Abstract Multiple myeloma is the second most common hematological malignancy and despite improved patient outcomes in the era of novel agents, it remains largely incurable. Clinical studies show that autologous stem cell transplantation (ASCT) remains an efficacious consolidation treatment for eligible patients and a subset of transplant recipients achieve long-term control of disease. Currently, the prolongation of plateau-phase induced by ASCT is attributed to the use of myeloablative chemotherapy and cytoreduction. However, ASCT generates inflammation and profound lymphodepletion, whilst disrupting the marrow microenvironment, all of which has the potential to induce anti-myeloma immunity. We have recently utilized novel preclinical models to provide definitive evidence that ASCT invokes myeloma-specific T cell immunity and the re-establishment of a state of immune equilibrium. Furthermore, we have demonstrated that disease progression after ASCT in these systems is a result of CD8 T cell exhaustion that is dependent on the accumulation of myeloid suppressive populations and the expression of multiple checkpoint molecules by CD8 T cells. These inhibitory pathways are highly amenable to immunotherapeutic approaches after ASCT that invoke long term survival. This proposal will utilize sophisticated protein and transcriptional based approaches to examine the relationship of T cell function in the peri-transplant period to subsequent survival and disease control in well-annotated clinical cohorts. A major focus will be the optimization of innovative immunotherapy approaches after ASCT in preclinical systems for clinical translation.