Showing papers by "Paul G. Richardson published in 2016"
Mayo Clinic1, University of Navarra2, Harvard University3, Cedars-Sinai Medical Center4, Memorial Sloan Kettering Cancer Center5, Emory University6, National and Kapodistrian University of Athens7, Mount Sinai Hospital8, University of Turin9, University of Texas MD Anderson Cancer Center10, Heidelberg University11, Alfred Hospital12, University Health System13, Carolinas Healthcare System14, University of Bologna15, Aalborg University16, Dalhousie University17, Erasmus University Rotterdam18, Roswell Park Cancer Institute19, Columbia University20, University of Toulouse21
TL;DR: Several aspects of disease response assessment are clarified, along with endpoints for clinical trials, and future directions for disease response assessments are highlighted, to allow uniform reporting within and outside clinical trials.
Abstract: Treatment of multiple myeloma has substantially changed over the past decade with the introduction of several classes of new effective drugs that have greatly improved the rates and depth of response. Response criteria in multiple myeloma were developed to use serum and urine assessment of monoclonal proteins and bone marrow assessment (which is relatively insensitive). Given the high rates of complete response seen in patients with multiple myeloma with new treatment approaches, new response categories need to be defined that can identify responses that are deeper than those conventionally defined as complete response. Recent attempts have focused on the identification of residual tumour cells in the bone marrow using flow cytometry or gene sequencing. Furthermore, sensitive imaging techniques can be used to detect the presence of residual disease outside of the bone marrow. Combining these new methods, the International Myeloma Working Group has defined new response categories of minimal residual disease negativity, with or without imaging-based absence of extramedullary disease, to allow uniform reporting within and outside clinical trials. In this Review, we clarify several aspects of disease response assessment, along with endpoints for clinical trials, and highlight future directions for disease response assessments.
1,681 citations
National and Kapodistrian University of Athens1, Karolinska University Hospital2, University of Navarra3, University of Calgary4, University College London5, University of Texas at Austin6, Poznan University of Medical Sciences7, New Generation University College8, Hadassah Medical Center9, Harvard University10, University Hospital Heidelberg11, German Cancer Research Center12, Princess Margaret Cancer Centre13, Genmab14, Janssen Pharmaceutica15
TL;DR: The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma.
Abstract: BackgroundDaratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1–2 study involving patients with relapsed or refractory multiple myeloma. MethodsIn this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival. ResultsAt a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan–Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in t...
1,100 citations
TL;DR: The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited.
Abstract: BackgroundIxazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma. MethodsIn this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receive ixazomib plus lenalidomide–dexamethasone (ixazomib group) or placebo plus lenalidomide–dexamethasone (placebo group). The primary end point was progression-free survival. ResultsProgression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P=0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of...
821 citations
Emory University1, University of Pennsylvania2, Carolinas Healthcare System3, Northwestern University4, Icahn School of Medicine at Mount Sinai5, University of Calgary6, Cross Cancer Institute7, City of Hope National Medical Center8, Cedars-Sinai Medical Center9, University of Salamanca10, New York University11, University of Texas MD Anderson Cancer Center12, University of British Columbia13, Oregon Health & Science University14, Sarah Cannon Research Institute15, Rutgers University16, Hôpital Maisonneuve-Rosemont17, University of Wisconsin-Madison18, University of Chicago19, Dalhousie University20, Harvard University21, Genmab22, Janssen Pharmaceutica23, University of North Carolina at Chapel Hill24
TL;DR: Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients.
680 citations
Instituto Português de Oncologia Francisco Gentil1, University of Zurich2, King Saud bin Abdulaziz University for Health Sciences3, Goethe University Frankfurt4, University of Liège5, American University of Beirut6, University of Regensburg7, Paris Diderot University8, Semmelweis University9, Claude Bernard University Lyon 110, Sheba Medical Center11, Trinity College, Dublin12, Keio University13, University of Cambridge14, LDS Hospital15, Harvard University16, University of Helsinki17, Vanderbilt University18, University of Gothenburg19, Lille University of Science and Technology20, Autonomous University of Madrid21
TL;DR: A new definition for diagnosis, and a severity-grading system for SOS/VOD in adult patients, are proposed on behalf of the European Society for Blood and Marrow Transplantation.
