Publications by authors named "Gareth J Morgan"

380 Publications

Copy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma.

Nat Commun 2021 08 27;12(1):5172. Epub 2021 Aug 27.

Myeloma Service, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.

Chromothripsis is detectable in 20-30% of newly diagnosed multiple myeloma (NDMM) patients and is emerging as a new independent adverse prognostic factor. In this study we interrogate 752 NDMM patients using whole genome sequencing (WGS) to investigate the relationship of copy number (CN) signatures to chromothripsis and show they are highly associated. CN signatures are highly predictive of the presence of chromothripsis (AUC = 0.90) and can be used identify its adverse prognostic impact. The ability of CN signatures to predict the presence of chromothripsis is confirmed in a validation series of WGS comprised of 235 hematological cancers (AUC = 0.97) and an independent series of 34 NDMM (AUC = 0.87). We show that CN signatures can also be derived from whole exome data (WES) and using 677 cases from the same series of NDMM, we are able to predict both the presence of chromothripsis (AUC = 0.82) and its adverse prognostic impact. CN signatures constitute a flexible tool to identify the presence of chromothripsis and is applicable to WES and WGS data.
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http://dx.doi.org/10.1038/s41467-021-25469-8DOI Listing
August 2021

Plasma cells expression from smouldering myeloma to myeloma reveals the importance of the PRC2 complex, cell cycle progression, and the divergent evolutionary pathways within the different molecular subgroups.

Leukemia 2021 Aug 7. Epub 2021 Aug 7.

Melvin and Bren Simon Comprehensive Cancer Center, Division of Hematology Oncology, Indiana University, Indianapolis, IN, USA.

Sequencing studies have shed some light on the pathogenesis of progression from smouldering multiple myeloma (SMM) and symptomatic multiple myeloma (MM). Given the scarcity of smouldering samples, little data are available to determine which translational programmes are dysregulated and whether the mechanisms of progression are uniform across the main molecular subgroups. In this work, we investigated 223 SMM and 1348 MM samples from the University of Arkansas for Medical Sciences (UAMS) for which we had gene expression profiling (GEP). Patients were analysed by TC-7 subgroup for gene expression changes between SMM and MM. Among the commonly dysregulated genes in each subgroup, PHF19 and EZH2 highlight the importance of the PRC2.1 complex. We show that subgroup specific differences exist even at the SMM stage of disease with different biological features driving progression within each TC molecular subgroup. These data suggest that MMSET SMM has already transformed, but that the other precursor diseases are distinct clinical entities from their symptomatic counterpart.
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http://dx.doi.org/10.1038/s41375-021-01379-yDOI Listing
August 2021

The Unusual Journey of a Pericardial Drainage Catheter in Pentalogy of Cantrell.

Case Rep Pediatr 2021 8;2021:2109934. Epub 2021 Jul 8.

Department of Pediatric Cardiology, Children's Hospital Colorado, Aurora, CO, USA.

A 4-month-old male infant diagnosed with Pentalogy of Cantrell presented to the cardiac catheterization laboratory with a large pericardial effusion. During an urgent pericardial drain placement, the patient, whose prior hemodynamics and clinical findings had suggested a noncritical cardiac lesion, had a profound desaturation, with echocardiography suggesting minimal or no flow across the right ventricular outflow tract (RVOT). The position of the drainage catheter on fluoroscopy and echocardiography suggested that the spell was being caused by obstruction of the main pulmonary artery (MPA) by the pericardial drain. After partially withdrawing the drain to reposition it, there was immediate resolution of the hypoxemia, and echocardiography once again showed adequate flow across the outflow tract.
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http://dx.doi.org/10.1155/2021/2109934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282392PMC
July 2021

Implementation of virtual reality for patient distraction during diagnostic cardiac catheterisation.

Cardiol Young 2021 Jul 26:1-5. Epub 2021 Jul 26.

The Heart Institute, Children's Hospital Colorado, Aurora, CO, USA.

Until now, the application of virtual reality as a distraction model has been widely described in the medical field, showing different benefits offered on patient's perception, particularly related to pain and anxiety. Previous clinical experience of virtual reality applications on surgical intervention has shown how during procedures with local anaesthesia, this modality improves patients' experience without changing times, costs, and clinical outcomes. Herein, we report our experience with three patients during diagnostic cardiac catheterisation, showing the effect of this technology on patients' perception and metrics during the procedure.
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http://dx.doi.org/10.1017/S1047951121002845DOI Listing
July 2021

Barriers to Small Molecule Drug Discovery for Systemic Amyloidosis.

Authors:
Gareth J Morgan

Molecules 2021 Jun 11;26(12). Epub 2021 Jun 11.

Section of Hematology and Medical Oncology, Amyloidosis Center, Department of Medicine, School of Medicine, Boston University, Boston, MA 02118, USA.

