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Novel Molecular Therapies and Genetic Landscape in Selected Rare Diseases with Hematologic Manifestations: A Review of the Literature.

Rare diseases affect less than 1 in 2000 people and are characterized by a serious, chronic, and progressive course. Among the described diseases, a mutation in a single gene caused mastocytosis, thrombotic thrombocytopenic purpura, Gaucher disease, and paroxysmal nocturnal hemoglobinuria (KIT, ADAMTS13, GBA1, and PIG-A genes, respectively). In Castleman disease, improper ETS1, PTPN6, TGFBR2, DNMT3A, and PDGFRB genes cause the appearance of symptoms. In histiocytosis, several mutation variants are described: BRAF, MAP2K1, MAP3K1, ARAF, ERBB3, NRAS, KRAS, PICK1, PIK3R2, and PIK3CA. Genes like H

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… Monozygotic twins and triplets have been reported [ 11 ]. However, family cases are rarely seen, and in the familial and childhood variants, no single gene has been identified [ 4 , 12 ]. …

Population pharmacokinetic/pharmacodynamic joint modeling of ixazomib efficacy and safety using data from the pivotal phase III TOURMALINE-MM1 study in multiple myeloma patients.

Ixazomib is an oral proteasome inhibitor approved in combination with lenalidomide and dexamethasone for the treatment of relapsed/refractory multiple myeloma (MM). Approval in the United States, Europe, and additional countries was based on results from the phase III TOURMALINE-MM1 (C16010) study. Here, joint population pharmacokinetic/pharmacodynamic time-to-event (TTE) and discrete time Markov models were developed to describe key safety (rash and diarrhea events, and platelet counts) and efficacy (myeloma protein [M-protein] and progression-free survival [PFS]) outcomes observed in TOURMAL

Comparing the efficacy of different dexamethasone regimens for maintenance treatment of multiple myeloma in standard-risk patients non-eligible for transplantation.

BackgroundMultiple myeloma (MM) is a plasma cell malignancy, while MM outcomes have significantly improved due to novel agents and combinations, MM remains an incurable disease. The key goal of treatment in MM is to achieve a maximal response and the subsequent consolidation of response after initial therapy. Many studies analyzed an improved progression-free survival (PFS) following lenalidomide alone maintenance versus placebo or observation after autologous stem cell transplant (ASCT) in patients with NDMM. In the SWOG S0777 clinical trial, patients newly diagnosed with MM (NDMM) without AS

Model-Informed Drug Development for Ixazomib, an Oral Proteasome Inhibitor.

Model-informed drug development (MIDD) was central to the development of the oral proteasome inhibitor ixazomib, facilitating internal decisions (switch from body surface area (BSA)-based to fixed dosing, inclusive phase III trials, portfolio prioritization of ixazomib-based combinations, phase III dose for maintenance treatment), regulatory review (model-informed QT analysis, benefit-risk of 4 mg dose), and product labeling (absolute bioavailability and intrinsic/extrinsic factors). This review discusses the impact of MIDD in enabling patient-centric therapeutic optimization during the develo

Drug Delivery Approaches for the Treatment of Cervical Cancer.

Cervical cancer is a highly prevalent cancer that affects women around the world. With the availability of new technologies, researchers have increased their efforts to develop new drug delivery systems in cervical cancer chemotherapy. In this review, we summarized some of the recent research in systematic and localized drug delivery systems and compared the advantages and disadvantages of these methods.

Revisiting the standards of cancer detection and therapy alongside their comparison to modern methods.

In accordance with the World Health Organization data, cancer remains at the forefront of fatal diseases. An upward trend in cancer incidence and mortality has been observed globally, emphasizing that efforts in developing detection and treatment methods should continue. The diagnostic path typically begins with learning the medical history of a patient; this is followed by basic blood tests and imaging tests to indicate where cancer may be located to schedule a needle biopsy. Prompt initiation of diagnosis is crucial since delayed cancer detection entails higher costs of treatment and hospita

Advancing gene editing therapeutics: Clinical trials and innovative delivery systems across diverse diseases.

Gene editing is a groundbreaking therapeutic approach that can potentially treat a broad spectrum of genetic and acquired diseases. This review highlights recent clinical trials employing advanced gene editing technologies such as CRISPR-Cas9, zinc-finger nucleases (ZFNs), and base editors across multiple disease areas including metabolic disorders, autoimmune diseases, muscular dystrophies, and inherited eye disorders. Central to the success of these therapies is the development of efficient and safe delivery systems, including lipid nanoparticles (LNPs), viral vectors (adenoviral and lentivi

Mechanisms of Action of the New Antibodies in Use in Multiple Myeloma.

