scholarly journals Diclofenac toxicity in susceptible bird species results from a combination of reduced glomerular filtration and plasma flow with subsequent renal tubular necrosis

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12002
Author(s):  
Bono Nethathe ◽  
John Chipangura ◽  
Ibrahim Zubairu Hassan ◽  
Neil Duncan ◽  
Emmanuel Oluwasegun Adawaren ◽  
...  
Keyword(s):  
Uric Acid ◽  
Plasma Flow ◽  
Renal Plasma Flow ◽  
Phase 1 ◽  
Bird Species ◽  
Renal Perfusion ◽  
Tubular Secretion ◽  
Phase 2 ◽  
Two Phase

Diclofenac caused the death of millions of vultures on the Asian subcontinent. Other non-steroidal anti-inflammatory drugs (NSAIDs) have since also been shown to be toxic to vultures with the exception of meloxicam. For this study, we evaluated the effect of diclofenac on renal uric acid transport and glomerulus filtration in an acute toxicity model. In a two-phase study with the same birds, healthy chickens (a validated model species) were treated intravenously with para-amino hippuric acid (PAH) and iohexol (IOH) in combination in phase 1. In phase 2, the same PAH and IOH combination was then combined with diclofenac (10 mg/kg). In both phases, blood and faeces were sequentially collected. In phase 1, the birds showed no signs of ill health. Moreover, PAH, IOH and uric acid clearance was rapid. In phase 2, two chickens showed early signs of hyperuricemia 8 hours after exposure and died approximately 24h later. Necropsy showed classic signs of renal damage and gout. Diclofenac had a rapid plasma half-life of elimination of less than 2 hours indicating that toxicity was likely due to an irreversible destruction of a physiological process. All the birds in phase 2 had decreased uric acid, PAH and IOH clearance in comparison to phase 1. The decrease in PAH clearance was variable between the birds (average of 71%) but was near 98% reduced in the two birds that died. It is concluded that diclofenac alters both renal perfusion and renal plasma flow, with death associated with tubular secretion being reduced to negligible functionality for a prolonged period. This would support previous in vitro findings of early cell death from ROS accumulation. However, further evaluation is needed to elucidate this final step.

scholarly journals CTNI-18. FINAL RESULTS OF A PHASE 2 STUDY OF EFFICACY, SAFETY AND INTRATUMORAL PHARMACOKINETICS (PK) OF SELINEXOR MONOTHERAPY IN RECURRENT GLIOBLASTOMA (rGBM)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii46-ii46
Author(s):  
Andrew Lassman ◽  
Patrick Wen ◽  
Martin van den Bent ◽  
Scott Plotkin ◽  
Annemiek Walenkamp ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Median Number ◽  
Recurrent Glioblastoma ◽  
Phase 2 ◽  
Nuclear Retention ◽  
Phase 2 Trial ◽  
Human Gbm

Abstract BACKGROUND Selinexor is an FDA-approved first-in-class, oral selective nuclear export inhibitor which forces nuclear retention of many tumor suppressor proteins. METHODS We conducted a phase 2 trial of selinexor monotherapy for adults with recurrent GBM including a surgical arm to explore intratumoral PK and 3 medical arms to optimize dosing. Prior treatment with radiotherapy and temozolomide was required; prior bevacizumab was exclusionary. The primary endpoint was 6-month progression-free survival (6mPFS) rate. RESULTS Selinexor administered ~2 hours pre-operatively yieleded average intratumoral concentration (136 nM, n=6) comparable to the in vitro IC50 (130 nM) from 7 primary human GBM cell lines. Among all 68 patients accrued to 3 medical arms (~85 mg BIW, n=24; 60 mg BIW, n=14; 80 mg QW, n=30), median age was 56 years (21–78). Median number of prior lines of therapies was 2 (1–7). At 80 mg QW, 28% patients were progression-free at the end of cycle 6; the 6mPFS was 17%; disese control rate by RANO was 37% (1 CR, 2 PRs, 7 SD) among 27 evaluable patients; responses were durable (median 11.1 months), and treatment lasted for 442, 547 and 1282 days in 3 responders, as of data lock, with one responder remaining on treatment off study; median overall survival was 10.2 months with 95% CI (7.0, 15.4). The ~85 mg BIW-schedule was abandoned due to poor tolerability. The related adverse events (all grades) in patients on ~85 mg BIW/60 mg BIW/80 mg QW were nausea (41.7%/64.3%/66.7%), fatigue (70.8%/71.4%/50.0%), neutropenia (29.2%/14.3%/33.3%), decreased appetite (45.8%/71.4%/26.7%), thrombocytopenia (66.7%/28.6%/23.3%) and weight loss (16.7%,/42.9%/6.7%). CONCLUSION Selinexor monotherapy demonstrated encouraging intratumoral penetration and efficacy, with durable disease control in rGBM. Monotherapy dose at 80 mg QW is recommended for further development in rGBM. A phase 1/2 study of combination therapy for newly diagnosed or rGBM has been initiated (NCT04421378).