Abstract: The advances in hematopoietic cell transplantation (HCT) over the last decade have led to a transplant-related mortality below 15%. Hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication of HCT that belongs to a group of diseases increasingly identified as transplant-related, systemic endothelial diseases. In most cases, SOS/VOD resolves within weeks; however, severe SOS/VOD results in multi-organ dysfunction/failure with a mortality rate >80%. A timely diagnosis of SOS/VOD is of critical importance, given the availability of therapeutic options with favorable tolerability. Current diagnostic criteria are used for adults and children. However, over the last decade it has become clear that SOS/VOD is significantly different between the age groups in terms of incidence, genetic predisposition, clinical presentation, prevention, treatment and outcome. Improved understanding of SOS/VOD and the availability of effective treatment questions the use of the Baltimore and Seattle criteria for diagnosing SOS/VOD in children. The aim of this position paper is to propose new diagnostic and severity criteria for SOS/VOD in children on behalf of the European Society for Blood and Marrow Transplantation.
365 citations
TL;DR: Recommendations were based on published data through December 2015, and were developed using the system developed by the Grading of Recommendation, Assessment, Development, and Evaluation Working Group.
Abstract: PurposeThe aim of the International Myeloma Working Group was to develop practical recommendations for the diagnosis and management of multiple myeloma–related renal impairment (RI).MethodsRecommendations were based on published data through December 2015, and were developed using the system developed by the Grading of Recommendation, Assessment, Development, and Evaluation Working Group.RecommendationsAll patients with myeloma at diagnosis and at disease assessment should have serum creatinine, estimated glomerular filtration rate, and electrolytes measurements as well as free light chain, if available, and urine electrophoresis of a sample from a 24-hour urine collection (grade A). The Chronic Kidney Disease Epidemiology Collaboration, preferably, or the Modification of Diet in Renal Disease formula should be used for the evaluation of estimated glomerular filtration rate in patients with stabilized serum creatinine (grade A). International Myeloma Working Group criteria for renal reversibility should b...
260 citations
Harvard University1, University of North Carolina at Chapel Hill2, Memorial Sloan Kettering Cancer Center3, University of Alabama at Birmingham4, University of Southern California5, Stanford University6, University of Pennsylvania7, Duke University8, University of Washington9, Oregon Health & Science University10, Loyola University Chicago11, Children's Memorial Hospital12, University of Manitoba13, University of Minnesota14, University of Texas Health Science Center at Houston15, Rutgers University16, Nationwide Children's Hospital17, Boston University18
TL;DR: Defibrotide was associated with significant improvement in day +100 survival and CR rate and the historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality.
228 citations
TL;DR: New molecular mechanisms of in vivo MM growth and immunosuppression critically dependent on BCMA and APRIL in the BM microenvironment are delineated, further supporting targeting this prominent pathway in MM.
221 citations
Harvard University1, University of California, San Francisco2, Karolinska University Hospital3, Memorial Hospital of South Bend4, University of North Carolina at Chapel Hill5, Aalborg University6, University of Cambridge7, Jagiellonian University Medical College8, Sahlgrenska University Hospital9, National University of Singapore10, Cross Cancer Institute11, Second Military Medical University12, University of Bologna13, Queen Mary University of London14, New York University15, Peking University16, Saint John Regional Hospital17, Royal Prince Alfred Hospital18, Dublin City University19, National and Kapodistrian University of Athens20, Roswell Park Cancer Institute21, University of Texas MD Anderson Cancer Center22, University of Navarra23, University of Turin24, Mayo Clinic25, Cedars-Sinai Medical Center26
TL;DR: This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics.
Abstract: The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.
189 citations
TL;DR: SAR is the first therapeutic monoclonal antibody mediating direct cytotoxicity against MM cells via multiple mechanisms of action, and data show that Pom augments both direct and effector cell-mediated MM cytot toxicity of SAR, providing the framework for combination clinical trials.
