conference reporter

62nd ASH Annual Meeting and Exposition

Updates on Multiple Myeloma and Immunoglobulin Light Chain Amyloidosis

by Robert Z. Orlowski, MD, PhD

Overview

Patients with multiple myeloma may develop immunoglobulin light chain (AL) amyloidosis during the course of their disease. Several abstracts presented at the 62nd ASH Annual Meeting and Exposition focused on the treatment of relapsed/refractory multiple myeloma and research on potential treatments for AL amyloidosis. 

Our featured expert, Robert Z. Orlowski, MD, PhD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD, and Dr Orlowski’s clinical perspectives on these abstracts are presented here. 

Robert Z. Orlowski, MD, PhD

Director of Myeloma Section
Department of Lymphoma/Myeloma
Florence Maude Thomas Cancer Research Professor
Department of Experimental Therapeutics
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, TX

“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.”

Robert Z. Orlowski, MD, PhD

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.

References

Afrough A, Alsfeld LC, Srour SA, et al. Outcome of patients with immunoglobulin light-chain amyloidosis with t(11;14) undergoing autologous hematopoietic stem cell transplantation [abstract 1512]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.

Bochtler T, Hegenbart U, Kunz C, et al. Translocation t(11;14) is associated with adverse outcome in patients with newly diagnosed AL amyloidosis when treated with bortezomib-based regimens. J Clin Oncol. 2015;33(12):1371-1378. doi:10.1200/JCO.2014.57.4947

Fotiou D, Dimopoulos MA, Kastritis E. Systemic AL amyloidosis: current approaches to diagnosis and management. Hemasphere. 2020;4(4):e454. doi:10.1097/HS9.0000000000000454

Khouri J, Anwer F, Samaras CJ, et al. Safety, tolerability and efficacy of Cael-101 in AL amyloidosis patients treated on a phase 2, open-label, dose selection study to evaluate the safety and tolerability of Cael-101 in patients with AL amyloidosis [abstract 729]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.

Kourelis TV, Kumar SK, Gertz MA, et al. Coexistent multiple myeloma or increased bone marrow plasma cells define equally high-risk populations in patients with immunoglobulin light chain amyloidosis. J Clin Oncol. 2013;31(34):4319-4324. doi:10.1200/JCO.2013.50.8499

Madan S, Dispenzieri A, Lacy MQ, et al. Clinical features and treatment response of light chain (AL) amyloidosis diagnosed in patients with previous diagnosis of multiple myeloma. Mayo Clin Proc. 2010;85(3):232-238. doi:10.4065/mcp.2009.0547

Merlini G. AL amyloidosis: from molecular mechanisms to targeted therapies. Hematology Am Soc Hematol Educ Program. 2017;2017(1):1-12. doi:10.1182/asheducation-2017.1.1

Parker TL, Rosenthal A, Sanchorawala V, et al. A phase II study of isatuximab (SAR650984) (NSC-795145) for patients with previously treated AL amyloidosis (SWOG S1702; NCT#03499808) [abstract 728]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.

Popkova T, Hajek R, Jelinek T. Monoclonal antibodies in the treatment of AL amyloidosis: co-targeting the plasma cell clone and amyloid deposits. Br J Haematol. 2020;189(2):228-238. doi:10.1111/bjh.16436

Van Doren L, Lentzsch S. Nonchemotherapy treatment of immunoglobulin light chain amyloidosis. Acta Haematol. 2020;143(4):373-380. doi:10.1159/000507724

Varga C, Lentzsch S, Comenzo RL. Beyond NEOD001 for systemic light-chain amyloidosis. Blood. 2018;132(18):1992-1993. doi:10.1182/blood-2018-07-865857

Vaxman I, Dispenzieri A, Muchtar E, Gertz M. New developments in diagnosis, risk assessment and management in systemic amyloidosis. Blood Rev. 2020;40:100636. doi:10.1016/j.blre.2019.100636


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