Myeloma Institute for Research and Therapy

Little Rock, AR, United States

Myeloma Institute for Research and Therapy

Little Rock, AR, United States

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PubMed | University of Arkansas for Medical Sciences, Centers for Disease Control and Prevention, Myeloma Institute for Research and Therapy and Infection Control
Type: Journal Article | Journal: Open forum infectious diseases | Year: 2015

In the era of cost-consciousness regarding healthcare , provision of medical services in an outpatient setting has become increasingly attractive. We report an influenza outbreak in an ambulatory stem cell transplant center in 2013 that highlights unique identification and infection control challenges in this setting.Nasopharyngeal swabs were performed on patients with suspected influenza-like illnesses (ILI), defined by subjective fever or measured temperature of 37.7C (100F) with cough or sore throat during July 25, 2013 through August 7, 2013. In addition, testing was triggered by an elevated C-reactive protein (CRP). Specimens were analyzed by using eSensor Respiratory Viral Panel. Clinical and epidemiologic information was collected in real time, and frequencies were calculated on demographics, baseline clinical parameters, treatment methods, comorbidities, and symptoms of affected persons.Thirty-one patients had influenza A (H3N2) infection during July 25, 2013 through August 7, 2013. Only 7 patients (23%) met the Centers for Disease Control and Prevention and Council of State and Territorial Epidemiologists ILI case definition. Twenty-five patients (81%) had received 1 transplant, with 13 (42%) having occurred within 1 year before the outbreak. Twenty-five patients (81%) had received B-cell active chemotherapy <60 days before influenza diagnosis, 6 (19%) were neutropenic, and 25 (81%) lymphopenic. Among clinical and laboratory markers analyzed, abnormal CRP was the most sensitive screening tool for influenza. Twelve (39%) patients were hospitalized (median stay, 10 days; range, 2-20). No deaths occurred.Immunocompromised hosts with influenza have atypical presentations. Existing surveillance case definitions might be insufficient to reliably identify influenza outbreaks in such patients.


Yong K.,University College London | Cavet J.,University of Manchester | Johnson P.,Southampton General Hospital | Morgan G.,Myeloma Institute for Research and Therapy | And 5 more authors.
British Journal of Cancer | Year: 2016

Background:KW-2478 is a novel, non-ansamycin, non-purine heat-shock protein 90 (Hsp90) inhibitor.Methods:In this phase I, multicentre study, KW-2478 was administered intravenously over 1 h at doses ranging from 14 to 176 mg m -2 once daily on days 1-5 of a 14-day cycle in a standard 3+3 design in 27 patients (22 with multiple myeloma and 5 with non-Hodgkin lymphoma). Patients enrolled had relapsed/refractory disease previously treated with ≥2 regimens.Results:There were no dose-limiting toxicities, thus the maximum-tolerated dose was not reached. KW-2478 was well tolerated and did not manifest significant retinal or ocular toxicity. The most common treatment-related adverse events were diarrhoea (33.3%), fatigue (29.6%), headache (25.9%), hypertension (22.2%), nausea (14.8%), vomiting (7.4%), and dizziness (7.4%). Plasma concentrations peaked at the end of infusion and decayed in a biphasic manner with a terminal half-life of ∼6 h. Target inhibition was inferred from the increase in Hsp70 levels in peripheral blood mononuclear cells at doses ≥71 mg m -2. Twenty-four of 25 (96%) evaluable patients showed stable disease, with five being free of disease progression for ≥6 months.Conclusions:Preliminary clinical response data were encouraging and warrant further investigation of KW-2478 in combination regimens for relapsed/refractory B-cell malignancies. © 2016 Cancer Research UK.


PubMed | Southampton General Hospital, Myeloma Institute for Research and Therapy, University of Nottingham, University of Manchester and 4 more.
Type: Clinical Trial, Phase I | Journal: British journal of cancer | Year: 2016

KW-2478 is a novel, non-ansamycin, non-purine heat-shock protein 90 (Hsp90) inhibitor.In this phase I, multicentre study, KW-2478 was administered intravenously over 1h at doses ranging from 14 to 176mgm(-2) once daily on days 1-5 of a 14-day cycle in a standard 3+3 design in 27 patients (22 with multiple myeloma and 5 with non-Hodgkin lymphoma). Patients enrolled had relapsed/refractory disease previously treated with 2 regimens.There were no dose-limiting toxicities, thus the maximum-tolerated dose was not reached. KW-2478 was well tolerated and did not manifest significant retinal or ocular toxicity. The most common treatment-related adverse events were diarrhoea (33.3%), fatigue (29.6%), headache (25.9%), hypertension (22.2%), nausea (14.8%), vomiting (7.4%), and dizziness (7.4%). Plasma concentrations peaked at the end of infusion and decayed in a biphasic manner with a terminal half-life of 6h. Target inhibition was inferred from the increase in Hsp70 levels in peripheral blood mononuclear cells at doses 71mgm(-2). Twenty-four of 25 (96%) evaluable patients showed stable disease, with five being free of disease progression for 6 months.Preliminary clinical response data were encouraging and warrant further investigation of KW-2478 in combination regimens for relapsed/refractory B-cell malignancies.