Endometrial Adenocarcinoma in SurePath™ Cervical Samples: Cytological Features Revisited

2016 ◽  
Vol 60 (1) ◽  
pp. 46-52 ◽  
Author(s):  
Nalini Gupta ◽  
John Crossley ◽  
Nick Dudding ◽  
John H.F. Smith
Keyword(s):  
Phase 1 ◽  
Endometrial Adenocarcinoma ◽  
Nuclear Chromatin ◽  
Phase 2 ◽  
Cervical Lesions ◽  
Two Phase ◽  
Endometrial Cells ◽  
Phase Study ◽  
Cytological Features ◽  
Liquid Based Cytology

Objective: The cytomorphological criteria of malignant endometrial lesions in cervical samples are less well described than those of cervical lesions. We wished to investigate if there were features in SurePath™ liquid-based cytology samples that would facilitate more accurate differentiation between benign and malignant endometrial cells. Study Design: This was a two-phase study, with a review of all SurePath™ samples reported as endometrial adenocarcinoma (n = 42) evaluating 12 cytological features in the first phase. In phase 2 (test set), all initial cases plus an additional 83 cases were reviewed using these 12 cytological features to predict the outcome. Results: Out of 12 cytological features evaluated in phase 1 (training set), nuclear chromatin pattern, apoptotic bodies and tingible body macrophages were found to be the most significant features determining malignant histological outcome. These 12 cytological features were re-evaluated in phase 2 (n = 125). Of 125 cases, 54 had a benign and 71 had a malignant or premalignant histological outcome, with a positive predictive value of 56.8%. Conclusion: Granular nuclear chromatin, tingible body macrophages and apoptosis in the background are the most significant factors in determining whether endometrial cells present in cervical samples represent malignancy or are benign. Using these features, relatively accurate predictions of endometrial pathology can be made.

PSVII-15 Effects of electrolyzed reduced water on intake, digestion and ruminal fermentation parameters in beef cattle

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 446-447
Author(s):  
Natasha L Bell ◽  
Daisy A Gonzalez ◽  
Kendrah DeLeon
Keyword(s):  
Transition Period ◽  
Rumen Fluid ◽  
Phase 1 ◽  
Analysis Data ◽  
Phase 2 ◽  
Ruminal Fermentation ◽  
Fermentation Parameters ◽  
Reduced Water ◽  
Electrolyzed Reduced Water

Abstract The effect of electrolyzed reduced water consumption by cattle is not well defined. The objective of this study was to evaluate the effect of electrolyzed reduced water on intake, in vitro true digestibility (IVTD), ORP and pH in four ruminally cannulated steers (4 Bos taurus; 317 kg BW). Steers were subjected to a two period (14 d), two treatment crossover design. Treatment included: 1) standard water (CON; pH = 7.0 ± 1.0) or 2) electrolyzed reduced water (ERW; pH = 9.0 ± 1.0). The project comprised of two studies where the effects of ERW were observed for steers consuming a roughage diet (phase 1) or concentrate diet (phase 2). During Phase 1, animals were provided bermudagrass hay ad libitum. A 14 d transition period followed phase 1 to allow transition of diets. In phase 2, animals were maintained on a concentrate diet. During each period, d 1–8 served as a treatment adaptation phase, d 9–13 allowed for measures of intake and digestion, and rumen fluid was collected at h 0, 2, 4, 8, and 12 after feeding on d 14 for VFA, pH and ORP analysis. Data were analyzed using the MIXED procedure of SAS 9.4 (SAS Inst. Inc., Cary, NC). Intake, digestion, and ruminal fermentation parameters were not different for CON vs ERW steers (P ≥ 0.06). Analysis of VFA data have not been finalized and will be reported later. Results indicate that ERW has no effect on intake, digestion or ruminal fermentation parameters of steers consuming roughage or concentrate diets.

