Showing papers by "Paul G. Richardson published in 2021"
University of California, Los Angeles1, Fred Hutchinson Cancer Research Center2, LSU Health Sciences Center New Orleans3, University of São Paulo4, Asociación Civil Impacta Salud y Educación5, Chiang Mai University6, Centers for Disease Control and Prevention7, University of Pennsylvania8, St. Jude Children's Research Hospital9, University of North Carolina at Chapel Hill10, University of Cape Town11, University of Alabama at Birmingham12, Rutgers University13, Cornell University14, Johns Hopkins University15, Anschutz Medical Campus16, Harvard University17, University of Miami18, National Institutes of Health19
TL;DR: In this paper, safe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preve...
Abstract: Background Safe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preve...
237 citations
Mayo Clinic1, University of Navarra2, University of Bologna3, University of Calgary4, City of Hope National Medical Center5, National and Kapodistrian University of Athens6, Oslo University Hospital7, University of California, San Francisco8, University College London9, Cedars-Sinai Medical Center10, university of lille11, Jagiellonian University Medical College12, Stanford University13, Harvard University14, VU University Amsterdam15, Emory University16, University of Iceland17, Columbia University18, University of Ostrava19, Erasmus University Rotterdam20, University of Freiburg21, University of Copenhagen22, University of Hamburg23, Sarah Cannon Research Institute24, University of Alabama at Birmingham25, Federal University of Rio de Janeiro26, Hackensack University Medical Center27, University of Cantabria28, St. Vincent's Health System29, University of St. Gallen30, French Institute of Health and Medical Research31, British Hospital32, University of the Republic33, National University of Singapore34, Poznan University of Medical Sciences35, University Hospital Heidelberg36, Ankara University37, Institute of Cancer Research38, Medical College of Wisconsin39, University of Nebraska Medical Center40, Peter MacCallum Cancer Centre41, Karolinska University Hospital42, St James's University Hospital43
TL;DR: The International Myeloma Working Group's clinical practice recommendations for the treatment of relapsed and refractory multiple myeloma were presented in this article, where the authors integrated the issue of drug access in both low-income and middle-income countries and in high income countries to help guide realworld practice and thus improve patient outcomes.
Abstract: This Policy Review presents the International Myeloma Working Group's clinical practice recommendations for the treatment of relapsed and refractory multiple myeloma. Based on the results of phase 2 and phase 3 trials, these recommendations are proposed for the treatment of patients with relapsed and refractory disease who have received one previous line of therapy, and for patients with relapsed and refractory multiple myeloma who have received two or more previous lines of therapy. These recommendations integrate the issue of drug access in both low-income and middle-income countries and in high-income countries to help guide real-world practice and thus improve patient outcomes.
102 citations
Harvard University1, University of Turin2, University of Barcelona3, University of Bologna4, University of Navarra5, University of Florida6, Memorial Sloan Kettering Cancer Center7, French Institute of Health and Medical Research8, Rush University Medical Center9, Scott & White Hospital10, University of Pittsburgh11, Novant Health12
TL;DR: Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.
Abstract: PURPOSEMelphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase I...
75 citations
Mayo Clinic1, University of Rochester Medical Center2, Cleveland Clinic3, City of Hope National Medical Center4, Wayne State University5, Emory University6, University of Wisconsin-Madison7, University of Chicago8, Cedars-Sinai Medical Center9, Harvard University10, University of Texas MD Anderson Cancer Center11
TL;DR: The SWOG-1211 trial as discussed by the authors compared eight cycles of lenalidomide (25 mg orally on days 1-14 every 21 days), bortezomib (1·3 mg/m2 subcutaneously, and dexamethasone (20 mg/kg intravenously on days1, 2, 4, 5, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 28, 30, 31, and 30,
62 citations
TL;DR: It is shown that bortezomib triggers immunogenic cell death (ICD), characterized by exposure of calreticulin on dying multiple myeloma cells, phagocytosis of tumor cells by dendritic cells, and induction of multipleMyeloma-specific immunity.
Abstract: Proteasome inhibitor bortezomib induces apoptosis in multiple myeloma (MM) cells, and has transformed patient outcome. Using in vitro as well as in vivo immunodeficient and immunocompetent murine MM models, we here show that bortezomib also triggers immunogenic cell death (ICD) characterized by exposure of calreticulin on dying MM cells, phagocytosis of tumor cells by dendritic cells, and induction of MM specific immunity. We identify a bortezomib-triggered specific ICD-gene signature associated with better outcome in two independent MM patient cohorts. Importantly, bortezomib stimulates MM cells immunogenicity via activation of cGAS/STING pathway and production of type-I interferons; and STING agonists significantly potentiate bortezomib-induced ICD. Our studies therefore delineate mechanisms whereby bortezomib exerts immunotherapeutic activity, and provide the framework for clinical trials of STING agonists with bortezomib to induce potent tumor-specific immunity and improve patient outcome in MM.
