Immunoglobulin Light Chain Amyloidosis Research Articles

Prognostic implications of clinical phenotype and severity of cardiac involvement in patients presenting with immunoglobulin light chain amyloidosis

Abstract Background Patients with systemic immunoglobulin light chain (AL) amyloidosis may present with a wide array of signs and symptoms due to the multi-systemic organ involved. The presence of cardiac involvement is the key determinant of survival. Cardiac magnetic resonance (CMR) has the unique ability to measure the continuum of cardiac amyloidosis (CA) infiltration providing a deep characterisation from early CA involvement to severe degree of CA burden. Purpose The aim of this study was to characterise the clinical profiles and the severity of organ involvement in patients presenting with AL amyloidosis and to investigate implications for long-term outcome. Methods Patients newly diagnosed with AL amyloidosis at the National Amyloidosis Centre underwent comprehensive clinical, laboratory and instrumental work up, including CMR imaging with left ventricular (LV) mass, late gadolinium enhancement (LGE) and extracellular volume (ECV). The clinical phenotypes were classified in cardiac, renal and other according to the symptoms at presentation. The degree of CA was investigated by CMR: 0= no features of CA (normal LV mass, no LGE and normal ECV); 1=early cardiac amyloid infiltration (normal LV mass, raised ECV no LGE); 2= characteristic of CA with normal mass (diffuse subendocardial or transmural LGE, altered gadolinium kinetics and raised ECV); 3= characteristic of CA with elevated mass (diffuse subendocardial or transmural LGE and raised ECV). The study outcome was all-cause mortality. Results The study population included 241 AL patients presenting with cardiac and renal (22.8%, n=55), cardiac (28.2%, n=68), renal (33.2%, n=80) and other (15.8% n=38) phenotypes. During a median follow up of 33 (IQR 7–52) months, cardiac phenotype either in isolation or in combination with renal phenotype was associated with a higher rate of all-cause mortality compared to the others (p<0.001) (Figure). On CMR imaging, 43.2% of patients without cardiac phenotype (49%, n=118/241) had characteristic scans of CA (CMR grade 2 and 3) whilst 13.8% of patients with cardiac phenotype (51%, n=123/241) had no features of CA on CMR images (CMR grade 0) in (p<0.001). With Kaplan Meier analysis, the risk of all-cause death increased in patients with characteristic features of CA on CMR scan (Figure 1) and in patients with cardiac phenotype and features of CA on CMR scans compared to the others (both p<0.001) (Figure). At multivariable analysis, age at diagnosis (hazard ratio [HR] 1.03, p=0.009), clinical phenotype at presentation (HR 1.35, p=0.014) and ECV measured by CMR (HR 56, p<0.001) emerged as independent prognostic parameters. Conclusions Patients with newly diagnosed AL amyloidosis present most frequently with renal and cardiac phenotypes. CMR detects CA in >40% of patients with non-cardiac phenotype. ECV is an independent predictor of all-cause mortality across the full clinical spectrum of AL amyloidosis. Funding Acknowledgement Type of funding sources: None.

Exploiting endogenous and therapy-induced apoptotic vulnerabilities in immunoglobulin light chain amyloidosis with BH3 mimetics

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.

S3686 Unusual Presentation of Immunoglobulin Light Chain (AL) Amyloidosis as a Gastric Subepithelial Lesion

S3686 Unusual Presentation of Immunoglobulin Light Chain (AL) Amyloidosis as a Gastric Subepithelial Lesion

Multi-Imaging Characterization of Cardiac Phenotype in Different Types of Amyloidosis

