Publications by authors named "Paul Richardson"

887 Publications

Defibrotide: Real World Management of Veno-Occlusive Disease/ Sinusoidal Obstructive Syndrome after Stem Cell Transplant.

Blood Adv 2021 Oct 19. Epub 2021 Oct 19.

Dana-Farber Cancer Institute, Boston, Massachusetts, United States.

Hepatic veno-occlusive disease or sinusoidal obstructive syndrome (VOD/ SOS) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). Defibrotide is the only FDA-approved medication for the management of severe VOD/ SOS after HSCT. We report our center's experience with commercially available defibrotide as treatment for patients with VOD/SOS. We retrospectively identified 28 cases of VOD/ SOS, based on the European Society for Blood and Marrow Transplantation criteria, from March 2016 through June 2019. The median day of VOD/ SOS onset was 25 days (range, 8 to 69) and defibrotide was initiated on day of diagnosis in 71% of patients. Complete resolution of VOD/ SOS occurred in 75% of patients. Day +100 survival was 64% for all HSCT patients and 53% for those with very severe VOD/ SOS. Response rates and survival were similar in patients with VOD/SOS after myeloablative or reduced intensity chemotherapy HSCT. Therapy related adverse events were mild and included hematuria (43%), epistaxis (18%) and hypotension (11%). Severe hemorrhagic adverse events occurred in 2 patients (pulmonary and upper gastrointestinal hemorrhage; 7%) and both in the setting of progressive VOD/SOS. Early diagnosis, prompt initiation of defibrotide, and minimizing dosing interruptions may be key to successful treatment of VOD/ SOS.
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http://dx.doi.org/10.1182/bloodadvances.2021005410DOI Listing
October 2021

Reply to G. R. Mohyuddin et al and A. Garfall et al.

J Clin Oncol 2021 Oct 15:JCO2102081. Epub 2021 Oct 15.

Paul G. Richardson, MD, Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and Philippe Moreau, MD, University Hospital Hotel Dieu, Nantes, France.

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http://dx.doi.org/10.1200/JCO.21.02081DOI Listing
October 2021

The importance of endothelial protection: the emerging role of defibrotide in reversing endothelial injury and its sequelae.

Bone Marrow Transplant 2021 Sep 28. Epub 2021 Sep 28.

Barcelona Endothelium Team, Josep Carreras Leukaemia Research Institute, Hospital Clinic/University of Barcelona Campus, Barcelona, Spain.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), a potentially life-threatening complication of hematopoietic cell transplantation (HCT), results from prolonged sinusoidal endothelial cell activation and profound endothelial cell damage, with sequelae. Defibrotide, the only drug approved in the United States and Europe for treating VOD/SOS post-HCT, has European Commission orphan drug designation for preventing graft-versus-host disease (GvHD), associated with endothelial dysfunction. This endothelial cell protector and stabilizing agent restores thrombo-fibrinolytic balance and preserves endothelial homeostasis through antithrombotic, fibrinolytic, anti-inflammatory, anti-oxidative, and anti-adhesive activity. Defibrotide also preserves endothelial cell structure by inhibiting heparanase activity. Evidence suggests that downregulating p38 mitogen-activated protein kinase (MAPK) and histone deacetylases (HDACs) is key to defibrotide's endothelial protective effects; phosphatidylinositol 3-kinase/Akt (PI3K/AKT) potentially links defibrotide interaction with the endothelial cell membrane and downstream effects. Despite defibrotide's being most extensively studied in VOD/SOS, emerging preclinical and clinical data support defibrotide for treating or preventing other conditions driven by endothelial cell activation, dysfunction, and/or damage, such as GvHD, transplant-associated thrombotic microangiopathy, or chimeric antigen receptor T-cell (CAR-T) therapy-associated neurotoxicity, underpinned by cytokine release syndrome and endotheliitis. Further preclinical and clinical studies will explore defibrotide's potential utility in a broader range of disorders resulting from endothelial cell activation and dysfunction.
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http://dx.doi.org/10.1038/s41409-021-01383-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477726PMC
September 2021

Bortezomib induces anti-multiple myeloma immune response mediated by cGAS/STING pathway activation.

Blood Cancer Discov 2021 Sep 23;2(5):468-483. Epub 2021 Apr 23.

Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA.

Proteasome inhibitor bortezomib induces apoptosis in multiple myeloma (MM) cells, and has transformed patient outcome. Using as well as 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 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.
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http://dx.doi.org/10.1158/2643-3230.bcd-21-0047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462183PMC
September 2021

A phase I/II study of ixazomib, pomalidomide, and dexamethasone for lenalidomide and proteasome inhibitor refractory multiple myeloma (Alliance A061202).

Am J Hematol 2021 Sep 24. Epub 2021 Sep 24.

Division of Hematology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.