49 citations
University of Barcelona1, Ankara University2, University of Bologna3, VU University Amsterdam4, Harvard University5, University of Maryland, Baltimore6, National and Kapodistrian University of Athens7, Mayo Clinic8, University of Freiburg9, Karolinska Institutet10, University of Ostrava11, University of Hamburg12, Instituto Português de Oncologia Francisco Gentil13, Columbia University14, University of Pavia15, University of Paris16, University of Toronto17, Erasmus University Rotterdam18, Vrije Universiteit Brussel19, Norwegian University of Science and Technology20
TL;DR: In this paper, two types of soft-tissue involvement in multiple myeloma are defined: extramedullary (EMD) with haematogenous spread involving only soft tissues and paraskeletal (PS) with tumour masses arising from skeletal lesions.
Abstract: In this review, two types of soft-tissue involvement in multiple myeloma are defined: (i) extramedullary (EMD) with haematogenous spread involving only soft tissues and (ii) paraskeletal (PS) with tumour masses arising from skeletal lesions. The incidence of EMD and PS plasmacytomas at diagnosis ranges from 1·7% to 4·5% and 7% to 34·4% respectively. EMD disease is often associated with high-risk cytogenetics, resistance to therapy and worse prognosis than in PS involvement. In patients with PS involvement a proteasome inhibitor-based regimen may be the best option followed by autologous stem cell transplantation (ASCT) in transplant eligible patients. In patients with EMD disease who are not eligible for ASCT, a proteasome inhibitor-based regimen such as lenalidomide-bortezomib-dexamethasone (RVD) may be the best option, while for those eligible for high-dose therapy a myeloma/lymphoma-like regimen such as bortezomib, thalidomide and dexamethasone (VTD)-RVD/cisplatin, doxorubicin, cyclophosphamide and etoposide (PACE) followed by SCT should be considered. In both EMD and PS disease at relapse many strategies have been tried, but this remains a high-unmet need population.
45 citations
TL;DR: The double-blind, placebo-controlled, phase III TOURMALINE-MM1 study demonstrated a statistically significant improvement in progression-free survival with ixazomib-lenalidomide-dexamethason.
Abstract: PURPOSEThe double-blind, placebo-controlled, phase III TOURMALINE-MM1 study demonstrated a statistically significant improvement in progression-free survival with ixazomib-lenalidomide-dexamethason...
44 citations
Harvard University1, University of Oslo2, Oslo University Hospital3, National and Kapodistrian University of Athens4, First Faculty of Medicine, Charles University in Prague5, University of São Paulo6, Chulalongkorn University7, University of Ostrava8, University of Debrecen9, Wrocław Medical University10, University of Barcelona11, Ankara University12, Mayo Clinic13, Icahn School of Medicine at Mount Sinai14, Emory University15, Monash University16, University of Navarra17
TL;DR: This trial investigated the activity and safety of three different dosing regimens of oral panobinostat in combination with subcutaneous bortezomib and oral dexamethasone for patients with relapsed or relapsed and refractory multiple myeloma.
Abstract: Summary Background Improved therapeutic options are needed for patients with relapsed or relapsed and refractory multiple myeloma. Subcutaneous bortezomib has replaced intravenous bortezomib as it is associated with a more favourable toxicity profile. We investigated the activity and safety of three different dosing regimens of oral panobinostat in combination with subcutaneous bortezomib and oral dexamethasone for this indication. Methods PANORAMA 3 is an open-label, randomised, phase 2 study being done at 71 sites (hospitals and medical centres) across 21 countries. Patients aged 18 years or older with relapsed or relapsed and refractory multiple myeloma (as per International Myeloma Working Group 2014 criteria), who had received one to four previous lines of therapy (including an immunomodulatory agent), and had an Eastern Cooperative Oncology Group performance status of 2 or lower, were randomly assigned (1:1:1) to receive oral panobinostat 20 mg three times weekly, 20 mg twice weekly, or 10 mg three times weekly, plus subcutaneous bortezomib and oral dexamethasone. All study drugs were administered in 21-day cycles. Randomisation was done by an interactive response technology provider, and stratified by number of previous treatment lines and age. The primary endpoint was overall response rate after up to eight treatment cycles (analysed in all randomly assigned patients by intention to treat). Safety analyses included all patients who received at least one dose of any study drug. No statistical comparisons between groups were planned. This trial is ongoing and registered with ClinicalTrials.gov , NCT02654990 . Findings Between April 27, 2016, and Jan 17, 2019, 248 patients were randomly assigned (82 to panobinostat 20 mg three times weekly, 83 to panobinostat 20 mg twice weekly, and 83 to 10 mg panobinostat three times weekly). Median duration of follow-up across all treatment groups was 14·7 months (IQR 7·8–24·1). The overall response rate after up to eight treatment cycles was 62·2% (95% CI 50·8–72·7; 51 of 82 patients) for the 20 mg three times weekly group, 65·1% (53·8–75·2; 54 of 83 patients) for the 20 mg twice weekly group, and 50·6% (39·4–61·8; 42 of 83 patients) for the 10 mg three times weekly group. Grade 3–4 adverse events occurred in 71 (91%) of 78 patients in the 20 mg three times weekly group, 69 (83%) of 83 patients in the 20 mg twice weekly group, and 60 (75%) of 80 patients in the 10 mg three times weekly group; the most common (≥20% patients in any group) grade 3–4 adverse events were thrombocytopenia (33 [42%] of 78, 26 [31%] of 83, and 19 [24%] of 83 patients) and neutropenia (18 [23%], 13 [16%], and six [8%]). Serious adverse events occurred in 42 (54%) of 78 patients in the 20 mg three times weekly group, 40 (48%) of 83 patients in the 20 mg twice weekly group, and 35 (44%) of 83 patients in the 10 mg three times weekly group; the most common serious adverse event (≥10% patients in any group) was pneumonia (nine [12%] of 78, ten [12%] of 83, and nine [11%] of 80 patients). There were 14 deaths during the study (five [6%] of 78 patients in the 20 mg three times weekly group, three [4%] of 83 in the 20 mg twice weekly group, and six [8%] of 80 in the 10 mg three times weekly group); none of these deaths was deemed treatment related. Interpretation The safety profile of panobinostat 20 mg three times weekly was more favourable than in previous trials of this regimen with intravenous bortezomib, suggesting that subcutaneous bortezomib improves the tolerability of the panobinostat plus bortezomib plus dexamethasone regimen. The overall response rate was highest in the 20 mg three times weekly and 20 mg twice weekly groups, with 10 mg three times weekly best tolerated. Funding Novartis Pharmaceuticals and Secura Bio.