BackgroundBone scintigraphy is extremely valuable when assessing patients with suspected cardiac amyloidosis (CA), but the clinical significance and associated phenotype of different degrees of cardiac uptake across different types is yet to be defined. ObjectivesThis study sought to define the phenotypes of patients with varying degrees of cardiac uptake on bone scintigraphy, across multiple types of systemic amyloidosis, using extensive characterization comprising biomarkers as well as echocardiographic and cardiac magnetic resonance (CMR) imaging. MethodsA total of 296 patients (117 with immunoglobulin light-chain amyloidosis [AL], 165 with transthyretin amyloidosis [ATTR], 7 with apolipoprotein AI amyloidosis [AApoAI], and 7 with apolipoprotein AIV amyloidosis [AApoAIV]) underwent deep characterization of their cardiac phenotype. ResultsAL patients with grade 0 myocardial radiotracer uptake spanned the spectrum of CMR findings from no CA to characteristic CA, whereas AL patients with grades 1 to 3 always produced characteristic CMR features. In ATTR, the CA burden strongly correlated with myocardial tracer uptake, except in Ser77Tyr. AApoAI presented with grade 0 or 1 and disproportionate right-sided involvement. AApoAIV always presented with grade 0 and characteristic CA. AL grade 1 patients (n = 48; 100%) had characteristic CA, whereas only ATTR grade 1 patients with Ser77Tyr had characteristic CA on CMR (n = 5; 11.4%). After exclusion of Ser77Tyr, AApoAI, and AApoAIV, CMR showing characteristic CA or an extracellular volume of >0.40 in patients with grade 0 to 1 cardiac uptake had a sensitivity and specificity of 100% for AL. ConclusionsThere is a wide variation in cardiac phenotype between different amyloidosis types across different degrees of cardiac uptake. The combination of CMR and bone scintigraphy can help to define the diagnostic differentials and the clinical phenotype in each individual patient.

One Patient's Journey from Amyloidosis to Transplant.

This story was written by a patient with immunoglobulin light chain amyloidosis who had a stem cell transplant and eventually a heart and kidney transplant. She was treated by Horacio E. Adrogue, MD, FASN, and a team of health care professionals in the Division of Nephrology, Transplantation, and Hypertension at Houston Methodist Hospital in Houston, Texas. We appreciate her willingness to share her story and hope it will inspire others.

Amyloidosis of the Heart and Kidney.

Amyloidosis encompasses a collection of disorders of pathological protein folding. The extracellular location where these “amyloid fibril” proteins are deposited determines the clinical presentation of the disease. The abnormal architecture of these fibrils makes them insoluble and not easily removed, leading to disruption of normal tissue structure and interference with normal physiology. Amyloidosis of the heart and kidney can be inherited, secondary to unrelated diseases, or due to a plasma cell disorder. This review will focus on immunoglobulin light chain amyloidosis, which is life-threatening and must be diagnosed as early as possible by employing precise and accurate typing to ensure timely and frequently curative therapy.

Incidence and effect of secondary cardiac amyloidosis on outcomes of patients with t(11;14) multiple myeloma

BackgroundThe t(11;14)(q13;32) is a common chromosome translocation in multiple myeloma (MM), but its prognostic value remains controversial. Immunoglobulin light chain amyloidosis is commonly secondary to multiple myeloma, which can rapidly cause heart failure and high mortality. We aimed to investigate the prevalence of secondary cardiac amyloidosis in MM patients with t(11;14) and to evaluate its impact on survival outcomes.MethodsWe retrospectively identified 52 MM patients with t(11;14) in our center between October 2015 and April 2022. The associations between cardiac amyloidosis and clinical and biological parameters were statistically analyzed, and the impacts of concomitant of cardiac amyloidosis on survival and prognosis of MM patients with t(11;14) were also assessed.ResultsConcomitant presence of cardiac amyloidosis was observed in 15 (28.8%) of all cases. Patients with cardiac amyloidosis had significantly higher NT-proBNP (p = 0.002) and higher hs-cTnT (p < 0.001), while the patients without cardiac amyloidosis had higher percentage of bone marrow plasma cells (p = 0.027), higher incidence of hemoglobin <80 g/L (p = 0.021) and bone destruction (p < 0.001). The median overall survival (OS) for all patients was 33.4 months after a median follow-up of 23.8 months. The amyloidosis group showed a significantly shorter OS than the non-amyloidosis group (15.3 vs. 41.8 months, p < 0.001). Besides, patients harboring NT-proBNP >1,800 pg/ml (p < 0.001) or hs-cTnT ≧40 pg/ml (p = 0.001) or light chain (LC) only isotype (p = 0.033) had a significantly shorter mean OS compared with patients with lower NT-proBNP or hs-cTnT or other M-protein isotype. Univariate analyses showed that NT-proBNP >1,800 pg/ml, hs-cTnT ≧40 pg/ml, LC only isotype, and concomitant presence of cardiac amyloidosis were independently associated with shorter OS, while NT-proBNP >1,800 pg/ml still retained the prognostic value for OS in multivariate analyses.ConclusionThe t(11;14) MM patients with coexisting cardiac amyloidosis may represent a distinct clinical entity that confers a poor outcome. These findings may have important clinical and biological implications.

