abt-199 and Immunoglobulin-Light-chain-Amyloidosis

Systemic AL amyloidosis is a protein-misfolding disorder that is characterized by the deposition of insoluble amyloid fibrils derived from kinetically unstable light chains. Achieving a rapid and deep hematologic response is critical for long-term survival.. This review covers the existing and emerging treatment options for systemic AL, divided into anti-plasma cell and fibril-directed therapies. The anti-CD38 monoclonal antibody daratumumab has demonstrated an unprecedented hematologic response rate and will become the new standard-of-care in newly diagnosed patients in combination with CyBorD/VCD. Other plasma cell-directed drugs that have prospective data on safety and efficacy in AL include proteasome inhibitors [bortezomib and ixazomib], immunomodulatory drugs [lenalidomide and pomalidomide], and alkylating agents [melphalan and bendamustine]. A major unmet need is the development of fibril-directed therapies with the goal of eliminating amyloid fibrils that are already deposited in vital organs.. The treatment of newly diagnosed AL in the future will likely include daratumumab-based therapy in conjunction with fibril-directed therapy. The most promising second line drugs are venetoclax [for t(11;14)] and pomalidomide, with several others in the pipeline, including antibody-drug conjugates. Minimal residual disease will emerge as a new endpoint for drug development and will potentially guide treatment duration.

Topics: Animals; Antibodies, Monoclonal; Bridged Bicyclo Compounds, Heterocyclic; Drug Development; Humans; Immunoglobulin Light-chain Amyloidosis; Immunologic Factors; Sulfonamides; Thalidomide

Immunoglobulin light chain amyloidosis (AL) should be considered in any patient that presents to a cancer care provider with nephrotic range proteinuria, heart failure with preserved ejection fraction, non-diabetic peripheral neuropathy, unexplained hepatomegaly or diarrhea. More importantly, patients being monitored for smoldering multiple myeloma and a monoclonal gammopathy of undetermined significance (MGUS) are at risk for developing AL amyloidosis. MGUS and myeloma patients that have atypical features, including unexplained weight loss; lower extremity edema, early satiety, and dyspnea on exertion should be considered at risk for light chain amyloidosis. Overlooking the diagnosis of light chain amyloidosis leading to therapy delay is common, and it represents an error of diagnostic consideration. Algorithms will be provided on how to evaluate patients with suspected AL amyloid as well as how to manage patients referred from other medical specialties with biopsy-proven amyloid. An organized stepwise approach to the treatment of patients with light chain amyloidosis, including established and investigational therapies, will be reviewed.

Topics: Aged; Algorithms; Antineoplastic Agents, Immunological; Biopsy; Bridged Bicyclo Compounds, Heterocyclic; Combined Modality Therapy; Disease Management; Female; Humans; Immunoglobulin A; Immunoglobulin Light-chain Amyloidosis; Monoclonal Gammopathy of Undetermined Significance; Organ Transplantation; Prealbumin; Proteasome Inhibitors; Sulfonamides

Immunoglobulin light chain (AL) amyloidosis is an incurable hematologic disorder typically characterized by the production of amyloidogenic light chains by clonal plasma cells. These light chains misfold and aggregate in healthy tissues as amyloid fibrils, leading to life-threatening multi-organ dysfunction. Here we show that the clonal plasma cells in AL amyloidosis are highly primed to undergo apoptosis and dependent on pro-survival proteins MCL-1 and BCL-2. Notably, this MCL-1 dependency is indirectly targeted by the proteasome inhibitor bortezomib, currently the standard of care for this disease and the related plasma cell disorder multiple myeloma, due to upregulation of pro-apoptotic Noxa and its inhibitory binding to MCL-1. BCL-2 inhibitors sensitize clonal plasma cells to multiple front-line therapies including bortezomib, dexamethasone and lenalidomide. Strikingly, in mice bearing AL amyloidosis cell line xenografts, single agent treatment with the BCL-2 inhibitor ABT-199 (venetoclax) produces deeper remissions than bortezomib and triples median survival. Mass spectrometry-based proteomic analysis reveals rewiring of signaling pathways regulating apoptosis, proliferation and mitochondrial metabolism between isogenic AL amyloidosis and multiple myeloma cells that divergently alter their sensitivity to therapies. These findings provide a roadmap for the use of BH3 mimetics to exploit endogenous and induced apoptotic vulnerabilities in AL amyloidosis.