43 citations
TL;DR: The addition of Isa to Pd improved PFS, ORR and renal response rates, and Isa pharmacokinetics were comparable between the subgroups, suggesting no need for dose adjustment in patients with RI.
Abstract: The randomized, phase 3 ICARIA-MM study investigated isatuximab (Isa) with pomalidomide and dexamethasone (Pd) versus Pd in patients with relapsed/refractory multiple myeloma and ≥2 prior lines. This prespecified subgroup analysis examined efficacy in patients with renal impairment (RI; estimated glomerular filtration rate <60 mL/min/1.73 m²). Isa 10 mg/kg was given intravenously once weekly in cycle 1, and every 2 weeks in subsequent 28-day cycles. Patients received standard doses of Pd. Median progression-free survival (PFS) for patients with RI was 9.5 months with Isa-Pd (n = 55) and 3.7 months with Pd (n = 49; hazard ratio [HR] 0.50; 95% confidence interval [CI], 0.30–0.85). Without RI, median PFS was 12.7 months with Isa-Pd (n = 87) and 7.9 months with Pd (n = 96; HR 0.58; 95% CI, 0.38–0.88). The overall response rate (ORR) with and without RI was higher with Isa-Pd (56 and 68%) than Pd (25 and 43%). Complete renal response rates were 71.9% (23/32) with Isa-Pd and 38.1% (8/21) with Pd; these lasted ≥60 days in 31.3% (10/32) and 19.0% (4/21) of patients, respectively. Isa pharmacokinetics were comparable between the subgroups, suggesting no need for dose adjustment in patients with RI. In summary, the addition of Isa to Pd improved PFS, ORR and renal response rates.
43 citations
TL;DR: The coronavirus disease 2019 (COVID•19) pandemic, a viral illness caused by the SARS•CoV2, has produced at the time of this writing nearly 33 million cases of infection, with over a million deaths in 235 countries, causing an unprecedented burden on healthcare systems and a severe global socioeconomic crisis as mentioned in this paper.
Abstract: The coronavirus disease 2019 (COVID‐19) pandemic, a viral illness caused by the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), 1 has produced at the time of this writing nearly 33 million cases of infection, with over a million deaths in 235 countries, 2 causing an unprecedented burden on healthcare systems and a severe global socioeconomic crisis. As the pandemic spreads, knowledge on the disease course, as well as potential risk factors and predictors of severity is increasing daily, and initial data from randomised controlled studies have allowed care providers to refine therapeutic strategies. Nonetheless, mortality is markedly elevated among those presenting with severe disease, long‐term sequelae among survivors are unknown, and vaccine‐based therapies currently remain at early stages of development.
Most reported cases are asymptomatic or present with mild symptoms; however, 7–26% of hospitalised patients experience severe disease, often requiring admission to intensive care units (ICUs), with progressive multiple organ dysfunction and high mortality. 3 , 4 , 5 Such differences in clinical outcomes have led physicians to initiate diverse pharmacological therapies at various stages of the disease, generating challenges as to the most appropriate therapeutic choice for COVID‐19. In this context, the use of dexamethasone has significantly reduced mortality rates in critically ill patients requiring supplemental oxygen or mechanical ventilation, 6 and remdesivir has demonstrated clinical benefit in hospitalised patients, but with unknown survival benefit to date 7 ; additional effective treatment options are therefore urgently needed.
In an initial attempt to provide a uniform and widely reproducible methodology to guide systematic treatment strategies, a three‐stage classification of COVID‐19 has been proposed. 8 The Stage I or ‘early infection’ occurs at the initial establishment of disease with high viral replication, and commonly presents with a range of complaints that can include mild and often non‐specific influenza‐like signs and symptoms. Stage II is the ‘pulmonary phase’, with preferential viral‐mediated injury of the lung parenchyma and this is characterised by shortness of breath, hypoxia and pulmonary infiltrates with some degree of lung inflammation. Stage III is characterised by an exaggerated host immune‐inflammatory response to the virus, leading to acute respiratory distress syndrome (ARDS) and multi‐organ failure (MOF).
