Objective: To investigate post-transplant immunotherapy with escalating donor-lymphocyte infusions (DLI) and novel agents (thalidomide, bortezomib, and lenalidomide) to target complete remission (CR). Materials and Methods: Thirty-two patients with multiple myeloma who achieved only partial remission after allogeneic stem cell transplantation were treated with DLI. If no CR was achieved, one of the novel agents was added to target CR. Results: CR defined either by European Group for Blood and Marrow Transplantation criteria, flow cytometry, or molecular methods as assessed by patient-specific immunoglobulin H-polymerase chain reaction or plasma cell chimerism polymerase chain reaction was accomplished in 59%, 63%, and 50% of patients, respectively. Achievement of CR resulted in improved 5-year progressive-free and overall survival, according to European Group for Blood and Marrow Transplantation criteria (53% vs 35%; p = 0.03 and 90% vs 62%; p = 0.06), flow cytometry (74% vs 15%; p = 0.001 and 100% vs 52%; p = 0.1), or molecular methods (84% vs 38%; p = 0.001 and 100% vs 71%; p = 0.03). Conclusions: Our finding demonstrates the clinical relevance of posttransplantation therapies to upgrade remission, and of remission's depth for long-term survival in myeloma patients.