Inhibition of amyloid fibril formation could benefit patients with systemic amyloidosis. In this group of diseases, deposition of amyloid fibrils derived from normally soluble proteins leads to progressive tissue damage and organ failure. Amyloid formation is a complex process, where several individual steps could be targeted. Several small molecules have been proposed as inhibitors of amyloid formation. However, the exact mechanism of action for a molecule is often not known, which impedes medicinal chemistry efforts to develop more potent molecules. Furthermore, commonly used assays are prone to artifacts that must be controlled for. Here, potential mechanisms by which small molecules could inhibit aggregation of immunoglobulin light-chain dimers, the precursor proteins for amyloid light-chain (AL) amyloidosis, are studied in assays that recapitulate different aspects of amyloidogenesis in vitro. One molecule reduced unfolding-coupled proteolysis of light chains, but no molecules inhibited aggregation of light chains or disrupted pre-formed amyloid fibrils. This work demonstrates the challenges associated with drug development for amyloidosis, but also highlights the potential to combine therapies that target different aspects of amyloidosis.
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http://dx.doi.org/10.3390/molecules26123571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230685PMC
June 2021

Baseline intracardiac echocardiography predicts haemodynamic changes and Doppler velocity patterns during follow-up after percutaneous pulmonary valve implantation.

Cardiol Young 2021 Jun 18:1-7. Epub 2021 Jun 18.

The Heart Institute, Children's Hospital Colorado, Aurora, Colorado, USA.

Background: Intracardiac echocardiography Doppler-derived gradients have previously been shown to correlate with post-procedure echocardiographic evaluations when compared with invasive gradients measured during percutaneous pulmonary valve implantation, suggesting that intracardiac echocardiography could offer an accurate and predictable starting point to estimate valve function after percutaneous pulmonary valve implantation.

Methods: We performed a retrospective chart review of 51 patients who underwent percutaneous pulmonary valve implantation between September 2018 and December 2019 in whom intracardiac echocardiography was performed immediately after valve implantation. We evaluated the correlation between intracardiac echocardiography gradients and post-procedural Doppler-derived gradients. Among the parameters assessed, those which demonstrated the strongest correlation were used to create a predictive model of expected echo-derived gradients after percutaneous pulmonary valve implantation. The equation was validated on the same sample data along with a subsequent cohort of 25 consecutive patients collected between January 2020 and July 2020.

Results: All the assessed correlation models between intracardiac echocardiography evaluation and post-procedure transthoracic echocardiographic assessments were statistically significant, presenting moderate to strong correlations. The strongest relationship was found between intracardiac echocardiography mean gradients and post-procedural transthoracic echocardiographic mean gradients. Therefore, an equation was created based on the intracardiac echocardiography-derived mean gradient, to allow prediction of the post-procedural and follow-up transthoracic echocardiographic-derived mean gradients within a range of ±5 mmHg from the observed value in more than 80% of cases.

Conclusions: There is a strong correlation between intracardiac echocardiography and post-procedure transthoracic echocardiographic. This allowed us to derive a predictive equation that defines the expected transthoracic echocardiographic Doppler-derived gradient following the procedure and at out-patient follow-up after percutaneous pulmonary valve implantation.
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http://dx.doi.org/10.1017/S1047951121002365DOI Listing
June 2021

Metalloproteinases and their inhibitors are associated with pulmonary arterial stiffness and ventricular function in pediatric pulmonary hypertension.

Am J Physiol Heart Circ Physiol 2021 07 4;321(1):H242-H252. Epub 2021 Jun 4.

Linda Crnic Institute for Down Syndrome, University of Colorado Denver, Aurora, Colorado.

Disturbed balance between matrix metalloproteinases (MMPs) and their respective tissue inhibitors (TIMPs) is a well-recognized pathophysiological component of pulmonary arterial hypertension (PAH). Both classes of proteinases have been associated with clinical outcomes as well as with specific pathological features of ventricular dysfunction and pulmonary arterial remodeling. The purpose of this study was to evaluate the circulating levels of MMPs and TIMPs in children with PAH undergoing the same-day cardiac magnetic resonance imaging (MRI) and right heart catheterization. Children with PAH ( = 21) underwent a same-day catheterization, comprehensive cardiac MRI evaluation, and blood sample collection for proteomic analysis. Correlative analysis was performed between protein levels and ) standard PAH indices from catheterization, ) cardiac MRI hemodynamics, and ) pulmonary arterial stiffness. MMP-8 was significantly associated with the right ventricular end-diastolic volume ( = 0.45, = 0.04). MMP-9 levels were significantly associated with stroke volume ( = -0.49, = 0.03) and pulmonary vascular resistance ( = 0.49, = 0.03). MMP-9 was further associated with main pulmonary arterial stiffness evaluated by relative area change ( = -0.79, < 0.01).TIMP-2 and TIMP-4 levels were further associated with the right pulmonary artery pulse wave velocity ( = 0.51, = 0.03) and backward compression wave ( = 0.52, = 0.02), respectively. MMPs and TIMPs warrant further clinically prognostic evaluation in conjunction with the conventional cardiac MRI hemodynamic indices. Metalloproteinases have been associated with clinical outcomes in pulmonary hypertension and with specific pathological features of ventricular dysfunction and pulmonary arterial remodeling. In this study, we demonstrated that plasma circulating levels of metalloproteinases and their inhibitors are associated with standard cardiac MRI hemodynamic indices and with the markers of proximal pulmonary arterial stiffness. Particularly, MMP-9 and TIMP-2 were associated with several different markers of pulmonary arterial stiffness. These findings suggest the interplay between the extracellular matrix (ECM) remodeling and overall hemodynamic status in children with PAH might be assessed using the peripheral circulating MMP and TIMP levels.
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http://dx.doi.org/10.1152/ajpheart.00750.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424580PMC
July 2021

Chromothripsis as a pathogenic driver of multiple myeloma.