38 citations
university of lille1, University of Alberta2, University of Calgary3, Ghent University Hospital4, Dalhousie University5, University of Lyon6, Seoul National University Hospital7, Osaka University8, Takeda Pharmaceutical Company9, University of Nantes10, Emory University11, Mayo Clinic12, Harvard University13
TL;DR: The TOURMALINE-MM2 trial as discussed by the authors showed that the oral proteasome inhibitor ixazomib is suitable for continuous dosing, with predictable, manageable toxicities.
TL;DR: In this article, the authors performed genome-scale CRISPR-Cas9-based gene editing studies and found that myeloma cell resistance to degraders of different targets (BET bromodomain proteins, CDK9) and operating through CRBN (degronimids) or VHL is primarily mediated by prevention of, rather than adaptation to, breakdown of the target oncoprotein; and this involves loss of function of the cognate E3 ligase or interactors/regulators of the respective cullin-RING ligase (C
National and Kapodistrian University of Athens1, University of Hamburg2, University of Texas Southwestern Medical Center3, Queen Elizabeth II Health Sciences Centre4, University of Navarra5, Erasmus University Rotterdam6, University Medical Center Freiburg7, University of Southampton8, Centre Hospitalier Universitaire de Sherbrooke9, Copenhagen University Hospital10, Bristol-Myers Squibb11, Harvard University12
TL;DR: The benefit of PVd at first relapse, including immediately after upfront lenalidomide treatment failure and other common first-line treatments, is demonstrated, with similar results regardless of prior bortezomib or SCT.
Abstract: In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone (PVd) demonstrated superior efficacy vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma previously treated with lenalidomide, including those refractory to lenalidomide. This analysis evaluated outcomes in patients at first relapse (N = 226) by lenalidomide-refractory status, prior bortezomib exposure, and prior stem cell transplant (SCT). Second-line PVd significantly improved PFS vs Vd in lenalidomide-refractory (17.8 vs 9.5 months; P = 0.0276) and lenalidomide-nonrefractory patients (22.0 vs 12.0 months; P = 0.0491), patients with prior bortezomib (17.8 vs 12.0 months; P = 0.0068), and patients with (22.0 vs 13.8 months; P = 0.0241) or without (16.5 vs 9.5 months; P = 0.0454) prior SCT. In patients without prior bortezomib, median PFS was 20.7 vs 9.5 months (P = 0.1055). Significant improvement in overall response rate was also observed with PVd vs Vd in lenalidomide-refractory (85.9% vs 50.8%; P < 0.001) and lenalidomide-nonrefractory (95.7% vs 60.0%; P < 0.001) patients, with similar results regardless of prior bortezomib or SCT. No new safety signals were observed. These data demonstrate the benefit of PVd at first relapse, including immediately after upfront lenalidomide treatment failure and other common first-line treatments.
TL;DR: In this paper, the level of each biomarker in all three COVID-19 groups and healthy donors as controls were compared with other intensive care unit (ICU) patients with septic shock (SS), sepsis (S, nâ´=â7), and noninfectious systemic inflammatory response syndrome (NI-SIRS, N, S, and NI SIRS).
Abstract: BACKGROUND: Endotheliopathy is a key element in COVID-19 pathophysiology, contributing to both morbidity and mortality. Biomarkers distinguishing different COVID-19 phenotypes from sepsis syndrome remain poorly understood. OBJECTIVE: To characterize circulating biomarkers of endothelial damage in different COVID-19 clinical disease stages compared with sepsis syndrome and normal volunteers. METHODS: Patients with COVID-19 pneumonia (nâ=â49) were classified into moderate, severe, or critical (life-threatening) disease. Plasma samples were collected within 48 to 72âh of hospitalization to analyze endothelial activation markers, including sVCAM-1, von Willebrand Factor (VWF), ADAMTS-13 activity, thrombomodulin (TM), and soluble TNF receptor I (sTNFRI); heparan sulfate (HS) for endothelial glycocalyx degradation; C5b9 deposits on endothelial cells in culture and soluble C5b9 for complement activation; circulating dsDNA for neutrophil extracellular traps (NETs) presence, and α2-antiplasmin and PAI-1 as parameters of fibrinolysis. We compared the level of each biomarker in all three COVID-19 groups and healthy donors as controls (nâ=â45). Results in critically ill COVID-19 patients were compared with other intensive care unit (ICU) patients with septic shock (SS, nâ=â14), sepsis (S, nâ=â7), and noninfectious systemic inflammatory response syndrome (NI-SIRS, nâ=â7). RESULTS: All analyzed biomarkers were increased in COVID-19 patients versus controls (Pâ<â0.001), except for ADAMTS-13 activity that was normal in both groups. The increased expression of sVCAM-1, VWF, sTNFRI, and HS was related to COVID-19 disease severity (Pâ<â0.05). Several differences in these parameters were found between ICU groups: SS patients showed significantly higher levels of VWF, TM, sTNFRI, and NETS compared with critical COVID-19 patients and ADAMTS-13 activity was significantly lover in SS, S, and NI-SIRS versus critical COVID-19 (Pâ<â0.001). Furthermore, α2-antiplasmin activity was higher in critical COVID-19 versus NI-SIRS (Pâ<â0.01) and SS (Pâ<â0.001), whereas PAI-1 levels were significantly lower in COVID-19 patients compared with NI-SIRS, S, and SS patients (Pâ<â0.01). CONCLUSIONS: COVID-19 patients present with increased circulating endothelial stress products, complement activation, and fibrinolytic dysregulation, associated with disease severity. COVID-19 endotheliopathy differs from SS, in which endothelial damage is also a critical feature of pathobiology. These biomarkers could help to stratify the severity of COVID-19 disease and may also provide information to guide specific therapeutic strategies to mitigate endotheliopathy progression.