Systemic Immunoglobulin Light Chain Amyloidosis Presenting as Painful Penile Ulcers

Immunoglobulin light chain (AL) amyloidosis is a systemic form of amyloidosis that commonly affects the heart, kidney, liver, and nervous system. Penile involvement in AL amyloidosis is rare and thus often not considered in the differential diagnosis for penile ulcers. We report a case of an elderly man with nonhealing, painful penile ulcers who had AL amyloidosis with cardiac, renal, and liver involvement. His penile lesions were successfully treated with surgical resection of the amyloid deposits. Even after serologic relapse of his systemic amyloidosis, he has not had recurrence of his penile ulcers many years later.

Targeting CD38 in Neoplasms and Non-Cancer Diseases.

Simple SummaryCD38 remains an interesting target for anticancer therapy. Its relatively high abundance in neoplasms and crucial impact on NAD+/cADPR metabolism and the activity of T cells allows for changing the immune response in autoimmune diseases, neoplasms, and finally the induction of cell death. Antibody-dependent cell cytotoxicity is responsible for cell death induced by targeting the tumor with anti-CD38 antibodies, such as daratumumab. A wide range of laboratory experiments and clinical trials show an especially promising role of anti-CD38 therapy against multiple myeloma, NK cell lymphomas, and CD19- B-cell malignancies. More studies are required to include more diseases in the therapeutic protocols involving the modulation of CD38 activity.CD38 is a myeloid antigen present both on the cell membrane and in the intracellular compartment of the cell. Its occurrence is often enhanced in cancer cells, thus making it a potential target in anticancer therapy. Daratumumab and isatuximab already received FDA approval, and novel agents such as MOR202, TAK079 and TNB-738 undergo clinical trials. Also, novel therapeutics such as SAR442085 aim to outrank the older antibodies against CD38. Multiple myeloma and immunoglobulin light-chain amyloidosis may be effectively treated with anti-CD38 immunotherapy. Its role in other hematological malignancies is also important concerning both diagnostic process and potential treatment in the future. Aside from the hematological malignancies, CD38 remains a potential target in gastrointestinal, neurological and pulmonary system disorders. Due to the strong interaction of CD38 with TCR and CD16 on T cells, it may also serve as the biomarker in transplant rejection in renal transplant patients. Besides, CD38 finds its role outside oncology in systemic lupus erythematosus and collagen-induced arthritis. CD38 plays an important role in viral infections, including AIDS and COVID-19. Most of the undergoing clinical trials focus on the use of anti-CD38 antibodies in the therapy of multiple myeloma, CD19- B-cell malignancies, and NK cell lymphomas. This review focuses on targeting CD38 in cancer and non-cancerous diseases using antibodies, cell-based therapies and CD38 inhibitors. We also provide a summary of current clinical trials targeting CD38.

Modified High-Dose versus High-Dose Melphalan Conditioning in Older Patients Undergoing Autologous Stem Cell Transplantation for Immunoglobulin Light Chain Amyloidosis

High-dose melphalan and autologous stem cell transplantation (HDM/SCT) induces deep hematologic responses (HR) in patients with newly diagnosed systemic immunoglobulin light-chain (AL) amyloidosis. Modifying melphalan conditioning dose (mHDM <140 mg/m2) is considered in older patients because of concerns regarding tolerability. Age does not predict frailty, and dose modification could compromise responses in an era where effective non-transplant regimens are available. We analyzed 43 patients ≥ 65 years with AL amyloidosis who underwent SCT at Boston University Amyloidosis Center between 2011 and 2020. Median age was 66 years (range 65-68) versus 69 years (range 65-76) in the HDM and mHDM groups, respectively. HR of ≥ very good partial response at 12 months was 66.7% versus 42.3% for patients treated with HDM versus mHDM. Median progression-free survival (PFS) from day 0 of SCT was not reached versus 12.0 months (P =.13); grade ≥ 3 non-hematologic transplant-related toxicities occurred in 87.5% versus 76.9%; and transplant-related mortality was 0% versus 2.3% in the HDM versus mHDM group, respectively. In carefully selected older patients with AL amyloidosis, HDM is well tolerated. Use of mHDM results in reduced HR and PFS; an important consideration with the advent of highly effective non-transplant therapies.

