Publications by authors named "Giampaolo Merlini"

385 Publications

Prospective urinary albumin/creatinine ratio for diagnosis, staging, and organ response assessment in renal AL amyloidosis: results from a large cohort of patients.

Clin Chem Lab Med 2022 Jan 13. Epub 2022 Jan 13.

Amyloidosis Research and Treatment Center, Foundation Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Policlinico San Matteo, Pavia, Italy.

Objectives: Quantification of 24 h-proteinuria is the gold standard for diagnosing, staging, and monitoring of patients with renal AL amyloidosis. However, 24 h-urine collection is cumbersome and may result in preanalytical error. In this prospective study, we investigated the role of urinary albumin/creatinine ratio (UACR) (cut-off: 300 mg/g) identifying renal involvement, evaluated a UACR-based staging system (UACR cut-off: 3,600 mg/g) and assessed whether UACR response (UACR decrease >30% without worsening in eGFR >25%) predicts renal outcome in 531 patients with newly-diagnosed AL amyloidosis.

Methods: From October 2013 paired 24 h-proteinuria and UACR (on first morning void) were measured in all newly-diagnosed patients with AL amyloidosis. Correlation between 24 h-proteinuria and UACR at baseline was assessed by Pearson's r test. Impact of UACR response on renal outcome was assessed in randomly created testing (n=354) and validation (n=177) cohorts.

Results: A strong linear correlation was found between 24 h-proteinuria and UACR at baseline (r=0.90; p<0.001). After a median follow-up of 31 months, 57 (11%) patients required dialysis. A UACR-based renal staging system identified three stages with significantly higher dialysis rate at 36 months comparing stage I with stage II and stage II with stage III. Achieving a renal response, according to a UACR-based criterion, resulted in lower dialysis rate in both testing and validation cohorts.

Conclusions: UACR is a reliable marker for diagnosis, prognosis, and organ response assessment in renal AL amyloidosis and can reliably replace 24 h-proteinuria in clinical trials and individual patients' management.
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http://dx.doi.org/10.1515/cclm-2021-0912DOI Listing
January 2022

Two-hit strategy for treating AL amyloidosis?

Blood 2021 12;138(25):2596-2598

Foundation Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo.

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http://dx.doi.org/10.1182/blood.2021013817DOI Listing
December 2021

Primary plasma cell leukemia: consensus definition by the International Myeloma Working Group according to peripheral blood plasma cell percentage.

Blood Cancer J 2021 12 2;11(12):192. Epub 2021 Dec 2.

Department of Hematology, Hospital Universitario de Salamanca-IBSAL, IBMCC (USAL-CSIC), Salamanca, Spain.

Primary plasma cell leukemia (PCL) has a consistently ominous prognosis, even after progress in the last decades. PCL deserves a prompt identification to start the most effective treatment for this ultra-high-risk disease. The aim of this position paper is to revisit the diagnosis of PCL according to the presence of circulating plasma cells in patients otherwise meeting diagnostic criteria of multiple myeloma. We could identify two retrospective series where the question about what number of circulating plasma cells in peripheral blood should be used for defining PCL. The presence of ≥5% circulating plasma cells in patients with MM had a similar adverse prognostic impact as the previously defined PCL. Therefore, PCL should be defined by the presence of 5% or more circulating plasma cells in peripheral blood smears in patients otherwise diagnosed with symptomatic multiple myeloma.
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http://dx.doi.org/10.1038/s41408-021-00587-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640034PMC
December 2021

Population Pharmacokinetics and Exposure-Response Modeling of Daratumumab Subcutaneous Administration in Patients With Light-Chain Amyloidosis.

J Clin Pharmacol 2021 Oct 28. Epub 2021 Oct 28.

Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.