Vanderbilt University Medical Center1, Medical College of Wisconsin2, University of Wisconsin-Madison3, Icahn School of Medicine at Mount Sinai4, Washington University in St. Louis5, Scripps Health6, University of Alabama at Birmingham7, Stanford University8, Mount Sinai Hospital9, Duke University10, University of Texas Southwestern Medical Center11, University of Vermont12, Mayo Clinic13, University of Pittsburgh14, Emory University15, Case Western Reserve University16, City of Hope National Medical Center17, Kaiser Permanente18, Medical University of South Carolina19, Harvard University20, Oregon Health & Science University21, Hackensack University Medical Center22
TL;DR: A ten year review of the sickle cell program in Muhimbili National Hospital, Tanzania and the World Health Organization and Health Action International's Measuring Medicine Price, Availability, Affordability and Price Component.
Abstract: 1. Makani J, Tluway F, Makubi A, et al. A ten year review of the sickle cell program in Muhimbili National Hospital, Tanzania. BMC Hematol. 2018;18:33. https://doi.org/10.1186/s12878-018-0125-0. 2. Steinberg MH. Treating sickle cell anemia: a new era dawns. Am J Hematol. 2020;95:338–342. https://doi.org/10.1002/ajh.25724. 3. Tshilolo L, Tomlinson G,Williams TN, et al. Hydroxyurea for children with sickle cell anemia in sub-SaharanAfrica.NEngl JMed. 2019;380:121-131. 4. World Health Organization and Health Action International, . Measuring Medicine Price, Availability, Affordability and Price Component. 2nd ed. Geneva: World Health Organization; 2008 http://www.who.int/ medicines/areas/access/OMS_Medicine_prices.pdf. Accessed June 15, 2020. 5. Government of the United Republic of Tanzania, Gazette of the United Republic of Tanzania, Supplement No. 24. Dar es Salaam: United Republic of Tanzania; 2013, 94, 26, 8, ISSN: 0856-034X. https:// www.ilo.org/dyn/natlex/natlex4.detail?p_lang=en&p_isn=94094. Accessed June 15, 2020 6. National Association of Boards of Pharmacy, Good compounding practices applicable to state-licensed pharmacies. Model State Pharmacy Act and Model Rules of the National Association of Boards of Pharmacy. Park Ridge, IL: National Association of Boards of Pharmacy; 1993:C.1-C.5. 7. Fischelis RP. Combating war prices by the use of galenicals. J Pharm Sci. 1916;5(4):411-414. 8. Luzzatto L, Makani J. Hydroxyurea: an essential medicine for sickle cell disease in Africa. N Engl J Med. 2019;380:187-189. 9. McNeil DG. In Desperately Poor Rwanda, Most Have Health Insurance. Section D. 15 June. New York, NY: The New York Times; 2010:1. https://www.nytimes.com/2010/06/15/health/policy/15rwanda.html. Accessed June 15, 2020. 10. Report of the United Nations. Secretary-General's High Level Panel on Access to Medicines. https://static1.squarespace.com/static/ 562094dee4b0d00c1a3ef761/t/57d9c6ebf5e231b2f02cd3d4/ 1473890031320/UNSG+HLP+Report+FINAL+12+Sept+2016.pdf. Accessed June 15, 2020 Received: 15 July 2020 Revised: 16 September 2020 Accepted: 22 September 2020
TL;DR: In this article, the clinical features of SARS-CoV-2 infection, the central role of the endothelium in COVID-19 and in other pathologies, and the potential of specific therapies aimed at protecting the endothelialium in patients are addressed.
Abstract: Patients with COVID-19 present a wide spectrum of disease severity, from asymptomatic cases in the majority to serious disease leading to critical care and even death. Clinically, four different scenarios occur within the typical disease timeline: first, an incubation and asymptomatic period; second, a stage with mild symptoms due mainly to the virus itself; third, in up to 20% of the patients, a stage with severe symptoms where a hyperinflammatory response with a cytokine storm driven by host immunity induces acute respiratory distress syndrome; and finally, a post-acute sequelae (PASC) phase, which present symptoms that can range from mild or annoying to actually quite incapacitating. Although the most common manifestation is acute respiratory failure of the lungs, other organs are also frequently involved. The clinical manifestations of the COVID-19 infection support a key role for endothelial dysfunction in the pathobiology of this condition. The virus enters into the organism via its interaction with angiotensin-converting enzyme 2-receptor that is present prominently in the alveoli, but also in endothelial cells, which can be directly infected by the virus. Cytokine release syndrome can also drive endothelial damage independently. Consequently, a distinctive feature of SARS-CoV-2 infection is vascular harm, with severe endothelial injury, widespread thrombosis, microangiopathy, and neo-angiogenesis in response to endothelial damage. Therefore, endothelial dysfunction seems to be the pathophysiological substrate for severe COVID-19 complications. Biomarkers of endothelial injury could constitute strong indicators of disease progression and severity. In addition, the endothelium could represent a very attractive target to both prevent and treat these complications. To establish an adequate therapy, the underlying pathophysiology and corresponding clinical stage should be clearly identified. In this review, the clinical features of COVID-19, the central role of the endothelium in COVID-19 and in other pathologies, and the potential of specific therapies aimed at protecting the endothelium in COVID-19 patients are addressed.
