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Deciphering N-Glycosylation Dynamics of Serum Monoclonal Immunoglobulins in Multiple Myeloma via EThcD-sceHCD-MS/MS.

Serum glycoprotein glycosylation changes can indicate disease onset and progression. However, the site-specific N-glycosylation of monoclonal immunoglobulins (M-proteins) in multiple myeloma (MM) and its clinical implications are unclear. In this study, we isolated pathogenic micromonoclonal IgA or IgG (approximately 2 μg) from IgA-MM patients (n = 22) and IgG-MM patients (n = 30), and normal polyclonal IgA and IgG from healthy controls (HCs) (n = 16). Using EThcD-sceHCD-MS/MS, the N-glycosylation dynamics of serum M-proteins in MM were determined. Compared with polyclonal IgA1 from HCs, monoc…

c-FOS Confers Stem Cell-like Features to Multiple Myeloma Cells in a Bone Marrow Microenvironment.

Multiple myeloma (MM) is the second most common hematologic malignancy and has a poor prognosis. Although the outcomes of MM have markedly improved with the approval of novel agents, the high incidence of relapse means that MM remains incurable. The bone marrow microenvironment (BMME) contributes to drug resistance and minimal residual disease (MRD), which is a major source of relapse in patients with MM. However, the underlying molecular mechanisms are not fully understood. We have previously shown that the upregulation of the AP-1 transcription factor c-FOS confers lenalidomide resistance by…

Real-World Outcomes of Sequential BCMA-directed therapies in Relapsed Refractory Multiple Myeloma After Belantamab Exposure.

BACKGROUND: While B-cell maturation antigen (BCMA) directed therapies are increasingly utilized for multiple myeloma, outcomes with sequential treatments with BCMA-directed therapies remain an area of active investigation. METHODS: In this multicenter retrospective analysis, we evaluated the real-world outcomes of patients treated with BCMA-directed therapies including CAR T and bispecific antibody (BsAb) following progression on the antibody-drug conjugate belantamab mafodotin. A total of 23 patients (14 CAR T, 9 BsAb) were included in the analysis. RESULTS: The median patient age was 68 (r…

The Two Sides of Bispecific Antibodies in Multiple Myeloma: Where Trial Promise Meets Real-World Practice.

The real-world effectiveness of the bispecific antibody teclistamab seems to be lower than the efficacy observed in pivotal registration trials. Understanding the drivers of this effectiveness-efficacy gap is essential for guiding the rational selection of patients most likely to benefit, optimizing bispecific antibody therapy in high-risk populations and ultimately advancing more personalized treatment strategies while supporting sustainable models of care. See related article by Razzo et al., p. 561.

Reduced ALDH1A1 expression in multiple myeloma cells increases resistance to daratumumab via downregulation of retinoic acid.

Multiple myeloma (MM) remains challenging in relapsed/refractory cases due to resistance to therapies like the proteosome inhibitors or anti-CD38 antibody daratumumab (Dara). This study investigates the dual role of ALDH1A1, an aldehyde dehydrogenase implicated in drug resistance, especially in modulating daratumumab efficacy. Clinical samples from newly diagnosed multiple myeloma (NDMM) patients and in vitro studies demonstrated that ALDH1A1 expression increases consistently with the development of drug resistance to proteasome inhibitor-based chemotherapy. However, paradoxically, daratumumab…

Bone marrow breakout lesions act as key sites for tumor-immune cell diversification in multiple myeloma.

The bone marrow microenvironment plays a crucial role in the development of multiple myeloma. As the disease progresses, malignant myeloma cells can evolve to survive outside the bone marrow. However, the processes underlying bone marrow independence and their consequences for immune control remain poorly understood. Here, we conducted single-cell and spatial multiomics analyses of bone marrow-confined intramedullary disease and paired breakout lesions that disrupt the cortical bone. These analyses revealed a distinct cellular microenvironment and architectural features of breakout lesions, ch…

Lactylation-related multigene signature in multiple myeloma: integrated prognostic stratification, immune landscape profiling, and therapeutic guidance.

Multiple myeloma (MM) is an incurable hematologic malignancy with high heterogeneity and poor prognosis. Lactylation, a novel post-translational modification, drives tumor progression and immune dysregulation, yet its prognostic value in MM remains uncharacterized. To explore the prognostic value of lactylation-related genes in multiple myeloma, our study aims to construct and validate a lactylation-related multigene signature, which can provide integrated prognostic stratification, immune landscape profiling, and therapeutic guidance for MM patients. This study integrated 1,417 MM patients (8…

Harnessing Targeted Photodynamic Therapy to Synergistically Activate T Cell and NK Cell Responses in Multiple Myeloma.