The purpose of this study is to characterize the population pharmacokinetics (popPK) of subcutaneous (SC) daratumumab in combination with bortezomib, cyclophosphamide, and dexamethasone and explore the relationship between daratumumab systemic exposure and selected efficacy and safety end points in patients with newly diagnosed systemic amyloid light-chain amyloidosis. The popPK analysis included pharmacokinetic and immunogenicity data from patients receiving daratumumab SC in combination with bortezomib, cyclophosphamide, and dexamethasone in the ANDROMEDA study (AMY3001; safety run-in, n = 28; randomized phase, n = 183). Nonlinear mixed-effects modeling was used to characterize the popPK and quantify the impact of potential covariates. The exposure-response (E-R) analysis included data from all patients in the randomized phase of ANDROMEDA (n = 388). Logistic regression and survival analysis were used to evaluate the relationships between daratumumab systemic exposure and efficacy end points. The E-R analysis on safety was conducted using quartile comparison and logistic regression analysis. The observed concentration-time data of daratumumab SC were well described by a 1-compartment popPK model with first-order absorption and parallel linear and nonlinear Michaelis-Menten elimination pathways. None of the investigated covariates were determined to be clinically meaningful. Daratumumab systemic exposure was generally similar across subgroups that achieved different levels of hematologic response, and there was no apparent relationship between daratumumab systemic exposure and the investigated safety end points. In conclusion, the popPK and E-R analyses supported the selected 1800-mg flat dose of daratumumab SC in combination with bortezomib, cyclophosphamide, and dexamethasone regimen for the treatment of light-chain amyloidosis. No dose adjustment was recommended for investigated covariates.
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http://dx.doi.org/10.1002/jcph.1994DOI Listing
October 2021

How I Treat AL Amyloidosis.

Blood 2021 Sep 13. Epub 2021 Sep 13.

University of Pavia, Pavia, Italy.

The treatment of patients with systemic light chain (AL) amyloidosis is a challenge to hematologists. Despite its generally small size, the underlying clone causes a rapidly progressing, often devastating multiorgan dysfunction through the toxic light chains that form amyloid deposits. Clinical manifestations are deceitful and too often recognized at an irreversible stage. However, hematologists are in the unique position to diagnose AL amyloidosis at a pre-symptomatic stage checking biomarkers of amyloid organ involvement in patients with monoclonal gammopathies at higher risk to develop the disease. Adequate technology and expertise are needed for a prompt and correct diagnosis, particularly for ruling out non-AL amyloidoses that are now also treatable. Therapy should be carefully tailored based on severity of organ involvement and clonal characteristics, and early and continual monitoring of response is critical. Three recent randomized clinical trials moved AL amyloidosis to evidence-based era. Above all, the daratumumab-bortezomib combination is a new standard-of-care for newly diagnosed patients inducing rapid and deep responses that translate into high rates of organ response. The availability of new effective drugs allows to better personalize the therapy, reduce toxicity, and improve outcomes. Patients should be treated within clinical trials whenever possible.
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http://dx.doi.org/10.1182/blood.2020008737DOI Listing
September 2021

In search of the most effective therapy for light chain amyloidosis.

Amyloid 2021 Sep 12:1-2. Epub 2021 Sep 12.

Amyloidosis Research and Treatment Center, Foundation "Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo", Department of Molecular Medicine, University of Pavia, Pavia, Italy.

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http://dx.doi.org/10.1080/13506129.2021.1974832DOI Listing
September 2021

Protease-sensitive regions in amyloid light chains: what a common pattern of fragmentation across organs suggests about aggregation.

FEBS J 2022 Jan 15;289(2):494-506. Epub 2021 Sep 15.

Amyloidosis Treatment and Research Center, Fondazione IRCCS Policlinico San Matteo and Università Degli Studi di Pavia, Italy.

Light-chain (AL) amyloidosis is characterized by deposition of immunoglobulin light chains (LC) as fibrils in target organs. Alongside the full-length protein, abundant LC fragments are always present in AL deposits. Herein, by combining gel-based and mass spectrometry analyses, we identified and compared the fragmentation sites of amyloid LCs from multiple organs of an AL λ amyloidosis patient (AL-55). The positions pinpointed here in kidney and subcutaneous fat, alongside those previously detected in heart of the same patient, were aligned and mapped on the LC's dimeric and fibrillar states. All tissues contain fragmented LCs along with the full-length protein; the fragment pattern is coincident across organs, although microheterogeneity exists. Multiple cleavage positions were detected; some are shared, whereas some are organ-specific, likely due to a complex of proteases. Cleavage sites are concentrated in 'proteolysis-prone' regions, common to all tissues. Several proteolytic sites are not accessible on native dimers, while they are compatible with fibrils. Overall, data suggest that the heterogeneous ensemble of LC fragments originates in tissues and is consistent with digestion of preformed fibrils, or with the hypothesis that initial proteolytic cleavage of the constant domain triggers the amyloidogenic potential of LCs, followed by subsequent proteolytic degradation. This work provides a unique set of molecular data on proteolysis from ex vivo amyloid, which allows discussing hypotheses on role and timing of proteolytic events occurring along amyloid formation and accumulation in AL patients.
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http://dx.doi.org/10.1111/febs.16182DOI Listing
January 2022