Papanikolaou X.,Myeloma Institute for Research and Therapy | Szymonifka J.,Cancer Research and Biostatistics | Rosenthal A.,Cancer Research and Biostatistics | Heuck C.J.,Myeloma Institute for Research and Therapy | And 11 more authors.
Haematologica | Year: 2013

Relapsed/refractory multiple myeloma represents a major challenge in multiple myeloma therapy. For patients with relapsed/refractory multiple myeloma, we developed a treatment schema of metronomically scheduled drug therapy. We identified 186 patients who had been treated with metronomic therapy between March 2004 and January 2012 with a median follow up of 24.2 months. Median age was 61 years (range 36-83). Median number of prior therapies was 14 (range 1-51). Median number of completed metronomic therapy cycles was 1 (range 1- 5), while 45 of 186 (25%) received 2 or more cycles. Responses included complete remission in 11 of 186 patients (6%), very good partial remission in 12 of 186 (7%), partial remission in 65 of 179 (36%), and minimal response in 29 of 186 (16%), for an overall response rate of 63% (117 of 186). Median overall survival and progression-free survival were 11.2 and 3.6 months, respectively. Hematologic toxicity grading was problematic as 146 of 186 (78%) of patients presented with at least grade 2 thrombocytopenia within 90 days prior to starting metronomic therapy. Grade 4 leukopenia, anemia, and/or thrombocytopenia following metronomic therapy occurred in 108 of 186 (58%), 12 of 186 (6%), and 147 of 186 (79%) patients, respectively. Incidence of grade 3-4 neutropenic fever was 4 of 186 (2%). Most patients (177 of 186, 95%) were treated in an outpatient unit and secondary admissions due to regimen-related toxicity occurred in 37 of 186 (20%). Treatment-related mortality was evident in 2 of 186 (1%). In conclusion, metronomic therapy is an effective late salvage treatment in relapsed/refractory multiple myeloma, with a high overall response rate and a favorable toxicity profile.


Chavan S.S.,University of Arkansas for Medical Sciences | Chavan S.S.,Myeloma Institute for Research and Therapy | Shaughnessy Jr. J.D.,Myeloma Institute for Research and Therapy | Edmondson R.D.,Myeloma Institute for Research and Therapy
Human Genomics | Year: 2011

Many primary biological databases are dedicated to providing annotation for a specific type of biological molecule such as a clone, transcript, gene or protein, but often with limited cross-references. Therefore, enhanced mapping is required between these databases to facilitate the correlation of independent experimental datasets. For example, molecular biology experiments conducted on samples (DNA, mRNA or protein) often yield more than one type of 'omics' dataset as an object for analysis (eg a sample can have a genomics as well as proteomics expression dataset available for analysis). Thus, in order to map the two datasets, the identifier type from one dataset is required to be linked to another dataset, so preventing loss of critical information in downstream analysis. This identifier mapping can be performed using identifier converter software relevant to the query and target identifier databases. This review presents the publicly available web-based biological database identifier converters, with comparison of their usage, input and output formats, and the types of available query and target database identifier types. © HENRY STEWART PUBLICATIONS.


PubMed | Myeloma Institute for Research and Therapy
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

8028 Background: CFZ is an epoxomicin derivative with ability to irreversibly inhibit proteosomes, with clinical activity. It has been shown in preclinical and early clinical studies to have activity in myeloma. We performed a phase II study evaluating the efficacy of this drug in RRMM.First cycle CFZ was given at 20mg/m2 IV day 1,2, then 27mg/m2 IV days 8,9,15,16 every 28 days; 4mg of dexamethasone (DEX) was given with each CFZ dose. In the absence of PR, CFZ dose was escalated to 36 mg/m2 IV and DEX increased to 20mg. Other drugs were added with subsequent cycles. Cox regression modeling was employed for OS/EFS.74 patients with RRMM were enrolled. Baseline characteristics included age >=65yr in 34%, ISS stage >=II was seen in 76% of patients, cytogenetic abnormalities (CA) in 71%, and GEP-defined high risk in 58% of patients. 73 patients had prior autologous stem cell transplant. 61 patients (82%) had at least 2 transplants. 67 patients had received regimens containing bortezomib, thalidomide, lenalidomide, melphalan and steroids. At least 1 cycle of treatment was administered to all 74 patients enrolled, 62% patients receiving >1 cycle of treatment and only 16% received >5 cycles. 54/74 patients discontinued therapy primarily due to progression, death or toxicity. 15/74 (20%) patients achieved nCR/CR, 53% had stable disease. EFS benefit was observed in patients receiving > 3 cycles on univariate (HR= 0.16, p=0.001) and multivariate (HR=0.04, p=0.006) analyses after adjusting for GEP defined risk status. Most common toxicities (grades 1-5) were: hyperglycemia (96%), thrombocytopenia (96%), anemia (95%), hypoalbuminemia (92%), leucopenia (89%), hypokalemia (86%), hypophosphatemia (82%) and fatigue (76%). Overall and event free survival at 6 months were 53% and 21%, respectively.In this far advanced patient population, CFZ seemed to have single agent activity, especially in combination with other agents an improvement in disease was seen in about half the patients.