Semin Cell Dev Biol 2021 May 3. Epub 2021 May 3.

Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA. Electronic address:

Analysis of the genetic basis for multiple myeloma (MM) has informed many of our current concepts of the biology that underlies disease initiation and progression. Studying these events in further detail is predicted to deliver important insights into its pathogenesis, prognosis and treatment. Information from whole genome sequencing of structural variation is revealing the role of these events as drivers of MM. In particular, we discuss how the insights we have gained from studying chromothripsis suggest that it can be used to provide information on disease initiation and that, as a consequence, it can be used for the clinical classification of myeloma precursor diseases allowing for early intervention and prognostic determination. For newly diagnosed MM, the integration of information on the presence of chromothripsis has the potential to significantly enhance current risk prediction strategies and to better characterize patients with high-risk disease biology. In this article we summarize the genetic basis for MM and the role played by chromothripsis as a critical pathogenic factor active at early disease phases.
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http://dx.doi.org/10.1016/j.semcdb.2021.04.014DOI Listing
May 2021

Discovery of Potent Coumarin-Based Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains Using Structure-Based Design.

J Med Chem 2021 05 3;64(9):6273-6299. Epub 2021 May 3.

Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States.

In immunoglobulin light-chain (LC) amyloidosis, transient unfolding or unfolding and proteolysis enable aggregation of LC proteins, causing potentially fatal organ damage. A drug that kinetically stabilizes LCs could suppress aggregation; however, LC sequences are variable and have no natural ligands, hindering drug development efforts. We previously identified high-throughput screening hits that bind to a site at the interface between the two variable domains of the LC homodimer. We hypothesized that extending the stabilizers beyond this initially characterized binding site would improve affinity. Here, using protease sensitivity assays, we identified stabilizers that can be divided into four substructures. Some stabilizers exhibit nanomolar EC values, a 3000-fold enhancement over the screening hits. Crystal structures reveal a key π-π stacking interaction with a conserved tyrosine residue that was not utilized by the screening hits. These data provide a foundation for developing LC stabilizers with improved binding selectivity and enhanced physicochemical properties.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428256PMC
May 2021

Short-Term Effects of Inhaled Nitric Oxide on Right Ventricular Flow Hemodynamics by 4-Dimensional-Flow Magnetic Resonance Imaging in Children With Pulmonary Arterial Hypertension.

J Am Heart Assoc 2021 Apr 6;10(8):e020548. Epub 2021 Apr 6.

Division of Cardiology Heart Institute Children's Hospital ColoradoUniversity of Colorado DenverAnschutz Medical Campus Aurora CO USA.

Background Pulmonary arterial hypertension (PAH) manifests with progressive right ventricular (RV) dysfunction, which eventually impairs the left ventricular function. We hypothesized that 4-dimensional-flow magnetic resonance imaging can detect flow hemodynamic changes associated with efficient intracardiac flow during noninvasive inhaled nitric oxide (iNO) challenge in children with PAH. Methods and Results Children with PAH (n=10) underwent 2 same-day separate iNO challenge tests using: (1) 4-dimensional-flow magnetic resonance imaging and (2) standard catheterization hemodynamics. Intracardiac flow was evaluated using the particle tracking 4-flow component analysis technique evaluating the , , , and . Respective flow hemodynamic changes were compared with the corresponding catheterization iNO challenge results. The RV analysis revealed decreased direct flow in patients with PAH when compared with controls (<0.001) and increase in residual volume (<0.001). Similarly, the left ventricular analysis revealed decreased direct flow in patients with PAH when compared with controls (=0.004) and increased proportion of the residual volume (=0.014). There was an increase in the RV direct flow during iNO delivery (=0.009), with parallel decrease in the residual volume (=0.008). Conclusions Children with PAH have abnormal biventricular flow associated with impaired diastolic filling. The flow efficiency is significantly improved in the RV on iNO administration with no change in the left ventricle. The changes in the RV flow have occurred despite the minimal change in catheterization hemodynamics, suggesting that flow hemodynamic evaluation might provide more quantitative insights into vasoreactivity testing in PAH.
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http://dx.doi.org/10.1161/JAHA.120.020548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174179PMC
April 2021

A proof-of-concept study for the pathogenetic role of enhancer hypomethylation of MYBPHL in multiple myeloma.

Sci Rep 2021 Mar 26;11(1):7009. Epub 2021 Mar 26.

Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam Road, Pokfulam, Hong Kong.

