg IV once daily on days 1–4 and 8–11; oral cyclophosphamide 50 mg once daily on days 1–21, every 28 days) after 2 previous chemotherapeutic treatments. Patient 3 received a bortezomib-based regimen (bortezomib 1.3 mg/m2 IV once daily on days 1, 4, 8, and 11; doxorubicin 9 mg/m2 IV once daily on days 1–4; and dexamethasone 40 mg IV once daily on days 1–4, 8–11, and 15–18 during cycle 1 and days 1–4 during subsequent cycles) after one previous chemotherapeutic regimen. In all 3 patients, circulating plasma cells persisted. Patients 1 and 2 were not considered candidates for autologous peripheral blood stem cell transplantation (PBSCT) because of their nonresponse to the bortezomib-based regimens and severe deterioration of their clinical conditions (kidney and liver failure) due to disease progression. The overall survivals after administration of the bortezomib- based regimens were 4 months in patient 1 and 1 month in patient 2. After further treatment according to the modified protocol for patients with acute lymphatic leukemia (cyclophosphamide 800 mg/m2 IV on day 1 and 200 mg/m2 IV on days 2–5; vincristine 1.5 mg/m2 IV once daily on days 1, 8, and 15; doxorubicin 40 mg/m2 IV on day 1; methotrexate 1200 mg/m2 /h IV + 240 mg/m2 /h IV for 23 hours modified CODOX-M protocol) due to the unavailability of a human leukocyte antigen-identical donor, patient 3 received high-dose (200 mg/m2 ) melphalan with autologous PBSCT, obtaining partial remission lasting 9 months. The patient died 5 months later because of disease progression. Conclusion: These 3 patients with primary or secondary PCL who received a bortezomib-based regimen as rescue medication did not respond to treatment.