There are some exciting developments in immunotherapy for patients with AL amyloidosis. Amyloidosis is a challenging area because these patients tend to be diagnosed later in their disease course and they often have organ involvement, including cardiac effects, neuropathy, renal effects, and gastrointestinal effects. Thus, they need additional therapies beyond just plasma cell–directed treatments.

The current standard of care has typically been the CyBorD combination (cyclophosphamide, bortezomib, and dexamethasone). Notably, in abstract 728, Parker et al reported intriguing data from a SWOG study of isatuximab (an anti-CD38 monoclonal antibody) about the efficacy of immunotherapy. Single-agent isatuximab was well tolerated in patients with relapsed or refractory systemic amyloidosis who had at least 1 prior line of therapy. Further, the overall hematologic response rate was 77%, which is really remarkable for a single agent and should translate later on to organ responses as well.

One of the opportunities to treat AL amyloidosis in a targeted way may relate to its higher rate of the t(11;14) translocation. In the average multiple myeloma cohort, approximately 10% to 15% of patients will have t(11;14) translocation, whereas in the setting of amyloidosis, the rate of t(11;14) ranges from 30% to 45%, or even higher, depending on the study. Multiple myeloma with t(11;14) or higher levels of BCL-2 expression can be targeted with venetoclax or other BCL-2 inhibitors that are in development. Anti–BCL-2 therapies are interesting in that they are antiapoptotic agents that can have single-agent activity and can enhance the efficacy of standard cytotoxic chemotherapies. This effect is relevant to abstract 1512, a single-center retrospective study presented at ASH 2020 that explored the outcome of patients with AL amyloidosis with or without t(11;14) who had undergone autologous hematopoietic stem cell transplantation. The study found that the outcomes of these patients were fairly similar, regardless of whether they had that translocation, which is certainly good news. However, this area is controversial, with some studies suggesting that those with t(11;14) may not do as well. The biologic mechanism for poorer outcomes could be that abnormal cells with higher levels of BCL-2 may be protected from apoptosis. To answer this question, we need a compilation of all of the published data to better determine whether BCL-2 levels have an impact.

Another challenge in amyloidosis is amyloid deposition in organs. CAEL-101 is an IgG1 monoclonal antibody that reacts to amyloid fibrils and could thus mobilize immune-mediated clearance of these amyloid deposits. This is important because other chemotherapies predominantly target the cells that make the amyloid but do not do as much—as far as we know—to reduce the amyloid that is already present. CAEL-101 has the potential to do that, and it has been shown to produce evidence of organ responses in the majority of patients treated. Abstract 729 provided an update on data on CAEL-101 in combination with the CyBorD regimen in patients with AL amyloidosis. The initial safety run-in showed that hematological responses were quite good, and early organ responses were seen during the course of therapy. Hopefully, this will translate into organ and long-term quality of life and survival benefits for patients.

I think that this will be an exciting area because of our emerging ability to target molecular abnormalities that are common in AL amyloidosis. The possibility of using immunotherapy to target both the neoplastic cells and the amyloid deposits is also exciting. If you only treat the plasma cell clone, it can take a long time to see an improvement in organ function. Thus, antibodies that directly target the fibrils provide an opportunity to not only improve the hematologic responses but also to maximize organ responses.