Enhancer DNA methylation and expression of MYBPHL was studied in multiple myeloma (MM). By bisulfite genomic sequencing, among the three CpGs inside the MYBPHL enhancer, CpG1 was significantly hypomethylated in MM cell lines (6.7-50.0%) than normal plasma cells (37.5-75.0%) (P = 0.007), which was negatively correlated with qPCR-measured MYBPHL expression. In RPMI-8226 and WL-2 cells, bearing the highest CpG1 methylation, 5-azadC caused enhancer demethylation and expression of MYBPHL. In primary samples, higher CpG1 methylation was associated with lower MYBPHL expression. By luciferase assay, luciferase activity was enhanced by MYBPHL enhancer compared with empty vector control, but reduced by site-directed mutagenesis of each CpG. RNA-seq data of newly diagnosed MM patients showed that MYBPHL expression was associated with t(11;14). MOLP-8 cells carrying t(11;14) express the highest levels of MYBPHL, and its knockdown reduced cellular proliferation and increased cell death. Herein, as a proof-of-concept, our data demonstrated that the MYBPHL enhancer, particularly CpG1, was hypomethylated and associated with increased MYBPHL expression in MM, which was implicated in myelomagenesis.
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http://dx.doi.org/10.1038/s41598-021-86473-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997988PMC
March 2021

Novel Minimal Radiation Approach for Percutaneous Pulmonary Valve Implantation.

Pediatr Cardiol 2021 Apr 15;42(4):926-933. Epub 2021 Feb 15.

The Heart Institute, Children's Hospital Colorado, 13123 East 16th Avenue, Box 100, Aurora, CO, USA.

The aim of the study is to evaluate the impact of multimodality imaging technology during percutaneous pulmonary valve implantation (PPVI). Among percutaneous procedures, PPVI traditionally has one of the highest patient radiation exposures. Different protocol modifications have been implemented to address this problem (i.e., improvements in guidance systems, delivery systems, valve design, post-implantation evaluation). Although the effectiveness of individual modifications has been proven, the effect of an approach which combines these changes has not been reported. We performed a retrospective chart review of 76 patients who underwent PPVI between January 2018 and December 2019. Patients were classified in "Traditional protocol," using routine biplane angiography and/or 3D rotational angiography (3DRA); and "Multimodality protocol" that included the use of VesselNavigator for guidance, selective 3DRA for coronary evaluation, Long DrySeal Sheath for valve delivery, and Intracardiac Echocardiography for valve evaluation after implantation. Radiation metrics, procedural time, and clinical outcomes were compared between groups. When the traditional protocol group was compared with the multimodality protocol group, a significant reduction was described for total fluoroscopy time (31.6 min vs. 26.2 min), dose of contrast per kilogram (1.8 mL/Kg vs. 0.9 mL/Kg), DAP/kg (26.6 µGy·m/kg vs. 19.9 µGy·m/kg), and Air Kerma (194 mGy vs. 99.9 mGy). A reduction for procedure time was noted (140 min vs. 116.5 min), but this was not statistically significant. There was no difference in clinical outcomes or the presence of complications between groups. The combination of novel technology in PPVI caused a significant reduction in radiation metrics without increasing the complication rate in our population.
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http://dx.doi.org/10.1007/s00246-021-02564-7DOI Listing
April 2021

Coronary compression testing by balloon interrogation during pulmonary valve implantation: room for doubt?

Cardiol Young 2021 Feb 10:1-7. Epub 2021 Feb 10.

The Heart Institute, Children's Hospital Colorado, Aurora, CO, USA.

Objective: To evaluate the reliability of balloon coronary compression testing during percutaneous pulmonary valve implantation.

Background: Despite the widespread use of the 'balloon coronary test' as the preferable method to rule out the risk of coronary compression, this adverse event has been described after pulmonary valve implantation where coronary balloon test suggested no risk or low risk, calling into question the accuracy of the test.

Methods: We performed a retrospective chart review of 84 patients who underwent pulmonary valve implantation between January 2018 and December 2019 and selected 36 patients whose archived imaging was suitable to perform quantitative analysis of the 'balloon coronary test'. We focused on the spatial disparity between the right ventricular outflow tract position defined by the inflated testing balloon and the eventual implanted valve position, to classify the test as inaccurate or accurate.

Results: In total, 36.1% of cases were classified as having an inaccurate coronary balloon test. Among the baseline characteristics, right ventricular outflow tract substrate was identified as a significant predictor of test accuracy. Related to this characteristic, the type of testing balloon used and the size of the eventually implanted valve were found to be associated with test accuracy.

Conclusions: Based on our findings, balloon coronary testing is not an accurate method of predicting final valve position with respect to fixed structures in the thorax. This may translate to a high false positive rate for the likelihood of coronary compression in pulmonary valve implantation.
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http://dx.doi.org/10.1017/S1047951121000366DOI Listing
February 2021

Bortezomib, Vorinostat, and Dexamethasone Combination Therapy in Relapsed Myeloma: Results of the Phase 2 MUK four Trial.