A nationwide prospective registry of bortezomib-based therapy in light chain (AL) amyloidosis.

Leuk Lymphoma 2022 Jan 27;63(1):205-211. Epub 2021 Aug 27.

Italian Medicines Agency, Rome, Italy.

Until recently, no drug was labeled for AL amyloidosis. In 2011, the Italian Medicines Agency started a program to grant access to upfront bortezomib to patients with AL amyloidosis. All subjects were enrolled in a prospective online registry. Response was evaluated after two cycles to assess the possibility of continuing treatment. A total of 764 patients were included until 2019, and 615 were evaluable. Sixteen percent of patents had advanced (stage-IIIb) heart involvement, and 27% had severe or end-stage renal failure. Bortezomib delivery was possible in stage-IIIb patients at a reduced dose. Bortezomib discontinuation was associated with increasing age, advanced heart involvement and bi-weekly administration. Fifty-nine percent of subjects attained a hematologic response and 14% a cardiac response. Bortezomib-based therapy tends to be discontinued early in elderly patients and in advanced disease. Nevertheless, early response to therapy is possible in this challenging population.
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http://dx.doi.org/10.1080/10428194.2021.1971215DOI Listing
January 2022

Biotechnological Agents for Patients With Tumor Necrosis Factor Receptor Associated Periodic Syndrome-Therapeutic Outcome and Predictors of Response: Real-Life Data From the AIDA Network.

Front Med (Lausanne) 2021 8;8:668173. Epub 2021 Jul 8.

Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, University of Siena, Siena, Italy.

To describe the role of biotechnological therapies in patients with tumor necrosis factor receptor associated periodic syndrome (TRAPS) and to identify any predictor of complete response. Clinical, laboratory, and therapeutic data from 44 Caucasian TRAPS patients treated with biologic agents were retrospectively collected in 16 Italian tertiary Centers. A total of 55 biological courses with anakinra ( = 26), canakinumab ( = 16), anti-TNF-α agents ( = 10), and tocilizumab ( = 3) were analyzed. A complete response was observed in 41 (74.5%) cases, a partial response in 9 (16.4%) cases and a treatment failure in 5 (9.1%) cases. The frequency of TRAPS exacerbations was 458.2 flare/100 patients-year during the 12 months prior to the start of biologic treatment and 65.7 flare/100 patients-years during the first 12 months of therapy ( < 0.0001). The median duration of attacks was 5.00 (IQR = 10.50) days at the start of biologics and 1.00 (IQR = 0.00) days at the 12-month assessment ( < 0.0001). Likewise, a significant reduction was observed in the Autoinflammatory Disease Activity Index during the study period ( < 0.0001). A significant corticosteroid sparing effect was observed as early as the first 12 months of treatment both in the number of patients requiring corticosteroids ( = 0.025) and in the dosages employed ( < 0.0001). A significant reduction was identified in the erythrocyte sedimentation rate ( < 0.0001), C reactive protein ( < 0.0001), serum amyloid A ( < 0.0001), and in the 24-h proteinuria dosage during follow-up ( = 0.001). A relapsing-remitting disease course (OR = 0.027, C.I. 0.001-0.841, = 0.040) and the frequency of relapses at the start of biologics (OR = 0.363, C.I. 0.301-0.953, = 0.034) were significantly associated with a complete response. No serious adverse events were observed. Treatment with biologic agents is highly effective in controlling clinical and laboratory TRAPS manifestations. Patients with a relapsing-remitting course and a lower frequency of flares at the start of treatment show more likely a complete response to biologic agents.
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http://dx.doi.org/10.3389/fmed.2021.668173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295690PMC
July 2021

Search for AL amyloidosis risk factors using Mendelian randomization.