Abstract: The anti-CD38 monoclonal antibody SAR650984 (SAR) is showing promising clinical activity in treatment of relapsed and refractory multiple myeloma (MM). Besides effector-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity, we here define molecular mechanisms of SAR-directed MM cell death and enhanced anti-MM activity triggered by SAR with Pomalidomide (Pom). Without Fc-cross-linking agents or effector cells, SAR specifically induces homotypic aggregation (HA)-associated cell death in MM cells dependent on the level of cell surface CD38 expression, actin cytoskeleton and membrane lipid raft. SAR and its F(ab)'2 fragments trigger caspase 3/7-dependent apoptosis in MM cells highly expressing CD38, even with p53 mutation. Importantly, SAR specifically induces lysosome-dependent cell death (LCD) by enlarging lysosomes and increasing lysosomal membrane permeabilization associated with leakage of cathepsin B and LAMP-1, regardless of the presence of interleukin-6 or bone marrow stromal cells. Conversely, the lysosomal vacuolar H+-ATPase inhibitor blocks SAR-induced LCD. SAR further upregulates reactive oxygen species. Pom enhances SAR-induced direct and indirect killing even in MM cells resistant to Pom/Len. Taken together, SAR is the first therapeutic monoclonal antibody mediating direct cytotoxicity against MM cells via multiple mechanisms of action. Our data show that Pom augments both direct and effector cell-mediated MM cytotoxicity of SAR, providing the framework for combination clinical trials.
170 citations
TL;DR: Although elotuzumab (anti-SLAMF7) has no single agent activity in advanced MM, randomized trials in relapsed/refractory MM have demonstrated significantly improved progression-free survival when elotzumab is added to lenalidomide-dexamethasone or bortezomib-dExamethAsone.
TL;DR: Preliminary evidence is provided that ricolinostat is a safe and well tolerated selective HDAC6 inhibitor, which might partner well with lenalidomide and dexamethasone to enhance their efficacy in relapsed or refractory multiple myeloma.
Abstract: Summary Background Histone deacetylase (HDAC) inhibitors are an important new class of therapeutics for treating multiple myeloma. Ricolinostat (ACY-1215) is the first oral selective HDAC6 inhibitor with reduced class I HDAC activity to be studied clinically. Motivated by findings from preclinical studies showing potent synergistic activity with ricolinostat and lenalidomide, our goal was to assess the safety and preliminary activity of the combination of ricolinostat with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma. Methods In this multicentre phase 1b trial, we recruited patients aged 18 years or older with previously treated relapsed or refractory multiple myeloma from five cancer centres in the USA. Inclusion criteria included a Karnofsky Performance Status score of at least 70, measureable disease, adequate bone marrow reserve, adequate hepatic function, and a creatinine clearance of at least 50 mL per min. Exclusion criteria included previous exposure to HDAC inhibitors; previous allogeneic stem-cell transplantation; previous autologous stem-cell transplantation within 12 weeks of baseline; active systemic infection; malignancy within the last 5 years; known or suspected HIV, hepatitis B, or hepatitis C infection; a QTc Fridericia of more than 480 ms; and substantial cardiovascular, gastrointestinal, psychiatric, or other medical disorders. We gave escalating doses (from 40–240 mg once daily to 160 mg twice daily) of oral ricolinostat according to a standard 3 + 3 design according to three different regimens on days 1–21 with a conventional 28 day schedule of oral lenalidomide (from 15 mg [in one cohort] to 25 mg [in all other cohorts] once daily) and oral dexamethasone (40 mg weekly). Primary outcomes were dose-limiting toxicities, the maximum tolerated dose of ricolinostat in this combination, and the dose and schedule of ricolinostat recommended for further phase 2 investigation. Secondary outcomes were the pharmacokinetics and pharmacodynamics of ricolinostat in this combination and the preliminary anti-tumour activity of this treatment. The trial is closed to accrual and is registered at ClinicalTrials.gov, number NCT01583283. Findings Between July 12, 2012, and Aug 20, 2015, we enrolled 38 patients. We observed two dose-limiting toxicities with ricolinostat 160 mg twice daily: one (2%) grade 3 syncope and one (2%) grade 3 myalgia event in different cohorts. A maximum tolerated dose was not reached. We chose ricolinostat 160 mg once daily on days 1–21 of a 28 day cycle as the recommended dose for future phase 2 studies in combination with lenalidomide 25 mg and dexamethasone 40 mg. The most common adverse events were fatigue (grade 1–2 in 14 [37%] patients; grade 3 in seven [18%]) and diarrhoea (grade 1–2 in 15 [39%] patients; grade 3 in two [5%]). Our pharmacodynamic studies showed that at clinically relevant doses, ricolinostat selectively inhibits HDAC6 while retaining a low and tolerable level of class I HDAC inhibition. The pharmacokinetics of ricolinostat and lenalidomide were not affected by co-administration. In a preliminary assessment of antitumour activity, 21 (55% [95% CI 38–71]) of 38 patients had an overall response. Interpretation The findings from this study provide preliminary evidence that ricolinostat is a safe and well tolerated selective HDAC6 inhibitor, which might partner well with lenalidomide and dexamethasone to enhance their efficacy in relapsed or refractory multiple myeloma. Funding Acetylon Pharmaceuticals.