Clin Lymphoma Myeloma Leuk 2021 03 3;21(3):154-161.e3. Epub 2020 Dec 3.

Department of Haematology, Southampton General Hospital, Southampton, UK. Electronic address:

Introduction: Outcomes continue to improve in relapsed myeloma as more effective treatment options emerge. We report a multicenter single-arm phase 2 trial evaluating toxicity and efficacy of the histone deacetylase (HDAC) inhibitor vorinostat in combination with bortezomib and dexamethasone.

Patients And Methods: Sixteen patients who had received a median of 1 prior treatment line received bortezomib subcutaneously 1.3 mg/m days 1, 4, 8, and 11; dexamethasone 20 mg orally days 1-2, 4-5, 8-9, and 11-12; vorinostat 400 mg orally days 1-4, 8-11, and 15-18 of a 21-day cycle. After receipt of a minimum of 3 cycles of therapy, participants received maintenance vorinostat (400 mg days 1-4 and 15-18 of a 28-day cycle).

Results: Overall response was 81.3%: complete response occurred in 4 of 16, very good partial response in 2 of 16, and partial response 7 of 16. Clinical benefit response rate was 100%; median progression-free survival was 11.9 months. A total of 75% patients experienced a dose reduction or stopped treatment as a result of intolerability.

Conclusion: Although toxicity and dose reductions were observed, this study demonstrates that the combination of vorinostat, bortezomib, and dexamethasone is effective in relapsed myeloma with good response rates, suggesting there is an ongoing rationale for further optimization of HDAC inhibitor-based combinations in the treatment of myeloma to improve tolerability and enhance efficacy.
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http://dx.doi.org/10.1016/j.clml.2020.11.019DOI Listing
March 2021

The molecular make up of smoldering myeloma highlights the evolutionary pathways leading to multiple myeloma.

Nat Commun 2021 01 12;12(1):293. Epub 2021 Jan 12.

Division of Hematology Oncology, Indiana University, Indianapolis, IN, USA.

Smoldering myeloma (SMM) is associated with a high-risk of progression to myeloma (MM). We report the results of a study of 82 patients with both targeted sequencing that included a capture of the immunoglobulin and MYC regions. By comparing these results to newly diagnosed myeloma (MM) we show fewer NRAS and FAM46C mutations together with fewer adverse translocations, del(1p), del(14q), del(16q), and del(17p) in SMM consistent with their role as drivers of the transition to MM. KRAS mutations are associated with a shorter time to progression (HR 3.5 (1.5-8.1), p = 0.001). In an analysis of change in clonal structure over time we studied 53 samples from nine patients at multiple time points. Branching evolutionary patterns, novel mutations, biallelic hits in crucial tumour suppressor genes, and segmental copy number changes are key mechanisms underlying the transition to MM, which can precede progression and be used to guide early intervention strategies.
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http://dx.doi.org/10.1038/s41467-020-20524-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804406PMC
January 2021

Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial.

PLoS Med 2021 01 11;18(1):e1003454. Epub 2021 Jan 11.

Perlmutter Cancer Center, NYU Langone Health, New York, New York, United States of America.

Background: Carfilzomib is a second-generation irreversible proteasome inhibitor that is efficacious in the treatment of myeloma and carries less risk of peripheral neuropathy than first-generation proteasome inhibitors, making it more amenable to combination therapy.

Methods And Findings: The Myeloma XI+ trial recruited patients from 88 sites across the UK between 5 December 2013 and 20 April 2016. Patients with newly diagnosed multiple myeloma eligible for transplantation were randomly assigned to receive the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) or a triplet of lenalidomide, dexamethasone, and cyclophosphamide (Rdc) or thalidomide, dexamethasone, and cyclophosphamide (Tdc). All patients were planned to receive an autologous stem cell transplantation (ASCT) prior to a randomisation between lenalidomide maintenance and observation. Eligible patients were aged over 18 years and had symptomatic myeloma. The co-primary endpoints for the study were progression-free survival (PFS) and overall survival (OS) for KRdc versus the Tdc/Rdc control group by intention to treat. PFS, response, and safety outcomes are reported following a planned interim analysis. The trial is registered (ISRCTN49407852) and has completed recruitment. In total, 1,056 patients (median age 61 years, range 33 to 75, 39.1% female) underwent induction randomisation to KRdc (n = 526) or control (Tdc/Rdc, n = 530). After a median follow-up of 34.5 months, KRdc was associated with a significantly longer PFS than the triplet control group (hazard ratio 0.63, 95% CI 0.51-0.76). The median PFS for patients receiving KRdc is not yet estimable, versus 36.2 months for the triplet control group (p < 0.001). Improved PFS was consistent across subgroups of patients including those with genetically high-risk disease. At the end of induction, the percentage of patients achieving at least a very good partial response was 82.3% in the KRdc group versus 58.9% in the control group (odds ratio 4.35, 95% CI 3.19-5.94, p < 0.001). Minimal residual disease negativity (cutoff 4 × 10-5 bone marrow leucocytes) was achieved in 55% of patients tested in the KRdc group at the end of induction, increasing to 75% of those tested after ASCT. The most common adverse events were haematological, with a low incidence of cardiac events. The trial continues to follow up patients to the co-primary endpoint of OS and for planned long-term follow-up analysis. Limitations of the study include a lack of blinding to treatment regimen and that the triplet control regimen did not include a proteasome inhibitor for all patients, which would be considered a current standard of care in many parts of the world.

