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Population Cellular Kinetics of Idecabtagene Vicleucel in Patients with Triple-Class-Exposed Relapsed/Refractory Multiple Myeloma.

BACKGROUND: Idecabtagene vicleucel (ide-cel, ABECMA) is an autologous, B-cell maturation antigen (BCMA)-directed, chimeric antigen receptor (CAR) T-cell therapy. The current modeling analyses aim to characterize the cellular kinetics (CK) of ide-cel and to assess the covariate effects impacting ide-cel cellular kinetics in patients with relapsed/refractory multiple myeloma. METHODS: A modified piecewise model was developed to characterize ide-cel CK through the nonlinear mixed effects method. The model parameterization was conducted using the ide-cel whole-blood transgene data in CK-evaluable…

MIR4726EccDNA drives bortezomib resistance in multiple myeloma by enhancing MIR4726-5p/NXF1/NKIRAS2 axis dependent autophagy.

BACKGROUND: Despite many new drugs, multiple myeloma (MM) remains an incurable plasma cell malignancy, and drug resistance is a long-standing topic in this field. Characterized by efficient transcription without being limited by the double helix structure and promoter, extrachromosomal circular DNA (EccDNA) has been proven to be widely involved in cancer development and drug resistance. METHODS: We performed circle-seq and mRNA-seq on samples from three MM patients at the time of complete response and relapse to screen EccDNA candidate molecules. Outward PCR and Sanger sequencing were used to…

Research progress of targeted BCMA CAR-T therapy for relapsed/refractory multiple myeloma antigen-negative relapse.

Chimeric antigen receptor T cell (CAR-T) therapy targeting B-cell maturation antigen (BCMA) has emerged as a novel and effective modality for the treatment of relapsed or refractory multiple myeloma (RRMM), achieving remarkable therapeutic outcomes. However, relapse remains a major problem impeding the long-term efficacy of this therapy, with antigen-negative relapse being a particularly challenging issue. The mechanisms underlying BCMA antigen-negative relapse encompass a spectrum of phenomena, including diminished or lost tumor antigen expression, BCMA shedding, impaired antigen presentation…

Bispecific T-cell engagers for relapsed/refractory multiple myeloma after solid organ transplantation: A case series.

The emergence of bispecific antibodies for multiple myeloma presents a critical unanswered question for solid organ transplant recipients: Can these T-cell dependent therapies overcome concurrent immunosuppression without triggering graft rejection? While teclistamab and similar agents demonstrate remarkable efficacy in immunocompetent patients, their mechanism demands functional T-cells-precisely what calcineurin inhibitors and antimetabolites suppress in transplant recipients. This creates a perilous therapeutic trilemma: (1) Maintaining standard immunosuppression risks blunting bispecific e…

NSUN2-mediated RNA m5C modification drives multiple myeloma progression by enhancing the stability of HIP1 mRNA.

RNA 5-methylcytosine (m5C) modification is a crucial epigenetic regulation, and aberrant m5C methylation is associated with the pathogenesis of certain cancers. However, the role and regulatory mechanisms of RNA m5C modification in multiple myeloma (MM) remain unclear. This study aimed to investigate the function and regulatory mechanisms of the primary m5C methyltransferase, NOP2/Sun RNA methyltransferase family member 2 (NSUN2), in MM. The results demonstrated NSUN2 overexpression in patients with MM, and higher NSUN2 levels were associated with poorer outcomes. In addition, elevated global …

Can we identify individuals at risk to develop multiple myeloma? A machine learning-based predictive model.

Multiple myeloma evolves unnoticed over years, and when diagnosed, organ damage is common. Electronic health records (EHR) can help in developing predictive models identifying 'Работает' people at risk. MM patients from Clalit Health Services (2002-2019) were matched with healthy controls. Stage I: EHR from 5 years prior to MM diagnosis were reviewed and >200 parameters were compared (patients vs. controls). Stage II: Establishing xgboost model predicting 5 year risk for MM, with validation. Stage III: A simplified logistic regression model for community, requiring 20 variables (Age; Hb; RBC; M…

Kaempferol induces mitophagy and disrupts iron metabolism via SFXN2 leading to apoptosis in multiple myeloma cells.