Preclinical studies have demonstrated activity of the oral proteasome inhibitor (PI) ixazomib (IXA) in bortezomib-resistant multiple myeloma (MM) and synergy with immunomodulatory drugs. We therefore conducted a phase I/II study to establish the safety and preliminary efficacy of IXA with pomalidomide (POM) and dexamethasone (DEX) in lenalidomide (LEN)/PI-refractory MM. Dose escalation established a 4 mg dose of POM and IXA and 20/40 mg dose of DEX as the maximum tolerated dose. The phase II portion of the trial was redesigned and started anew after six patients had been randomized to IXA-POM-DEX due to a rapidly changing treatment landscape. Among the 29 evaluable LEN/PI-refractory patients treated with IXA-POM-DEX in phase I/II, the overall response rate (partial response or better) was 51.7% with a median duration of response of 16.8 months (range 56 days to 4.1 years), median progression-free survival of 4.4 months (95% confidence interval [CI]: 3.0-18.4), and median overall survival of 34.3 months (95% CI: 19.2 to not reached). Hematologic, gastrointestinal, and constitutional adverse events were common and consistent with the side-effect profiles of the individual agents. Our results support further evaluation of this all-oral regimen in relapsed/refractory MM.
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http://dx.doi.org/10.1002/ajh.26361DOI Listing
September 2021

Isatuximab for relapsed/refractory multiple myeloma: review of key subgroup analyses from the Phase III ICARIA-MM study.

Future Oncol 2021 Sep 15. Epub 2021 Sep 15.

Department of Clinical Therapeutics, National & Kapodistrian University of Athens, Athens 157 72, Greece.

In the Phase III ICARIA-MM study (NCT02990338), the addition of the anti-CD38 monoclonal antibody isatuximab to pomalidomide and dexamethasone led to increased progression-free survival and improved response rates in patients with relapsed/refractory multiple myeloma. There is an unmet treatment need, particularly among patients with poor prognoses, including those with high-risk cytogenetics, those who have renal impairment, those who are elderly and those who are refractory to prior lines of treatment. In this review, the subgroup analyses from the ICARIA-MM study, representing subpopulations with poor prognostic factors, are discussed. Overall, the addition of isatuximab to pomalidomide and dexamethasone improved progression-free survival and disease response rates across different subgroups, regardless of prognostic factor.
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http://dx.doi.org/10.2217/fon-2021-0568DOI Listing
September 2021

Endothelial dysfunction and its critical role in COVID-19-associated coagulopathy: Defibrotide as an endothelium-protective, targeted therapy.

EJHaem 2021 Jun 22. Epub 2021 Jun 22.

Department of Medicine Hematopoietic Transplant and Cellular Therapy Unit IMIB-Arrixaca Virgen de la Arrixaca University Hospital University of Murcia Murcia Spain.

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http://dx.doi.org/10.1002/jha2.198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426874PMC
June 2021

Single-Cell Profiling Reveals Metabolic Reprogramming as a Resistance Mechanism in -Mutated Multiple Myeloma.

Clin Cancer Res 2021 Sep 13. Epub 2021 Sep 13.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Purpose: Although remarkably effective in some patients, precision medicine typically induces only transient responses despite initial absence of resistance-conferring mutations. Using -mutated myeloma as a model for resistance to precision medicine we investigated if 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 -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 model of dabrafenib resistance using genetically homogeneous single-cell clones from two cell lines with established 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.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2040DOI Listing
September 2021

Pomalidomide, bortezomib, and dexamethasone at first relapse in lenalidomide-pretreated myeloma: A subanalysis of OPTIMISMM by clinical characteristics.

Eur J Haematol 2021 Sep 8. Epub 2021 Sep 8.

National and Kapodistrian University of Athens, Athens, Greece.

Objective: We evaluated the efficacy and safety of pomalidomide, bortezomib, and dexamethasone (PVd) vs bortezomib and dexamethasone (Vd) by age, renal function, and high-risk cytogenetic abnormalities in lenalidomide-pretreated patients with multiple myeloma at first relapse.

Methods: OPTIMISMM was a phase 3, multicenter, open-label, randomized study (NCT01734928; N = 559). The primary endpoint was progression-free survival (PFS).

Results: Overall, 226 patients had received one prior line of therapy. PVd significantly prolonged PFS vs Vd in patients aged ≤65 years (median, 22.0 vs 13.1 months; P = .0258) and >65 years (median, 17.6 vs 9.9 months; P = .0369). Median PFS in patients with renal impairment (RI; creatinine clearance <60 mL/min) was 15.1 months with PVd vs 9.5 months with Vd (hazard ratio [HR], 0.67 [95% CI, 0.34-1.34]). In patients without RI, median PFS was 22.0 vs 13.1 months (HR, 0.45 [95% CI, 0.27-0.76]). In patients with high-risk cytogenetics, median PFS was 14.7 vs 9.9 months (HR, 0.39 [95% CI, 0.13-1.17]). PVd significantly improved overall response rate vs Vd in all subgroups. The safety profile of PVd was consistent with previous reports.

Conclusions: These findings confirmed the benefits of PVd at first relapse, including in patients with poor prognostic factors.
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http://dx.doi.org/10.1111/ejh.13706DOI Listing
September 2021

Quality of life analyses in patients with multiple myeloma: results from the Selinexor (KPT-330) Treatment of Refractory Myeloma (STORM) phase 2b study.

BMC Cancer 2021 Sep 6;21(1):993. Epub 2021 Sep 6.

Lineberger Comprehensive Cancer Center at University of North Carolina-Chapel Hill, Chapel Hill, USA.

