Clonal Plasma Cells in AL Amyloidosis Are Dependent on Anti-Apoptotic BCL-2 Family Proteins

Background: Immunoglobulin light chain (AL) amyloidosis is characterized by the production of clonal serum free light chains, which misfold and accumulate in tissues causing life threatening organ dysfunction and ultimately death. The treatment of AL amyloidosis targets the underlying population of clonal plasma cells, but existing therapies are not curative and ineffectively control the disease in many patients. Recent data have shown tremendous success in targeting anti-apoptotic BCL-2 family proteins as a novel therapy in hematologic disorders due to alterations in apoptosis and the function of anti-apoptotic proteins in malignant cells. BH3 profiling, a quantitative and functional assay that measures apoptotic priming and dependence on anti-apoptotic BCL-2 family members, has been used to identify and target apoptotic dependencies in hematologic disorders. Novel inhibitors of anti-apoptotic proteins, referred to as BH3 mimetics, have not yet been explored in AL amyloidosis due to insufficient understanding of apoptotic dependencies in this disease.

Methods: To date, bone marrow aspirates have been collected from 44 patients with newly diagnosed or relapsed/refractory AL amyloidosis being evaluated at the Amyloidosis Center at Boston University. BH3 profiling was performed on clonal plasma cells to measure dependencies on anti-apoptotic BCL-2 family proteins. Clonal cells were also treated with BH3 mimetics in vitro, including BCL-2, BCL-xL, and MCL-1 inhibitors as single agents, as well as in combination with current standard therapies (bortezomib, ixazomib, lenalidomide, and pomalidomide).

Results: Of the 44 enrolled patients, 16 are female (36%) and 28 are male (64%). The median age is 70 years (range, 47 to 84). Six patients were treatment naïve and the remainder had previous or current treatment for AL amyloidosis. Data obtained with BH3 profiling demonstrated that clonal plasma cells exhibit strong dependencies on anti-apoptotic BCL-2 family proteins, which may be altered by concurrent treatment with standard therapies. In the majority of patients, clonal plasma cells are highly dependent on the anti-apoptotic protein MCL-1 and undergo apoptosis when treated with an MCL-1 inhibitor. Intriguingly, this dependence is altered by treatment with proteasome inhibitors: clonal plasma cells become highly dependent on BCL-2 and undergo apoptosis in response to co-treatment with bortezomib and the FDA-approved BCL-2 inhibitor venetoclax.

Conclusions: BH3 profiling can effectively measure apoptotic dependencies in clonal plasma cells derived from bone marrow aspirates in patients with AL amyloidosis. Dependencies on BCL-2 family proteins (particularly MCL-1) are strong, but some variability between patients was observed, especially in combination with standard therapies. Biomarker-driven deployment of BH3 mimetics for treatment of AL amyloidosis would likely be highly effective.