Conclusions: The KRdc combination was well tolerated and was associated with both an increased percentage of patients achieving at least a very good partial response and a significant PFS benefit compared to immunomodulatory-agent-based triplet therapy.

Trial Registration: ClinicalTrials.gov ISRCTN49407852.
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http://dx.doi.org/10.1371/journal.pmed.1003454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799846PMC
January 2021

Revealing the impact of structural variants in multiple myeloma.

Blood Cancer Discov 2020 Nov 15;1(3):258-273. Epub 2020 Sep 15.

Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

The landscape of structural variants (SVs) in multiple myeloma remains poorly understood. Here, we performed comprehensive analysis of SVs in a large cohort of 752 multiple myeloma patients by low coverage long-insert whole genome sequencing. We identified 68 SV hotspots involving 17 new candidate driver genes, including the therapeutic targets BCMA (), and Catastrophic complex rearrangements termed chromothripsis were present in 24% of patients and independently associated with poor clinical outcomes. Templated insertions were the second most frequent complex event (19%), mostly involved in super-enhancer hijacking and activation of oncogenes such as and . Importantly, in 31% of patients two or more seemingly independent putative driver events were caused by a single structural event, demonstrating that the complex genomic landscape of multiple myeloma can be acquired through few key events during tumor evolutionary history. Overall, this study reveals the critical role of SVs in multiple myeloma pathogenesis.
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http://dx.doi.org/10.1158/2643-3230.bcd-20-0132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774871PMC
November 2020

Transcatheter Pulmonary Valve Replacement With the Sapien Prosthesis.

J Am Coll Cardiol 2020 12;76(24):2847-2858

Lucile Packard Children's Hospital Stanford, Palo Alto, California, USA.

Background: There are limited published data focused on outcomes of transcatheter pulmonary valve replacement (TPVR) with either a Sapien XT or Sapien 3 (S3) valve.

Objectives: This study sought to report short-term outcomes in a large cohort of patients who underwent TPVR with either a Sapien XT or S3 valve.

Methods: Data were entered retrospectively into a multicenter registry for patients who underwent attempted TPVR with a Sapien XT or S3 valve. Patient-related, procedural, and short-term outcomes data were characterized overall and according to type of right ventricular outflow tract (RVOT) anatomy.

Results: Twenty-three centers enrolled a total of 774 patients: 397 (51%) with a native/patched RVOT; 183 (24%) with a conduit; and 194 (25%) with a bioprosthetic valve. The S3 was used in 78% of patients, and the XT was used in 22%, with most patients receiving a 29-mm (39%) or 26-mm (34%) valve. The implant was technically successful in 754 (97.4%) patients. Serious adverse events were reported in 67 patients (10%), with no difference between RVOT anatomy groups. Fourteen patients underwent urgent surgery. Nine patients had a second valve implanted. Among patients with available data, tricuspid valve injury was documented in 11 (1.7%), and 9 others (1.3%) had new moderate or severe regurgitation 2 grades higher than pre-implantation, for 20 (3.0%) total patients with tricuspid valve complications. Valve function at discharge was excellent in most patients, but 58 (8.5%) had moderate or greater pulmonary regurgitation or maximum Doppler gradients >40 mm Hg. During limited follow-up (n = 349; median: 12 months), 9 patients were diagnosed with endocarditis, and 17 additional patients underwent surgical valve replacement or valve-in-valve TPVR.

Conclusions: Acute outcomes after TPVR with balloon-expandable valves were generally excellent in all types of RVOT. Additional data and longer follow-up will be necessary to gain insight into these issues.
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http://dx.doi.org/10.1016/j.jacc.2020.10.041DOI Listing
December 2020

Copy number evolution and its relationship with patient outcome-an analysis of 178 matched presentation-relapse tumor pairs from the Myeloma XI trial.

Leukemia 2021 07 1;35(7):2043-2053. Epub 2020 Dec 1.

Division of Molecular Pathology, The Institute of Cancer Research, London, UK.

Structural chromosomal changes including copy number aberrations (CNAs) are a major feature of multiple myeloma (MM), however their evolution in context of modern biological therapy is not well characterized. To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis-relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, P = 0.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR = 2.00; P = 0.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse.
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http://dx.doi.org/10.1038/s41375-020-01096-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257500PMC
July 2021

Bone marrow microenvironments that contribute to patient outcomes in newly diagnosed multiple myeloma: A cohort study of patients in the Total Therapy clinical trials.

PLoS Med 2020 11 4;17(11):e1003323. Epub 2020 Nov 4.

Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.