Background: Selinexor is an oral, selective nuclear export inhibitor. STORM was a phase 2b, single-arm, open-label, multicenter trial of selinexor with low dose dexamethasone in patients with penta-exposed relapsed/refractory multiple myeloma (RRMM) that met its primary endpoint, with overall response of 26% (95% confidence interval [CI], 19 to 35%). Health-related quality of life (HRQoL) was a secondary endpoint measured using the Functional Assessment of Cancer Therapy - Multiple Myeloma (FACT-MM). This study examines impact of selinexor treatment on HRQoL of patients treated in STORM and reports two approaches to calculate minimal clinically important differences for the FACT-MM.

Methods: FACT-MM data were collected at baseline, on day 1 of each 4-week treatment cycle, and at end of treatment (EOT). Changes from baseline were analyzed for the FACT-MM total score, FACT-trial outcome index (TOI), FACT-General (FACT-G), and the MM-specific domain using mixed-effects regression models. Two approaches for evaluating minimal clinically important differences were explored: the first defined as 10% of the instrument range, and the second based on estimated mean baseline differences between Eastern Cooperative Oncology Group performance status (ECOG PS) scores. Post-hoc difference analysis compared change in scores from baseline to EOT for treatment responders and non-responders.

Results: Eighty patients were included in the analysis; the mean number of prior therapies was 7.9 (standard deviation [SD] 3.1), and mean duration of myeloma was 7.6 years (SD 3.4). Each exploratory minimal clinically important difference threshold yielded consistent results whereby most patients did not experience HRQoL decline during the first six cycles of treatment (range: 53.9 to 75.7% for the first approach; range: 52.6 to 72.9% for the second). Treatment responders experienced less decline in HRQoL from baseline to EOT than non-responders, which was significant for the FACT-G, but not for other scores.

Conclusion: The majority of patients did not experience decline in HRQoL based on minimal clinically important differences during early cycles of treatment with selinexor and dexamethasone in the STORM trial. An anchor-based approach utilizing patient-level data (ECOG PS score) to define minimal clinically important differences for the FACT-MM gave consistent results with a distribution-based approach.

Trial Registration: This trial was registered on ClinicalTrials.gov under the trial-ID NCT02336815 on January 8, 2015.
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http://dx.doi.org/10.1186/s12885-021-08453-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419947PMC
September 2021

Engaging People Who Inject Drugs Living With HIV in Antiretroviral Treatment and Medication for Opioid Use Disorder: Extended Follow-up of HIV Prevention Trials Network (HPTN) 074.

Open Forum Infect Dis 2021 Aug 29;8(8):ofab281. Epub 2021 May 29.

Division of Infectious Diseases, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Background: People who inject drugs (PWID) living with HIV experience inadequate access to antiretroviral treatment (ART) and medication for opioid use disorders (MOUD). HPTN 074 showed that an integrated intervention increased ART use and viral suppression over 52 weeks. To examine durability of ART, MOUD, and HIV viral suppression, participants could re-enroll for an extended follow-up period, during which standard-of-care (SOC) participants in need of support were offered the intervention.

Methods: Participants were recruited from Ukraine, Indonesia and Vietnam and randomly allocated 3:1 to SOC or intervention. Eligibility criteria included: HIV-positive; active injection drug use; 18-60 years of age; ≥1 HIV-uninfected injection partner; and viral load ≥1,000 copies/mL. Re-enrollment was offered to all available intervention and SOC arm participants, and SOC participants in need of support (off-ART or off-MOUD) were offered the intervention.

Results: The intervention continuation group re-enrolled 89 participants, and from week 52 to 104, viral suppression (<40 copies/mL) declined from 41% to 29% (estimated 9.4% decrease per year, 95% CI -17.0%; -1.8%). The in need of support group re-enrolled 94 participants and had increased ART (re-enrollment: 55%, week 26: 69%) and MOUD (re-enrollment: 16%, week 26: 25%) use, and viral suppression (re-enrollment: 40%, week 26: 49%).

Conclusions: Viral suppression declined in year 2 for those who initially received the HPTN 074 intervention and improved maintenance support is warranted. Viral suppression and MOUD increased among in need participants who received intervention during the study extension. Continued efforts are needed for widespread implementation of this scalable, integrated intervention.
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http://dx.doi.org/10.1093/ofid/ofab281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391093PMC
August 2021

Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women.