scholarly journals Developing a realist theory of psychosocial rehabilitation: the Clubhouse model

2021 ◽  
Author(s):  
Christina Mutschler ◽  
Jen Rouse ◽  
Kelly McShane ◽  
Criss Habal-Brosek
Keyword(s):  
Phase 1 ◽  
Psychosocial Rehabilitation ◽  
Theory Development ◽  
Realist Evaluation ◽  
Self Determination ◽  
Phase 2 ◽  
Two Phase ◽  
Realist Theory ◽  
Clubhouse Model ◽  
Two Phases

Background Psychosocial rehabilitation is a service that supports recovery from mental illness by providing opportunities for skill development, self-determination, and social interaction. One type of psychosocial rehabilitation is the Clubhouse model. The purpose of the current project was to create, test, and refine a realist theory of psychosocial rehabilitation at Progress Place, an accredited Clubhouse. Method Realist evaluation is a theory driven evaluation that uncovers contexts, mechanisms, and outcomes, in order to develop a theory as to how a program works. The current study involved two phases, encompassing four steps: Phase 1 included (1) initial theory development and (2) initial theory refinement; and Phase 2 included (3) theory testing and (4) refinement. Results The data from this two-phase approach identified three demi-regularities of recovery comprised of specific mechanisms and outcomes: the Restorative demi-regularity, the Reaffirming demi-regularity, and the Re-engaging demi-regularity. The theory derived from these demi-regularities suggests that there are various mechanisms that produce outcomes of recovery from the psychosocial rehabilitation perspective, and as such, it is necessary that programs promote a multifaceted, holistic perspective on recovery. Conclusions The realist evaluation identified that Progress Place promotes recovery for members. Additional research on the Clubhouse model should be conducted to further validate that the model initiates change and promotes recovery outcomes.

scholarly journals Simultaneous Measurement of Glomerular Filtration Rate, Effective Renal Plasma Flow and Tubular Secretion in Different Poultry Species by Single Intravenous Bolus of Iohexol and Para-Aminohippuric Acid

Animals ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 1027
Author(s):  
Lenka Stroobant ◽  
Siska Croubels ◽  
Laura Dhondt ◽  
Joske Millecam ◽  
Siegrid De Baere ◽  
...  
Keyword(s):  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Plasma Flow ◽  
Simultaneous Measurement ◽  
Filtration Rate ◽  
Renal Plasma Flow ◽  
Tubular Secretion ◽  
Effective Renal Plasma Flow ◽  
High Dose ◽  
Potential Marker

The aim of the current study was to investigate the simultaneous measurement of plasma p-aminohippuric acid (PAH) clearance as a potential marker to assess effective renal plasma flow (eRPF) and tubular secretion (TS), and the plasma clearance of iohexol (IOH) as a marker of the glomerular filtration rate in poultry species. The PAH was administered intravenously (IV) to broiler chickens, layers, turkeys, Muscovy ducks, and pigeons. Each animal received successively a single bolus dose of 10 mg PAH/kg bodyweight (BW) and 100 mg PAH/kg BW to assess the eRPF and TS, respectively. Simultaneously with both PAH administrations, a single IV bolus of 64.7 mg/kg BW of IOH was administered. A high linear correlation (R2 = 0.79) between eRPF, based on the clearance of the low dose of PAH, and BW was observed for the poultry species. The correlation between TS, based on the clearance of the high dose of PAH, and BW was moderate (R2 = 0.50). Finally, a moderate correlation (R2 = 0.68) was demonstrated between GFR and eRPF and between GFR and TS (R2 = 0.56). This presented pharmacokinetic approach of the simultaneous administration of IOH and PAH enabled a simultaneous evaluation of eRPF/TS and GFR, respectively, in different poultry species.

scholarly journals P27 The juvenile pig as animal model for unraveling renal drug elimination processes in children