Intérêt du daratumumab dans l’amylose AL réfractaire chez une patiente de 96 ans

Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+plasma cells, resulting in organ dysfunction. Cardiac involvement has a major prognostic value. Antiplasma cell chemotherapy reduces the synthesis of immunoglobulin light chains (precursors of amyloid deposits). We describe a case of AL amyloidosis in a 95-year-old patient. Our patient responded poorly to treatment with rituximab, cyclophosphamide-bortezomib-dexamethasone, and rituximab-bendamustine. Finally, the anti-CD38 antibody daratumumab was associated with the best hematologic responsiveness without significant adverse effects. In conclusion, our case suggests that daratumumab is an effective and well-tolerated alternative to chemotherapy in the treatment af AL amyloidosis in very elderly patients.

P-004: Successful ex-plantation of left ventricular assist device after cardiac recovery with daratumumab therapy in a patient with end stage heart failure due to immunoglobulin light-chain (AL) amyloidosis

P-004: Successful ex-plantation of left ventricular assist device after cardiac recovery with daratumumab therapy in a patient with end stage heart failure due to immunoglobulin light-chain (AL) amyloidosis

Restrictive Atrial Dysfunction in Cardiac Amyloidosis: Differences between Immunoglobulin Light Chain and Transthyretin Cardiac Amyloidosis Patients.

Background: In cardiac amyloidosis, the prevalence of thromboembolic events and atrial fibrillation is higher in transthyretin amyloidosis compared to immunoglobulin light chain amyloidosis. Therefore, we hypothesize that transthyretin cardiac amyloidosis patients have worse atrial function. Purpose: To explore the left atrial function by conventional ultrasound and strain analysis in immunoglobulin light chain- and transthyretin cardiac amyloidosis patients. Methods: In cardiac amyloidosis patients in our Amyloidosis Expert Center, echocardiographic strain analysis was performed using speckle tracking. Results: The data of 53 cardiac amyloidosis patients (83% male, mean age 70 years) were analyzed. Transthyretin cardiac amyloidosis patients (n = 24, 45%) were older (75 ± 5.6 vs. 65 ± 7.2 years, p < 0.001) and had more left ventricular (LV) hypertrophy than immunoglobulin light chain cardiac amyloidosis patients (n = 29, 55%). However, LV systolic and diastolic function did not differ, nor did left atrial dimensions (LAVI 56(24) vs. 50(31) mL/m2). Left atrial reservoir strain was markedly lower in transthyretin cardiac amyloidosis (7.4(6.2) vs. 13.6(14.7), p = 0.017). This association was independent of other measurements of the left atrial and ventricular function. Conclusions: Transthyretin cardiac amyloidosis patients had lower left atrial reservoir function compared to immunoglobulin light chain cardiac amyloidosis patients although the left atrial geometry was similar. Interestingly, this association was independent of left atrial- and LV ejection fraction and global longitudinal strain. Further research is warranted to assess the impact of impaired left atrial dysfunction in transthyretin cardiac amyloidosis on atrial fibrillation burden and prognosis.

Bilateral yellow plaques on the upper eyelids

Bilateral yellow plaques on the upper eyelids

Early cardiac response is possible in stage IIIb cardiac AL amyloidosis and is associated with prolonged survival

AbstractPatients with immunoglobulin light chain (AL) amyloidosis and stage IIIb cardiac involvement have a dismal outcome despite the introduction of novel treatments. However, a rapid hematologic response translates in better survival. We evaluated the impact of early cardiac response and its depth on outcome in 249 patients with newly diagnosed stage IIIb cardiac AL amyloidosis. Hematologic and cardiac responses were evaluated by intent to treat. After a median follow-up of 52 months, 219 (84%) patients died, and median survival was 4.2 months. The 30- and 90-day hematologic response rates were 22% (at least very good partial response [VGPR] in 9%) and 24% (at least VGPR in 15%), respectively. Early hematologic response resulted in better survival. At 90 days, 21 (8%) patients achieved a cardiac response (cardiac very good partial response [cardiac VGPR] in 12 cases and cardiac partial response [cardiac PR] in 9). At the 90-day landmark analysis, cardiac response resulted in longer survival (median, 54 months), also in those patients who have achieved at least VGPR (median, 62 vs 26 months, P = .011). Patients with cardiac VGPR had a longer survival than those with cardiac PR (median, 92 vs 24 months; P = .027), whereas patients without cardiac response had a poor survival (median, 6 months). A baseline difference of involved/uninvolved free light chains > 50 mg/L (odds ratio [OR], 0.21, P = .024) and a bone marrow plasma cell infiltrate > 10% (OR, 0.23, P = .040) were negative predictors of 90-day cardiac response. Early cardiac responses are rare but possible in stage IIIb AL amyloidosis and translate to longer survival.