Multiple myeloma (MM) remains an incurable malignancy, with immune suppression in the bone marrow microenvironment playing a critical role in disease progression and relapse. Restoring both adaptive and innate immunity represents a promising therapeutic strategy. In this study, a novel photodynamic therapy (PDT) platform is developed that simultaneously activates both adaptive immunity through T cells and innate immunity through natural killer (NK) cells, thereby fostering a synergistic anti-tumor immune response in MM. A series of aggregation-induced emission luminogen (AIEgen)-based photosen…

Enhanced Detection of Multiple Myeloma Cells by Next-Generation Flow Cytometry Following Density Gradient Medium Separation.

INTRODUCTION: Following treatment, relapse of Multiple Myeloma (MM) occurs due to measurable residual disease (MRD). As therapeutic options expand, advances in response assessment become more critical, necessitating more sensitive MRD detection methods. METHOD: This study aimed to improve the efficiency and sensitivity of a flow cytometry assay for MM MRD detection in blood and bone marrow. To achieve this, three pre-enrichment methods were compared using 32 samples from patients with active MM and 122 samples from MM patients in remission. The methods compared were the Euroflow recommended e…

Bispecific BAFF-R/BCMA CAR T cells control growth of heterogeneous plasma cells in multiple myeloma.

Multiple myeloma treatment has experienced tremendous advances through chimeric antigen receptor (CAR) therapies directed to the B cell maturation antigen (BCMA), but remissions are usually transient. To mitigate the risk of BCMA immune escape, we aimed for a simultaneous targeting of BCMA together with the B cell-activating factor receptor (BAFF-R). Single-cell RNA sequencing discovered increased BAFF-R gene (TNFRSF13C) expression in relapsed and refractory multiple myeloma cases, and it emerged as prognostic marker for long-term complete responses. BAFF-R was expressed in plasma cells at ear…

Immune MRD Status Informs Tumor MRD Outcome Prognostication in Patients with Multiple Myeloma on Lenalidomide Maintenance.

PURPOSE: Lenalidomide (Len) maintenance is the most frequently utilized approach for newly diagnosed patients with multiple myeloma following induction therapy with/without consolidative high-dose melphalan and autologous stem cell transplantation. Baseline and longitudinal measurable residual disease (MRD) negative status is a well-established positive predictive sign in Len maintenance patients. However, the clinical utility of serial MRD assessments remains uncertain, as there is no consensus on the clinical management of MRD resurgence (MRDres) or stable remissions in patients positive for…

Integrated clinical and single-cell profiling of BCMA CAR-T therapy in relapsed/refractory multiple myeloma.

BACKGROUND: Despite therapeutic advances, multiple myeloma (MM) remains incurable, especially in relapsed/refractory (R/R) disease. B-cell maturation antigen (BCMA)-targeted CAR-T therapy, exemplified by FDA-approved agents like ide-cel and cilta-cel, offers promise, yet accessibility barriers necessitate local production. METHODS: This single-arm trial evaluated safety/efficacy of autologous BCMA CAR-T cells in six R/R MM patients. RESULTS: Cytokine release syndrome (CRS) occurred in 83% (grade 1), managed with tocilizumab without neurotoxicity. Toxicities were transient and resolved. Serum…

Patient preferences for triple-class-exposed relapsed or refractory multiple myeloma treatment: a discrete-choice study.

AimsTo quantify patient preferences for attributes of novel treatments for triple-class-exposed (TCE) relapsed and/or refractory multiple myeloma (RRMM).MethodsUsing a discrete-choice experiment, we elicited preferences for 7 attributes: objective response rate (ORR), overall survival (OS), all-grade cytokine release syndrome risk, all-grade immune effector cell-associated neurotoxicity syndrome risk, serious infection risk (grade 3+), treatment administration, and initial hospitalization requirements.ResultsOS was the most important attribute (conditional relative importance [CRI] 32.0% for a…

Evidence-based Korean guidelines for the clinical management of multiple myeloma: addressing 12 key clinical questions.

Multiple myeloma (MM), a hematological malignancy, is characterized by malignant plasma cell proliferation in the bone marrow. Recent treatment advances have significantly improved patient outcomes associated with MM. In this study, we aimed to develop comprehensive, evidence-based guidelines for the diagnosis, prognosis, and treatment of MM. We identified 12 key clinical questions essential for MM management, guiding the extensive literature review and meta-analysis of the study. Our guidelines provide evidence-based recommendations by integrating patient preferences with survey data. These r…

Boanmycin overcomes bortezomib resistance by inducing DNA damage and endoplasmic reticulum functional impairment in multiple myeloma.