Monoclonal antibodies (mAbs) directed against antigen-specific of multiple myeloma (MM) cells have Fc-dependent immune effector mechanisms, such as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP), but the choice of the antigen is crucial for the development of effective immuno-therapy in MM. Recently new immunotherapeutic options in MM patients have been developed against different myeloma-related antigens as drug conjugate-antibody, bispecific T-cell engagers (BiTEs) and chimeric antigen receptor (CA

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… Target | Therapeutic format | Advantage | Disadvantage CD38 | Naked monoclonal antibody | High clinical activity in triplets and quadruplets (dara-based regimens are novel standard of care for elderly patients). | Reduction of CD38+ activated T-cells. Perturbation of T-cell compartment. … However, SLAMF7 expression is retained in MM patients with relapsed/refractory disease, and after intensive prior therapy. | Lack of relevant clinical efficacy of elotuzumab as single agent or in triplets given frontline; it requires to be part of combination regimens Bispecific antibody | T-cell mediated …

Геномический диагноз детских расстройств: революция и эволюция.

Мощные, последние достижения в технологиях анализа генома оказали глубокое воздействие на практику медицинской генетики как в лаборатории, так и в клинике. Более широкое использование общегеномных тестов, таких, как анализ хромосомных микроарра и последовательность экзомов, привело к переходу к "генотипному" подходу. В настоящее время имеются многочисленные методы диагностики конкретного синдрома или фенотипа, и, хотя традиционные методы остаются эффективными инструментами в некоторых ситуациях, технологии с более высокой производительностью фактически стали лабораторным инструментом диагности

Продвижение многомерной миеломной терапии: систематический анализ кортикостероидов и моноклонных антител в качестве двух терапевтических агентов.

Множественная миелома (ММ) — неизлечимая гематопоэтическая порча, которая определяется клональным расширением неопластических плазменных клеток костного мозга. Кортикостероиды и моноклонные антитела (mAbs) были утверждены для обработки MM в прошлом 20 годы и в настоящее время являются ключевыми компонентами режима лечения, повышая клинические результаты. Кортикостероиды (дексаметазон и преднизон) часто используются в сочетании с другими агентами [протеозными ингибиторами и иммуномодулятивными препаратами (ИМИД)], в то время как mAbs (daratumumumab, elotuzumab и isatuximab) изменили парадигмы л

Venetoclax-Dexamethasone Versus Pomalidomide-Dexamethasone в t()11;14)-Positive replaped/recractory multieloma: первичные результаты случайного исследования, этап III CANOVA.

ЦЕЛЬ: Венетоклакс, устный перевод BCL-2 ингибитор, имеет эффективность в t(11;14)-положительное повторное/восстановительное несколько миэлом (RRMM), которое усиливается дексаметазоном, который поощряет BCL-2 Зависимость. МЕТОДЫ: случайная, открытая маркировка, этап III исследования CANOVA (индивидуальный идентификатор Clinical Processors.gov): NCT03539744) зачисленные взрослые, имеющие t()11;14) - положительный RRM, получивший ≥2 предыдущие линии терапии. Пациенты были назначены по случайному назначению ( " .1::1) на венетоклакс-дексаметазон или помалидомид-дексазон до прогресса или невын

Глобальные, региональные и национальные факторы метаболического риска, связанные с множественной миеломой, 1990-2021:: анализ на основе глобального исследования бремени болезней; 2021.

Цель настоящего исследования заключалась в изучении глобального бремени болезней, связанных с множественной миеломой (ММ), которая связана с метаболическими факторами. Использование данных GHDx тарирования 1990-2021, случаи MM были выявлены через ICD-10 коды (C90.0). Были проанализированы ключевые показатели, включая коэффициент смертности и коэффициент лет жизни с поправкой на инвалидность (DALY); стандартизированные по возрасту показатели (ASMR, ASDR) и расчетные годовые процентные изменения (EAPC) были рассчитаны с использованием R для сопоставления различий между регионами, полами и возрас

Treatment Outcomes of Multiple Myeloma in Developing Countries: A Systematic Review and Meta-Analysis.

Multiple myeloma (MM) treatment outcomes in developing countries may be impacted by resource constraints. This systematic review and meta-analysis evaluated efficacy outcomes of MM treatments across developing regions. Comprehensive searches in five major databases identified 37 eligible studies from Asia, Africa, Latin America, and Eastern Europe. The Newcastle-Ottawa Scale was used to assess risk of bias. Newer novel agents including daratumumab, carfilzomib, and pomalidomide showed limited use across studies. For patients receiving autologous stem cell transplantation (ASCT), the pooled ove

Реальные результаты новых диагностированных пациентов из числа миеломы, лечившихся до эры Anti-CD38 Антитела: EMMY Cort 2017 в адрес 2020.

