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Blood Advances Oct 2023Patients with advanced cardiac immunoglobulin light chain (AL) amyloidosis have a poor prognosis. Early hematologic and cardiac responses can prolong survival, but...
Patients with advanced cardiac immunoglobulin light chain (AL) amyloidosis have a poor prognosis. Early hematologic and cardiac responses can prolong survival, but predictors of these outcomes have yet to be clarified. We report on 142 patients with newly diagnosed stage IIIb AL amyloidosis. After a median follow-up of 60 months, the median overall survival (OS) was 9 months. Independent baseline factors associated with shorter OS were symptom onset to diagnosis >6 months (hazard ratio [HR], 1.94; P = .003); bone marrow plasmacytosis ≥ 10% (HR, 1.98; P = .01); troponin I > 0.635 ng/mL (HR, 1.62; P = .04); New York Heart Association class III or IV (HR, 1.67; P = .04); and 6-minute walk test distance < 200 m (HR, 1.85; P = .01). Early hematologic (within 1 month) and cardiac (within 3 months) responses were significantly associated with longer survival. In a 1-month landmark analysis, patients with a hematologic very good partial response, partial response, and no response had a median OS of 47, 25, and 5 months, respectively (P < .0001). Patients with cardiac response at 3 months had significantly longer OS (47 vs 11 months; P < .0001). On multivariable modeling, bortezomib use was associated with early hematologic and cardiac responses and longer OS. Symptom onset to diagnosis duration of >6 months and difference between the involved and uninvolved free light chain > 350 mg/L were independently associated with lower odds of an early cardiac response. This study identified factors predictive of treatment outcomes and survival in advanced cardiac AL amyloidosis.
Topics: Humans; Immunoglobulin Light-chain Amyloidosis; Retrospective Studies; Immunoglobulin Light Chains; Treatment Outcome; Proportional Hazards Models
PubMed: 37581513
DOI: 10.1182/bloodadvances.2023010324 -
The Journal of Dermatological Treatment Dec 2023Schnitzler syndrome (SchS) is a rare autoimmune and inflammatory disease mediated by interleukin-1 beta (IL-1β). Recurrent monoclonal gammopathy and chronic urticarial...
Schnitzler syndrome (SchS) is a rare autoimmune and inflammatory disease mediated by interleukin-1 beta (IL-1β). Recurrent monoclonal gammopathy and chronic urticarial rash are the symptoms required for diagnosis according to the Strasbourg criteria. The low prevalence of this syndrome (around 300 cases have been reported) and confusion with other inflammatory disorders may delay the diagnosis for up to 5 years. Although the most effective treatment for SchS is anakinra, some patients do not respond to this treatment. We report a case of SchS in a 64-year-old woman with multiple episodes of fever, severe rash, erythema, arthralgia and dyspnea. The patient was successfully treated with canakinumab after anakinra intolerance and failure of colchicine, prednisone, methotrexate and dapsone. After the first dose of canakinumab the skin wounds rapidly improved and the patient did not require any concomitant treatments. The cause of SchS is still unknown and a differential diagnosis is recommended, especially with adult-onset Still´s disease due to their similar symptoms. Canakinumab, a specific anti-IL-1β antibody, blocks its binding to receptors, thereby preventing IL-1β-induced gene activation and production of inflammatory mediators. Canakinumab has proven to be an effective drug in SchS, providing an alternative to anakinra.
