ABSTRACT Immunoglobulin light chain (AL) amyloidosis is a highly lethal disorder characterized by the production and deposition of fibrillogenic immunoglobulin light chains in vital organs. These misfolded light chains are produced by a clonal population of diseased plasma cells, which are therapeutically targeted with the use of proteasome inhibitors and immunomodulatory agents. However, these treatment regimens were developed for the more common plasma cell disease multiple myeloma and have only limited efficacy in AL amyloidosis as demonstrated by the 2-3 year median survival for patients that do not receive an autologous stem cell transplant. Improved therapies for patients diagnosed with AL amyloidosis are therefore urgently needed, especially well-tolerated treatments that are able to facilitate long-term remissions. We have previously discovered that the state of the apoptosis pathway in cells, both in vitro and in the clinic, profoundly alters their chemosensitivity and clinical outcomes. In addition, a preponderance of evidence demonstrates that upregulation of pro-survival proteins from the BCL-2 family including BCL-2, BCL-XL and MCL-1 can be major drivers of therapy resistance across multiple cancer types, highlighting the importance of this pathway in governing responses to chemotherapy. The recent development of novel small-molecule inhibitors of the major pro-survival proteins from the BCL-2 family has created an unprecedented opportunity to target apoptotic dependencies in cancer cells, a strategy that may be particularly effective in the dysfunctional clonal plasma cells that drive AL amyloidosis. However, the landscape of apoptotic dependencies in AL amyloidosis and how they may be exploited to improve patient responses is not known. Using primary bone marrow-derived clonal plasma cells from both treatment-naïve and treated AL amyloidosis patients, we have recently discovered that clonal plasma cells exhibit strong dependencies on BCL-2 family proteins, which change dramatically in response to treatment with existing front-line therapies. Our central hypothesis is that BH3 mimetics will be highly effective agents for the treatment of clonal plasma cells in patients with AL amyloidosis, both as single agents and in combination with front-line therapies. To test this hypothesis, we will 1) identify apoptotic dependencies in clonal plasma cells from AL amyloidosis patients at baseline and during treatment with front- line and experimental therapies; 2) investigate molecular mechanisms regulating apoptotic dependencies in AL amyloidosis clonal plasma cells and how they may be used as clinical biomarkers; and 3) develop mouse PDX models of AL amyloidosis to study disease development and progression as well as BH3 mimetic efficacy and toxicity. This study addresses the important problem of limited therapeutic options for patients diagnosed with AL amyloidosis by identifying highly-efficacious therapeutic approaches utilizing BH3 mimet...