Blood Adv 2021 07;5(13):2725-2731

Biomedical Center, Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, Pilsen, Czech Republic; and.

In amyloid light chain (AL) amyloidosis, amyloid fibrils derived from immunoglobulin light chain are deposited in many organs, interfering with their function. The etiology of AL amyloidosis is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited by Mendelian randomization (MR) methodology to search for factors influencing AL amyloidosis risk. We performed a 2-sample MR analyzing 72 phenotypes, proxied by 3461 genetic variants, and summary genetic data from a GWAS of 1129 AL amyloidosis cases and 7589 controls. Associations with a Bonferroni-defined significance level were observed for genetically predicted increased monocyte counts (P = 3.8 × 10-4) and the tumor necrosis factor receptor superfamily member 17 (TNFRSF17) gene (P = 3.4 × 10-5). Two other associations with the TNFRSF (members 6 and 19L) reached a nominal significance level. The association between genetically predicted decreased fibrinogen levels may be related to roles of fibrinogen other than blood clotting. be related to its nonhemostatic role. It is plausible that a causal relationship with monocyte concentration could be explained by selection of a light chain-producing clone during progression of monoclonal gammopathy of unknown significance toward AL amyloidosis. Because TNFRSF proteins have key functions in lymphocyte biology, it is entirely plausible that they offer a potential link to AL amyloidosis pathophysiology. Our study provides insight into AL amyloidosis etiology, suggesting high circulating levels of monocytes and TNFRSF proteins as risk factors.
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http://dx.doi.org/10.1182/bloodadvances.2021004423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288669PMC
July 2021

Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis.

N Engl J Med 2021 07;385(1):46-58

From the Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens (E.K., M.A.D.); the Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, and the Department of Molecular Medicine, University of Pavia, Pavia, Italy (G.P., G.M.); the Department of Hematology, University Medical Center Utrecht, University Utrecht, Utrecht (M.C.M.), the Amyloidosis Center of Expertise, University of Groningen, University Medical Center Groningen, Groningen (W.R.), and Janssen Research and Development, Leiden (B.T., J. Vermeulen) - all in the Netherlands; University College London, London (A.D.W.); Centre Hospitalier Universitaire (CHU) and Reference Center for AL Amyloidosis, Limoges (A.J.), Département de Néphrologie et Transplantation d'Organes, Centre de Référence des Maladies Rénales Rares, Hôpital Rangueil, CHU de Toulouse, Toulouse (A.H.), and the Department of Hematology, CHU Lille, University of Lille, Lille (S.M.) - all in France; the Department of Lymphoma and Myeloma, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston (H.C.L.); the Amyloidosis Center, Boston University School of Medicine and Boston Medical Center (V.S.), and the Division of Hematology/Oncology, John C. Davis Myeloma and Amyloid Program, Tufts Medical Center (R.L.C.) - both in Boston; the Victorian and Tasmanian Amyloidosis Service, Department of Haematology, Monash University Eastern Health Clinical School, Melbourne, VIC (S.G.), the Department of Haematology, Princess Alexandra Hospital and University of Queensland Medical School, Brisbane (P.M.), and the Department of Clinical Haematology, Westmead Hospital, Westmead, NSW (F.K.) - all in Australia; Cross Cancer Institute, University of Alberta, Edmonton (C.P.V.), the Division of Hematology, London Health Sciences Centre, London Regional Cancer Program, Western University, London, ON (S.L.), and the Division of Hematology, Vancouver General Hospital, BC Cancer, University of British Columbia, Vancouver (K. Song) - all in Canada; Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Collaborative Innovation Center of Hematology, Beijing (J.L.); Medical Department V (Hematology/Oncology/Rheumatology), Amyloidosis Center, Heidelberg University Hospital, Heidelberg (S.S.), and Hämatologisch-Onkologische Praxis Altona, Hamburg (T.H.) - both in Germany; the Department of Hematology, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem (M.E.G.); the Department of Hematology, Japanese Red Cross Medical Center, Tokyo (K. Suzuki), and the Department of Hematology, Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center, Kyoto (C.S.) - both in Japan; the Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine (K.K.), and the Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine (J.-S.K.) - both in Seoul, South Korea; the Amyloidosis and Myeloma Unit, Hospital Clinic of Barcelona, August Pi i Sunyer Biomedical Research Institute, Barcelona (M.T.C.); the Department of Hematology, Ankara University, Ankara, Turkey (M.B.); the Division of Medical Oncology, Department of Medicine, University of Washington, Seattle (E.L.); the Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland (J. Valent), and the Division of Hematology, Ohio State University Comprehensive Cancer Center, Columbus (N.B.) - both in Ohio; Clínica São Germano, São Paulo (V.H.), and Clinica CEHON, Rede D'Or Oncologia, Salvador (E.C.) - both in Brazil; the Department of Medicine, University of California, San Francisco, San Francisco (S.W.W.), the Department of Hematology and Hematopoietic Cell Transplantation, Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Duarte (M.R.), and Janssen Research and Development, Los Angeles (N.T.) - all in California; the Department of Internal Medicine, Division of Hematology/Oncology, Columbia University Medical Center, New York (D.B.); the Penn Amyloidosis Program, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia (A.J.W.), and Janssen Research and Development, Spring House (X.Q., S.Y.V., B.M.W.) - both in Pennsylvania; Vanderbilt University Medical Center and Veterans Affairs Tennessee Valley Healthcare System, Nashville (S.A.G.); the Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit (J.A.Z.); the Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (K.J.); and Genmab US, Princeton (T.A.), and Janssen Research and Development, Raritan (J.M.S., S.H.Z.) - both in New Jersey.

