Truncation of the constant domain drives amyloid formation by immunoglobulin light chains.

AL amyloidosis is a life-threatening disease caused by deposition of immunoglobulin light chains. While the mechanisms underlying light chains amyloidogenesis in vivo remain unclear, several studies have highlighted the role that tissue environment and structural amyloidogenicity of individual light chains have in the disease pathogenesis. AL natural deposits contain both full-length light chains and fragments encompassing the variable domain (VL) as well as different length segments of the constant region (CL), thus highlighting the relevance that proteolysis may have in the fibrillogenesis pathway. Here, we investigate the role of major truncated species of the disease-associated AL55 light chain that were previously identified in natural deposits. Specifically, we study structure, molecular dynamics, thermal stability, and capacity to form fibrils of a fragment containing both the VL and part of the CL (133-AL55), in comparison with the full-length protein and its variable domain alone, under shear stress and physiological conditions. Whereas the full-length light chain forms exclusively amorphous aggregates, both fragments generate fibrils, although, with different kinetics, aggregate structure, and interplay with the unfragmented protein. More specifically, the VL-CL 133-AL55 fragment entirely converts into amyloid fibrils microscopically and spectroscopically similar to their ex vivo counterpart and increases the amorphous aggregation of full-length AL55. Overall, our data support the idea that light chain structure and proteolysis are both relevant for amyloidogenesis in vivo and provide a novel biocompatible model of light chain fibrillogenesis suitable for future mechanistic studies.

Response matters in light chain amyloidosis, whatever it takes.

Access to upfront daratumumab for AL amyloidosis is expanding, but it is not universal. Bomsztyk et al. show that patients who do not receive front-line daratumumab can be effectively rescued with this agent, indicating that deep haematological response should be pursued tenaciously. Commentary on: Bomsztyk et al. Response rates to second-line treatment with daratumumab bortezomib dexamethasone (DVD) in relapsed/refractory light chain (AL) amyloidosis after initial bortezomib-based regime. Br J Haematol 2024;205:138-145.

Thrombotic and bleeding complications in patients with AL amyloidosis.

Haemostatic abnormalities and deregulated coagulation are common complications in AL amyloidosis. The relevant risks of thromboembolic and haemorrhagic events have not been thoroughly evaluated. To describe clinically significant thrombotic/haemorrhagic events in 450 consecutive patients with AL amyloidosis. Venous thromboembolic events (VTEs) were reported in 6% and arterial embolic events (AEEs) in 5% of patients, respectively, during a 55-month median follow-up. Lower albumin, lower eGFR, higher BM infiltration, soft tissue involvement, IMiD-based therapy and prior thrombosis were associated with VTE risk. Prior thrombosis was the only independent prognostic variable (HR 9.3, p = 0.001). Coronary arterial disease, prior AEE, 24-h proteinuria and higher platelet counts were associated with AEE risk. Significant bleeding events were reported in 9%, and associated mortality was 19%. Liver involvement, higher serum creatinine and higher baseline VWF:Ag levels were linked to bleeding risk. Using competing risk analysis, the cumulative probability of thrombosis/bleeding was higher during the first year following diagnosis, but a stable lower risk for both events remained for the duration of follow-up. In AL amyloidosis patients, the risk of thrombotic/arterial embolic events is significant, but the bleeding risk is also high. A multiparametric assessment is required to initiate anti-thrombotic or anti-platelet therapy appropriately.

A real-life study of daratumumab combinations in newly diagnosed patients with light chain (AL) amyloidosis.