TL;DR: A review of the available treatments for multiple myeloma (MM) can be found in this paper, where the authors discuss how to tailor treatments according to individual patients' needs.
TL;DR: In this paper, the authors show that patients with lower levels of circulating (PCs) have the same adverse prognosis, challenging the clinical disease definition, but supporting the adverse impact of circulating PCs.
Abstract: Primary plasma cell leukemia (pPCL) is an aggressive plasma cell disorder with a guarded prognosis. The diagnosis is confirmed when peripheral blood plasma cells (PCs) exceed 20% of white blood cells or 2000/μL. Emerging data demonstrates that patients with lower levels of circulating (PCs) have the same adverse prognosis, challenging the clinical disease definition, but supporting the adverse impact of circulating PCs. The cornerstone of treatment consists of combination therapy incorporating a proteasome inhibitor, an immunomodulatory agent, steroids, and/or anthracyclines and alkylators as part of more-intensive chemotherapy, followed by consolidative autologous hematopoietic cell transplantation in eligible patients and then maintenance therapy. Monoclonal antibodies are also currently being evaluated in this setting with a strong rationale for their use based on their activity in multiple myeloma (MM). Due to limited therapeutic studies specifically evaluating pPCL, patients with pPCL should be considered for clinical trials. In contrast to MM, the outcomes of patients with pPCL have only modestly improved with novel therapies, and secondary PCL arising from MM in particular is associated with a dismal outlook. Newer drug combinations, immunotherapy, and cellular therapy are under investigation, and these approaches hopefully will demonstrate efficacy to improve the prognosis of pPCL.
TL;DR: In this paper, the authors discuss the strategic employment of fluorine substitution in the design and development of bioisosteres in medicinal chemistry and discuss the classic exploitation of trifluoroethylamine group as an amide bio-isostere.
Abstract: Introduction There continues to be an exponential rise in the number of small molecule drugs that contain either a fluorine atom or a fluorinated fragment. While the unique properties of fluorine enable the precise modulation of a molecule's physicochemical properties, strategic bioisosteric replacement of fragments with fluorinated moieties represents an area of significant growth.Areas covered This review discusses the strategic employment of fluorine substitution in the design and development of bioisosteres in medicinal chemistry. In addition, the classic exploitation of trifluoroethylamine group as an amide bioisostere is discussed. In each of the case studies presented, emphasis is placed on the context-dependent influence of the fluorinated fragment on the overall properties/binding of the compound of interest.Expert opinion Whereas utilization of bioisosteric replacements to modify molecular structures is commonplace within drug discovery, the overarching lesson to be learned is that the chances of success with this strategy significantly increase as the knowledge of the structure/environment of the biological target grows. Coupled to this, breakthroughs and learnings achieved using bioisosteres within a specific program are context-based, and though may be helpful in guiding future intuition, will not necessarily be directly translated to future programs. Another important point is to bear in mind what implications a structural change based on a bioisosteric replacement will have on the candidate molecule. Finally, the development of new methods and reagents for the controlled regioselective introduction of fluorine and fluorinated moieties into biologically relevant compounds particularly in drug discovery remains a contemporary challenge in organic chemistry.
Rosanna Asselta1, Elvezia Maria Paraboschi1, Alessio Gerussi2, Heather J. Cordell3 +614 more•Institutions (213)
TL;DR: In this article, the authors performed a chrX-wide association study, including genotype data from five genome-wide associations (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals).
TL;DR: In this paper, the authors identify and validate blockade of LAG3/GAL-3, alone or in combination with immune strategies including XBP1/CD138/CS1 multipeptide vaccination, to enhance anti-tumor responses and improve patient outcome in MM.
Abstract: Immune profiling in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma (MM) provides the framework for developing novel immunotherapeutic strategies. Here, we demonstrate decreased CD4+ Th cells, increased Treg and G-type MDSC, and upregulation of immune checkpoints on effector/regulatory and CD138+ cells in MM patients, compared MGUS/SMM patients or healthy individuals. Among the checkpoints profiled, LAG3 was most highly expressed on proliferating CD4+ Th and CD8+ Tc cells in MM patients BMMC and PBMC. Treatment with antibody targeting LAG3 significantly enhanced T cells proliferation and activities against MM. XBP1/CD138/CS1-specific CTL generated in vitro displayed anti-MM activity, which was further enhanced following anti-LAG3 treatment, within the antigen-specific memory T cells. Treg and G-type MDSC weakly express LAG3 and were minimally impacted by anti-LAG3. CD138+ MM cells express GAL-3, a ligand for LAG3, and anti-GAL-3 treatment increased MM-specific responses, as observed for anti-LAG3. Finally, we demonstrate checkpoint inhibitor treatment evokes non-targeted checkpoints as a cause of resistance and propose combination therapeutic strategies to overcome this resistance. These studies identify and validate blockade of LAG3/GAL-3, alone or in combination with immune strategies including XBP1/CD138/CS1 multipeptide vaccination, to enhance anti-tumor responses and improve patient outcome in MM.