Supportive Care and Symptom Management for Patients With Immunoglobulin Light Chain (AL) Amyloidosis.

Immunoglobulin light chain (AL) amyloidosis is a disorder of clonal plasma cells characterized by deposition of amyloid fibrils in a variety of tissues, leading to end-organ injury. Renal or cardiac involvement is most common, though any organ outside the central nervous system can develop amyloid deposition, and symptomatic presentations may consequently vary. The variability and subtlety of initial clinical presentations may contribute to delayed diagnoses, and organ involvement is often quite advanced and symptomatic by the time a diagnosis is established. Additionally, while organ function can improve with plasma-cell-directed therapy, such improvement lags behind hematologic response. Consequently, highly effective supportive care, including symptom management, is essential to improve quality of life and to maximize both tolerance of therapy and likelihood of survival. Considering the systemic nature of the disease, close collaboration between clinicians is essential for effective management.

P874: DECIPHERING PLASMA CELL HETEROGENEITY AND TUMOR MICROENVIRONMENT IN LIGHT-CHAIN AMYLOIDOSIS USING SINGLE CELL RNA-SEQUENCING

Background: Immunoglobulin light-chain amyloidosis (AL) is a rare disease caused by plasma cell secretion of misfolded light chains that assemble as amyloid fibrils, which deposit on vital organs causing organ dysfunction. Similar to AL, multiple myeloma (MM) is also caused by atypical plasma cell (PC) expansion in the bone marrow. Although, much research has been done on MM to understand disease mechanisms and to develop effective treatments, knowledge related to AL is still limited. Notably, there is little information available regarding the associated tumor microenvironment (TME) of AL. As the TME plays an important role in disease development and treatment response, comprehensive investigation of the AL TME could improve disease diagnosis and treatment. Furthermore, information distinguishing PCs from AL and MM patients is relatively sparse, but could help determine if treatments developed for MM would also be applicable for the treatment of AL. Aims: The main objective of our study was to decipher the underlying disease mechanisms of the AL at cellular and molecular level by analyzing AL patient samples using single cell RNA sequencing (scRNAseq). To achieve this, we aimed to understand heterogeneity within AL vs MM plasma cells and the TME at the cellular and gene expression level. Methods: The Finnish Hematology Research Biobank provided 23 viably frozen bone marrow mononuclear cell (BM-MNC) samples from 22 AL patients and 24 samples from 23 MM patients. The BM-MNCs were thawed and sorted based on their CD138 expression and cell viability (7AAD dead cell marker). The viable CD138+ and CD138- cells were mixed in a ratio where CD138+ were enriched, but not exceeding 50%. The Chromium Single Cell 3’RNAseq run and library preparation were done using Chromium™ Single Cell 3’ Reagent version 3 chemistry. 10x Genomics Cell Ranger v3.0.1 pipelines were used for the initial data processing. Further, the quality control and data preprocessing was performed using Seurat 4.1.0. For cell type annotations to identify the clusters, specific cell type markers for the immune cells were obtained from sctype database, GSEA-MSigDB and manual curation. Results: From the integrated analysis of scRNAseq data from 22 AL patient samples, we identified a total of 27 distinct clusters of cells belonging to 10 unique cell types. Out of the 27 clusters, 10 clusters were identified as PC sub-populations. The proportions of PCs in the samples negatively correlated to the other major cell types such as NK cells, T cells, gamma delta T cells and monocytes. High transcriptional variability was observed between the PC clusters of the AL patients indicating a high degree of heterogeneity among the AL PCs. Analysis of the MM scRNAseq data resulted in 14 PC clusters, however variability between these clusters was not much distinct as compared to AL. A comparison between AL and MM PC clusters resulted in overlapping transcriptional profiles of 2 AL PC clusters with one MM PC cluster. 5 out of 10 clusters of PCs in AL patients were found to be associated with protein processing in the endoplasmic reticulum and apoptosis pathway. Summary/Conclusion: Within the AL TME, we observed negative correlation of major immune cell types with PCs, suggesting that immune cells may contribute to controlling tumor cell burden in AL. In addition, PC sub-populations in amyloidosis patients are very heterogeneous at the inter-individual level compared to MM patients further indicating that AL patients may benefit from more tailored treatment approaches.