Daratumumab-based regimens are the new standard of care for newly diagnosed patients with AL amyloidosis based on the results of the ANDROMEDA study. However, real-world data on daratumumab efficacy in upfront therapy in unselected patients are scanty. In the framework of a prospective observational study, we investigated the efficacy and safety of daratumumab in 88 newly diagnosed patients, including subjects with IIIb cardiac stage (26%) or myeloma defining events (29%). Daratumumab was administered with bortezomib in 50 (56%) patients, lenalidomide in 31 (35%), and monotherapy in 7 (8%). The rate of serious adverse events was low (16%). The overall hematologic response rate was 75% with 52 (59%) patients attaining at least a very good partial response (VGPR) at six months. Amongst patients evaluable for organ response, the rate of cardiac and renal responses at 6 months was 31% and 21%, respectively. Comparing stage IIIb patients with the remaining ones, the rate of profound hematologic response was not significantly different (≥VGPR 57% vs. 59%, p 0.955) likewise the rate of cardiac (33% vs. 30%, p 0.340) and renal (40% vs. 16%, p 0.908) responses. Daratumumab-based regimens demonstrated to be safe and effective in treatment-naïve AL amyloidosis even in advanced stage disease.

Novel monoclonal antibodies: A really specific therapy for light chain amyloidosis.

Light chain amyloidosis is a rare disease caused by clonal plasma cells in the bone marrow generating an excessive amount of immunoglobulin light chains. These chains misfold and produce insoluble fibrils that deposit in various organs, including the heart, kidneys, liver, nervous system, and digestive tract. Life expectancy and symptoms during the course of the disease vary depending on which and how many organs are affected. Targeted plasma cell therapy has significantly advanced the clinical management of amyloidosis, with ongoing progress. However, current clinical studies are investigating innovative targets, drug combinations and treatment strategies to improve therapeutic outcomes by minimizing adverse effects and refining patient prognosis in these challenging hematological conditions. In this paper, we review the state of the art regarding the use of anti-amyloid antibodies, as a revolutionary and innovative approach in the current scenario of amyloid treatment.

Hepatic, gastric and bone marrow AL amyloidosis that began with Budd-Chiari syndrome: a case report.

Amyloid Light Chain (AL) Amyloidosis is a rare disorder of protein misfolding and metabolism characterized by insoluble fibrils deposition in various tissues and organs, which could quickly progress and become fatal. The most frequently affected organ is heart being its involvement the most adverse prognostic feature. Kidney and liver could be other organ localizations, defining AL Amyloidosis as a multisystem disorder. Being Budd-Chiari syndrome (BCS) an uncommon congestive hepatopathy caused by blockage of hepatic veins in the absence of cardiac disorders, it could be rarely caused by a massive deposition of amyloid proteins into hepatic sinusoidal spaces, giving an uncommon clinical presentation of AL Amyloidosis.

Options for Rescue Treatment of Patients with AL Amyloidosis Exposed to Upfront Daratumumab.

PURPOSE OF REVIEW: This review aims to assess the therapeutic strategies available for relapsed/refractory patients with immunoglobulin light chain (AL) amyloidosis who received upfront daratumumab-based regimens. RECENT FINDINGS: The treatment landscape of AL amyloidosis has changed radically thanks to the introduction in the upfront setting of daratumumab in combination with bortezomib, cyclophosphamide and dexamethasone (DaraCyBorD) which improved patients' outcomes increasing the rate of hematologic and organ responses. However, many patients eventually relapse or are refractory to daratumumab and the best salvage therapy is not well defined yet. In this contest, we reviewed the available therapeutic options after daratumumab failure, and we look towards the current advances in Bcl-2 inhibitors, novel immunotherapeutic agents as chimeric antigen receptor (CAR-T) therapy and bispecific antibodies (bsAbs). Relapsed/refractory AL amyloidosis represent an unmet clinical need and novel targeted drugs require urgent prospective assessment.

Feasibility and safety of left bundle branch area pacing in cardiac amyloidosis. A single center experience.