N Engl J Med 2021 08;385(7):595-608

From the Center for Clinical AIDS Research and Education, David Geffen School of Medicine, University of California, Los Angeles (R.J.L., R.M.K.), the Lundquist Institute at Harbor-UCLA Medical Center, Torrance (E.D.), the San Francisco Department of Public Health, San Francisco (H.S.), and Gilead Sciences, Foster City (J.F.R.) - all in California; the Fred Hutchinson Cancer Research Center, Seattle (D.D., B.H., L. Cottle, M.L., Z.W.); the Louisiana State University Health Sciences Center, New Orleans (M.E.C.); Instituto Nacional de Infectologia Evandro Chagas-Fiocruz, Rio de Janeiro (L. Coelho, B.G.), University of São Paulo (E.G.K.), and Centro de Referência e Treinamento DST-AIDS-SP (J.V.M.), São Paulo, and Hospital Nossa Senhora da Conceição, Porto Alegre (B.S.) - all in Brazil; Via Libre (R.C.), Universidad Nacional Mayor de San Marcos (J.A.G.-C.), and Asociacion Civil Impacta Salud y Educacion (P.G., J.V.H.), Lima, and Asociacion Civil Selva Amazonica, Iquitos (J.C.H.) - all in Peru; the Research Institute for Health Sciences, Chiang Mai University, Chiang Mai (S.C.), and the Institute of HIV Research and Innovation, Bangkok (N.P.) - both in Thailand; the Division of HIV-AIDS Prevention, Centers for Disease Control and Prevention (E.F.D.), the School of Medicine (C.F.K., C.R.), and Rollins School of Public Health (C.R.), Emory University - both in Atlanta; the Perelman School of Medicine, University of Pennsylvania, Philadelphia (I.F.), and Pennsylvania State University, State College (S.D.F.) - both in Pennsylvania; St. Jude Children's Research Hospital, Memphis, TN (A.H.G.); University of North Carolina at Chapel Hill, Chapel Hill (H.V.T., J.J.E., M.S.C.), FHI 360, Durham (A. Asmelash, M.B., C.B., J.L., N.D.S., K.G.-F., A.J., M.M.), and ViiV Healthcare, Research Triangle (K.Y.S., W.S., D.M., A.R.) - all in North Carolina; Hospital General de Agudos José María Ramos Mejia (M.H.L.) and Fundación Huésped (O.S.) - both in Buenos Aires; the Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa (K.M.); University of Alabama at Birmingham, Birmingham (E.T.O., J.M.); Rutgers New Jersey Medical School, Newark (S. Swaminathan); Weill Cornell Medicine, New York (R.M.G.); Johns Hopkins University, Baltimore (P.R., P.S., E.P.-M., M.M., C.H., T.T.B., S.H.E., J.S.); University of Colorado Anschutz Medical Campus, Aurora (P.A.); Massachusetts General Hospital, Boston (C.P.); University of Miami, Coral Gables, FL (S. Safren); the Office of AIDS Research (T.H.H.) and Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD (K.S., A. Adeyeye).

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 preventing HIV infection.

Methods: We conducted a randomized, double-blind, double-dummy, noninferiority trial to compare long-acting injectable cabotegravir (CAB-LA, an integrase strand-transfer inhibitor [INSTI]) at a dose of 600 mg, given intramuscularly every 8 weeks, with daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for the prevention of HIV infection in at-risk cisgender men who have sex with men (MSM) and in at-risk transgender women who have sex with men. Participants were randomly assigned (1:1) to receive one of the two regimens and were followed for 153 weeks. HIV testing and safety evaluations were performed. The primary end point was incident HIV infection.

Results: The intention-to-treat population included 4566 participants who underwent randomization; 570 (12.5%) identified as transgender women, and the median age was 26 years (interquartile range, 22 to 32). The trial was stopped early for efficacy on review of the results of the first preplanned interim end-point analysis. Among 1698 participants from the United States, 845 (49.8%) identified as Black. Incident HIV infection occurred in 52 participants: 13 in the cabotegravir group (incidence, 0.41 per 100 person-years) and 39 in the TDF-FTC group (incidence, 1.22 per 100 person-years) (hazard ratio, 0.34; 95% confidence interval, 0.18 to 0.62). The effect was consistent across prespecified subgroups. Injection-site reactions were reported in 81.4% of the participants in the cabotegravir group and in 31.3% of those in the TDF-FTC group. In the participants in whom HIV infection was diagnosed after exposure to CAB-LA, INSTI resistance and delays in the detection of HIV infection were noted. No safety concerns were identified.

Conclusions: CAB-LA was superior to daily oral TDF-FTC in preventing HIV infection among MSM and transgender women. Strategies are needed to prevent INSTI resistance in cases of CAB-LA PrEP failure. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 083 ClinicalTrials.gov number, NCT02720094.).
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http://dx.doi.org/10.1056/NEJMoa2101016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448593PMC
August 2021

Panobinostat From Bench to Bedside: Rethinking the Treatment Paradigm for Multiple Myeloma.

Clin Lymphoma Myeloma Leuk 2021 Jun 26. Epub 2021 Jun 26.

Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY. Electronic address:

Relapsed and refractory multiple myeloma (RRMM) presents a therapeutic challenge due to the development of drug resistance. Panobinostat is an oral histone deacetylase inhibitor (HDACi) that affects multiple cellular pathways and has demonstrated the ability to resensitize refractory-multiple myeloma cells in preclinical studies, as well as in patients with RRMM in clinical trials. Synergy of panobinostat with a number of different classes of antimyeloma drugs (proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies) has also been shown. Panobinostat is a promising HDACi for the treatment of multiple myeloma. Here, we present a comprehensive review of preclinical and clinical studies of panobinostat.
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http://dx.doi.org/10.1016/j.clml.2021.06.020DOI Listing
June 2021

Targeting LAG3/GAL-3 to overcome immunosuppression and enhance anti-tumor immune responses in multiple myeloma.

Leukemia 2021 Jul 21. Epub 2021 Jul 21.

Dana-Farber Cancer Institute, Boston, MA, USA.

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.
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http://dx.doi.org/10.1038/s41375-021-01301-6DOI Listing
July 2021

Enhancement of peripheral seal of medical face masks using a 3-dimensional-printed custom frame.