Background: The tumor microenvironment (TME) is increasingly appreciated as an important determinant of cancer outcome, including in multiple myeloma (MM). However, most myeloma microenvironment studies have been based on bone marrow (BM) aspirates, which often do not fully reflect the cellular content of BM tissue itself. To address this limitation in myeloma research, we systematically characterized the whole bone marrow (WBM) microenvironment during premalignant, baseline, on treatment, and post-treatment phases.

Methods And Findings: Between 2004 and 2019, 998 BM samples were taken from 436 patients with newly diagnosed MM (NDMM) at the University of Arkansas for Medical Sciences in Little Rock, Arkansas, United States of America. These patients were 61% male and 39% female, 89% White, 8% Black, and 3% other/refused, with a mean age of 58 years. Using WBM and matched cluster of differentiation (CD)138-selected tumor gene expression to control for tumor burden, we identified a subgroup of patients with an adverse TME associated with 17 fewer months of progression-free survival (PFS) (95% confidence interval [CI] 5-29, 49-69 versus 70-82 months, χ2 p = 0.001) and 15 fewer months of overall survival (OS; 95% CI -1 to 31, 92-120 versus 113-129 months, χ2 p = 0.036). Using immunohistochemistry-validated computational tools that identify distinct cell types from bulk gene expression, we showed that the adverse outcome was correlated with elevated CD8+ T cell and reduced granulocytic cell proportions. This microenvironment develops during the progression of premalignant to malignant disease and becomes less prevalent after therapy, in which it is associated with improved outcomes. In patients with quantified International Staging System (ISS) stage and 70-gene Prognostic Risk Score (GEP-70) scores, taking the microenvironment into consideration would have identified an additional 40 out of 290 patients (14%, premutation p = 0.001) with significantly worse outcomes (PFS, 95% CI 6-36, 49-73 versus 74-90 months) who were not identified by existing clinical (ISS stage III) and tumor (GEP-70) criteria as high risk. The main limitations of this study are that it relies on computationally identified cell types and that patients were treated with thalidomide rather than current therapies.

Conclusions: In this study, we observe that granulocyte signatures in the MM TME contribute to a more accurate prognosis. This implies that future researchers and clinicians treating patients should quantify TME components, in particular monocytes and granulocytes, which are often ignored in microenvironment studies.
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http://dx.doi.org/10.1371/journal.pmed.1003323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641353PMC
November 2020

Monitoring treatment response and disease progression in myeloma with circulating cell-free DNA.

Eur J Haematol 2021 Feb 10;106(2):230-240. Epub 2020 Nov 10.

Division of Hematology Oncology, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, IN, USA.

Circulating cell-free DNA (cfDNA) has the potential to capture spatial genetic heterogeneity in myeloma (MM) patients. We assessed whether cfDNA levels vary according to risk status defined by the 70 gene expression profile (GEP70). cfDNA levels in 77 patients were significantly higher in the GEP70 high-risk (HR) group compared to the low-risk (LR) group and correlated weakly with clinical markers including lactate dehydrogenase, β -microglobulin, and ISS. Patients with high cfDNA levels were associated with a worse PFS (hazard ratio 6.4; 95% CI of ratio 1.9-22) and OS (hazard ratio 4.4; 95% CI of ratio 1.2-15.7). Circulating tumor DNA (ctDNA) was elevated in the HR group and ctDNA correlated strongly with GEP70 risk score (Spearman r = .69, P = .0027). cfDNA concentrations were significantly elevated between days 3-5 after chemotherapy before falling back to baseline levels. ctDNA in two patients showed a similar spike in levels between days 3 and 5 after chemotherapy with a concomitant increase in allele fraction of KRAS mutations. We assessed cfDNA levels in 25 patients with smoldering myeloma with serial samples and showed increased allele fraction of mutated KRAS at progression in cfDNA. Our study shows that cfDNA is a dynamic tool to capture genetic events in myeloma.
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http://dx.doi.org/10.1111/ejh.13541DOI Listing
February 2021

The Process of Amyloid Formation due to Monoclonal Immunoglobulins.

Hematol Oncol Clin North Am 2020 12 12;34(6):1041-1054. Epub 2020 Sep 12.

Amyloidosis and Cancer Theranostics Program, Preclinical and Diagnostic Molecular Imaging Laboratory, The University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37920, USA.

Monoclonal antibodies secreted by clonally expanded plasma cells can form a range of pathologic aggregates including amyloid fibrils. The enormous diversity in the sequences of the involved light chains may be responsible for complexity of the disease. Nevertheless, important common features have been recognized. Two recent high-resolution structures of light chain fibrils show related but distinct conformations. The native structure of the light chains is lost when they are incorporated into the amyloid fibrils. The authors discuss the processes that lead to aggregation and describe how existing and emerging therapies aim to prevent aggregation or remove amyloid fibrils from tissues.
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http://dx.doi.org/10.1016/j.hoc.2020.07.003DOI Listing
December 2020

International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM).

Blood Cancer J 2020 10 16;10(10):102. Epub 2020 Oct 16.

Clinica Universidad de Navarra, CIMA, CIBERONC, IDISNA, Pamplona, Spain.