BACKGROUND: Conventional right ventricle (RV) pacemaker stimulation has been associated with worse clinical outcomes in patients with cardiac amyloidosis (CA). Left bundle branch area pacing (LABPP) has been suggested as a promising alternative. We sought to assess the safety, feasibility, and outcomes of LABPP in patients with CA. METHODS: We retrospectively analyzed echocardiography and pacing parameters and clinical outcomes in 23 consecutive patients with CA and LBBAP implanted from June 2020 to October 2022. RESULTS: LBBAP was successfully performed in 22 over 23 patients (19 male, 78.6 ± 11.7 years, 20 ATTR, mean LVEF 45.5 ± 16.2%). After the procedure, 9 patients showed Qr pattern and 11 a qR pattern in V1 on ECG. Average procedure time was 67 ± 28 min. After 7.7 ± 5.2 months follow-up, no procedure-related complications had occurred. Although, a significant reduction in QRS width (p = .001) was achieved, we did not observe significant changes in LVEF and Nt ProBNP at 6 months of follow-up. Pacing parameters were stable during follow-up: LBB capture threshold and R wave amplitude were 1.0 ±  0.5 V and 10.6 ± 6.0 mV versus 0.8 ±  0.1 V, p = .21 and 10.6 ± 5.1 mV (p = .985) at follow up. CONCLUSION: LBBAP is safe and feasible pacing technique for patients with CA. LBBAP is associated with significant narrowing of QRSd without worsening in LVEF and Nt-proBNP.

Clinical and imaging characteristics of patients with cardiac amyloidosis- a single center observational study.

Amyloidosis is a disease characterized by the deposition of protein fibrils. Cardiac involvement is a significant factor in determining prognosis. This study aimed to examine the clinical profile, outcomes, and long-term mortality rates in patients with transthyretin (ATTR) and amyloid light-chain (AL) amyloidosis. The retrospective cohort study included 94 patients with amyloidosis (69 with AL and 25 with ATTR amyloidosis) diagnosed between 2010 and 2022. The study involved multimodality imaging (ECG, echocardiography and cardiac magnetic resonance (CMR) data and survival analyses. Patients with ATTR amyloidosis were older and had a higher proportion of males compared to those with AL amyloidosis. Cardiac involvement was more prevalent in the ATTR group, including atrial fibrillation (AF), while pleural and pericardial effusion were more frequent in the AL group. Biomarkers such as NT-proBNP and troponin T were significantly elevated in both groups and were associated with all-cause mortality only in univariate analyses. CMR data, especially typical late gadolinium enhancement (LGE) was not associated with increased mortality, while pleural effusion and left atrial dilatation on echocardiography were identified as powerful predictors of mortality. In conclusion, both AL and ATTR amyloidosis exhibited poor outcomes. Cardiac involvement, particularly dilated left atrium and pleural effusion on echocardiography were associated with an increased risk of mortality, while typical LGE on CMR was not.

Widespread amyloidogenicity potential of multiple myeloma patient-derived immunoglobulin light chains.

BACKGROUND: In a range of human disorders such as multiple myeloma (MM), immunoglobulin light chains (IgLCs) can be produced at very high concentrations. This can lead to pathological aggregation and deposition of IgLCs in different tissues, which in turn leads to severe and potentially fatal organ damage. However, IgLCs can also be highly soluble and non-toxic. It is generally thought that the cause for this differential solubility behaviour is solely found within the IgLC amino acid sequences, and a variety of individual sequence-related biophysical properties (e.g. thermal stability, dimerisation) have been proposed in different studies as major determinants of the aggregation in vivo. Here, we investigate biophysical properties underlying IgLC amyloidogenicity. RESULTS: We introduce a novel and systematic workflow, Thermodynamic and Aggregation Fingerprinting (ThAgg-Fip), for detailed biophysical characterisation, and apply it to nine different MM patient-derived IgLCs. Our set of pathogenic IgLCs spans the entire range of values in those parameters previously proposed to define in vivo amyloidogenicity; however, none actually forms amyloid in patients. Even more surprisingly, we were able to show that all our IgLCs are able to form amyloid fibrils readily in vitro under the influence of proteolytic cleavage by co-purified cathepsins. CONCLUSIONS: We show that (I) in vivo aggregation behaviour is unlikely to be mechanistically linked to any single biophysical or biochemical parameter and (II) amyloidogenic potential is widespread in IgLC sequences and is not confined to those sequences that form amyloid fibrils in patients. Our findings suggest that protein sequence, environmental conditions and presence and action of proteases all determine the ability of light chains to form amyloid fibrils in patients.