TL;DR: Steady-state daily dosing serum TFV and PBMC TFV-DP was consistent with highly effective PrEP clinical trials and TFV/FTC was consistently quantifiable 2 weeks after the last dose for the ≥4/week regimens.
Abstract: Oral preexposure prophylaxis (PrEP) trials report disparate efficacy attributed to variable adherence. HPTN 066 was conducted to establish objective, quantitative benchmarks for discrete, regular levels of adherence using directly observed dosing of tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC). Healthy, HIV-uninfected men and women were randomized to one of four oral regimens of fixed-dose TDF 300 mg/FTC 200 mg tablet for 5 weeks with all doses observed: one tablet weekly (one/week), one tablet twice weekly (two/week), two tablets twice weekly (four/week), or one tablet daily (seven/week). Trough serum TFV and FTC, peripheral blood mononuclear cell (PBMC), and CD4+ TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) concentrations were determined throughout dosing and 2 weeks after the last dose. Rectosigmoidal, semen, and cervicovaginal samples were collected for drug assessment at end of dosing and 2 weeks later in a subset of participants. The 49 enrolled participants toler...
TL;DR: BH3 profiling identifies heterogeneous dependency on Bcl-2 family members in multiple myeloma and predicts sensitivity to BH3 mimetics.
Abstract: BH3 profiling identifies heterogeneous dependency on Bcl-2 family members in multiple myeloma and predicts sensitivity to BH3 mimetics
University of Navarra1, Seoul National University Hospital2, Ankara University3, National and Kapodistrian University of Athens4, Alexandria University5, Medical University of Warsaw6, University of Kiel7, King Chulalongkorn Memorial Hospital8, Siriraj Hospital9, Harvard University10, Emory University11, Gachon University12, University of Würzburg13, Novartis14
TL;DR: The overall survival benefit with panobinostat over placebo with bortezomib and dexamethasone was modest, however, optimisation of the regimen could potentially prolong treatment duration and improve patients' outcomes, although further trials will be required to confirm this.
Harvard University1, New Generation University College2, Ankara University3, National and Kapodistrian University of Athens4, Alexandria University5, Medical University of Warsaw6, University of Kiel7, King Chulalongkorn Memorial Hospital8, Siriraj Hospital9, Emory University10, Gachon University11, University of Würzburg12, Novartis13, University of Navarra14
TL;DR: This analysis demonstrated a clear PFS benefit of 7.8 months with PAN-BTZ-Dex among patients who received ≥2 prior regimens including bortezomib and an IMiD, a population with limited treatment options and poorer prognosis.
TL;DR: An HDAC6-selective small molecule inhibitor is designed and developed and used to define mechanisms of anti-MM activity, both alone and in combination with proteasome inhibitors in in vitro and in vivo studies, and validates an in vivo quality chemical probe for broad use by the research community.
Abstract: Multiple myeloma (MM) has proven clinically susceptible to modulation of pathways of protein homeostasis Blockade of proteasomal degradation of polyubiquitinated misfolded proteins by the proteasome inhibitor bortezomib (BTZ) achieves responses and prolongs survival in MM, but long-term treatment with BTZ leads to drug-resistant relapse in most patients In a proof-of-concept study, we previously demonstrated that blocking aggresomal breakdown of polyubiquitinated misfolded proteins with the histone deacetylase 6 (HDAC6) inhibitor tubacin enhances BTZ-induced cytotoxicity in MM cells in vitro However, these foundational studies were limited by the pharmacologic liabilities of tubacin as a chemical probe with only in vitro utility Emerging from a focused library synthesis, a potent, selective, and bioavailable HDAC6 inhibitor, WT161, was created to study the mechanism of action of HDAC6 inhibition in MM alone and in combination with BTZ WT161 in combination with BTZ triggers significant accumulation of polyubiquitinated proteins and cell stress, followed by caspase activation and apoptosis More importantly, this combination treatment was effective in BTZ-resistant cells and in the presence of bone marrow stromal cells, which have been shown to mediate MM cell drug resistance The activity of WT161 was confirmed in our human MM cell xenograft mouse model and established the framework for clinical trials of the combination treatment to improve patient outcomes in MM
TL;DR: The combination was well tolerated and consistent with the safety profiles observed with lenalidomide/dexamethasone or daratumumab monotherapy, and resulted in rapid, deep, durable responses.
