In January 2021, the FDA approved the first (and only) treatment for patients newly-diagnosed with AL amyloidosis, stage I-IIIA: the combination of CD38-targeting antibody, daratumumab; the alkylating agent, cyclophosphamide; the boronic acid proteasome inhibitor, bortezomib; and the steroid drug, dexamethasone (DaraCyBorD). The seminal, phase III, global study Andromeda compared CyBorD, the de facto standard of care regimen for newly-diagnosed stage I-IIIA AL amyloidosis patients, to DaraCyBorD and showed clear superiority of the latter in frequency and depth of hematological responses; frequency of cardiac and renal responses and improvement of composite endpoint of major organ deterioration (cardiac or renal transplant or death); and hematologic progression-free survival (PFS) and major organ deterioration progression-free survival (MOD-PFS). The use of DaraCyBorD frontline in the real world has resulted in unprecedented rapid and deep hematological remission, translating in more frequent organ responses even in critically ill patients and radically changing the lives of patients affected by this rapidly progressive disease. With adequate supportive care, we have safely administered this regimen to frail patients, including the elderly and patients with stage IIIB cardiac involvement.
AL amyloidosis is a unique disease within the field of oncology, as the imminent morbidity and mortality risk that patients face stems not from the expansion of clonal cells but rather from the deposition of fibrillary aggregates of misfolded immunoglobulin light chains in distant organs, such as the heart, leading to architectural disruption and progressive failure. Further, a direct cytotoxic effect of light chains has been demonstrated in vitro. Thus, while AL amyloidosis arises as a plasma cell disorder in the bone marrow, the determinants of outcome are based on the extent and severity of cardiac involvement. There is evidence that amyloid fibrils can be removed by macrophages and other immune cells with phagocytic function. However, this process is inefficient and can only effectively occur once ongoing deposition of new amyloid fibrils is stopped or substantially decreased.
There is growing interest in using bispecific T-cell engagers (BiTEs) as an off-the-shelf therapy to achieve rapid and deep normalization of light chains. These novel immunotherapy agents consist of single chain variable fragments (scFv) binding to a T-cell surface marker (i.e.: CD3) connected via a flexible linker to a scFv binding a cancer-specific antigen (such as B-cell maturation antigen (BCMA). Two BCMA-targeting BiTEs, teclistimab and elranatamab, are FDA-approved in relapsed/refractory multiple myeloma, and small retrospective series have shown these agents to be highly effective and well-tolerated overall in AL amyloidosis patients. Prospective studies of elranatamab and teclistimab are ongoing. Our multicenter, investigator-sponsored clinical trial of open label, single agent, elranatamab in relapsed and/or refractory AL amyloidosis after DaraCyBorD is currently open and enrolling with encouraging early results. Prospective clinical trials examining venetoclax in combinations with other therapies are ongoing, including a phase I/Ia clinical study of all oral combination venetoclax, ixazomib, and dexamethasone in relapsed and refractory, t(11;14) AL amyloidosis patients currently open at our center for the 50-60% of AL amyloidosis patients harboring a t(11;14). In this patient population, venetoclax has led to rapid and persistent hematologic remissions and organ response in a retrospective series.
While a hematological remission is necessary for organ response and thus short- and long-term survival, it is unfortunately not sufficient. Via mechanisms that remain unclear, it is thought that a fibrotic reaction takes place in response to persistent amyloid fibril deposition, leading to irreversible organ damage. It is unknown exactly when the transition from repairable to non-repairable damage occurs, and there are no biomarkers or imaging techniques capable of rendering this information. Unfortunately, it is a common occurrence that patients with advanced AL amyloidosis cardiomyopathy may succumb to their disease secondarily due to cardiac causes and despite achievement of a rapid and adequate hematologic response. On the other hand, patients with AL amyloidosis cardiomyopathy who achieve a cardiac remission appear to have a life expectancy comparable to age-matched controls. Even the most effective plasma cell-directed therapy studied to date, DaraCyBorD, has no direct effect on the removal of amyloid fibrils from the heart and other organs.
Thanks to fundamental basic science discoveries in amyloid chemistry, biophysics, and biochemistry, anti-fibrillary antibodies have been developed to fill this critical unmet need. As a class, these agents recognize and interact with either an epitope specific to certain type of amyloid fibrils (i.e.: AL versus ATTR, etc.) or amyloid fibrils components that are shared across distinct types of amyloidoses. Once bound to the amyloid fibrils, the anti-fibrillary antibodies "flag" it for reabsorption by phagocytic cells, presumably accelerating the process of amyloid reabsorption. Birtamimab and anselamimab are two distinct anti-fibrillary antibodies in phase III, randomized, double blind clinical development in combination with standard-of-care plasma-cell directed therapies in patients with newly-diagnosed, advanced AL amyloid cardiomyopathy. While anselamimab studies in AL amyloidosis patients with stage IIIA and IIIB Mayo 2004 AL amyloidosis completed their accrual in the spring/summer of 2023, the AFFIRM-AL study in patients with Mayo 2012 stage IV is currently open to accrual and available at our center. We are eagerly awaiting results from these seminal studies.
This is an exciting time for the amyloidosis community as we are witnessing fast and unprecedented improvement in the quality and length of life of AL amyloidosis patients. As we strive to educate and raise awareness about this disease so that it is diagnosed earlier, translating in better outcomes, we must continue to strengthen our multidisciplinary approach to the care of patients so that we can best support them and their families in whatever needs they may be faced with during this long and impervious journey. Finally, basic science remains essential to understanding the intrinsic vulnerabilities of AL amyloidosis plasma cells and targeting organs as well as their respective microenvironments. Only through scrupulous science and by thinking outside the box will we be able to further improve outcomes for AL amyloidosis patients and finally declare this disease curable.