Background: Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.

Methods: We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.

Results: A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.

Conclusions: Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).
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http://dx.doi.org/10.1056/NEJMoa2028631DOI Listing
July 2021

A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis.

Leukemia 2022 Jan 24;36(1):225-235. Epub 2021 Jun 24.

Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo, Department of Molecular Medicine, University of Pavia, Pavia, Italy.

In the first phase 3 study in relapsed/refractory AL amyloidosis (TOURMALINE-AL1 NCT01659658), 168 patients with relapsed/refractory AL amyloidosis after 1-2 prior lines were randomized to ixazomib (4 mg, days 1, 8, 15) plus dexamethasone (20 mg, days 1, 8, 15, 22; n = 85) or physician's choice (dexamethasone ± melphalan, cyclophosphamide, thalidomide, or lenalidomide; n = 83) in 28-day cycles until progression or toxicity. Primary endpoints were hematologic response rate and 2-year vital organ deterioration or mortality rate. Only the first primary endpoint was formally tested at this interim analysis. Best hematologic response rate was 53% with ixazomib-dexamethasone vs 51% with physician's choice (p = 0.76). Complete response rate was 26 vs 18% (p = 0.22). Median time to vital organ deterioration or mortality was 34.8 vs 26.1 months (hazard ratio 0.53; 95% CI, 0.32-0.87; p = 0.01). Median treatment duration was 11.7 vs 5.0 months. Adverse events of clinical importance included diarrhea (34 vs 30%), rash (33 vs 20%), cardiac arrhythmias (26 vs 15%), nausea (24 vs 14%). Despite not meeting the first primary endpoint, all time-to-event data favored ixazomib-dexamethasone. These results are clinically relevant to this relapsed/refractory patient population with no approved treatment options.
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http://dx.doi.org/10.1038/s41375-021-01317-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8727292PMC
January 2022

Age-related amyloidosis outside the brain: A state-of-the-art review.