Topics: Adult; Female; Humans; Middle Aged; Schnitzler Syndrome; Interleukin 1 Receptor Antagonist Protein; Antibodies, Monoclonal, Humanized; Exanthema
PubMed: 37551725
DOI: 10.1080/09546634.2023.2242705 -
Blood Advances May 2024Newer immune-based approaches based on recruitment and redirection of endogenous and/or synthetic immunity such as chimeric antigen receptor T cells or bispecific... (Review)
Review
Newer immune-based approaches based on recruitment and redirection of endogenous and/or synthetic immunity such as chimeric antigen receptor T cells or bispecific antibodies are transforming the clinical management of multiple myeloma (MM). Contributions of the immune system to the antitumor effects of myeloma therapies are also increasingly appreciated. Clinical malignancy in MM originates in the setting of systemic immune alterations that begin early in myelomagenesis and regional changes in immunity affected by spatial contexture. Preexisting and therapy-induced changes in immune cells correlate with outcomes in patients with MM including after immune therapies. Here, we discuss insights from and limitations of available data about immune status and outcomes after immune therapies in patients with MM. Preexisting variation in systemic and/or regional immunity is emerging as a major determinant of the efficacy of current immune therapies as well as vaccines. However, MM is a multifocal malignancy. As with solid tumors, integrating spatial aspects of the tumor and consideration of immune targets with the biology of immune cells may be critical to optimizing the application of immune therapy, including T-cell redirection, in MM. We propose 5 distinct spatial immune types of MM that may provide an initial framework for the optimal application of specific immune therapies in MM: immune depleted, immune permissive, immune excluded, immune suppressed, and immune resistant. Such considerations may also help optimize rational patient selection for emerging immune therapies to improve outcomes.
Topics: Humans; Multiple Myeloma; Immunotherapy; Patient Selection
PubMed: 38564776
DOI: 10.1182/bloodadvances.2023011242 -
JAMA Oncology Sep 2023
Topics: Humans; Monoclonal Gammopathy of Undetermined Significance; Disease Progression; Multiple Myeloma
PubMed: 37498610
DOI: 10.1001/jamaoncol.2023.2278 -
Clinical and Experimental Rheumatology Sep 2023
Topics: Humans; Lupus Nephritis; Paraproteinemias
PubMed: 37199177
DOI: 10.55563/clinexprheumatol/mqfpi4 -
Cancer Discovery Nov 2023The next-generation cereblon-targeting agent mezigdomide shows early signs of clinical efficacy in patients with heavily pretreated multiple myeloma, highlighting the...
The next-generation cereblon-targeting agent mezigdomide shows early signs of clinical efficacy in patients with heavily pretreated multiple myeloma, highlighting the potential of rational drug design to improve the potency of immunomodulatory therapies that function as molecular glues.
Topics: Humans; Multiple Myeloma; Treatment Outcome
PubMed: 37694945
DOI: 10.1158/2159-8290.CD-NB2023-0065 -
The Medical Letter on Drugs and... Sep 2023
Topics: Humans; Multiple Myeloma; Antibodies, Bispecific
PubMed: 37682687
DOI: 10.58347/tml.2023.1684e -
Haematologica Dec 2023Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic precursor condition that precedes multiple myeloma and related disorders but has also been...
Disease associations with monoclonal gammopathy of undetermined significance can only be evaluated using screened cohorts: results from the population-based iStopMM study.
Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic precursor condition that precedes multiple myeloma and related disorders but has also been associated with other medical conditions. Since systematic screening is not recommended, MGUS is typically diagnosed due to underlying diseases and most cases are not diagnosed. Most previous studies on MGUS disease associations have been based on clinical cohorts, possibly resulting in selection bias. Here we estimate this selection bias by comparing clinically diagnosed and screened individuals with MGUS with regards to demographics, laboratory features, and comorbidities. A total of 75,422 participants in the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study were screened for MGUS by serum protein electrophoresis, immunofixation and free light chain assay (clinicaltrials gov. Identifier: NCT03327597). We identified 3,352 individuals with MGUS, whereof 240 had previously been clinically diagnosed (clinical MGUS), and crosslinked our data with large, nationwide registries for information on comorbidities. Those with clinical MGUS were more likely to have at least one comorbidity (odds ratio=2.24; 95% confidence interval: 1.30-4.19), and on average had more comorbidities than the screened MGUS group (3.23 vs. 2.36, mean difference 0.68; 95% confidence interval: 0.46-0.90). They were also more likely to have rheumatological disease, neurological disease, chronic kidney disease, liver disease, heart failure, or endocrine disorders. These findings indicate that individuals with clinical MGUS have more comorbidities than the general MGUS population and that previous studies have been affected by significant selection bias. Our findings highlight the importance of screening data when studying biological and epidemiological implications of MGUS.
