Immunoglobulin light chain amyloidosis is the most common form of systemic amyloidosis and is characterized by rapidly progressive organ failure and eventually patient demise, if not promptly recognized and treated.
Giada Bianchi, MD
Associate Director of the Brigham and Women’s Hospital/Dana-Farber Cancer Institute’s Amyloidosis Program
Attending Physician, the Jerome Lipper Multiple Myeloma Center,
Dana-Farber Cancer Institute,
Instructor in Medicine,
Systemic amyloidosis is a heterogenous family of diseases characterized by deposition of fibrillary aggregates of a precursor protein in target organs, such as the heart and kidneys (Figures 1 and 2).1 The identity of the amyloidogenic precursor protein, such as transthyretin (TTR) or immunoglobulin light chain (AL), dictates the pattern of organ deposition and clinical presentation and determines the therapeutic approach (ie, chemotherapy or chemoimmunotherapy for AL versus TTR stabilizer or gene silencing for TTR amyloidosis).2 AL amyloidosis is the most common form of systemic amyloidosis and is characterized by rapidly progressive organ failure and eventually patient demise, if not promptly recognized and treated. The pathogenetic mechanism in AL amyloidosis is deposition of fibrils of misfolded immunoglobulin free light chains (FLC), typically produced by clonal plasma cells and, less often, B cells.
The FLC is λ in 75% of cases and a small pool of Ig light chain variable (IGVL) genotypes underlies most AL amyloidosis cases, suggesting that amyloidogenicity is an intrinsic characteristic of the amino acid sequence of the FLC.3 Progression of AL amyloidosis from precursor plasma cell dyscrasia such as monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM) can occur and hematologists must carefully monitor these patients for signs or symptoms concerning AL amyloidosis.4
Navigating the AL Maze
Epidemiologic studies suggest that AL amyloidosis is not a rare disease, but rather underdiagnosed.5,6 The vague nature of early symptoms, such as fatigue and weight loss, contributes to diagnostic delay, potentially causing irreversible organ damage and high risk of early mortality. There is no FDA-approved treatment for AL amyloidosis; however, chemotherapy targeting plasma cells, such as cyclophosphamide, bortezomib (Velcade), and dexamethasone (CyBorD), and/or autologous stem cell transplant, are standard of care and can elicit deep and durable hematologic responses.7-9
Figure 1. Histopathologic Appearance of Cardiac Amyloidosis (Click to Enlarge)
Figure 2. Histopathologic Appearance of Renal λ Light Chain AL Amyloidosis (Click to Enlarge)
Figure 3. Critical Areas of Research Effort in AL Amyloidosis (Click to Enlarge)
With the FDA approval of inotersen (Tegsedi) and patisiran (Onpattro) for hereditary TTR amyloidosis (ATTR)-related neuropathy and tafamidis (Vyndamax) for ATTR-related cardiomyopathy, it has become even more critical to accurately distinguish ATTR versus AL amyloidosis.11-13 Significant epidemiological and clinical overlap exists for ATTR and AL amyloidosis and an expedited, careful diagnostic work up with definitive confirmation of precursor amyloid protein via liquid chromatography and mass spectrometry (LC-MS) or immunogold on tissue biopsy is thus critical.14-16
Research efforts to identify MGUS/SMM patients at high risk for AL amyloidosis transformation include the study of serum FLC N-glycosylation via LC-MS and in vitro fibrillogenic competition assay with circulating FLC.17,18 The SAVE clinical study (NCT02741999) evaluates asymptomatic patients with a provisional diagnosis of λ light chain MGUS/ SMM to identify IGVL genotypes associated with highest risk of amyloidogenicity and ensure patients are screened accordingly.19 Innovative molecular imaging modalities detecting AL fibrils in a highly specific manner are being investigated as a tool to assess amyloid deposition and distribution even before overt clinical manifestations.20,21
Challenges in Treating Patients
The major hurdle in treating patients with AL amyloidosis using multiple myeloma (MM)-directed chemotherapy is decreased tolerance, particularly in patients with advanced cardiomyopathy or nephrotic syndrome, rather than lack of efficacy. As a single agent, the CD38-targeting antibody daratumumab (Darzalex) has shown unprecedented effectiveness in inducing rapid and profound hematologic responses in patients with heavily pretreated AL amyloidosis, but large volume infusion and high steroid dosing limited tolerability.22,23 Excitingly, the FDA approved the subcutanous formulation of fixed dose daratumumab and and hyaluronidase-fihj (Darzalex Faspro) for all previously approved indications of intravenous daratumumab.