J Am Dent Assoc 2021 Jul;152(7):542-550

Background: During the COVID-19 pandemic, American Society for Testing and Materials level 3 and level 2 medical face masks (MFMs) have been used for most health care workers and even for the first responders owing to a shortage of N95 respirators. However, the MFMs lack effective peripheral seal, leading to concerns about their adequacy to block aerosol exposure for proper protection. The purpose of this study was to evaluate the peripheral seal of level 3 and level 2 MFMs with a 3-dimensional (3D-) printed custom frame.

Methods: Level 3 and level 2 MFMs were tested on 10 participants with and without a 3D-printed custom frame; the efficiency of mask peripheral seal was determined by means of quantitative fit testing using a PortaCount Fit Tester based on ambient aerosol condensation nuclei counter protocol.

Results: The 3D-printed custom frame significantly improved the peripheral seal of both level 3 and level 2 MFMs compared with the masks alone (P < .001). In addition, both level 3 and level 2 MFMs with the 3D-printed custom frame met the quantitative fit testing standard specified for N95 respirators.

Practical Implications: The 3D-printed custom frame over level 3 and level 2 MFMs can offer enhanced peripheral reduction of aerosols when using collapsible masks. With the shortage of N95 respirators, using the 3D-printed custom frame over a level 3 or level 2 MFM is considered a practical alternative to dental professionals.
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http://dx.doi.org/10.1016/j.adaj.2021.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486490PMC
July 2021

Distinctive Biomarker Features in The Endotheliopathy of COVID-19 and Septic Syndromes.

Shock 2021 Jun 24. Epub 2021 Jun 24.

Medical Intensive Care Unit, Hospital Clinic, Barcelona, Spain Hematopathology, Pathology Department, CDB, Hospital Clinic, Barcelona, Spain Barcelona Endothelium Team, Barcelona, Spain IDIBAPS, Barcelona, Spain Josep Carreras Leukaemia Research Institute, Hospital Clinic, University of Barcelona, Barcelona, Spain School of Medicine, University of Barcelona, Barcelona, Spain Frank H. Netter M.D. School of Medicine at Quinnipiac University, North Haven, Connecticut Department of Surgery, Yale University School of Medicine, New Haven, Connecticut Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, Virgen de la Arrixaca University Hospital, University of Murcia, Murcia, Spain Department of Oncology and Hematology, Humanitas Clinical and Research Center-IRCCS, Rozzano-Milano, Italy Department of Biomedical Sciences, Humanitas University, Rozzano-Milano, Italy Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Boston, Massachusetts.

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 (n = 49) were classified into moderate, severe, or critical (life-threatening) disease. Plasma samples were collected within 48 to 72 h 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 (n = 45). Results in critically ill COVID-19 patients were compared with other intensive care unit (ICU) patients with septic shock (SS, n = 14), sepsis (S, n = 7), and noninfectious systemic inflammatory response syndrome (NI-SIRS, n = 7).

Results: All analyzed biomarkers were increased in COVID-19 patients versus controls (P < 0.001), 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 (P < 0.05). 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 (P < 0.001). Furthermore, α2-antiplasmin activity was higher in critical COVID-19 versus NI-SIRS (P < 0.01) and SS (P < 0.001), whereas PAI-1 levels were significantly lower in COVID-19 patients compared with NI-SIRS, S, and SS patients (P < 0.01).

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.
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http://dx.doi.org/10.1097/SHK.0000000000001823DOI Listing
June 2021

Defibrotide: potential for treating endothelial dysfunction related to viral and post-infectious syndromes.

Expert Opin Ther Targets 2021 06 25;25(6):423-433. Epub 2021 Jun 25.

Department of Medicine, Stem Cell Transplant and Cell Therapy Unit, IMIB-Arrixaca, Virgen De La Arrixaca University Hospital, University of Murcia, Murcia, Spain.

Introduction: Defibrotide (DF) is a polyribonucleotide with antithrombotic, pro-fibrinolytic, and anti-inflammatory effects on endothelium. These effects and the established safety of DF present DF as a strong candidate to treat viral and post-infectious syndromes involving endothelial dysfunction.

Areas Covered: We discuss DF and other therapeutic agents that have the potential to target endothelial components of pathogenesis in viral and post-infectious syndromes. We introduce defibrotide (DF), describe its mechanisms of action, and explore its established pleiotropic effects on the endothelium. We describe the established pathophysiology of Coronavirus Disease 2019 (COVID-19) and highlight the processes specific to COVID-19 potentially modulated by DF. We also present influenza A and viral hemorrhagic fevers, especially those caused by hantavirus, Ebola virus, and dengue virus, as viral syndromes in which DF might serve therapeutic benefit. Finally, we offer our opinion on novel treatment strategies targeting endothelial dysfunction in viral infections and their severe manifestations.

Expert Opinion: Given the critical role of endothelial dysfunction in numerous infectious syndromes, in particular COVID-19, therapeutic pharmacology for these conditions should increasingly prioritize endothelial stabilization. Several agents with endothelial protective properties should be further studied as treatments for severe viral infections and vasculitides, especially where other therapeutic modalities have failed.
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http://dx.doi.org/10.1080/14728222.2021.1944101DOI Listing
June 2021

Final Overall Survival Analysis of the TOURMALINE-MM1 Phase III Trial of Ixazomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma.