Ten questions for the cardiologist about cardiac scintigraphy with bone tracers, amyloidosis and the heart

Although traditionally considered a rare and incurable condition, the perspective on cardiac amyloidosis (CA) has changed deeply over the last 10 years following major advances in diagnosis and treatment options. First, the development of non-invasive diagnostic methods, predominantly cardiac scintigraphy with bone tracers, has dramatically changed the epidemiology of the disease, revealing the real prevalence of the transthyretin-related form (ATTR), and has consistently reduced the need for histological amyloid confirmation by endomyocardial biopsy. Second, the availability of new specific therapies, such as tafamidis, has made CA early recognition a clinical need with major impact on patients' management and natural history. Since the demonstration of the essential role of bone tracer scintigraphy to non-invasively differentiate ATTR from immunoglobulin light-chain amyloidosis (AL), this imaging technique has become part of the vocabulary and clinical practice of physicians of many specialties, including cardiologists managing patients with cardiomyopathies.In this paper, we address the main questions regarding cardiac scintigraphy with bone tracers and CA, providing cardiologists with the knowledge to guide clinical indications, evaluation and clinical interpretation of images.

An N-glycosylation hotspot in immunoglobulin κ light chains is associated with AL amyloidosis.

Immunoglobulin light chain (AL) amyloidosis is caused by a small, minimally proliferating B-cell/plasma-cell clone secreting a patient-unique, aggregation-prone, toxic light chain (LC). The pathogenicity of LCs is encrypted in their sequence, yet molecular determinants of amyloidogenesis are poorly understood. Higher rates of N-glycosylation among clonal κ LCs from patients with AL amyloidosis compared to other monoclonal gammopathies indicate that this post-translational modification is associated with a higher risk of developing AL amyloidosis. Here, we exploited LC sequence information from previously published amyloidogenic and control clonal LCs and from a series of 220 patients with AL amyloidosis or multiple myeloma followed at our Institutions to define sequence and spatial features of N-glycosylation, combining bioinformatics, biochemical, proteomics, structural and genetic analyses. We found peculiar sequence and spatial pattern of N-glycosylation in amyloidogenic κ LCs, with most of the N-glycosylation sites laying in the framework region 3, particularly within the E strand, and consisting mainly of the NFT sequon, setting them apart with respect to non-amyloidogenic clonal LCs. Our data further support a potential role of N-glycosylation in determining the pathogenic behavior of a subset of amyloidogenic LCs and may help refine current N-glycosylation-based prognostic assessments for patients with monoclonal gammopathies.

Multidisciplinary supportive care in systemic light chain amyloidosis.

The immunoglobulin light-chain amyloidosis is a multisystemic disease which manifests by damage to the vital organs by light chain-derived amyloid fibril. Traditionally, the treatment has been directed to the underlying plasma cell clone with or without high dose chemotherapy followed by autologous stem cell transplantation using melphalan based conditioning. Now with the approval of highly tolerable anti-CD38 monoclonal antibody daratumumab based anti-plasma cell therapy in 2021, high rates of hematologic complete responses are possible even in patients who are otherwise deemed not a candidate for autologous stem cell transplantation. However, despite the progress, there remains a limitation in the strategies to improve symptoms particularly in patients with advanced cardiac involvement, those with nephrotic syndrome and autonomic dysfunction due to underlying systemic AL amyloidosis. The symptoms can be an ordeal for the patients and their caregivers and effective strategies are urgently needed to address them. The supportive care is aimed to counteract the symptoms of the disease and the effects of the treatment on involved organs’ function and preserve patients’ quality of life. Here we discuss multidisciplinary approach in a system-based fashion to address the symptom management in this dreadful disease. In addition to achieving excellent anti-plasma cell disease control, using treatment directed to remove amyloid from the vital organs can theoretically hasten recovery of the involved organs thereby improving symptoms at a faster pace. Ongoing phase III clinical trials of CAEL-101 and Birtamimab will address this question.