The ANDROMEDA trial (NCT03201965), a phase 3, randomized trial comparing CyBorD alone or in combination with subcutaneous daratumumab, closed to accrual in August 2019. Data on the 28 patients enrolled in the safety run-in phase showed an overall response rate of 96% with 82% of those very good partial responses or better, including 36% complete responses.24 The quadruple combination was well tolerated overall and may become frontline, standard of care.
The phase 3 TOURMALINE-AL1 trial (NCT01659658) that randomized patients to receive either ixazomib (Ninlaro) plus dexamethasone or clinician’s choice was closed early due to lack of significant improvement in overall hematologic response. However, patients in the ixazomib arm enjoyed a doubling of hematologic response duration compared with controls (46.5 vs 20.2 months, respectively),suggesting a potential role for ixazomib as maintenance therapy.25
Translocation t(11;14) is the most common cytogenetic abnormality in AL amyloidosis and is present in approximately 40% of patients. It is a poor prognostic factor for overall survival and a negative predictive factor of response to bortezomib- containing regimens.26 However, in MM, t(11;14) is a biomarker of high BCL-2 expression and a predictive factor of response to the BCL-2 inhibitor venetoclax (Venclexta).27 Several clinical trials of venetoclax in MM have been halted due to excess mortality from infectious complications noted in patients receiving venetoclax in combination with bortezomib and dexamethasone in the phase 3 BELLINI study (NCT02755597).28
As benefits seem to outweigh risks for patients with t(11;14), the amyloidosis community is eagerly awaiting the FDA to lift the hold so that venetoclax can be tested in clinical trials in patients with t(11;14) AL amyloidosis. The BCMA-targeting antibody-drug conjugate belantamab mafodotin and melflufen, a melphalan derivative, showed promising results in MM, and clinical trials are underway or anticipated in AL amyloidosis.29-31
Although overall survival of patients with AL amyloidosis has substantially improved thanks to more effective chemotherapy, early mortality remains largely unaffected and mostly related to delayed diagnosis leading to advanced cardiac dysfunction. Thus, a significant research effort has been funneled toward developing therapeutics to facilitate the reabsorption of deposited amyloid. The antimicrobial doxycycline was shown to rescue cardiomyocyte from direct FLC toxicity and to interfere with fibrillogenesis in preclinical models.32,33
Retrospective and phase 2 studies confirmed that adding doxycycline to standard chemotherapy reduces early cardiac mortality and its use is suggested in patients with AL amyloidosis- related cardiomyopathy in combination with chemotherapy.34,35 The antifibrillary antibody birtamimab (NEOD001) showed promising results in improving cardiac dysfunction in early-phase clinical studies.36 However, drug development was halted based on lack of benefit in a large phase 3 study.37
In a phase 1a/b study enrolling patients with relapsed/refractory AL amyloidosis, CAEL-101, a novel antibody recognizing an epitope solely exposed by misfolded FLC, showed rapid and frequent cardiac and renal responses independently of hematologic response with no patient experiencing organ progression while they were on the study.38 A phase 2/3 study (NCT04304144) of CAEL-101 in combination with CyBorD in patients with treatment-naÏve AL amyloidosis with cardiac dysfunction is currently recruiting.
The upfront use of antifibrillary antibodies and highly effective, combinatory chemotherapy could profoundly affect the natural history of this devastating condition and finally improve early mortality. Together with an effort to educate clinicians to think about amyloidosis in their daily practice, studies focusing on early recognition or diagnosis in high-risk groups such as African Americans and patients with a preexisting MGUS/SMM diagnosis are likely to have a major impact from a public health standpoint.
This is an exciting time for the AL amyloidosis community as patient advocacy groups, academia, pharmaceutical companies, and regulatory agencies are joining in an effort to develop safe and effective treatments for patients with AL amyloidosis.
Clinical research efforts in AL amyloidosis have focused on 3 main areas: (1) early diagnosis; (2) effective chemotherapy; and (3) antifibrillary drugs (Figure 3).
Chemotherapy does not directly target the deposited amyloid fibrils but it halts progressive organ dysfunction by abating FLC secretion and thus amyloid deposition. In patients who achieve a hematologic remission, the deposited amyloid is then removed over a period of months or years.10 The causes of inefficient amyloid removal remain poorly understood.