BACKGROUND: The role of kaempferol, a natural flavonoid, in the apoptosis of multiple myeloma cells has not been fully investigated. This study investigated the effects of kaempferol on MM cell apoptosis and its underlying mechanisms. METHODS: In vitro, cell viability was measured using the CCK-8 and EdU assays, and apoptosis was assessed using flow cytometry. Mitochondrial damage and autophagy were analyzed using JC-1 staining, MitoTracker Green staining, and fluorescence microscopy. Western blot and qRT-PCR were used to assess SFXN2 and autophagy-related molecule levels. Intracellular Fe2+ …

Cyanidin-3-O-glucoside-mediated reduction of regulatory T cells: a therapeutic strategy for multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a malignant plasma cell tumor. Regulatory T cells (Tregs), key components of the immunosuppressive tumor immune microenvironment (TIME), play a significant role in MM progression. One mechanism of anti-MM activity of anti-CD38 monoclonal antibodies is reducing CD38+ Tregs. Cyanidin-3-O-glucoside (C3G), a natural CD38 inhibitor, effectively suppresses enzymatic activity of CD38. Consequently, we investigated whether C3G could serve as a novel therapeutic agent for MM by targeting Tregs. METHODS: A MM-bearing mouse model was established and treated with C3G …

B-cell maturation antigen targeted PET/CT imaging in multiple myeloma: a first-in-human study.

B-cell maturation antigen (BCMA)-targeted positron emission tomography/computed tomography (PET/CT) represents a promising tool for the management of multiple myeloma, enabling noninvasive and quantitative evaluation across different disease stages. This novel technique specifically addresses two major diagnostic challenges: the limited specificity of conventional 18F-FDG PET/CT and the focal sampling constraints of bone marrow biopsies. In this prospective study, a 68Ga-labeled nanobody-based BCMA tracer demonstrated improved detection compared with 18F-FDG PET/CT, effectively visualizing par…

NGS-based monitoring of secondary acute lymphoblastic leukemia dynamics following lenalidomide maintenance in multiple myeloma patients.

We report on a series of three patients diagnosed with secondary acute lymphoblastic leukemia (sALL) following treatment for multiple myeloma (MM) where serial, commercially available, next-generation sequencing (NGS) based tracking of measurable residual disease (MRD) using the clonoSEQ assay provided valuable clinical insight. Each of the patients in this series had been treated for their MM with regimens that had included autologous stem cell transplantation following high dose melphalan chemotherapy and had been on maintenance treatment with the immunomodulatory drug lenalidomide for at le…

Machine learning-assisted prognosis of multiple myeloma side population cells via SRGs and OCLR stemness index.

BACKGROUND AND OBJECTIVE: Relapse in Multiple Myeloma, driven by therapy-resistant cancer stem cells, necessitates the development of more specific and accurate prognostic models. Existing stemness indices often lack specificity for the unique biology of Multiple Myeloma. This study aimed to develop, validate, and optimize a novel prognostic gene signature derived from Side Population cells, a well-defined cancer stem cell-enriched subpopulation in Multiple Myeloma. METHODS: A core stemness gene module was identified from Side Population cell transcriptomes (GSE109651) using Weighted Gene Co-…

CD38-specific nanobody-based bispecific antibody recruiters (BARs) redirect complement-dependent cytotoxicity toward multiple myeloma cells.

Bispecific antibody recruiters (BARs) are an innovative class of immunotherapeutics that redirect endogenous antibodies to tumor cells. BARs … g. Our results demonstrate the feasibility of CD38-specific nanobody-based BARs as therapeutics for multiple myeloma.

Microbiota-reprogrammed phosphatidylcholine inactivates cytotoxic CD8 T cells through UFMylation via exosomal SerpinB9 in multiple myeloma.

Gut microbiome influences tumorigenesis and tumor progression through regulating the tumor microenvironment (TME) and modifying blood metabolites. However, the mechanisms by which gut microbiome and blood metabolites regulate the TME in multiple myeloma (MM) remain unclear. By employing16S rRNA gene sequencing coupled with metagenomics and ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry, we find that Lachnospiraceae are high and phosphatidylcholine (PC) are low in MM patients. We further show that Lachnospiraceae inhibits PC production from MM c…

MRD-driven phase 2 study of daratumumab, carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma.

In newly diagnosed multiple myeloma (NDMM), measurable residual disease (MRD) status is prognostically important, but its role in treatment decisions remains unclear. In a phase 2 trial, we assessed daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) induction followed by a next-generation sequencing-based MRD-adapted strategy. The primary outcome was complete response (CR) and stringent CR (≥CR) after induction. Flow cytometry was used to profile T cells. Among 39 patients, 21 (54%) achieved ≥CR after induction (P = .375), with MRD-negative rates of 59% (10-5) and 41% (10-6).…

Real-world treatment patterns for teclistamab and talquetamab in multiple myeloma (MM): experience from 609 patients.