Последние агенты коренным образом изменили пейзаж миеломы (ММ). Их реальные последствия необходимо оценивать в долгосрочной перспективе. МЕТОДЫ: ЭММИ является неинтервенционной, перспективной динамичной когортой, осуществляемой во Франции, поскольку 2017, с 900 Пациенты ежегодно зачисляются в школу. Новый диагноз MM (NDMM) 2017 в адрес 2020 здесь описано. РЕЗУЛЬТАТЫ: Всего 1036 пациенты, имеющие право на нетрансплантацию (НПТ) (средний возраст: 74.9 годы) и 561 пациенты, получившие аутологическую трансплантацию стволовых клеток (ASCT) (средний возраст): 60.6 ), были зачислены. Для пациентов AC

Minimal Residual Disease-Adapted Therapy in Multiple Myeloma: Current Evidence and Opinions.

Purpose of reviewMultiple myeloma (MM) is a biologically heterogeneous malignancy with relatively uniform treatment paradigms. This review aims to assess the growing role of Minimal Residual Disease (MRD) assessment in facilitating response-adapted therapeutic decision making to individualize therapy in MM.Recent findingsMRD has been repeatedly demonstrated to provide strong prognostic information, superseding traditional IMWG response criteria. The use of MRD to modulate therapy remains controversial. Here, we review the existing landscape of MRD-adapted trial designs in both induction/consol

Diversity, Equity, and Inclusion in Multiple Myeloma: A Call to Action.

BackgroundAlthough advancements in multiple myeloma therapy have rapidly evolved, pervasive racial and social inequities prevent uniform benefit across diverse patient populations. This affects access to US Food and Drug Administration-approved treatments and to clinical studies. The impact of health-care inequities is not well understood and thus, the development of effective strategies is inadequate. We identify different disparities including race, age, socioeconomic status, and sexual preference/orientation and their effect on patient care. We explore recommendations for the advanced pract

Цифровая двойная модель для подкрепления клинического решения на основе фактических данных при многократном лечении миэломы.

За последнее десятилетие в области лечения миеломы (ММ) был достигнут значительный прогресс. Несмотря на эффективность новых веществ, реакция пациентов, как правило, остается весьма непредсказуемой. С ростом когнитивной нагрузки, создаваемой за счет сложного и меняющегося ландшафта лечения, инструменты оказания помощи, основанные на данных, становятся все более популярными. Подходы, основанные на модели, такие как цифровые близнецы (ДТ), позволяют имитировать возможные ответы на набор входных параметров, основанных на ретроспективных наблюдениях. В контексте поддержки принятия решений о лечени

How I approach smoldering multiple myeloma.

The current standard of care in smoldering multiple myeloma (SMM) is close surveillance, outside of clinical trials. Efforts are being made to understand the pathobiologic process that leads to the progression of SMM to active MM. This review provides a critical description of available data, including risk factors and risk models of progression, as well as clinical trials investigating interventions for this patient population. We describe 2 cases in which patients were seen before the concept of a myeloma-defining event was established. Today, based on the International Myeloma Working Group

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… Trials that use lenalidomide, 27 Rd, 28 or single-agent daratumumab 30 are potentially undertreating active MM, because doublets are inferior to triplets, and ASCT remains an integral part of therapy for transplantation-eligible patients with MM. …

Systemic AL Amyloidosis: Current Approaches to Diagnosis and Management.

AL amyloidosis is characterized by a low-level expansion of an indolent, small plasma cell clone that produces amyloidogenic light chains. Amyloid aggregates or preceding intermediaries cause direct cell damage through their proteotoxicity, and amyloid deposits distort tissue architecture, and, eventually, lead to organ impairment. It is a rare, underdiagnosed disease with a diverse clinical presentation depending on the organ tropism of the amyloid fibrils; cardiac and renal involvement is most common, but any organ can be affected, excluding the central nervous system. A high level of awaren

Treatment of Smoldering Multiple Myeloma: Ready for Prime Time?

The current standard of care for smoldering multiple myeloma (SMM) is observation until there is end-organ involvement. With newer and more effective treatments available, a question that is increasingly asked is whether early intervention in patients with SMM will alter the natural history of their disease. Herein, we review the evolving definition of SMM and risk stratification models. We discuss evidence supporting early intervention for SMM-both as a preventative strategy to delay progression and as an intensive treatment strategy with a goal of potential cure. We highlight ongoing trials