TL;DR: Although supervised exercise effectively reduced liver fat, improving peripheral IR in NAFLD, the reduction in liver fat was insufficient to improve hepatic IR.
Abstract: Non-alcoholic fatty liver disease (NAFLD) is associated with multi-organ (hepatic, skeletal muscle, adipose tissue) insulin resistance (IR). Exercise is an effective treatment for lowering liver fat but its effect on IR in NAFLD is unknown. We aimed to determine whether supervised exercise in NAFLD would reduce liver fat and improve hepatic and peripheral (skeletal muscle and adipose tissue) insulin sensitivity. Sixty nine NAFLD patients were randomized to 16 weeks exercise supervision (n=38) or counselling (n=31) without dietary modification. All participants underwent MRI/spectroscopy to assess changes in body fat and in liver and skeletal muscle triglyceride, before and following exercise/counselling. To quantify changes in hepatic and peripheral insulin sensitivity, a pre-determined subset (n=12 per group) underwent a two-stage hyperinsulinaemic euglycaemic clamp pre- and post-intervention. Results are shown as mean [95% confidence interval (CI)]. Fifty participants (30 exercise, 20 counselling), 51 years (IQR 40, 56), body mass index (BMI) 31 kg/m(2) (IQR 29, 35) with baseline liver fat/water % of 18.8% (IQR 10.7, 34.6) completed the study (12/12 exercise and 7/12 counselling completed the clamp studies). Supervised exercise mediated a greater reduction in liver fat/water percentage than counselling [Δ mean change 4.7% (0.01, 9.4); P<0.05], which correlated with the change in cardiorespiratory fitness (r=-0.34, P=0.0173). With exercise, peripheral insulin sensitivity significantly increased (following high-dose insulin) despite no significant change in hepatic glucose production (HGP; following low-dose insulin); no changes were observed in the control group. Although supervised exercise effectively reduced liver fat, improving peripheral IR in NAFLD, the reduction in liver fat was insufficient to improve hepatic IR.
TL;DR: This was the first clinical study to evaluate the safety, tolerability, maximal‐tolerated dose (MTD), dose‐limiting toxicity (DLT), pharmacokinetics, and preliminary clinical activity of TAK‐228, an oral TORC1/2 inhibitor, in patients with MM, NHL, or WM.
Abstract: The PI3K/AKT/mTOR signaling pathways are frequently dysregulated in multiple human cancers, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Waldenstrom's macroglobulinemia (WM). This was the first clinical study to evaluate the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and preliminary clinical activity of TAK-228, an oral TORC1/2 inhibitor, in patients with MM, NHL, or WM. Thirty-nine patients received TAK-228 once daily (QD) at 2, 4, 6, or 7 mg, or QD for 3 days on and 4 days off each week (QDx3d QW) at 9 or 12 mg, in 28-day cycles. The overall median age was 61.0 years (range 46-85); 31 patients had MM, four NHL, and four WM. Cycle 1 DLTs occurred in five QD patients (stomatitis, urticaria, blood creatinine elevation, fatigue, and nausea and vomiting) and four QDx3d QW patients (erythematous rash, fatigue, asthenia, mucosal inflammation, and thrombocytopenia). The MTDs were determined to be 4 mg QD and 9 mg QDx3d QW. Thirty-six patients (92%) reported at least one drug-related toxicity; the most common grade ≥3 drug-related toxicities were thrombocytopenia (15%), fatigue (10%), and neutropenia (5%). TAK-228 exhibited a dose-dependent increase in plasma exposure and no appreciable accumulation with repeat dosing; mean plasma elimination half-life was 6-8 hr. Of the 33 response-evaluable patients, one MM patient had a minimal response, one WM patient achieved partial response, one WM patient had a minor response, and 18 patients (14 MM, two NHL, and two WM) had stable disease. These findings encourage further studies including combination strategies.
TL;DR: Using genetic and biochemical studies in vitro and in human MM xenograft models, it is shown that SIRT6 depletion both enhances proliferation and confers sensitization to DNA-damaging agents, providing insights into the functional interplay between SIRT 6 and DNA repair mechanisms.