Ageing Res Rev 2021 09 8;70:101388. Epub 2021 Jun 8.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Electronic address:

Inside and outside the brain, accumulation of amyloid fibrils plays key roles in the pathogenesis of fatal age-related diseases such as Alzheimer's and Parkinson's diseases and wild-type transthyretin amyloidosis. Although the incidence of all amyloidoses increases with age, for some types of amyloidosis aging is known as the main direct risk factor, and these types are typically diseases of elderly people. More than 10 different precursor proteins are known to cause age-associated amyloidosis; these proteins include amyloid β protein, α-synuclein, transthyretin, islet amyloid polypeptide, atrial natriuretic factor, and the newly discovered epidermal growth factor-containing fibulin-like extracellular matrix protein 1. Except for intracerebral amyloidoses, most age-related amyloidoses have been little studied. Indeed, in view of the increasing life expectancy in our societies, understanding how aging is involved in the process of amyloid fibril accumulation and the effects of amyloid deposits on the aging body is extremely important. In this review, we summarize current knowledge about the nature of amyloid precursor proteins, the prevalence, clinical manifestations, and pathogenesis of amyloidosis, and recent advances in our understanding of age-related amyloidoses outside the brain.
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http://dx.doi.org/10.1016/j.arr.2021.101388DOI Listing
September 2021

Be SMART About AL Amyloidosis.

Mayo Clin Proc 2021 06;96(6):1390-1392

Amyloidosis Research and Treatment Center, Foundation "Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo" and Department of Molecular Medicine University of Pavia, Pavia, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.mayocp.2021.04.014DOI Listing
June 2021

Quality of life assessment in amyloid transthyretin (ATTR) amyloidosis.

Eur J Clin Invest 2021 Nov 22;51(11):e13598. Epub 2021 May 22.

Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.

Background: Amyloid transthyretin (ATTR) amyloidosis is caused by the systemic deposition of transthyretin molecules, either normal (wild-type ATTR, ATTRwt) or mutated (variant ATTR, ATTRv). ATTR amyloidosis is a disease with a severe impact on patients' quality of life (QoL). Nonetheless, limited attention has been paid to QoL so far, and no specific tools for QoL assessment in ATTR amyloidosis currently exist. QoL can be evaluated through patient-reported outcome measures (PROMs), which are completed by patients, or through scales, which are compiled by clinicians. The scales investigate QoL either directly or indirectly, i.e., by assessing the degree of functional impairment and limitations imposed by the disease.

Design: Search for the measures of QoL evaluated in phase 2 and phase 3 clinical trials on ATTR amyloidosis.

Results: Clinical trials on ATTR amyloidosis have used measures of general health status, such as the Short Form 36 Health Survey (SF-36), or tools developed in other disease settings such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) or adaptations of other scales such as the modified Neuropathy Impairment Score +7 (mNIS+7).

Conclusions: Scales or PROMs for ATTR amyloidosis would be useful to better characterize newly diagnosed patients and to assess disease progression and response to treatment. The ongoing ITALY (Impact of Transthyretin Amyloidosis on Life qualitY) study aims to develop and validate 2 PROMs encompassing the whole phenotypic spectrum of ATTRwt and ATTRv amyloidosis, that might be helpful for patient management and may serve as surrogate endpoints for clinical trials.
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http://dx.doi.org/10.1111/eci.13598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8596396PMC
November 2021

The Clinical Impact of Proteomics in Amyloid Typing.

Mayo Clin Proc 2021 05 9;96(5):1122-1127. Epub 2021 Apr 9.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. Electronic address:

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http://dx.doi.org/10.1016/j.mayocp.2020.12.002DOI Listing
May 2021

Psychosocial burden and professional and social support in patients with hereditary transthyretin amyloidosis (ATTRv) and their relatives in Italy.

Orphanet J Rare Dis 2021 04 7;16(1):163. Epub 2021 Apr 7.

Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

Background: Hereditary transthyretin amyloidosis (hATTR), alias ATTR variant (ATTRv) is a severe and disabling disease causing sensory and motor neuropathy, autonomic dysfunction, and cardiomyopathy. The progressive decline of patient's functional autonomy negatively affects the patient's quality of life and requires increasing involvement of relatives in the patient's daily life. Family caregiving may become particularly demanding when the patient is no longer able to move independently. This study is focused on the psychosocial aspects of ATTRv from the patient and relative perspectives. In particular, it explored: the practical and psychological burdens experienced by symptomatic patients with ATTRv and their key relatives and the professional and social network support they may rely on; whether burden varied in relation to patients' and relatives' socio-demographic variables, patients' clinical variables, and perceived professional and social network support; and, any difference in burden and support between patients and their matched relatives.