Renal impairment in monoclonal gammopathies and multiple myeloma.

The incidence of monoclonal gammopathy (MG) increases with age. In individuals over 80 years of age, we can diagnose the presence of monoclonal immunoglobulin (MIg) in up to 10 % of cases. Not only malignant diseases such as multiple myeloma (MM), but also benign forms such as MGUS (monoclonal gammopathy of undetermined significance) can lead to renal involvement. The light chains of immunoglobulins (LC) are the most damaging to the kidneys, as they are freely filtered into the urine due to their molecular weight. Detection of MIg relies mainly on a combination of immunofixation electrophoresis of serum (IELFO) and urine and determination of free light chains (FLC) of kappa and lambda and their ratio (κ/λ) in serum. The combination of these tests will detect the presence of MIg with 99 % sensitivity. Renal damage in MG may be caused by direct deposition of MIg in the glomeruli (e.g. AL amyloidosis, LC deposition disease) or tubules (in the distal tubule as a myeloma kidney or in the proximal tubule as Fanconi syndrome or proximal tubulopathy). Typical urinary findings in these diseases are moderate or severe proteinuria or nephrotic syndrome. Acute kidney injury (AKI) can be expected especially when serum FLC is >500 mg/l. Renal biopsy is crucial to establish an accurate diagnosis and thus initiate the correct treatment. Treatment of these types of renal damage involves the same treatment regimens used in the treatment of MM, including proteasome inhibitors or daratumumab.

[Bilateral vestibulopathy and sensorineural hearing loss in necrobiotic xanthogranuloma, multiple myeloma and amiloidosis]. / Dvustoronnyaya vestibulopatiya i sensonevral'naya tugoukhost' u patsienta s nekroticheskoi ksantogranulemoi, mnozhestvennoi mielomoi i amiloidozom.

This article describes a rare case of necrotic xanthogranuloma in a 46-year-old patient who presented with the development of periorbital xanthelasms, progressive bilateral sensorineural hearing loss and bilateral vestibulopathy, followed by multiple myeloma and amyloidosis. For several years, the patient underwent standard rehabilitation for chronic sensorineural hearing loss and was fitted with a hearing aid. During hospitalisation for exacerbation of chronic bronchitis, monoclonal gammopathy was identified, and later, after careful examination and repeated biopsies, necrotic xanthogranuloma, multiple myeloma and AL-amyloidosis were confirmed. Targeted immunochemotherapy resulted in improvement of hearing and significant recovery of the vestibuloocular reflex bilaterally.

Outcomes of patients with light chain (AL) amyloidosis after failure of daratumumab-based therapy.

As daratumumab use in AL amyloidosis increases, more patients will either relapse after or become refractory to daratumumab. We present the outcome of 33 patients with AL who failed on daratumumab (due to haematological relapse in 21 [64%] patients and inadequate haematological response in 12 [36%]) and received further treatment. Overall response rate in the post-daratumumab failure treatment was 55% (CR/VGPR: 14 [42%] and PR: 3 [9%] patients). Patients retreated with daratumumab and patients harbouring +1q21 had lower rates of response. Treatment of patients with AL who fail daratumumab therapy is feasible when non-cross-resistant drugs or other targeted therapies are available.

Is there a representative quality-of-life questionnaire for patients with AL amyloidosis?-systematic literature review.