TL;DR: The results indicate that the KDM3A–KLF2–IRF4 pathway plays an essential role in MM cell survival and homing to the bone marrow, and therefore represents a therapeutic target.
Abstract: KDM3A is implicated in tumorigenesis; however, its biological role in multiple myeloma (MM) has not been elucidated. Here we identify KDM3A-KLF2-IRF4 axis dependence in MM. Knockdown of KDM3A is toxic to MM cells in vitro and in vivo. KDM3A maintains expression of KLF2 and IRF4 through H3K9 demethylation, and knockdown of KLF2 triggers apoptosis. Moreover, KLF2 directly activates IRF4 and IRF4 reciprocally upregulates KLF2, forming a positive autoregulatory circuit. The interaction of MM cells with bone marrow milieu mediates survival of MM cells. Importantly, silencing of KDM3A, KLF2 or IRF4 both decreases MM cell adhesion to bone marrow stromal cells and reduces MM cell homing to the bone marrow, in association with decreased ITGB7 expression in MAF-translocated MM cell lines. Our results indicate that the KDM3A-KLF2-IRF4 pathway plays an essential role in MM cell survival and homing to the bone marrow, and therefore represents a therapeutic target.
TL;DR: Safety and efficacy resultswere consistent with prior studies of defibrotide in hepatic VOD/SOS, and subgroup analyses lend support to the use of the 25 mg/kg/day dose.
TL;DR: It is demonstrated that RRx-001 decreases the viability of MM cell lines and primary patient cells, as well as overcomes drug resistance, and the rationale for translation of RRX-001, either alone or in combination, to clinical evaluation in MM is provided.
Abstract: The hypoxic bone marrow (BM) microenvironment confers growth/survival and drug resistance in multiple myeloma (MM) cells. Novel therapies targeting the MM cell in its hypoxic BM milieu may overcome drug resistance. Recent studies led to the development of a novel molecule RRx-001 with hypoxia-selective epigenetic and nitric oxide-donating properties. Here, we demonstrate that RRx-001 decreases the viability of MM cell lines and primary patient cells, as well as overcomes drug resistance. RRx-001 inhibits MM cell growth in the presence of BM stromal cells. RRx-001-induced apoptosis is associated with: (i) activation of caspases; (ii) release of ROS and nitrogen species; (iii) induction of DNA damage via ATM/γ-H2AX; and (iv) decrease in DNA methyltransferase (DNMT) and global methylation. RNA interference study shows a predominant role of DNMT1 in MM cell survival versus DNMT3a or DNMT3b. The deubiquitylating enzyme USP7 stimulates DNMT1 activity, and conversely, USP7-siRNA reduced DNMT1 activity and decreased MM cell viability. RRx-001 plus USP7 inhibitor P5091 triggered synergistic anti-MM activity. MM xenograft studies show that RRx-001 is well tolerated, inhibits tumor growth and enhances survival. Combining RRx-001 with pomalidomide, bortezomib or SAHA induces synergistic anti-MM activity. Our results provide the rationale for translation of RRx-001, either alone or in combination, to clinical evaluation in MM.
TL;DR: MRZ was generally well tolerated, and results suggest activity in previously treated RRMM patients, and Combination studies using pomalidomide and dexamethasone are now underway.
TL;DR: Pre-clinical observations suggest efficacy of AIN457 in myeloma and provide the rationale for its clinical evaluation for anti-myeloma effects and for improvement of bone disease.
Abstract: We have previously demonstrated that interleukin-17A (IL-17) producing T helper 17 cells are significantly elevated in blood and bone marrow (BM) in multiple myeloma (MM) and IL-17A promotes MM cell growth via the expression of IL-17 receptor. In this study, we evaluated anti-human IL-17A human monoclonal antibody (mAb), AIN457 in MM. We observe significant inhibition of MM cell growth by AIN457 both in the presence and the absence of BM stromal cells (BMSCs). Although IL-17A induces IL-6 production, AIN457 significantly downregulated IL-6 production and MM cell adhesion in MM-BMSC co-culture. AIN457 also significantly inhibited osteoclast cell differentiation. More importantly, in the SCIDhu model of human myeloma administration of AIN457 weekly for 4 weeks after the first detection of tumor in mice led to a significant inhibition of tumor growth and reduced bone damage compared with isotype control mice. To understand the mechanism of action of anti-IL-17A mAb, we report, here, that MM cells express IL-17A. We also observed that IL-17A knockdown inhibited MM cell growth and their ability to induce IL-6 production in co-cultures with BMSC. These pre-clinical observations suggest efficacy of AIN457 in myeloma and provide the rationale for its clinical evaluation for anti-myeloma effects and for improvement of bone disease.