J Clin Oncol 2021 Aug 11;39(22):2430-2442. Epub 2021 Jun 11.

University Hospital Hôtel Dieu, Nantes, France.

Purpose: The double-blind, placebo-controlled, phase III TOURMALINE-MM1 study demonstrated a statistically significant improvement in progression-free survival with ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd in patients with relapsed or refractory multiple myeloma. We report the final analyses for overall survival (OS).

Patients And Methods: Patients were randomly assigned to ixazomib-Rd (n = 360) or placebo-Rd (n = 362), stratified by number of prior therapies (1 2 or 3), previous proteasome inhibitor (PI) exposure (yes no), and International Staging System disease stage (I or II III). OS (intent-to-treat population) was a key secondary end point.

Results: With a median follow-up of 85 months, median OS with ixazomib-Rd versus placebo-Rd was 53.6 versus 51.6 months (hazard ratio, 0.939; = .495). Lower hazard ratios, indicating larger magnitude of OS benefit with ixazomib-Rd versus placebo-Rd, were seen in predefined subgroups: refractory to any (0.794) or last (0.742) treatment line; age > 65-75 years (0.757); International Staging System stage III (0.779); 2/3 prior therapies (0.845); high-risk cytogenetics (0.870); and high-risk cytogenetics and/or 1q21 amplification (0.862). Following ixazomib-Rd versus placebo-Rd, 71.7% versus 69.9% of patients received ≥ 1 anticancer therapy, of whom 24.7% versus 33.9% received daratumumab and 71.8% versus 76.9% received PIs (next-line therapy: 47.5% 55.8%). Rates of new primary malignancies were similar with ixazomib-Rd (10.3%) and placebo-Rd (11.9%). There were no new or additional safety concerns.

Conclusion: Median OS values in both arms were the longest reported in phase III studies of Rd-based triplets in relapsed or refractory multiple myeloma at the time of this analysis; progression-free survival benefit with ixazomib-Rd versus placebo-Rd did not translate into a statistically significant OS benefit on intent-to-treat analysis. OS benefit was greater in subgroups with adverse prognostic factors. OS interpretation was confounded by imbalances in subsequent therapies received, especially PIs and daratumumab.
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http://dx.doi.org/10.1200/JCO.21.00972DOI Listing
August 2021

Is the Endothelium the Missing Link in the Pathophysiology and Treatment of COVID-19 Complications?

Cardiovasc Drugs Ther 2021 Jun 7. Epub 2021 Jun 7.

School of Medicine, University of Barcelona, Barcelona, Spain.

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.
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http://dx.doi.org/10.1007/s10557-021-07207-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181544PMC
June 2021

Merging C(sp)-H activation with DNA-encoding.

Chem Sci 2020 Sep 7;11(45):12282-12288. Epub 2020 Sep 7.

Department of Chemistry, The Scripps Research Institute 10550 North Torrey Pines Road, La Jolla CA 92037 USA

DNA-encoded library (DEL) technology has the potential to dramatically expedite hit identification in drug discovery owing to its ability to perform protein affinity selection with millions or billions of molecules in a few experiments. To expand the molecular diversity of DEL, it is critical to develop different types of DNA-encoded transformations that produce billions of molecules with distinct molecular scaffolds. Sequential functionalization of multiple C-H bonds provides a unique avenue for creating diversity and complexity from simple starting materials. However, the use of water as solvent, the presence of DNA, and the extremely low concentration of DNA-encoded coupling partners (0.001 M) have hampered the development of DNA-encoded C(sp)-H activation reactions. Herein, we report the realization of palladium-catalyzed C(sp)-H arylation of aliphatic carboxylic acids, amides and ketones with DNA-encoded aryl iodides in water. Notably, the present method enables the use of alternative sets of monofunctional building blocks, providing a linchpin to facilitate further setup for DELs. Furthermore, the C-H arylation chemistry enabled the on-DNA synthesis of structurally-diverse scaffolds containing enriched C(sp) character, chiral centers, cyclopropane, cyclobutane, and heterocycles.
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http://dx.doi.org/10.1039/d0sc03935gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162953PMC
September 2020

ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment.

Sci Adv 2021 Jun 4;7(23). Epub 2021 Jun 4.

Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Immunomodulatory drugs (IMiDs) have markedly improved patient outcome in multiple myeloma (MM); however, resistance to IMiDs commonly underlies relapse of disease. Here, we identify that tumor necrosis factor (TNF) receptor-associated factor 2 () knockdown (KD)/knockout (KO) in MM cells mediates IMiD resistance via activation of noncanonical nuclear factor κB (NF-κB) and extracellular signal-regulated kinase (ERK) signaling. Within MM bone marrow (BM) stromal cell supernatants, TNF-α induces proteasomal degradation of TRAF2, noncanonical NF-κB, and downstream ERK signaling in MM cells, whereas interleukin-6 directly triggers ERK activation. RNA sequencing of MM patient samples shows nearly universal ERK pathway activation at relapse on lenalidomide maintenance therapy, confirming its clinical relevance. Combination MEK inhibitor treatment restores IMiD sensitivity of KO cells both in vitro and in vivo. Our studies provide the framework for clinical trials of MEK inhibitors to overcome IMiD resistance in the BM microenvironment and improve patient outcome in MM.
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http://dx.doi.org/10.1126/sciadv.abg2697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177702PMC
June 2021

Applications of fluorine to the construction of bioisosteric elements for the purposes of novel drug discovery.