Topics: Humans; Multiple Myeloma; Monoclonal Gammopathy of Undetermined Significance; Iceland; Paraproteinemias; Comorbidity; Disease Progression
PubMed: 37439374
DOI: 10.3324/haematol.2023.283191 -
Frontiers in Immunology 2023The adaptive immune system of jawed vertebrates generates a highly diverse repertoire of antibodies to meet the antigenic challenges of a constantly evolving biological... (Review)
Review
The adaptive immune system of jawed vertebrates generates a highly diverse repertoire of antibodies to meet the antigenic challenges of a constantly evolving biological ecosystem. Most of the diversity is generated by two mechanisms: V(D)J gene recombination and somatic hypermutation (SHM). SHM introduces changes in the variable domain of antibodies, mostly in the regions that form the paratope, yielding antibodies with higher antigen binding affinity. However, antigen recognition is only possible if the antibody folds into a stable functional conformation. Therefore, a key force determining the survival of B cell clones undergoing somatic hypermutation is the ability of the mutated heavy and light chains to efficiently fold and assemble into a functional antibody. The antibody is the structural context where the selection of the somatic mutations occurs, and where both the heavy and light chains benefit from protective mechanisms that counteract the potentially deleterious impact of the changes. However, in patients with monoclonal gammopathies, the proliferating plasma cell clone may overproduce the light chain, which is then secreted into the bloodstream. This places the light chain out of the protective context provided by the quaternary structure of the antibody, increasing the risk of misfolding and aggregation due to destabilizing somatic mutations. Light chain-derived (AL) amyloidosis, light chain deposition disease (LCDD), Fanconi syndrome, and myeloma (cast) nephropathy are a diverse group of diseases derived from the pathologic aggregation of light chains, in which somatic mutations are recognized to play a role. In this review, we address the mechanisms by which somatic mutations promote the misfolding and pathological aggregation of the light chains, with an emphasis on AL amyloidosis. We also analyze the contribution of the variable domain (V) gene segments and somatic mutations on light chain cytotoxicity, organ tropism, and structure of the AL fibrils. Finally, we analyze the most recent advances in the development of computational algorithms to predict the role of somatic mutations in the cardiotoxicity of amyloidogenic light chains and discuss the challenges and perspectives that this approach faces.
Topics: Animals; Humans; Multiple Myeloma; Friends; Ecosystem; B-Lymphocytes; Paraproteinemias
PubMed: 37520549
DOI: 10.3389/fimmu.2023.1203425 -
Biomaterials Science Jul 2023Multiple myeloma (MM) is a neoplasm of aberrant plasma cells and ranks second among hematologic malignancies. Despite a substantial improvement in clinical outcomes with...
Multiple myeloma (MM) is a neoplasm of aberrant plasma cells and ranks second among hematologic malignancies. Despite a substantial improvement in clinical outcomes with advances in therapeutic modalities over the past two decades, MM remains incurable, necessitating the development of new and potent therapies. Herein, we engineered a daratumumab-polymersome-DM1 conjugate (DPDC) based highly potent and CD38-selective immuno-nano-DM1 toxin for depleting MM cells . DPDC with controllable daratumumab density and disulfide-linked DM1 is of small size (51-56 nm), with high stability and reduction-triggered DM1 release. DPDC potently inhibited the proliferation of CD38-overexpressed LP-1 and MM.1S MM cells with IC values of 2.7 and 1.2 ng DM1 equiv. per mL, about 4-fold stronger than non-targeted PDC. Moreover, DPDC effectively and safely depleted LP-1-Luc MM cells in an orthotopic mouse model at a low DM1 dosage of 0.2 mg kg, thus alleviating osteolytic bone lesion and extending the median survival by 2.8-3.5-fold compared to all controls. This CD38-selective DPDC provides a safe and potent treatment strategy for MM.
Topics: Mice; Animals; Multiple Myeloma; ADP-ribosyl Cyclase 1; Hematologic Neoplasms; Cell Line, Tumor
PubMed: 37334506
DOI: 10.1039/d3bm00470h