Smoldering multiple myeloma (SMM) is an asymptomatic precursor state of multiple myeloma (MM). Recently, MM was redefined to include biomarkers predicting a high risk of progression from SMM, thus necessitating a redefinition of SMM and its risk stratification. We assembled a large cohort of SMM patients meeting the revised IMWG criteria to develop a new risk stratification system. We included 1996 patients, and using stepwise selection and multivariable analysis, we identified three independent factors predicting progression risk at 2 years: serum M-protein >2 g/dL (HR: 2.1), involved to uninvolved free light-chain ratio >20 (HR: 2.7), and marrow plasma cell infiltration >20% (HR: 2.4). This translates into 3 categories with increasing 2-year progression risk: 6% for low risk (38%; no risk factors, HR: 1); 18% for intermediate risk (33%; 1 factor; HR: 3.0), and 44% for high risk (29%; 2-3 factors). Addition of cytogenetic abnormalities (t(4;14), t(14;16), +1q, and/or del13q) allowed separation into 4 groups (low risk with 0, low intermediate risk with 1, intermediate risk with 2, and high risk with ≥3 risk factors) with 6, 23, 46, and 63% risk of progression in 2 years, respectively. The 2/20/20 risk stratification model can be easily implemented to identify high-risk SMM for clinical research and routine practice and will be widely applicable.
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http://dx.doi.org/10.1038/s41408-020-00366-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567803PMC
October 2020

An enhanced genetic model of relapsed IGH-translocated multiple myeloma evolutionary dynamics.

Blood Cancer J 2020 10 14;10(10):101. Epub 2020 Oct 14.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SM2 5NG, UK.

Most patients with multiple myeloma (MM) die from progressive disease after relapse. To advance our understanding of MM evolution mechanisms, we performed whole-genome sequencing of 80 IGH-translocated tumour-normal newly diagnosed pairs and 24 matched relapsed tumours from the Myeloma XI trial. We identify multiple events as potentially important for survival and therapy-resistance at relapse including driver point mutations (e.g., TET2), translocations (MAP3K14), lengthened telomeres, and increased genomic instability (e.g., 17p deletions). Despite heterogeneous mutational processes contributing to relapsed mutations across MM subtypes, increased AID/APOBEC activity is particularly associated with shorter progression time to relapse, and contributes to higher mutational burden at relapse. In addition, we identify three enhanced major clonal evolution patterns of MM relapse, independent of treatment strategies and molecular karyotypes, questioning the viability of "evolutionary herding" approach in treating drug-resistant MM. Our data show that MM relapse is associated with acquisition of new mutations and clonal selection, and suggest APOBEC enzymes among potential targets for therapy-resistant MM.
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http://dx.doi.org/10.1038/s41408-020-00367-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560599PMC
October 2020

Proteomic profiling identifies key differences between inter-stage infants with single ventricle heart disease and healthy controls.

Transl Res 2021 03 9;229:24-37. Epub 2020 Oct 9.

Department of Pediatrics, Section of Cardiology, University of Colorado, Aurora, Colorado.

Despite significant morbidity among infants with single ventricle heart disease (SVHD), clinical monitoring is limited by poor understanding of the underlying pathobiology. Proteomics can identify novel biomarkers and important pathways in complex disease. No prior study has evaluated whether the proteome of SVHD infants differs from healthy controls, how it shifts after stage 2 palliation, or whether differences can predict post-operative outcomes. We present a prospective cohort study of cardiovascular proteomic phenotyping in infants with SVHD undergoing stage 2 palliation. Twenty-nine pre-stage-2 SVHD infants and 25 healthy controls were enrolled. Outcomes included postoperative hypoxemia and endotracheal intubation time. Serum samples were drawn pre-operatively (systemic and pulmonary vein) and at 24 hours postoperation. Targeted cardiovascular proteomic analysis included 184 proteins. Partial least squares discriminant analysis distinguished cases from controls (Accuracy = 0.98, R = 0.93, Q = 0.81) with decreased inflammatory mediators and increased modulators of vascular tone. Partial least squares discriminant analysis also distinguished cases pre-operation vs. post-operation (Accuracy=0.98, R=0.99, Q = 0.92) with postoperative increase in both inflammatory and vascular tone mediators. Pre-operation pulmonary vein tissue inhibitor of metalloproteinase-1 (1.8x-fold, p=1.6 × 10) and nidogen-1 (1.5x-fold, p=1.7 × 10) were higher in subjects with longer endotracheal intubation time. Postoperation matrix metalloproteinase 7 levels were higher in subjects with greater postoperative hypoxemia (1.5x-fold, P= 1.97 × 10). Proteomic analysis identifies significant changes among SVHD infants pre- and post-stage 2, and healthy controls. Tissue inhibitor of metalloproteinase-1, nidogen-1, and matrix metalloproteinase 7 levels are higher in SVHD cases with greater morbidity suggesting an important role for regulation of extracellular matrix production. Proteomic profiling may identify high-risk SVHD infants.
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http://dx.doi.org/10.1016/j.trsl.2020.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191179PMC
March 2021
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