2019 ◽  
Vol 104 (6) ◽  
pp. e28.1-e28
Author(s):  
L Dhondt ◽  
S Croubels ◽  
P De Paepe ◽  
P De Cock ◽  
M Devreese
Keyword(s):  
Animal Model ◽  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Plasma Flow ◽  
Filtration Rate ◽  
Renal Plasma Flow ◽  
Tubular Secretion ◽  
Tubular Reabsorption ◽  
Drug Elimination ◽  
Renal Drug Elimination

BackgroundOver the years pigs were promoted as potential animal model for humans due to their high degree of anatomical and physiological similarities with humans. Gasthuys et al. demonstrated that the maturation of the kidney function in terms of the glomerular filtration rate (GFR) in growing pigs was comparable to humans, but no data are currently available on renal plasma flow, renal tubular secretion and reabsorption.1 The aim of this pilot study was to unravel the contribution of distinct renal elimination processes in juvenile pigs and to compare with reported human values.MethodsEight seven-week-old pigs were intravenously administered a single bolus of a cocktail of following renal markers: iohexol (64.7 mg/kg body weight (BW), GFR), para-aminohippuric acid (PAH, 10 mg/kg BW, effective renal plasma flow (ERPF) and anion secretion), pindolol (0.05 mg/kg BW, cation secretion) and fluconazole (0.5 mg/kg, tubular reabsorption). Plasma and urinary concentrations were determined for PAH, pindolol and fluconazole at several time points. Only plasma concentrations were assessed for iohexol. PK modelling was performed with Phoenix® WinNonlin®.ResultsThe clearance of iohexol was 97.9 ± 16.1 ml/min/m² (mean ± SD). The ERPF, calculated as the renal clearance of PAH, was 9.5 ± 2.1 ml/min/kg. These GFR and ERPF values are approximately a factor 1.3 higher than the values observed in humans, namely 63.5–75.0 mL/min/m² and 6.5 ± 2.0 mL/min/kg.2,3 The net tubular secretion of PAH was 5.4 ± 1.8 mL/min/kg, which was comparable with the values obtained in humans (5.0 ± 1.8 mL/min/kg).3 Results for cation secretion and tubular reabsorption are not yet available (to be presented at the congress).ConclusionThe net tubular secretion of PAH was comparable between the juvenile pigs and humans. The GFR and ERPF were generally a factor 1.3 higher in juvenile pigs compared to humans.ReferencesGasthuys E., et al., Postnatal maturation of the glomerular filtration rate in conventional growing piglets as potential juvenile animal model for preclinical pharmaceutical research. Frontiers in Pharmacology 2017. 8.Schwartz GJ, Furth SL. Glomerular filtration rate measurement and estimation in chronic kidney disease. Pediatric Nephrology 2007;22(11):1839–1848.Gross AS, et al., Simultaneous administration of a cocktail of markers to measure renal drug elimination pathways: absence of a pharmacokinetic interaction between fluconazole and sinistrin, p-aminohippuric acid and pindolol. British Journal of Clinical Pharmacology 2001. 51(6):547–555.Disclosure(s)This study was funded by the Special Research Fund of Ghent University (BOF16/DOC/285).

scholarly journals Whole system approaches to health in higher education

2019 ◽  
Vol 119 (4) ◽  
pp. 246-258
Author(s):  
Mark Dooris ◽  
Alan Farrier ◽  
Susan Powell ◽  
Maxine Holt
Keyword(s):  
Higher Education ◽  
Phase 1 ◽  
International Perspective ◽  
Phase 2 ◽  
Structured Interviews ◽  
Two Phase ◽  
Content Type ◽  
Key Issues ◽  
Strategic Influence ◽  
The Uk

Purpose The purpose of this paper is to report on an evaluation of the UK Healthy Universities Network (UKHUN), which explored engagement of network members; identified what members value about the network; examined facilitators and barriers to engagement; and informed the network’s future development. Design/methodology/approach The study was a two phase mixed-method study, with participants being staff from Higher Education institutions. Phase 1 involved a documentary review and an online 14-question survey (n=32). Phase 2 comprised follow-up semi-structured interviews and focus groups, conducted using Skype (n=11). These were audio recorded and transcripts were thematically analysed in a two-stage process. Findings A number of key themes emerged from the thematic analysis: value of network meetings and events; popularity of the network website; increased communication and collaboration; sense of leadership offered by the network; interest and inclusion of an international perspective; importance of institutional support. Research limitations/implications Only six universities who are involved in the network took part in Phase 2. Although a range of organisations were chosen purposively, it is possible that additional key issues at other universities were excluded. Originality/value The UKHUN is valued by its membership, particularly its biannual meetings, online presence, leadership, ethos and communication methods. Key barriers include the capacity of staff to attend meetings and contribute to the network, influenced by a lack of institutional commitment and prioritisation. Findings from the evaluation have informed a “refresh” of the network’s website and a revision of its membership structure, as well as guiding its positioning to achieve greater strategic influence.