Topics: Amyloid; Animals; Antineoplastic Agents; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Dexamethasone; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Lenalidomide; Mice; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Proteasome Inhibitors; Proteomics; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Venetoclax is efficacious in relapsed/refractory t(11;14) multiple myeloma, thus warranting investigation in light-chain amyloidosis (AL). This retrospective cohort includes 43 patients with previously treated AL, from 14 centers in the US and Europe. Thirty-one patients harbored t(11;14), 11 did not, and one t(11;14) status was unknown. Patients received a venetoclax-containing regimen for at least one 21- or 28-day cycle; the median prior treatments was three. The hematologic response rate for all patients was 68%; 63% achieved VGPR/CR. t(11;14) patients had higher hematologic response (81% vs. 40%) and higher VGPR/CR rate (78% vs. 30%, odds ratio: 0.12, 95% CI 0.02-0.62) than non-t(11;14) patients. For the unsegregated cohort, median progression-free survival (PFS) was 31.0 months and median OS was not reached (NR). For t(11;14), median PFS was NR and for non-t(11;14) median PFS was 6.7 months (HR: 0.14, 95% CI 0.04-0.53). Multivariate analysis incorporating age, sex, prior lines of therapy, and disease stage suggested a risk reduction for progression or death in t(11;14) patients. Median OS was NR for either subgroup. The organ response rate was 38%; most responders harbored t(11;14). Grade 3 or higher adverse events occurred in 19% with 7% due to infections. These promising results require confirmation in a randomized clinical trial.

Topics: Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Middle Aged; Neoplasm Recurrence, Local; Progression-Free Survival; Retrospective Studies; Sulfonamides; Translocation, Genetic; Treatment Outcome

Topics: Adult; Aged; Aged, 80 and over; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Middle Aged; Retrospective Studies; Sulfonamides

Immunoglobulin light-chain amyloidosis (AL) is a disease with limited treatment options due to the frailty of patients caused by organ damage. Since the clonal plasma cells often contain the cytogenetic aberration t(11;14), the Bcl-2 inhibitor venetoclax is suggested to have a role in the treatment of AL. Here, we report of a heart-transplanted patient, refractory to multiple therapies, reaching a rapid complete response with single-agent venetoclax.

Topics: Antineoplastic Agents; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Dexamethasone; Female; Heart Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Translocation, Genetic

Immunoglobulin light chain amyloidosis (AL) is a plasma cell disorder characterized by accumulation of misfolded proteins, which can induce organ damage. Venetoclax is active in multiple myeloma patients, in particular those with t(11;14) translocation. t(11;14) translocation is the most common cytogenetic abnormality in AL patients; venetoclax may thus be a useful additional treatment option for this disease. However, a recent trial in multiple myeloma patients (BELLINI) reported increased mortality associated with venetoclax versus placebo in combination with bortezomib and dexamethasone. In this report, we describe an AL patient who had suffered from recurrent infection during previous treatment, but who responded to and tolerated well single-agent venetoclax for more than 1 year. The present report indicates that venetoclax monotherapy may be active and safe for refractory AL amyloidosis.

Topics: Adult; Bridged Bicyclo Compounds, Heterocyclic; Chromosomes, Human, Pair 11; Dexamethasone; Drug Therapy, Combination; Frailty; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Safety; Sulfonamides; Translocation, Genetic; Treatment Outcome

Topics: Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Middle Aged; Sulfonamides; Translocation, Genetic; Treatment Outcome

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Boron Compounds; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Dexamethasone; Glycine; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Male; Remission Induction; Sulfonamides

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Drug Administration Schedule; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Kidney; Myocardium; Sulfonamides; Translocation, Genetic; Treatment Outcome

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Cyclophosphamide; Dexamethasone; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Remission Induction; Sulfonamides; Translocation, Genetic