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.

Pre-Clinical Assessment of SAR442257, a CD38/CD3xCD28 Trispecific T Cell Engager in Treatment of Relapsed/Refractory Multiple Myeloma.

Current treatment strategies for multiple myeloma (MM) are highly effective, but most patients develop relapsed/refractory disease (RRMM). The anti-CD38/CD3xCD28 trispecific antibody SAR442257 targets CD38 and CD28 on MM cells and co-stimulates CD3 and CD28 on T cells (TCs). We evaluated different key aspects such as MM cells and T cells avidity interaction, tumor killing, and biomarkers for drug potency in three distinct cohorts of RRMM patients.

The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma.

Acquisition of a hyperdiploid (HY) karyotype or immunoglobulin heavy chain (IgH) translocations are considered key initiating events in multiple myeloma (MM). To explore if other genomic events can precede these events, we analyzed whole-genome sequencing data from 1173 MM samples. By integrating molecular time and structural variants within early chromosomal duplications, we indeed identified pregain deletions in 9.

Daratumumab and antineoplastic therapy versus antineoplastic therapy only for adults with newly diagnosed multiple myeloma ineligible for transplant.

Background: Multiple myeloma (MM) is a haematological malignancy that is characterised by proliferation of malignant plasma cells in the bone marrow. For adults ineligible to receive high-dose chemotherapy and autologous stem cell transplant, the recommended treatment combinations in first-line therapy generally consist of combinations of alkylating agents, immunomodulatory drugs, and proteasome inhibitors. Daratumumab is a CD38-targeting, human IgG1k monoclonal antibody recently developed and approved for the treatment of people diagnosed with MM.

Clinical and serological characterization of acute pleuropericarditis suggests an autoinflammatory pathogenesis and highlights risk factors for recurrent attacks.

Purpose: We describe the manifestations and course of patients with pleuropericarditis (PP). Serum parameters were analyzed to evaluate the contribution of autoimmune and autoinflammatory mechanisms to PP pathogenesis. Finally, we outline risk factors for recurrent PP attacks.

High-throughput electron tomography identifies centriole over-elongation as an early event in plasma cell disorders.

Plasma cell disorders are clonal outgrowths of pre-malignant or malignant plasma cells, characterized by extensive chromosomal aberrations. Centrosome abnormalities are a major driver of chromosomal instability in cancer but their origin, incidence, and composition in primary tumor cells is poorly understood. Using cutting-edge, semi-automated high-throughput electron tomography, we characterized at nanoscale 1386 centrioles in CD138 plasma cells from eight healthy donors and 21 patients with plasma cell disorders, and 722 centrioles from different control populations.

Application of an artificial intelligence-based tool in [F]FDG PET/CT for the assessment of bone marrow involvement in multiple myeloma.

Purpose: [F]FDG PET/CT is an imaging modality of high performance in multiple myeloma (MM). Nevertheless, the inter-observer reproducibility in PET/CT scan interpretation may be hampered by the different patterns of bone marrow (BM) infiltration in the disease. Although many approaches have been recently developed to address the issue of standardization, none can yet be considered a standard method in the interpretation of PET/CT.

Resolving therapy resistance mechanisms in multiple myeloma by multiomics subclone analysis.

Intratumor heterogeneity as a clinical challenge becomes most evident after several treatment lines, when multidrug-resistant subclones accumulate. To address this challenge, the characterization of resistance mechanisms at the subclonal level is key to identify common vulnerabilities. In this study, we integrate whole-genome sequencing, single-cell (sc) transcriptomics (scRNA sequencing), and chromatin accessibility (scATAC sequencing) together with mitochondrial DNA mutations to define subclonal architecture and evolution for longitudinal samples from 15 patients with relapsed or refractory multiple myeloma.

Idecabtagene Vicleucel Is Well Tolerated and Effective in Relapsed/Refractory Myeloma Patients with Prior Allogeneic Stem Cell Transplantation.

BCMA-specific chimeric-antigen receptor (CAR-) T cell therapy has led to high response rates and durable remissions in patients with relapsed refractory multiple myeloma. However, little data are available for patients after prior allogeneic stem cell transplantation (allo-SCT) in whom T cells are chimeric. In this study, we aimed to assess the safety and efficacy of patient-derived donor CAR-T therapy in myeloma patients with prior allo-SCT, particularly with regard to graft-versus-host disease (GVHD).

Non-Adherence in Adult Male Patients with Community-Acquired Pneumonia: Relative Forgiveness of Amoxicillin versus Respiratory Fluoroquinolones.

The consequences of non-adherence to treatment (NAT) on antimicrobial efficacy may depend on drug forgiveness-a property that should account for pharmacokinetics (PK) and pharmacodynamics (PD) as well as interindividual variability. In this simulation study, relative forgiveness (RF) in NAT, defined as the probability of a successful PK/PD target (PTA) attained under perfect adherence compared to imperfect adherence, was evaluated for amoxicillin (AMOX) (oral 1000 mg/8 h) and two respiratory fluoroquinolones-levofloxacin (LFX) (oral 750 mg/24 h) and moxifloxacin (MOX) (oral 400 mg/24 h)-in virtual outpatients with community-acquired pneumonia for . Several NAT scenarios (delay in dose intake and a missed dose) were considered.

Impact of novel agent therapies on immune cell subsets and infectious complications in patients with relapsed/refractory multiple myeloma.