An ultrastructural analysis of cyst wall development in the metacestode ofHymenolepis diminuta(Cestoda)

Parasitology ◽  
1984 ◽  
Vol 89 (3) ◽  
pp. 537-566 ◽  
Author(s):  
K. Sylvia Richards ◽  
C. Arme
Keyword(s):  
Cyst Wall ◽  
Phase 1 ◽  
Basal Membrane ◽  
Hymenolepis Diminuta ◽  
Phase 2 ◽  
Phase 3 ◽  
Muscle System ◽  
Initial Development ◽  
Final Maturation

SUMMARYA series of development stages (I–XI) have been devised to describe the development of the cyst wall of the metacestode ofHymenolepis diminuta. The cyst wall possesses tegumentary, muscular, fibrous and inner cyst tissues, the developmental rates and differentiation patterns of which are not identical. The tegumentary tissue differentiates posteriorly. Its microvillus-bearing distal cytoplasm remains simple until scolex retraction, after which rapid increase in depth followed by vacuolation occurs and basal membrane infoldings surround Phase 3 fibrogenesis fibrils. Senescence, which also affects the tegumentary cytons, then ensues. The muscle system development is posteriad and maturation, completed before scolex retraction, is followed by myocyton senescence. Posteriorly differentiated fibroblasts commence Phase 1 fibrogenesis after scolex retraction and the primary fibrous zone is fully established within approximately 6 days. Phase 2 and 3 fibrogenesis develop centrifugally, the fibrils of Phase 2 surrounding the tegumentary cytons and myocytons prior to their senescence, and those of Phase 3 lying more peripherally. The inner cyst tissue, established posteriorly, differentiates anteriorly, centripetally and early, the penultimate stage commencing just before scolex retraction, about 6 days after which the final maturation junctional complexes start development. Neitherin vitroexcystment nor infectivity of the definitive host can be satisfactorily achieved before the initial development of the primary fibrous zone. This may play a skeletal role during excystment, and is shown to be unaffected by the digestive enzymes which cause loss of cytoplasmic integrity in the outer regions of the cyst.

A computationally fast approach to maximum‐likelihood deconvolution

Geophysics ◽  
1984 ◽  
Vol 49 (5) ◽  
pp. 550-565 ◽  
Author(s):  
Chong‐Yung Chi ◽  
Jerry M. Mendel ◽  
Dan Hampson
Keyword(s):  
Maximum Likelihood ◽  
Initial Conditions ◽  
Phase 1 ◽  
Real Data ◽  
Phase 2 ◽  
Statistical Parameters ◽  
Two Phase ◽  
Nonminimum Phase ◽  
Fast Approach ◽  
Fine Adjustment

In this paper we derive and implement a maximum‐likelihood deconvolution (MLD) algorithm, based on the same channel and statistical models used by Kormylo and Mendel (1983a), that leads to many fewer computations than their MLD algorithm. Both algorithms can simultaneously estimate a nonminimum phase wavelet and statistical parameters, detect locations of significant reflectors, and deconvolve the data. Our MLD algorithm is implemented by a two‐phase block component method (BCM). The phase‐1 block functions like a coarse adjustment of unknown quantities and provides a set of good initial conditions for the phase‐2 block, which functions like a fine adjustment of unknown quantities. We demonstrate good performance of our algorithm for both synthetic and real data.