Emory University1, University of Hamburg2, VU University Amsterdam3, Peter MacCallum Cancer Centre4, University of Navarra5, Vancouver General Hospital6, St. Vincent's Health System7, University of Wisconsin-Madison8, Utrecht University9, Princess Margaret Cancer Centre10, GlaxoSmithKline11, Karolinska University Hospital12, Harvard University13
TL;DR: In this paper, the authors describe the rationale and design of DREAMM-5, an ongoing Phase I/II platform study evaluating the safety and efficacy of Belamaf combined with novel agents, including GSK3174998 (OX40 agonist), feladilimab (an ICOS; GSK3359609), nirogacestat (a gamma secretase inhibitor; PF-03084014) and dostarlimab (a PD-1 blocker) versus belamaf monotherapy for patients with relapsed/refractory multiple myel
Abstract: Belantamab mafodotin (belamaf) is a BCMA-targeted antibody-drug conjugate recently approved as monotherapy for adults with relapsed/refractory multiple myeloma who have received ≥4 prior therapies. Belamaf binds to BCMA and eliminates myeloma cells by multimodal mechanisms of action. The cytotoxic and potential immunomodulatory properties of belamaf have led to novel combination studies with other anticancer therapies. Here, we describe the rationale and design of DREAMM-5, an ongoing Phase I/II platform study evaluating the safety and efficacy of belamaf combined with novel agents, including GSK3174998 (OX40 agonist), feladilimab (an ICOS; GSK3359609), nirogacestat (a gamma-secretase inhibitor; PF-03084014) and dostarlimab (a PD-1 blocker) versus belamaf monotherapy for patients with relapsed/refractory multiple myeloma. Clinical trial registration: NCT04126200 (ClinicalTrials.gov).
TL;DR: The ICARIA-MM trial as discussed by the authors showed that isatuximab plus pomalidomide-dexamethasone prolonged median progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma.
TL;DR: In this paper, microvesicles from antibody-exposed cells were analysed for differential gene and microRNA expression, and for phenotypic characterisation of MM cells and subsequent events when anti-CD38 is targeted by therapeutic antibodies.
Abstract: Multiple functions of CD38 need exploring to expand clinical application of anti-CD38 antibodies in multiple myeloma (MM) We investigated membrane dynamics of MM cells and subsequent events when CD38 is targeted by therapeutic antibodies Human MM cells (BF01) were co-cultured in vitro with therapeutic antibody (or control immunoglobulin G) and analysed using gene expression profiling Microvesicles from antibody-exposed cells were analysed for differential gene and microRNA (miRNA) expression, and for phenotypic characterisation Exposure of BF01 cells to anti-CD38 antibody resulted in CD38 membrane redistribution, upregulation of metabolism-related genes and downregulation of genes involved in cell cycle processes Microvesicles derived from antibody-exposed cells showed increased CD73 and CD39 expression, presence of programmed death-ligand 1 and significant up-/down-modulation of miRNAs Microvesicles accumulated around immunoglobulin Fc receptor-positive (FcR+ ) cells Upon internalisation, natural killer cells displayed significantly increased expression of genes related to activation and immune response, and downregulation of genes involved in the cell cycle Cells may use microvesicles to transmit signals distally as part of a survival strategy Microvesicles are equipped on their surface with enzymatic machinery leading to production of tolerogenic adenosine Further, they are internalised in FcR+ cells with significant functional modifications These observations have relevance for improving anti-CD38 therapeutic antibodies through targeting this mechanism and its sequelae
TL;DR: In this paper, the authors use single-cell transcriptome and chromatin accessibility profiling to show that distinct transcriptional states co-exist in individual cancer cells and that differential transcriptional regulon usage and enhancer rewiring underlie these alternative transcriptional state.
Abstract: While there is extensive evidence for genetic variation as a basis for treatment resistance, other sources of variation result from cellular plasticity. Using multiple myeloma as an example of an incurable lymphoid malignancy, we show how cancer cells modulate lineage restriction, adapt their enhancer usage and employ cell-intrinsic diversity for survival and treatment escape. By using single-cell transcriptome and chromatin accessibility profiling, we show that distinct transcriptional states co-exist in individual cancer cells and that differential transcriptional regulon usage and enhancer rewiring underlie these alternative transcriptional states. We demonstrate that exposure to standard treatment further promotes transcriptional reprogramming and differential enhancer recruitment while simultaneously reducing developmental potential. Importantly, treatment generates a distinct complement of actionable immunotherapy targets, such as CXCR4, which can be exploited to overcome treatment resistance. Our studies therefore delineate how to transform the cellular plasticity that underlies drug resistance into immuno-oncologic therapeutic opportunities.
TL;DR: The phase 2 GRIFFIN study of daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) for transplant-eligible, newly diagnosed multiple myeloma included a safety run-in phase followed by a randomized phase as mentioned in this paper.
TL;DR: In this article, a two-phase, fragment-based drug discovery (FBDD) effort was proposed to identify isoquinoline fragments that disrupt TNFα ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures.