Methods: The study was carried out on symptomatic patients included in the ATTRv Italian national registry and living with at least one adult relative not suffering from severe illness and being free from ATTRv symptoms. Patients and relatives' assessments were performed using validated self-reported tools.

Results: Overall, 141 patients and 69 relatives were evaluated. Constraints of leisure activities, feelings of loss and worries for the future were the consequences of ATTRv most frequently reported by patients and relatives. Both in patients and their relatives, the burden increased with the duration of symptoms and the level of help in daily activities needed by the patient. In the 69 matched patient-relative pairs, the practical burden was significantly higher among the patients than among their relatives, while the psychological burden was similar in the two groups. Moreover, compared to their relatives, patients with ATTRv reported higher levels of professional and social network support.

Conclusions: These results show that ATTRv is a disease affecting quality of life of both patients and their families. Supporting interventions should be guaranteed to patients, to facilitate their adaptation to the disease, and to their families, to cope as best as possible with the difficulties that this pathology may involve.
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http://dx.doi.org/10.1186/s13023-021-01812-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028211PMC
April 2021

Diagnosis and treatment of cardiac amyloidosis. A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.

Eur J Heart Fail 2021 04 7;23(4):512-526. Epub 2021 Apr 7.

2nd Department of Medicine, Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic.

Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.
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http://dx.doi.org/10.1002/ejhf.2140DOI Listing
April 2021

Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases.

Eur Heart J 2021 04;42(16):1554-1568

2nd Department of Medicine, Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic.

Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.
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http://dx.doi.org/10.1093/eurheartj/ehab072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060056PMC
April 2021

Daratumumab in the Treatment of Light-Chain (AL) Amyloidosis.

Cells 2021 03 4;10(3). Epub 2021 Mar 4.

Amyloidosis Research and Treatment Center, Foundation "Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo", 27100 Pavia, Italy.

Systemic light-chain (AL) amyloidosis is caused by a small B cell, most commonly a plasma cell (PC), clone that produces toxic light chains (LC) that cause organ dysfunction and deposits in tissues. Due to the production of amyloidogenic, misfolded LC, AL PCs display peculiar biologic features. The small, indolent plasma cell clone is an ideal target for anti-CD38 immunotherapy. A recent phase III randomized study showed that in newly diagnosed patients, the addition of daratumumab to the standard of care increased the rate and depth of the hematologic response and granted more frequent organ responses. In the relapsed/refractory setting, daratumumab alone or as part of combination regimens gave very promising results. It is likely that daratumumab-based regimens will become new standards of care in AL amyloidosis. Another anti-CD38 monoclonal antibody, isatuximab, is at an earlier stage of development as a treatment for AL amyloidosis. The ability to target CD38 on the amyloid PC offers new powerful tools to treat AL amyloidosis. Future studies should define the preferable agents to combine with daratumumab upfront and in the rescue setting and assess the role of maintenance. In this review, we summarize the rationale for using anti-CD38 antibodies in the treatment of AL amyloidosis.
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http://dx.doi.org/10.3390/cells10030545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998921PMC
March 2021

Clinical Amyloid Typing by Proteomics: Performance Evaluation and Data Sharing Between Two Centres.

Molecules 2021 Mar 29;26(7). Epub 2021 Mar 29.

Wolfson Drug Discovery Unit and National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London WC1E6BT, UK.

Amyloidosis is a relatively rare human disease caused by the deposition of abnormal protein fibres in the extracellular space of various tissues, impairing their normal function. Proteomic analysis of patients' biopsies, developed by Dogan and colleagues at the Mayo Clinic, has become crucial for clinical diagnosis and for identifying the amyloid type. Currently, the proteomic approach is routinely used at National Amyloidosis Centre (NAC, London, UK) and Istituto di Tecnologie Biomediche-Consiglio Nazionale delle Ricerche (ITB-CNR, Milan, Italy). Both centres are members of the European Proteomics Amyloid Network (EPAN), which was established with the aim of sharing and discussing best practice in the application of amyloid proteomics. One of the EPAN's activities was to evaluate the quality and the confidence of the results achieved using different software and algorithms for protein identification. In this paper, we report the comparison of proteomics results obtained by sharing NAC proteomics data with the ITB-CNR centre. Mass spectrometric raw data were analysed using different software platforms including Mascot, Scaffold, Proteome Discoverer, Sequest and bespoke algorithms developed for an accurate and immediate amyloid protein identification. Our study showed a high concordance of the obtained results, suggesting a good accuracy of the different bioinformatics tools used in the respective centres. In conclusion, inter-centre data exchange is a worthwhile approach for testing and validating the performance of software platforms and the accuracy of results, and is particularly important where the proteomics data contribute to a clinical diagnosis.
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http://dx.doi.org/10.3390/molecules26071913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037974PMC
March 2021