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… Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387:495–505. 2. Chari A, Minnema MC, Berdeja JG, Oriol A, van de Donk N, Rodríguez-Otero P, et al. Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med. 2022;387:2232–44. 3. … Real-world schedule de-escalation of teclistamab in patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2024;42:7536. 5. Mohan M, Monge J, Shah N, Luan D, Forsberg M, Bhatlapenumarthi V, et al. Teclistamab in relapsed refractory multiple myeloma: multi-institutional real-world study. …

Dexamethasone dose intensity does not impact outcomes in newly diagnosed multiple myeloma: a secondary SWOG analysis.

AbstractDexamethasone is a key component of induction for newly diagnosed multiple myeloma (NDMM), despite common toxicities, including hyperglycemia and insomnia. In the randomized ECOG E4A03 trial, dexamethasone 40 mg once weekly was associated with lower mortality than higher doses. However, the performance of dexamethasone dose reductions below this threshold with regard to progression-free survival (PFS) and overall survival (OS) in NDMM has not been fully characterized. We conducted a secondary pooled analysis of the SWOG 0777 and SWOG 1211 studies of NDMM, which used lenalidomide and de…

Профилактика иммуноглобулина должна начинаться после двухразовой антителной терапии в нескольких миеломах, независимо от уровня игГ.

Резюме по конкретным антителам (bsAbs), таким, как теклистамаб, эль-Ранатамаб, linvoseltamb и талькетамаб, обладают впечатляющей эффективностью в миеломе (ММ), но сопряжены с существенными инфекционными рисками, которые не рассеиваются с течением времени. Иммуноглобулиновая заместительная терапия (IgRT), включающая иммуноглобулины IV и подкожные иммуноглобулины (SC), может снизить эти риски. В этой точке зрения мы противопоставляем первичную профилактику IgRT (начинание вне зависимости от уровней IgG) с упреждающим лечением IgRT (начинаем только после того, как уровни IgG опускаются ниже опред

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AbstractBispecific antibodies (bsAbs), such as teclistamab, elranatamab, linvoseltamab, and talquetamab, have impressive efficacy in multiple myeloma (MM) but come with substantial infectious risks that do not dissipate over time. Immunoglobulin replacement therapy (IgRT), which includes IV and subcutaneous (SC) immunoglobulins, may lower these risks. In thi…

Прогнозирующие детерминанты долгосрочной смертности у пожилых пациентов с новой диагностированной множественной миеломой.

Фон/цели: Множественная миелома (ММ) — опухоль плазменной клетки, диагностированная преимущественно у пожилых людей. Вместе с тем еще предстоит твердо установить значение определения слабой стороны пациента, а также определения наиболее подходящих и надежных инструментов для его оценки. Методы: Это ретроспективное исследование 36 больные в возрасте 65 - лица более старшего возраста, прошедшие комплексную гериатрическую оценку (CGA). Средний возраст пациентов 76 (СД) 6.22) с 33.3% быть женщиной. Оценка пациентов проводилась с использованием индекса упругости Международной рабочей группы по миел…

Attrition rates and treatment outcomes in multiple myeloma: real-world data over a 40-year period.

The treatment landscape of multiple myeloma (MM) has evolved significantly over four decades, driven by novel therapies and optimized supportive care. However, the attrition rate (AR), defined as the proportion of patients who die without advancing to the next line of therapy (LOT) after treatment failure, remains a major challenge. To assess how treatment patterns and outcomes have evolved, we analyzed 1,297 MM patients treated between 1980 and 2020, stratified by diagnosis period and age. ARs declined from 38-55% in the 1980s to 15-20% in 2010-2020, but remained high in older patients, with …

Optimal MRD-based end point to support response-adapted treatment cessation in newly diagnosed multiple myeloma.

AbstractThe therapeutic success of first-line quadruplet (QUAD) induction therapy and autologous stem cell transplantation (ASCT) has reinvigorated an interest in fixed-duration therapy, yet optimal short-term efficacy end point for treatment cessation is unknown. Using data from a phase 2 clinical trial and a prospective institutional database, we tested the predictive performance of 5 short-term efficacy end points among 221 patients who received QUAD + ASCT followed by treatment cessation if minimal residual disease (MRD) by next-generation sequencing negative for 2 consecutive time points.