Introduction: Infections are a leading cause of morbidity and mortality in patients with multiple myeloma (MM).

Methods: To examine the effects of modern second-generation novel agent therapy on immune cell subsets, in particular CD4+-T-cells, and infectious complications in patients with relapsed/refractory MM (RRMM), we conducted a prospective cohort study in 112 RRMM patients.

Results: Substantially decreased CD4+-T-cells <200/µl before initiation of relapse therapy were detected in 27.

Characterizing the role of the immune microenvironment in multiple myeloma progression at a single-cell level.

Early alterations within the bone marrow microenvironment that contribute to the progression of multiple myeloma (MM) from its precursor stages could be the key to identifying novel therapeutic approaches. However, the intrinsic variability in cellular populations between patients and the differences in sample processing and analysis methods have made it difficult to identify consistent changes between data sets. Here, we used single-cell RNA sequencing of bone marrow cells from precursor stages, monoclonal gammopathy of unknown significance, smoldering MM, and newly diagnosed MM and analyzed our data in combination with a previously published data set that used a similar patient population and sample processing.

Proceedings from the Blood and Marrow Transplant Clinical Trials Network Myeloma Intergroup Workshop on Immune and Cellular Therapy in Multiple Myeloma.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Myeloma Intergroup conducted a workshop on Immune and Cellular Therapy in Multiple Myeloma on January 7, 2022. This workshop included presentations by basic, translational, and clinical researchers with expertise in plasma cell dyscrasias. Four main topics were discussed: platforms for myeloma disease evaluation, insights into pathophysiology, therapeutic target and resistance mechanisms, and cellular therapy for multiple myeloma.

Midkine Promotes Metastasis and Therapeutic Resistance via mTOR/RPS6 in Uveal Melanoma.

Unlabelled: Uveal melanoma is a rare form of melanoma that originates in the eye, exerts widespread therapeutic resistance, and displays an inherent propensity for hepatic metastases. Because metastatic disease is characterized by poor survival, there is an unmet clinical need to identify new therapeutic targets in uveal melanoma. Here, we show that the pleiotropic cytokine midkine is expressed in uveal melanoma.

Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single-cell transcriptomics.

Virtually all patients with multiple myeloma become unresponsive to treatment over time. Relapsed/refractory multiple myeloma (RRMM) is accompanied by the clonal evolution of myeloma cells with heterogeneous genomic aberrations and profound changes of the bone marrow microenvironment (BME). However, the molecular mechanisms that drive drug resistance remain elusive.

Application of a dual mechanistic approach to support bilastine dose selection for older adults.

The objective of this study was to evaluate bilastine dosing recommendations in older adults and overcome the limitation of insufficient data from phase I studies in this underrepresented population. This was achieved by integrating bilastine physicochemical, in vitro and in vivo data in young adults and the effect of aging in the pharmacology by means of two alternative approaches: a physiologically-based pharmacokinetic (PBPK) model and a semi-mechanistic population pharmacokinetic (Senescence) model. Intestinal apical efflux and basolateral influx transporters were needed in the PBPK model to capture the observations from young adults after single i.

Pathway-Directed Therapy in Multiple Myeloma.

Multiple Myeloma (MM) is a malignant plasma cell disorder with an unmet medical need, in particular for relapsed and refractory patients. Molecules within deregulated signaling pathways, including the RAS/RAF/MEK/ERK, but also the PI3K/AKT-pathway belong to the most promising evolving therapeutic targets. Rationally derived compounds hold great therapeutic promise to target tumor-specific abnormalities rather than general MM-associated vulnerabilities.

[Current Recommendations for the First-Line Therapy of Symptomatic Multiple Myeloma].

Due to the introduction of novel therapeutic agents, the prognosis of Multiple Myeloma has greatly improved over the last decades. The current standard for fit patients is a bortezomib-based induction therapy, followed by high-dose chemotherapy and autologous stem cell transplantation and lenalidomide-based maintenance therapy. For older, non-transplant-eligible patients, daratumumab in combination with bortezomib or lenalidomide offers a well-tolerated, effective treatment option.

Evaluation of Pd→B Interactions in Diphosphinoborane Complexes and Impact on Inner-Sphere Reductive Elimination.

The dative Pd→B interaction in a series of DPB Pd and Pd complexes ( DPB =(o-PR C H ) BR', diphosphinoborane) was analyzed using XRD, B NMR spectroscopy and NBO/NLMO calculations. The borane acceptor discriminates between the oxidation state Pd and Pd , stabilizing the latter. Reaction of lithium amides with [( DPB )Pd (4-NO C H )I] chemoselectively yields the C-N coupling product.

Synthesis and structures of gallaarsenes LGaAsGa(X)L featuring a Ga-As double bond.

Three equivalents of LGa {L = HC[C(Me)N(2,6-i-PrCH)]} react with AsX (X = Cl, Br) by insertion into two As-X bonds, followed by the elimination of LGaX and formation of LGaAsGa(Cl)L (1) and LGaAsGa(Br)L (2). According to single crystal X-ray analysis, 1 and 2 each exhibit one Ga-As single bond and one Ga-As double bond. The π-bonding contribution (9.

Model-informed pediatric development applied to bilastine: Analysis of the clinical PK data and confirmation of the dose selected for the target population.

Bilastine is a non-sedating second-generation H antihistamine approved for treatment of allergic rhinoconjunctivitis (AR) and urticaria (U) in adults at the oral (p.o.) dose of 20 mg once daily (OD).