PubMed | Myeloma Institute for Research and Therapy
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

8068 Background: Therapeutic advances have extended MM survival so that ~50% of newly diagnosed patients can expect to be living 10yr after treatment initiation. In our clinical practice, EMD is a rare primary disease manifestation but appears to evolve with repeated relapses.Our MM database was interrogated for patients treated between 1989-2010 presenting with EMD pre-transplant (EMD-1), or developed EMD at relapse (EMD-2). We focused on 936 patients in TT protocols, 240 patients in non-TT protocols and 789 non-protocol patients who had baseline PET scans prior to transplantation at MIRT (total n=1965).EMD-1 sites >10% included Chest-Wall, Liver, Lymph Nodes, Skin/Soft Tissue and CNS. EMD-2 showed a preponderance of liver disease (34.3% EMD-2 v 21.2% EMD-1). Median EFS/OS were shorter in EMD-1 (EFS: 1.1 v 5.0 yrs, p< 0.001; OS: 1.2 v 7.3 yrs, p< 0.001). EMD-1 was documented in 2.41% of TT protocol patients, 4.35% non-TT protocol patients and 4.5% non-protocol patients, while 5-yr post-transplant estimates totaled 3.43% TT protocol patients, 5.2% non-TT protocol patients and 7.24% non-protocol patients. EMD-1 patients were compared to non-EMD patients using Fishers exact or Chi-square tests. EMD-1 was significantly linked to GEP-defined risk, pre-transplant cytogenetic abnormalities (CA), low levels of hemoglobin and low platelet counts. Cumulative incidence of EMD at 5 years from transplant increased for GEP-defined high risk patients (11.5% vs 2.0%, p<0.001) as well as with pre-transplant CA (7.0% vs 4.1%, p=0.004). GEP data was available for 46 EMD and 1105 non-EMD patients, along with19 samples from EMD sites.While uncommon at presentation, EMD-2 represents a common terminal pathway of MM, linked with increased hepatic preponderance. Cumulative incidence of EMD was significantly increased in GEP-defined high-risk MM at baseline and associated with grave prognosis. We are evaluated available GEP data to determine any distinguishing features that may predict EMD potential on baseline GEP samples, as well as uncover differences between concomitant random marrow GEP and EMD-GEP at time of EMD presentation (data to be presented).


PubMed | Myeloma Institute for Research and Therapy
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

7603 Introduction: V, a proteasome inhibitor with potent anti-myeloma activity, is thought to act through effects on malignant PC and the ME. However, the in vivo effects of this drug have never been examined at the molecular level.Serial GEP analyses were performed of paired purified PC and bone marrow biopsies from 46 patients, obtained prior to and 48hr following administration of a single V dose at 1mg/mFollowing V, 36 ME-associated genes (MAGs) were up-regulated, among them the osteoinductive factor osteoglycin (OGN), consistent with a V effect on osteoblastogenesis; CYR61, an angiogenesis inducer, significantly over-expressed in myeloma relative to normal marrow, was one of only 3 significantly down-regulated genes. V is known to induce expression of proteasome genes and PSMA6, PSMA1, and PSMA14 were among 15 genes up-regulated in PC. In contrast, early growth response (EGR1, EGR2, and EGR3), Krupple-like factor (KLR4, KLR5, KLR6, and KLR7) and nuclear receptor (NR4A1, NR4A2, and NR4A3) family members were down-regulated in PC by V. These differential PC and ME expression changes were only noted in low-risk MM, lacking over-expression of CKS1B.We report here, for the first time, on the differential molecular consequences of a single in-vivo dose of V on both tumor cells and cells of the microenvironment. The clinical implications of these findings are being further investigated and will be presented. [Table: see text].

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