Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus.

Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy).

An overview of drugs currently under investigation for the treatment of transthyretin-related hereditary amyloidosis.

Introduction: Transthyretin (TTR)-related hereditary amyloidosis is an adult-onset, dominantly inherited, systemic neurodegenerative disease endemic in some populations. Stabilization of the native structure of TTR by small-molecule ligands has recently proved effective in slowing neurological progression. Two drugs, tafamidis and diflunisal, are now available for most patients, particularly in the early stage of the disease.

Pathogenesis of renal failure in multiple myeloma: any role of contrast media?

The spectrum of kidney disease-associated monoclonal immunoglobulin and plasma cell malignancies is remarkably broad and encompasses nearly all nephropathologic entities. Multiple myeloma with kidney impairment at presentation is a medical emergency since the recovery of kidney function is associated with survival benefits. In most cases, kidney impairment may be the first clinical manifestation of malignant plasma cell dyscrasias like multiple myeloma and light chain amyloidosis.

The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up.

Objective: To analyze the clinical manifestations and response to treatment in a cohort of adult patients presenting with recurrent inflammatory attacks and carrying low-penetrance TNFRSF1A variants, as well as to provide data on their long-term follow-up.

Methods: We performed a retrospective chart review of 36 patients carrying low-penetrance TNFRSF1A variants. Moreover, 60 genetically negative patients treated for recurrent inflammatory attacks and 13 patients with structural TNFRSF1A mutations were also analyzed.

Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial.

Importance: Familial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro.

Objective: To determine the effect of diflunisal on polyneuropathy progression in patients with familial amyloid polyneuropathy.

Immunoglobulin light chain amyloidosis.

Primary light chain amyloidosis is the most common form of systemic amyloidosis and is caused by misfolded light chains that cause proteotoxicity and rapid decline of vital organ function. Early diagnosis is essential in order to deliver effective therapy and prevent irreversible organ damage. Accurate diagnosis requires clinical skills and advanced technologies.

Systemic amyloidoses: what an internist should know.

Systemic amyloidoses are rare, complex diseases caused by misfolding of autologous proteins. Although these diseases are fatal, effective treatments exist that can alter their natural history, provided that they are started before irreversible organ damage has occurred. The cornerstones of the management of systemic amyloidoses are early diagnosis, accurate typing, appropriate risk-adapted therapy, tight follow-up, and effective supportive treatment.

A strategy for synthesis of pathogenic human immunoglobulin free light chains in E. coli.

Monoclonal immunoglobulin light chains are normally synthesized in excess compared to the heavy chain partners and can be detected in serum and urine ("free" LC). Occasionally free LC are per se cause of organ toxicity, as in free LC-related disorders. In AL amyloidosis, the most common of these conditions, free LC with peculiar biophysical properties related to their primary structure damage target organs and organize in amyloid fibrils.

Malnutrition at diagnosis predicts mortality in patients with systemic immunoglobulin light-chain amyloidosis independently of cardiac stage and response to treatment.

Background: Nutrition status was shown to be a prognostic factor in patients with immunoglobulin light-chain amyloidosis (AL). However, malnutrition was associated with cardiac involvement, thus suggesting potential interactions. This study aim was to clarify the association among nutrition status, cardiac stage, and mortality in AL.

Systemic light chain amyloidosis: an update for treating physicians.

In immunoglobulin light chain amyloidosis a small, indolent plasma cell clone synthesizes light chains that cause devastating organ damage. Early diagnosis, based on prompt recognition of "red-flags" before advanced cardiomyopathy ensues, is essential for improving outcomes. Differentiation from other systemic amyloidoses may require advanced technologies.

Diagnostic challenges of amyloidosis in Waldenström macroglobulinemia.

Amyloidosis associated with immunoglobulin M clones is a distinct clinical entity that poses specific challenges to clinicians. Although there is substantial overlap, the pattern of organ involvement is peculiar, with higher frequencies of lung, lymph nodes, and peripheral nervous system involvement. Early diagnosis is vital to start effective therapy before irreversible organ damage has occurred and should be based on markers of initial, asymptomatic organ dysfunction, such as natriuretic peptides for heart involvement and albuminuria for renal amyloidosis.

Differential diagnosis of monoclonal gammopathy of undetermined significance.

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic plasma cell disorder occurring in 4.2% of adults > 50 years of age, which can progress into symptomatic diseases either through proliferation of the plasma cell clone, giving rise to multiple myeloma and other lymphoplasmacellular neoplasms, or through organ damage caused by the monoclonal protein, as seen in light-chain amyloidosis and related conditions. Differential diagnosis of asymptomatic and symptomatic monoclonal gammopathies is the determinant for starting therapy.

The challenge of systemic immunoglobulin light-chain amyloidosis (Al).

The cardiac involvement and associated mortality that occur in systemic AL amyloidosis remain among the most challenging aspects of the systemic amyloid-related diseases. Monoclonal immunoglobulin light chains produced by a clone of plasma cells are usually the cause of symptoms and organ dysfunction via both poorly understood toxic effects of misfolded species and accumulation of interstitial amyloid fibrils in key viscera. Treatment is aimed at eliminating the clonal cells in order to eliminate toxic light chain production.

A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis.

Immune-modulatory drugs are active in immunoglobulin light-chain amyloidosis and the addition of alkylating agents can potentiate their action. In this phase II prospective trial we used cyclophosphamide, lenalidomide and dexamethasone in the treatment of 21 patients who were refractory (n=13, 62%) or relapsed (n=8, 38%) after prior treatment including melphalan in all cases, bortezomib in 4 and thalidomide in 6. Median number of cycles administered was 4 (range 2-9 cycles).

Risk stratification in Waldenström macroglobulinemia.

Waldenström macroglobulinemia is characterized by the production of serum monoclonal IgM and lymphoplasmacytic bone marrow infiltration. At least 25% of patients are asymptomatic at diagnosis and treatment is only mandatory in cases of symptomatic disease. Beside reports on treatment results, reviewing risk assessment is another way to describe the clinical course of the disease.

Best use of cardiac biomarkers in patients with AL amyloidosis and renal failure.

In AL amyloidosis prognosis depends on the severity of heart dysfunction which is best assessed by natriuretic peptides (BNP and NT-proBNP). However, their clearance relies on glomerular filtration rate (GFR) and their concentration increases with renal failure. We evaluated the diagnostic and prognostic performance of NT-proBNP and BNP in 248 patients with AL amyloidosis with different degrees of renal failure.

Proteomic typing of amyloid deposits in systemic amyloidoses.

Amyloidoses are characterized by the presence of extracellular amyloid deposits, constituted by fibrillar aggregates of misfolded proteins. Despite the similar morphologic appearance of fibrils, at least 28 different proteins have been detected as causative agents of human amyloidoses, 14 of which associated with systemic forms. Unequivocal typing of the amyloid deposits is a key step in the management of these diseases.

Midregional proadrenomedullin (MR-proADM) is a powerful predictor of early death in AL amyloidosis.

Background: Cardiac biomarkers play a major role in the identification of patients at risk of early death in AL amyloidosis, and a staging system based on amino-terminal pro-natriuretic peptide type-B (NT-proBNP) and troponins (cTn) is used for prognostic stratification. Adrenomedullin is produced by several tissues including the heart, and portends a poor prognosis in heart diseases. We investigated the ability of midregional proadrenomedullin (MR-proADM) to predict early death in AL amyloidosis.