Multiple myeloma (MM) is characterized by the clonal expansion and metastatic spread of malignant plasma cells to multiple sites in the bone marrow (BM). Recently, we implicated the sialyltransferase ...ST3Gal-6, an enzyme critical to the generation of E-selectin ligands, in MM BM homing and resistance to therapy. Since E-selectin is constitutively expressed in the BM microvasculature, we wished to establish the contribution of E-selectin ligands to MM biology. We report that functional E-selectin ligands are restricted to a minor subpopulation of MM cell lines which, upon expansion, demonstrate specific and robust interaction with recombinant E-selectin in vitro. Moreover, an increase in the mRNA levels of genes involved in the generation of E-selectin ligands was associated with inferior progression-free survival in the CoMMpass study. In vivo, E-selectin ligand-enriched cells induced a more aggressive disease and were completely insensitive to Bortezomib. Importantly, this resistance could be reverted by co-administration of GMI-1271, a specific glycomimetic antagonist of E-selectin. Finally, we report that E-selectin ligand-bearing cells are present in primary MM samples from BM and peripheral blood with a higher proportion seen in relapsed patients. This study provides a rationale for targeting E-selectin receptor/ligand interactions to overcome MM metastasis and chemoresistance.
The phase 1b 16-BCNI-001/CTRIAL-IE 16-02 CyBorD-DARA trial investigated the combination of Daratumumab with cyclophosphamide, bortezomib and dexamethasone in patients with newly diagnosed multiple ...myeloma (NDMM), followed by autologous stem cell transplantation and Daratumumab maintenance. CR/sCR rates were 50% after transplant and 62.5% at end of treatment. The overall percentage of patients achieving complete response or better was 77.8%. Progression-free survival rate at end of maintenance was 81.3% and estimated 2-year overall survival was 88.9%. 37.5% of patients demonstrated sustained MRD negativity to a level of 10−5 from transplant to analysis at EOT. In this phase 1b study, we have shown CyBorD-DARA to be an effective and well-tolerated immunomodulatory agent-free regiment in transplant-eligible NDMM.
The phase 1b 16-BCNI-001/CTRIAL-IE 16-02 CyBorD-DARA trial investigated the combination of Daratumumab with cyclophosphamide, bortezomib and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM), followed by autologous stem cell transplantation and Daratumumab maintenance. CR/sCR rates were 50% after transplant and 62.5% at end of treatment. Progression-free survival rate at end of maintenance was 81.3% and estimated 2-year overall survival was 88.9%. 37.5% of patients demonstrated sustained MRD negativity to a level of 10−5.
Daratumumab (DARA) has shown impressive activity in combination with other agents for the treatment of multiple myeloma (MM). We conducted a phase 1b study to assess the safety and preliminary ...efficacy, as well as potential mechanisms of action, of DARA (16 mg/kg) in combination with a weekly schedule of subcutaneous bortezomib (1.3-1.5 mg/m2), cyclophosphamide (150-300 mg/m2), and dexamethasone (40 mg) (CyBorD DARA) as initial induction before autologous stem cell transplantation (ASCT). Eligible patients were ≤70 years of age with untreated MM requiring treatment and who lacked significant comorbidities. A total of 18 patients were enrolled. Their median age was 56 years (range, 32-66 years), and all patients had Eastern Cooperative Oncology Group performance status ≤1. The International Staging System stages were I, II, and III in 78%, 17%, and 6% of patients, respectively; 28% of patients had high-risk genetic features. There was no dose-limiting toxicity, and the incidence of grade 3 or 4 infection or neutropenia was <10%. On an intention-to-treat basis, 94% achieved ≥very good partial response with ≥complete response in 44% of patients. Among 14 of 15 patients who underwent ASCT and were evaluable for response, all 14 achieved at least very good partial response, with 8 (57%) of 14 achieving complete response. After ASCT, 10 (83%) of 12 patients in whom minimal residual disease analysis was possible were negative at a sensitivity of 10−5 (56% on intention-to-treat/whole study population) according to next-generation sequencing. Flow cytometry analysis of patient samples indicated CyBorD DARA induced activation of macrophage-mediated antibody-dependent cellular phagocytosis. This trial was registered at www.clinicaltrials.gov as #NCT02955810.
•CyBorD DARA as induction is well tolerated and induces deep responses when used in conjunction with ASCT for MM.•Mechanism of action studies indicate that CyBorD DARA enhances macrophage activation, which may play a role in its clinical efficacy.
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Discusses the mechanism of action, pharmacology and pharmacokinetics of daratumumab, a first in-class human IgG1 monoclonal antibody that targets CD38 - a 46 kDa type II transmembrane glycoprotein ...that is highly expressed on myeloma cells - and has antimyeloma effects through several mechanisms. Reviews the available clinical data in detail. Examines how daratumumab interferes with transfusion testing due to the expression of CD38 on the red blood cells, leading to potential difficulties releasing blood products. Considers the potential of daratumumab for increased minimal residual disease negativity and improved progression-free survival of multiple myeloma, even in high-risk groups. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.
Diverse emergent correlated electron phenomena have been observed in twisted graphene layers due to electronic interactions with the moiré superlattice potential. Many electronic structure ...predictions have been reported exploring this new field, but with few momentum-resolved electronic structure measurements to test them. Here we use angle-resolved photoemission spectroscopy (ARPES) to study the twist-dependent (\(1^\circ < \theta < 8^\circ\)) electronic band structure of few-layer graphenes, including twisted bilayer, monolayer-on-bilayer, and double-bilayer graphene (tDBG). Direct comparison is made between experiment and theory, using a hybrid \(\textbf{k}\cdot\textbf{p}\) model for interlayer coupling and implementing photon-energy-dependent phase shifts for photo-electrons from consecutive layers to simulate ARPES spectra. Quantitative agreement between experiment and theory is found across twist angles, stacking geometries, and back-gate voltages, validating the models and revealing displacement field induced gap openings in twisted graphenes. However, for tDBG at \(\theta=1.5\pm0.2^\circ\), close to the predicted magic-angle of \(\theta=1.3^\circ\), a flat band is found near the Fermi-level with measured bandwidth of \(E_w = 31\pm5\) meV. Analysis of the gap between the flat band and the next valence band shows significant deviations between experiment (\(\Delta_h=46\pm5\)meV) and the theoretical model (\(\Delta_h=5\)meV), indicative of the importance of lattice relaxation in this regime.
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