BackgroundMultiple myeloma (MM) is a hematological malignancy characterized by uncontrolled proliferation of plasma cells and is currently incurable. Despite advancements in therapeutic strategies, resistance to proteasome inhibitors, particularly bortezomib (BTZ), poses a substantial challenge to disease management. This study aimed to explore the efficacy of boanmycin, a novel antitumor antibiotic, in overcoming resistance to BTZ in MM.MethodsBTZ-resistant cells were generated over a period of at least 6 months by gradually increasing the concentration of BTZ. The viability of MM cell lines …

Улучшение выживаемости в миеломе после предварительного обнаружения состояния прекурсоров: общенациональное исследование реального мира.

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… MGUS monoclonal gammopathy of undetermined significance, SMM smoldering multiple myeloma, MM symptomatic multiple myeloma, OS overall survival, HR Hazard ratio, CI Confidence interval. After IPTW adjustment for demographics, comorbidities, and treatment patterns (Fig. … Smoldering multiple myeloma current treatment algorithms. Blood Cancer J. 2022;12:129. 4. Dispenzieri A, Stewart AK, Chanan-Khan A, Rajkumar SV, Kyle RA, Fonseca R, et al. Smoldering multiple myeloma requiring treatment: time for a new definition?. Blood. 2013;122:4172–81. 5. …

Тандем автологическая трансплантация стволовых клеток у нескольких пациентов миэломы с минимальными остаточными заболеваниями: взрывное исследование.

Объективная аутологическая трансплантация стволовых клеток (tASCT) является жизнеспособным вариантом для пациентов с множественным миэломой (MM) повышенного риска. Минимальная остаточная болезнь (МСД), являющаяся суррогатным показателем бремени заболеваний в режиме реального времени, служит ценной мерой реагирования на эти заболевания. В ходе этого исследования была проведена оценка воздействия TAST на динамику MRD у пациентов MM.MetodsWe анализ данных из многоцентрового реестра 28 пациентов, прошедших ТАШТ в качестве прифронтового лечения в период с января 2019 и октябрь 2024. Критерии предос

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PurposeTandem autologous stem cell transplantation (tASCT) is a viable option for high-risk multiple myeloma (MM) patients. Minimal residual disease (MRD), a real-time surrogate marker of disease burden, serves as a valuable measure of treatment response. This study evaluated the impact of tASCT on MRD dynamics in MM patients.MethodsWe analyzed data from a m…

From Toxicity to Immunity: Evaluating CAR‐T and Conventional Therapies in Multiple Myeloma Through QALY Outcomes

Background: Over the past century, numerous pharmacological regimens have been developed for multiple myeloma (MM), yet relapse remains inevitable. Although these regimens prolong overall survival (OS), repetitive treatment cycles and cumulative toxicity progressively impair quality of life (QoL). This study aimed to compare conventional stepwise therapies with CAR-T cell therapy in terms of QoL, toxicity, cost, and ethical value. Methods: Kaplan-Meier survival curves were analyzed to estimate overall (OS) and progression-free survival (PFS). Based on these durations, treatment costs were calc…

Интенсивность бриджирования связана с плохим гематопоиетическим восстановлением после терапии BCMA CAR-T для нескольких миелом.

Abstractchimeric антиген-рецептор (CAR) T-клеток (CAR-T) представляет собой значительный прогресс в лечении повторной/охлажденной множественной миеломы (RRMM). Однако продолжительный период времени от лейкофереза до фактического вливания CAR-T часто требует проведения цеховой терапии. Из-за ограниченных знаний о воздействии стыковки на клинические курсы и результаты после КАР-Т выбор вариантов лечения сопряжен с трудностями. В этом многоцентральном международном исследовании мы изучили влияние переходной терапии на гематопоиетическое восстановление 158 :: пациенты с RRMM лечатся антигенной тер…

Putative multiple myeloma susceptibility genes identified by exome sequencing of 347 familial and early-onset cases.

Multiple myeloma (MM) is the second most common blood malignancy, with several lines of evidence supporting an inherited genetic component. Here, we sequenced 177 affected individuals from 128 families, and 170 early-onset MM cases diagnosed before 55 years of age. Samples were identified and collected through nationwide efforts in France, Sweden, and Greece. We focused on rare germline protein truncating and likely deleterious missense variants in genes harboring variants in at least two families showing variant-disease segregation, and in additional index (≥2) and/or early-onset (≥2) cases. …