Systemic AL amyloidosis is an incurable condition with various presentations and may cause multiple complications related to organ involvement. As survival has improved, disease and therapy-related quality of life (QoL) is becoming an increasingly important treatment endpoint. We review the literature summarising the utilised QoL questionnaires (QLQs) and assess their validity according to COSMIN (Consensus-based Standards for the Selection of Health Measurement Instruments) standards. Thirteen retrospective observational studies and thirty-two prospective clinical trials were analysed. Most QLQs are generic or only validated in populations with distinct complications of the disease. None meet 'strong evidence' for validation in this context. There is a need to develop a disease-specific QLQ, which could inform treatment choices and facilitate the approval of novel therapies.

Role of individual factor X concentrate pharmacokinetic studies in perioperative management of AL amyloidosis-associated acquired factor X deficiency.

BACKGROUND: AL amyloidosis is associated with acquired factor X (FX) deficiency. Experience related to its management is limited to case reports and series using prothrombin complex concentrate, fresh frozen plasma, plasma exchange, recombinant activated factor seven, and desmopressin with limited and variable efficacy. FX concentrate has not been widely used in its management. STUDY DESIGN AND METHODS: We report our experience with the perioperative use of FX concentrate (Coagadex) in two patients with AL amyloidosis-associated acquired FX deficiency requiring surgery, using their individual pharmacokinetic studies to manage perioperative hemostasis. Pharmacokinetic studies involved obtaining post-infusion FX activity at 10 min, 2, and 4 h following the administration of FX concentrate to calculate the FX half-life. RESULTS: Both patients' plasma FX activity was successfully increased to provide perioperative hemostatic support. Monitoring FX activity post-surgery was also utilized to maintain FX activity levels to prevent post-operative bleeding. CONCLUSION: Pharmacokinetic studies have a useful role in tailoring preoperative FX repletion in patients with AL amyloidosis associated with acquired FX deficiency.

Immunoglobulin Light Chain Amyloidosis: Diagnosis and Risk Assessment.

Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder with multiple clinical presentations. The diagnosis of AL amyloidosis requires a high index of suspicion, making a delay in diagnosis common, which contributes to the high early mortality seen in this disease. Establishing the diagnosis of AL amyloidosis requires the demonstration of tissue deposition of amyloid fibrils. A bone marrow biopsy and fat pad aspirate performed concurrently have a high sensitivity for the diagnosis of AL amyloidosis and negate the need for organ biopsies in most patients. An accurate diagnosis requires amyloid typing via additional testing, including tissue mass spectrometry. Prognostication for AL amyloidosis is largely driven by the organs impacted. Cardiac involvement represents the single most important prognostic marker, and the existing staging systems are driven by cardiac biomarkers. Apart from organ involvement, plasma cell percentage on the bone marrow biopsy, specific fluorescence in situ hybridization findings, age at diagnosis, and performance status are important prognostic markers. This review elaborates on the diagnostic testing and prognostication for patients with newly diagnosed AL amyloidosis.

Epidemiology and clinical outcomes of light-chain amyloidosis in Sweden: A nationwide population-based study.

OBJECTIVES: This study evaluated data from six Swedish national registries to fill current evidence gaps on the epidemiology, clinical burden, and overall survival (OS) associated with light-chain (AL) amyloidosis. METHODS: Patients newly diagnosed with AL amyloidosis were identified using six linked Swedish nationwide population-based registers. For each case, individuals from the general population were selected and matched with a maximum ratio of 1:5 based on age, sex, calendar year, and county. RESULTS: 846 patients newly diagnosed with AL amyloidosis and 4227 demographically matched individuals were identified. From 2011 to 2019, annual AL amyloidosis incidence increased from 10.5 to 15.1 cases per million. At baseline, patients with AL amyloidosis had a significantly higher disease burden including higher rates of cardiac and renal failure relative to the comparison group. Among patients with AL amyloidosis, 21.5% had incident heart failure and 17.1% had incident renal failure after initial diagnosis. Median OS for patients with AL amyloidosis was 56 months versus not reached in the matched general population comparison group. CONCLUSION: The incidence of newly diagnosed AL amyloidosis in Sweden increased over time with AL amyloidosis being associated with a higher risk of cardiac/renal failure and all-cause mortality compared with the general population.