Expert review on soft-tissue plasmacytomas in multiple myeloma: definition, disease assessment and treatment considerations.

Br J Haematol 2021 08 16;194(3):496-507. Epub 2021 Mar 16.

Berlín, Germany.

In this review, two types of soft-tissue involvement in multiple myeloma are defined: (i) extramedullary (EMD) with haematogenous spread involving only soft tissues and (ii) paraskeletal (PS) with tumour masses arising from skeletal lesions. The incidence of EMD and PS plasmacytomas at diagnosis ranges from 1·7% to 4·5% and 7% to 34·4% respectively. EMD disease is often associated with high-risk cytogenetics, resistance to therapy and worse prognosis than in PS involvement. In patients with PS involvement a proteasome inhibitor-based regimen may be the best option followed by autologous stem cell transplantation (ASCT) in transplant eligible patients. In patients with EMD disease who are not eligible for ASCT, a proteasome inhibitor-based regimen such as lenalidomide-bortezomib-dexamethasone (RVD) may be the best option, while for those eligible for high-dose therapy a myeloma/lymphoma-like regimen such as bortezomib, thalidomide and dexamethasone (VTD)-RVD/cisplatin, doxorubicin, cyclophosphamide and etoposide (PACE) followed by SCT should be considered. In both EMD and PS disease at relapse many strategies have been tried, but this remains a high-unmet need population.
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http://dx.doi.org/10.1111/bjh.17338DOI Listing
August 2021

Perspectives in developments of mass spectrometry for improving diagnosis and monitoring of multiple myeloma and other plasma cell disorders.

Clin Chem Lab Med 2021 02 19;59(4):633-635. Epub 2021 Feb 19.

Amyloidosis Research and Treatment Center, IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy.

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http://dx.doi.org/10.1515/cclm-2021-0181DOI Listing
February 2021

Minimal residual disease negativity by next-generation flow cytometry is associated with improved organ response in AL amyloidosis.

Blood Cancer J 2021 02 16;11(2):34. Epub 2021 Feb 16.

Amyloidosis Research and Treatment Center, "Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo", Pavia, Italy.

Light chain (AL) amyloidosis is caused by a small B-cell clone producing light chains that form amyloid deposits and cause organ dysfunction. Chemotherapy aims at suppressing the production of the toxic light chain (LC) and restore organ function. However, even complete hematologic response (CR), defined as negative serum and urine immunofixation and normalized free LC ratio, does not always translate into organ response. Next-generation flow (NGF) cytometry is used to detect minimal residual disease (MRD) in multiple myeloma. We evaluated MRD by NGF in 92 AL amyloidosis patients in CR. Fifty-four percent had persistent MRD (median 0.03% abnormal plasma cells). There were no differences in baseline clinical variables in patients with or without detectable MRD. Undetectable MRD was associated with higher rates of renal (90% vs 62%, p = 0.006) and cardiac response (95% vs 75%, p = 0.023). Hematologic progression was more frequent in MRD positive (0 vs 25% at 1 year, p = 0.001). Altogether, NGF can detect MRD in approximately half the AL amyloidosis patients in CR, and persistent MRD can explain persistent organ dysfunction. Thus, this study supports testing MRD in CR patients, especially if not accompanied by organ response. In case MRD persists, further treatment could be considered, carefully balancing residual organ damage, patient frailty, and possible toxicity.
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http://dx.doi.org/10.1038/s41408-021-00428-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887224PMC
February 2021
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