Abstract: Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFα has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFα ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures. The second phase of discovery focused on the de novo design and optimization of fragments with improved binding efficiency and drug-like properties. The 3-indolinone-based lead presented here displays oral, in vivo efficacy in a mouse glucose-6-phosphate isomerase (GPI)-induced paw swelling model comparable to that seen with a TNFα antibody.
TL;DR: In this paper, a full-length single-cell RNA sequencing (scRNA-seq) was conducted on 3 patients with BRAF-mutated myeloma and 1 healthy donor to investigate if BRAFmutated cancer cells have the ability to ensure their survival by rapidly adapting to BRAF inhibitor treatment.
Abstract: Purpose: Although remarkably effective in some patients, precision medicine typically induces only transient responses despite initial absence of resistance-conferring mutations. Using BRAF-mutated myeloma as a model for resistance to precision medicine we investigated if BRAF-mutated cancer cells have the ability to ensure their survival by rapidly adapting to BRAF inhibitor treatment. Experimental Design: Full-length single-cell RNA (scRNA) sequencing (scRNA-seq) was conducted on 3 patients with BRAF-mutated myeloma and 1 healthy donor. We sequenced 1,495 cells before, after 1 week, and at clinical relapse to BRAF/MEK inhibitor treatment. We developed an in vitro model of dabrafenib resistance using genetically homogeneous single-cell clones from two cell lines with established BRAF mutations (U266, DP6). Transcriptional and epigenetic adaptation in resistant cells were defined by RNA-seq and H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq). Mitochondrial metabolism was characterized by metabolic flux analysis. Results: Profiling by scRNA-seq revealed rapid cellular state changes in response to BRAF/MEK inhibition in patients with myeloma and cell lines. Transcriptional adaptation preceded detectable outgrowth of genetically discernible drug-resistant clones and was associated with widespread enhancer remodeling. As a dominant vulnerability, dependency on oxidative phosphorylation (OxPhos) was induced. In treated individuals, OxPhos was activated at the time of relapse and showed inverse correlation to MAPK activation. Metabolic flux analysis confirmed OxPhos as a preferential energetic resource of drug-persistent myeloma cells. Conclusions: This study demonstrates that cancer cells have the ability to rapidly adapt to precision treatments through transcriptional state changes, epigenetic adaptation, and metabolic rewiring, thus facilitating the development of refractory disease while simultaneously exposing novel vulnerabilities.
TL;DR: Estimated longer term outcomes, including time to next treatment (TTNT), overall survival (OS), time from randomization to disease progression on first subsequent therapy or death (PFS2), and safety are assessed, showing a significant improvement in TTNT and PFS2 compared with Pd.
Abstract: 8017Background: Isa is an approved monoclonal antibody that binds to a specific epitope on the CD38 receptor. The Phase 3 ICARIA-MM study (NCT02990338) demonstrated significantly improved progressi...
Imperial College London1, National and Kapodistrian University of Athens2, Academy of Medical Sciences, United Kingdom3, Charles University in Prague4, French Institute of Health and Medical Research5, University of Ostrava6, King's College7, Nil Ratan Sircar Medical College and Hospital8, Indira Gandhi Institute of Medical Sciences9, University of Alberta10, University Hospitals of Leicester NHS Trust11, St. Vincent's Health System12, Icahn School of Medicine at Mount Sinai13, Baylor University Medical Center14, University of Maryland, College Park15, University of Texas Southwestern Medical Center16, University of Calgary17, University of Bologna18, Harvard University19, Medical University of Silesia20
TL;DR: The phase 3 Boston trial as mentioned in this paper showed that once-weekly selinexor and bortezomib with low-dose dexamethasone (XVd) improved PFS and ORR compared with standard twice-weekly borteasomib and moderate-dose DDA in patients with previously treated multiple myeloma.
Abstract: Elderly and frail patients with multiple myeloma (MM) are more vulnerable to the toxicity of combination therapies, often resulting in treatment modifications and suboptimal outcomes. The phase 3 BOSTON study showed that once-weekly selinexor and bortezomib with low-dose dexamethasone (XVd) improved PFS and ORR compared with standard twice-weekly bortezomib and moderate-dose dexamethasone (Vd) in patients with previously treated MM. This is a retrospective subgroup analysis of the multicenter, prospective, randomized BOSTON trial. Post hoc analyses were performed to compare XVd versus Vd safety and efficacy according to age and frailty status (<65 and ≥65 years, nonfrail and frail). Patients ≥65 years with XVd had higher ORR (OR 1.77, p = .024), ≥VGPR (OR, 1.68, p = .027), PFS (HR 0.55, p = .002), and improved OS (HR 0.63, p = .030), compared with Vd. In frail patients, XVd was associated with a trend towards better PFS (HR 0.69, p = .08) and OS (HR 0.62, p = .062). Significant improvements were also observed in patients <65 (ORR and TTNT) and nonfrail patients (PFS, ORR, ≥VGPR, and TTNT). Patients treated with XVd had a lower incidence of grade ≥ 2 peripheral neuropathy in ≥65 year-old (22% vs. 37%; p = .0060) and frail patients (15% vs. 44%; p = .0002). Grade ≥3 TEAEs were not observed more often in older compared to younger patients, nor in frail compared to nonfrail patients. XVd is safe and effective in patients <65 and ≥65 and in nonfrail and frail patients with previously treated MM.