Differences in patient-reported outcomes (PROs) by disease severity in light chain (AL) amyloidosis.

OBJECTIVE: To assess the impact of organ involvement on patient-reported outcomes (PROs) in light chain (AL) amyloidosis. METHODS: PROs were evaluated using the KCCQ-12, PROMIS-29 + 2, and SF-36 in individuals with AL amyloidosis. The 2004 Mayo system was used to stage disease and cardiac, neurologic, and renal involvement was considered. Global physical and mental health (MH) scores, physical function (PF), fatigue, social function (SF), pain, sleep, and MH domains were evaluated. Effect sizes between scores were measured using Cohen's d. RESULTS: Of 297 respondents, the median age at diagnosis was 60 years with 58% cardiac, 58% renal, and 30% neurologic involvement. Fatigue, PF, SF, and global physical health with PROMIS and SF-36 discriminated the most by stage. Significant discrimination in PROMIS and/or SF-36 was seen in PF, fatigue, and global physical health with cardiac involvement. For neurologic involvement, PF, fatigue, SF, pain, sleep, global physical, and MH with PROMIS and role physical, vitality, pain, general health, and physical component summary with SF-36 were discriminatory. For renal amyloid, pain by SF-36 and PROMIS, and SF-36 MH and role emotional subscales were significant. CONCLUSIONS: Fatigue, PF, SF, and global physical health can discriminate stage, cardiac and neurologic, but not renal, AL amyloidosis involvement.

Systemic light chain amyloidosis myopathy responsive to daratumumab monotherapy.

BACKGROUND AND PURPOSE: Amyloid myopathy is a rare and severe manifestation of systemic light chain (AL) amyloidosis. Early diagnosis and staging are mandatory for optimal therapy, given the rapid progression of muscle weakness. Despite the efficacy of bortezomib-based treatment regimens, there is a lack of therapeutic alternatives in non-responsive patients. METHOD: The case report of a patient with systemic AL amyloidosis myopathy treated with daratumumab is presented. RESULTS: A 70-year-old man displayed severe proximal muscle weakness which had developed over a 10-month period. Blood tests revealed an immunoglobulin A lambda monoclonal gammopathy, whilst muscle biopsy showed amyloid deposits within the arteriolar walls, confirming the diagnosis of amyloid myopathy associated with AL amyloidosis. Initial treatment with a bortezomib-based regimen showed no clinical or hematological improvement. After switching to daratumumab monotherapy, our patient achieved a favorable evolution with respect to functional muscle scoring and a complete hematological response. CONCLUSION: To our knowledge, this is the first case report of an amyloid myopathy showing a remarkable clinical improvement in response to daratumumab monotherapy. It thereby highlights the potential of daratumumab as a monotherapeutical approach to the treatment of amyloid myopathy complicating AL amyloidosis.

A case of disappearing amyloid on technetium pyrophosphate scan.

Technetium-99mm pyrophosphate (Tc-PYP) scintigraphy is a highly accurate non-invasive method for the diagnosis of transthyretin (ATTR) cardiac amyloidosis. Prognosis for this disease is improved following treatment with the transthyretin (TTR) stabilizer tafamidis. Although tafamidis slows disease progression, its effects on myocardial amyloid and Tc-PYP uptake remain unclear. We present a patient with ATTR cardiac amyloidosis who had a strongly positive initial Tc-PYP scan, with a dramatic decrease in Tc-PYP uptake on repeat scan after 3 years of tafamidis treatment. However, myocardial biopsy showed persistent diffuse amyloid deposits. This case highlights the need for further studies regarding the utility of serial Tc-PYP scans in monitoring the progress of ATTR cardiomyopathy.