TL;DR: This review highlights the importance of fluorinated compounds in drug discovery, and provides an overview on the synthetic strategies and methodologies developed to access them both in discovery and development, as well as investigating the extension of these methods for PET-labelling.
Abstract: Introduction: The pivotal role that the element fluorine plays in modulating the properties of bioactive molecules is reflected by the growth of its presence in approved drugs. In 1970, approximately 2% of drugs contained fluorine with this number rising to 25% by 2011. The synthetic chemistry regarding incorporation of fluorine into organic molecules has also evolved over this time with a paradigm shift from harsh, toxic, hazardous reagents utilized primarily by specialist vendors to new deoxyfluorination reagents and metal-mediated techniques capable of the precise introduction of fluorine into complex organic substrates under relatively mild conditions.Areas covered: This review highlights the importance of fluorinated compounds in drug discovery, and provides an overview on the synthetic strategies and methodologies developed to access them both in discovery and development.Expert opinion: The development of new reagents for the safe and precise regioselective fluorination of biologically rele...
TL;DR: A prospectively planned MA assessed the OS of LEN vs placebo/no MNTC (control; CTL) after ASCT and identified 17 randomized controlled trials using LEN post ASCT using prespecified inclusion criteria.
Abstract: 8001Background: Several studies demonstrate that LEN MNTC post ASCT reduces the risk of disease progression or death in patients (pts) with MM by ≈ 50% (Attal NEJM 2012; McCarthy NEJM 2012; Palumbo NEJM 2014). However, these studies were not powered for OS. To assess the effect of LEN MNTC post ASCT on OS, an MA was conducted. Methods: A prospectively planned MA assessed the OS of LEN vs placebo/no MNTC (control; CTL) after ASCT. A search identified 17 randomized controlled trials (RCTs) using LEN post ASCT. 3 RCTs (IFM 2005-02, CALGB 100104 [Alliance], GIMEMA RV-209) met prespecified inclusion criteria (had pt-level data, a CTL arm, and achieved database lock for primary efficacy analysis of NDMM pts receiving LEN post ASCT). A March 2015 cutoff of the 3 RCTs enabled sufficient OS events to test treatment effect (HR = 0.78). Results: In the 3 RCTs, 1209 pts were randomized from 2005 to 2009 to receive LEN (n = 605) 10 mg/day on days 1-21/28 (GIMEMA) or 1-28/28 (IFM and CALGB) or CTL (n = 604). With a med...
TL;DR: The results of this study are consistent with previously reported experiences with defibrotide, confirm the poor outcome of this syndrome, and suggest defib rotide is effective in the treatment of severe VOD.
TL;DR: It is suggested that melflufen triggers a rapid, robust, and an irreversible DNA damage which may account for its ability to overcome melphalan‐resistance in MM cells.
Abstract: Our prior study utilized both in vitro and in vivo multiple myeloma (MM) xenograft models to show that a novel alkylator melphalan-flufenamide (Melflufen) is a more potent anti-MM agent than melphalan and overcomes conventional drug resistance. Here we examined whether this potent anti-MM activity of melflufen versus melphalan is due to their differential effect on DNA damage and repair signalling pathways via γ-H2AX/ATR/CHK1/Ku80. Melflufen-induced apoptosis was associated with dose- and time-dependent rapid phosphorylation of γ-H2AX. Melflufen induces γ-H2AX, ATR, and CHK1 as early as after 2 h exposure in both melphalan-sensitive and -resistant cells. However, melphalan induces γ-H2AX in melphalan-sensitive cells at 6 h and 24 h; no γ-H2AX induction was observed in melphalan-resistant cells even after 24 h exposure. Similar kinetics was observed for ATR and CHK1 in meflufen- versus melphalan-treated cells. DNA repair is linked to melphalan-resistance; and importantly, we found that melphalan, but not melflufen, upregulates Ku80 that repairs DNA double-strand breaks. Washout experiments showed that a brief (2 h) exposure of MM cells to melflufen is sufficient to initiate an irreversible DNA damage and cytotoxicity. Our data therefore suggest that melflufen triggers a rapid, robust, and an irreversible DNA damage which may account for its ability to overcome melphalan-resistance in MM cells.