Authors:
Paul Richardson

Expert Opin Drug Discov 2021 Jun 10:1-26. Epub 2021 Jun 10.

Oncology Medicinal Chemistry, WRD, Pfizer-La Jolla, USA.

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. 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. 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.
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http://dx.doi.org/10.1080/17460441.2021.1933427DOI Listing
June 2021

Selinexor, bortezomib, and dexamethasone versus bortezomib and dexamethasone in previously treated multiple myeloma: Outcomes by cytogenetic risk.

Am J Hematol 2021 09 5;96(9):1120-1130. Epub 2021 Jul 5.

Karyopharm Therapeutics Inc., Newton, Massachusetts, USA.

In the phase 3 BOSTON study, patients with multiple myeloma (MM) after 1-3 prior regimens were randomized to once-weekly selinexor (an oral inhibitor of exportin 1 [XPO1]) plus bortezomib-dexamethasone (XVd) or twice-weekly bortezomib-dexamethasone (Vd). Compared with Vd, XVd was associated with significant improvements in median progression-free survival (PFS), overall response rate (ORR), and lower rates of peripheral neuropathy, with trends in overall survival (OS) favoring XVd. In BOSTON, 141 (35.1%) patients had MM with high-risk (presence of del[17p], t[4;14], t[14;16], or ≥4 copies of amp1q21) cytogenetics (XVd, n = 70; Vd, n = 71), and 261 (64.9%) exhibited standard-risk cytogenetics (XVd, n = 125; Vd, n = 136). Among patients with high-risk MM, median PFS was 12.91 months for XVd and 8.61 months for Vd (HR, 0.73 [95% CI, (0.4673, 1.1406)], p = 0.082), and ORRs were 78.6% and 57.7%, respectively (OR 2.68; p = 0.004). In the standard-risk subgroup, median PFS was 16.62 months for XVd and 9.46 months for Vd (HR 0.61; p = 0.004), and ORRs were 75.2% and 64.7%, respectively (OR 1.65; p = 0.033). The safety profiles of XVd and Vd in both subgroups were consistent with the overall population. These data suggest that selinexor can confer benefits to patients with MM regardless of cytogenetic risk. ClinicalTrials.gov identifier: NCT03110562.
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http://dx.doi.org/10.1002/ajh.26261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457116PMC
September 2021

Final results of a phase 1b study of isatuximab short-duration fixed-volume infusion combination therapy for relapsed/refractory multiple myeloma.

Leukemia 2021 May 28. Epub 2021 May 28.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Part B of this phase 1b study (ClinicalTrials.gov number, NCT02283775) evaluated safety and efficacy of a fixed-volume infusion of isatuximab, an anti-CD38 monoclonal antibody, in combination with pomalidomide and dexamethasone (Pd) in relapsed/refractory multiple myeloma patients. Isatuximab (10 mg/kg weekly for 4 weeks, then every other week) was administered as a fixed-volume infusion of 250 mL (mL/h infusion rate) with standard doses of Pd on 28-day cycles. Patients (N = 47) had a median of three prior treatment lines (range, 1-8). Median duration of exposure was 36.9 weeks and median duration of first, second, and 3+ infusions were 3.7, 1.8, and 1.2 h, respectively. The most common non-hematologic treatment-emergent adverse events were fatigue (63.8%), infusion reactions (IRs), cough, and upper respiratory tract infection (40.4% each). IRs were all grade 2 and occurred only during the first infusion. The overall response rate was 53.2% in all patients (55.5% in response-evaluable population, 60.0% in daratumumab-naïve patients). Efficacy and safety findings were consistent with data from the isatuximab plus Pd infusion schedule in Part A of this study and also from the phase 3 ICARIA-MM study, and these new data confirm the safety, efficacy, and feasibility of fixed-volume infusion of isatuximab.
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http://dx.doi.org/10.1038/s41375-021-01262-wDOI Listing
May 2021

A clinical investigation of dental evacuation systems in reducing aerosols.

J Am Dent Assoc 2021 06;152(6):455-462

Background: The route of transmission of severe acute respiratory syndrome coronavirus 2 has challenged dentistry to improve the safety for patients and the dental team during various treatment procedures. The purpose of this study was to evaluate and compare the effectiveness of dental evacuation systems in reducing aerosols during oral prophylactic procedures in a large clinical setting.

Methods: This was a single-center, controlled clinical trial using a split-mouth design. A total of 93 student participants were recruited according to the inclusion and exclusion criteria. Aerosol samples were collected on blood agar plates that were placed around the clinic at 4 treatment periods: baseline, high-volume evacuation (HVE), combination (HVE and intraoral suction device), and posttreatment. Student operators were randomized to perform oral prophylaxis using ultrasonic scalers on 1 side of the mouth, using only HVE suction for the HVE treatment period and then with the addition of an intraoral suction device for the combination treatment period. Agar plates were collected after each period and incubated at 37 °C for 48 hours. Colony-forming unit (CFU) counts were determined using an automatic colony counter.