A Phase 1/2 Study Of KW-2478, An Hsp 90 Inhibitor, In Combination With Bortezomib (BTZ) In Patients (Pts) With Relapsed/Refractory (R/R) Multiple Myeloma (MM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1967-1967
Author(s):  
Cavanagh Jamie ◽  
Honorata Giongco Baylon ◽  
Priscilla B. Caguioa ◽  
Faith E. Davies ◽  
Mecide Gharibo ◽  
...  
Keyword(s):  
Phase 1 ◽  
Single Agent ◽  
Xenograft Model ◽  
Clinical Activity ◽  
Synergistic Activity ◽  
Dependent Manner ◽  
Phase 2 ◽  
Hsp90 Inhibition ◽  
Hsp 90

Abstract Background KW-2478 is a potent Hsp 90 inhibitor that binds to Hsp 90 with an IC50 value of 3.8 nmol/L. In preclinical studies, KW-2478 inhibited the in vitro growth of myeloma cell lines at GI50 values of 0.12 – 0.39 µM and markedly inhibited the growth of myeloma xenografts in SCID mice in a dose-dependent manner. In vitro, KW-2478 and BTZ demonstrated synergistic activity against OPM-2/GFP cells and in the NCI-H929 xenograft model, the combination of KW-2478 and BTZ showed greater anti-growth activity than either agent alone. A single-agent Phase 1 study (KW-2478 administered daily x 5 every 14 days), showed no dose limiting toxicity (DLT) and Hsp90 inhibition was observed at doses >71 mg/m2. Aim To establish safety, tolerability and recommended Phase 2 dose (RP2D) of KW-2478 plus BTZ in pts with R/R myeloma and assess overall response rate (ORR) based on International Myeloma Working Group (IMWG) response criteria. The PK and PD of KW-2478 plus BTZ were characterized and progression-free survival (PFS) was investigated. Methods All patients had MM by IMWG criteria, had received at least 1 and no more than 3 prior MM regimens and had not responded or had relapsed, and had adequate renal function. Patients who received prior BTZ could not be refractory. This open-label study had 2 parts: A Phase 1 dose escalation (3 + 3 design) part followed by a Simon 2-stage Phase 2. KW-2478 and BTZ were administered on Days 1, 4, 8 and 11 of a 21-day cycle. In Phase 1, the doses of KW-2478 and BTZ were sequentially escalated until observation of DLT, MTD, or achievement of the maximal planned dose levels (KW-2478 175 mg/m2, BTZ 1.3 mg/m2). PK and PD samples were collected in C1 on Days 1 and 11, and Days 1, 4, 8, and 11, respectively. In Phase 2, if 11 or more responses were observed in the first 27 evaluable pts, then an additional 50 evaluable pts would be enrolled. Response was assessed at the end of each cycle and safety was assessed continuously. Results The study enrolled 95 pts who received at least one dose of study drug: 15 in Phase 1 and 80 in Phase 2; 86 pts received the RP2D (highest planned dose of KW-2478 175 mg/m2 /bortezomib 1.3 mg/m2). Median age was 65; 57% of pts were male. There was 1 DLT (presyncope) in Phase 1. The most common adverse events (AEs) were diarrhea (74%), nausea (61%), fatigue (55%), constipation (46%), vomiting (40%) and peripheral neuropathy (30%). Most AEs were Grade 2; 5 pts had Grade 4 AEs. Five pts had a Grade 4 thrombocytopenia and 3 pts had a Grade 4 neutropenia. The PK profiles for KW-2478 plus BTZ in combination were comparable to each agent’s individual PK profile. In the Phase 1 portion of the trial, Hsp70 levels, a marker of Hsp90 inhibition, increased in the peripheral blood mononuclear cells in all subjects (N = 13). Of the pts who received the RP2D, 79 pts were evaluable for IMWG response. The ORR was 39% (4% CR, 14% VGPR, and 22% PR); in pts who were bortezomib naïve (n = 50), the ORR was 48%. Median PFS was 26.4 weeks and median duration of response had not been reached at the time of this report. Six pts continue treatment at the time of data cut-off. Conclusions KW-2478 plus BTZ was well-tolerated when administered at the doses and schedule studied. Clinical activity was demonstrated in pts with R/R MM (ORR of 39%). PFS was 26.4 weeks Disclosures: Akinaga: Kyowa Kirin Pharmaceuticals: Employment, Equity Ownership. Kurman:Kyowa Kirin Pharmaceuticals: Consultancy. Novak:Kyowa Kirin Pharmaceuticals: Employment.

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