Results: The use of a combination of devices resulted in significant reductions in CFUs compared with the use of the intraoral suction device alone (P < .001). The highest amounts of CFUs were found in the operating zone and on patients during both HVE and combination treatment periods.

Conclusions: Within limitations of this study, the authors found significant reductions in the amount of microbial aerosols when both HVE and an intraoral suction device were used.

Practical Implications: The combination of HVE and intraoral suction devices significantly decreases microbial aerosols during oral prophylaxis procedures.
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http://dx.doi.org/10.1016/j.adaj.2021.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142318PMC
June 2021

Subgroup analysis of ICARIA-MM study in relapsed/refractory multiple myeloma patients with high-risk cytogenetics.

Br J Haematol 2021 Jul 25;194(1):120-131. Epub 2021 May 25.

Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Treatment benefit in multiple myeloma (MM) patients with high-risk cytogenetics remains suboptimal. The phase 3 ICARIA-MM trial (NCT02990338) showed that isatuximab plus pomalidomide-dexamethasone prolongs median progression-free survival (mPFS) in patients with relapsed/refractory MM (RRMM). This subgroup analysis of ICARIA-MM compared the benefit of isatuximab in high-risk [defined by the presence of del(17p), t(4;14) or t(14;16)] versus standard-risk patients. The efficacy of isatuximab in patients with gain(1q21) abnormality was also assessed in a retrospective subgroup analysis. In ICARIA-MM, 307 patients received isatuximab-pomalidomide-dexamethasone (n = 154) or pomalidomide-dexamethasone (n = 153). Isatuximab (10 mg/kg intravenously) was given weekly in the first 28-day cycle, and every other week thereafter. Standard pomalidomide-dexamethasone doses were given. Isatuximab-pomalidomide-dexamethasone improved mPFS (7·5 vs 3·7 months; HR, 0·66; 95% CI, 0·33-1·28) and overall response rate (ORR, 50·0% vs 16·7%) in high-risk patients. In patients with isolated gain(1q21), isatuximab addition improved mPFS (11·2 vs 4·6 months; HR, 0·50; 95% CI, 0·28-0·88) and ORR (53·6% vs 27·6%). More grade ≥3 adverse events occurred in high-risk patients receiving isatuximab (95·7%) versus the control group (67·6%); however, isatuximab did not increase events leading to discontinuation or treatment-related mortality. Isatuximab-pomalidomide-dexamethasone provides a consistent benefit over pomalidomide-dexamethasone treatment in RRMM patients regardless of cytogenetic risk.
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http://dx.doi.org/10.1111/bjh.17499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361732PMC
July 2021

Selinexor for the treatment of patients with previously treated multiple myeloma.

Expert Rev Hematol 2021 Aug 21;14(8):697-706. Epub 2021 Jul 21.

Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Introduction: Multiple myeloma (MM) is an increasingly treatable but still incurable hematologic malignancy. Prognosis has improved significantly over recent years, although further advances remain urgently needed, especially for patients with heavily pre-treated and resistant disease for whom there are limited options. Selinexor is a first-in-class, oral, selective inhibitor of nuclear export (SINE) compound that triggers apoptosis in malignant cells by inducing nuclear retention of oncogene messenger RNAs (mRNAs) and reactivation of tumor suppressor proteins (TSPs). In clinical studies of patients with relapsed and/or refractory MM, selinexor has demonstrated both manageable toxicity and encouraging efficacy.

Areas Covered: This review will provide an overview of the mechanism of action of selinexor as well as the efficacy and safety data from clinical studies using selinexor for the treatment of multiple myeloma.

Expert Opinion: Long-term outcomes for patients with MM will continue to improve due to numerous recent and imminent therapeutic advances, although critical areas of unmet need remain. Oral selinexor is likely to contribute to the meeting of these needs and the further advancement of MM therapy in a meaningful way.
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http://dx.doi.org/10.1080/17474086.2021.1923473DOI Listing
August 2021

Improving outcomes for patients with relapsed multiple myeloma: Challenges and considerations of current and emerging treatment options.

Blood Rev 2021 09 9;49:100808. Epub 2021 Feb 9.

Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Boston, MA, USA.

Despite the recent introduction of new therapies for multiple myeloma (MM), it remains an incurable disease. As MM progresses, patients experience cycles of relapse and remission, with remission periods becoming increasingly shorter as the disease becomes less treatment-sensitive. The treatment of relapsed refractory MM (RRMM) remains a significant clinical challenge. Patients with RRMM are a highly heterogeneous group and choosing the most appropriate treatment requires careful consideration. Furthermore, the number of treatment options for MM is continually growing with no definitive consensus to guide treating clinicians. The emergence of second-generation proteasome inhibitors (e.g., carfilzomib and ixazomib), immunomodulatory drugs (e.g., pomalidomide) and monoclonal antibodies (e.g., isatuximab) has expanded an already complex treatment landscape. This review provides a clear summary of the available treatments for MM and discusses how to tailor treatments to individual patients' needs. Novel treatments currently under clinical development, including venetoclax, melflufen and CAR T-cell therapies, are also discussed.
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http://dx.doi.org/10.1016/j.blre.2021.100808DOI Listing
September 2021
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