Citations

Abstract Abstract 4651 Introduction Graft versus host disease remains a major cause of mortality and morbidity following matched unrelated hematopoietic stem cell transplantation. Campath-1H (Alemtuzumab) is a humanized monoclonal antibody to CD52, an antigen expressed on T and B lymphocytes, monocytes and natural killer cells and is thought to reduce GVHD incidence through in vivo T cell depletion. Through the same mechanism it can potentially increase the risk of relapse by reducing the graft vs. leukemia effect and also possibly increase the risk of infection due to delayed immune recovery. This study looks at our experience with Campath-1H substituted in place of the conventional anti-thymocyte globulin (ATG) in our transplant conditioning regimen. Patients and Methods This retrospective case study included 17 pediatric (9 male; 8 female) matched unrelated bone marrow transplants done in our institution between January 2003 and June 2009 with Campath-1H as part of the pretransplant conditioning regimen. The primary transplant indication was leukemia/lymphoma (n=9), MDS/ MDS evolving into AML (n= 3), severe aplastic anemia (n=4) and Fanconi anemia (n=1). The conditioning regimen included Campath-1H given with cytoxan/ total body irradiation (TBI) in 14 patients, fludarabine/ TBI in 2 patients, and melphalan/ fludarabine in 1 patient. Campath-1H dosing was body weight based: 3mg (if between 5-15kg), 5 mg (if between 16-30kg) and 10 mg (if >30 kg) and 3 doses were administered when underlying condition was a malignancy and 4 doses when it was a bone marrow failure state. The last dose was given at least 24 hours prior to the bone marrow/ peripheral stem cell infusion. GVHD prophylaxis was with tacrolimus/methotrexate (n=12), tacrolimus (n=4) and cyclosporine/methotrexate (n=1). Standard institutional infectious prophylaxis was followed. Results The median age at transplant was 12.2 years (range; 0.7-19.7 years). All but one patient engrafted with a median of 21 days (range; 14-25 days). 5 out of 17 developed Grade I-II acute GVHD which resolved with steroids. No patient developed chronic GVHD. One patient had a CMV reactivation but no patient developed active CMV disease. 4 patients had varicella one of whom died of disseminated infection (day +376). The same patient also had adeno viral infection and BK viremia. 1 patient developed PCP pneumonia and retinal toxoplasmosis. 5 patients (6 transplants) relapsed (range; 40-641 days) with 3 relapsing within +100 days. 1 patient developed PTLD which was successfully treated with rituximab. Of the 4 patient deaths 3 were due to relapse and one due to disseminated varicella infection. The median follow-up time was 719 days (range; 147-2175 days). Overall survival as calculated using the Kaplan-Meir analysis was 100 % at 100 days and 94% at 1 year. Event free survival censoring for death, relapse and rejection was 76% at 100 days and 64% at 1 year. Conclusions Based on our experience, Campath-1H used as part of pretransplant conditioning regimen in pediatric matched unrelated transplants seems to reduce the risk of serious GVHD. This is in concordance with other published literature. T cell depletion is considered to increase the risk of life threatening infections. Our study had one infection related death. There were no patients with active CMV disease. This may in part be attributed to strict prophylactic measures and increased surveillance. Longer duration of follow-up is required to adequately analyze the relapse rates. Also, given our small patient numbers the effect of primary disease state and stage on relapse could not be assessed. Larger studies in the pediatric population with longer duration of follow-up comparing Campath-1H with conventional regimens are required to further assess its role with regards to graft vs. leukemia effect and also to establish if the decreased incidence of GVHD is sustained in larger cohorts. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3926 Introduction. Chronic lymphocytic leukemia (CLL) patients will have significant variation in signs and symptoms at initial presentation and across lines of therapy, with concomitant effect on patient health-related quality of life (HRQOL). HRQOL and other patient-reported outcomes, together with clinical outcomes, provide a more complete perspective on the burden of disease and facilitate a broader view of the impact of treatment regimens. This analysis evaluates whether the HRQOL of patients with CLL in the United States (US) varies at the time the patients are about to embark on various lines of therapy, and offers a baseline report from which subsequent longitudinal analysis post-treatment will be possible. Methods. Clinical and HRQOL data were collected in Connect®CLL, a prospective observational registry initiated in March 2010 involving centers in the US. Physicians provided data on the demographics and clinical characteristics of patients receiving therapy. HRQOL was self-reported by patients at enrollment using the Brief Fatigue Inventory (BFI, a symptom assessment tool), the EQ-5D (a non-disease-specific HRQOL instrument), and the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu, a leukemia-specific HRQOL instrument). We characterized patients who had initial (First Line), second (Second Line) or subsequent (Higher Line) treatment regimens prior to initiation of regimens. Reported mean overall and/or domain-specific BFI, EQ-5D and FACT-Leu scores were analyzed by line of therapy. Statistical significance of score differences among sub-cohorts was ascertained by ANOVA using SAS 9.1. Results. Evaluable data were reported on 1005 patients, enrolled from 161 centers (93% community, 7% academic). Patients were predominantly male (62%) and white (89%) with mean age at 69 (standard deviation [SD] 11) years. HRQOL scores by line of therapy are presented: The total FACT-Leu and FACT-G results, and the total EQ-5D Index and Visual Analogue Scale (VAS) results, consistently suggest that patients initiating first line therapy have somewhat better HRQOL compared with those initiating subsequent lines of therapy. FACT-Leu total scores of patients initiating first line therapy were associated with better physical and leukemia-specific considerations, and the EQ-5D total score was associated with better mobility and pain/discomfort. Conclusions. Initial results from the Connect® CLL Registry indicate that HRQOL prior to treatment is better among patients initiating first line therapy compared to patients initiating later lines of treatment. Future analyses should be conducted to determine what clinical or other factors may be associated with the HRQOL deterioration in patients initiating subsequent lines of therapy, so as to inform clinician decision making. Also, subsequent longitudinal analyses should be undertaken to determine how HRQOL might be affected by the different lines of therapy and the specific treatment regimens, as well as by their initial HRQOL and other patient factors. Disclosures: Kay: Celgene: Research Funding. Flowers:Celgene: Consultancy; Prescription Solutions: Consultancy; Seattle Genetics: Consultancy; Millennium: Research Funding, Unpaid consultancy, Unpaid consultancy Other; Genentech: Unpaid consultancy, Unpaid consultancy Other; Gilead: Research Funding; Spectrum: Research Funding; Janssen lymphoma research foundation: Membership on an entity's Board of Directors or advisory committees. Weiss:Celgene: Consultancy. Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Flinn:Celgene: Research Funding. Grinblatt:Celgene: Honoraria, Speakers Bureau. Kipps:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kozloff:Celgene: Consultancy. Lerner:Celgene Connect: Membership on an entity's Board of Directors or advisory committees. Sharman:Celgene: Consultancy; Pharmacyclics: Honoraria; Calistoga: Honoraria; Portola pharmaceuticals: Consultancy. Khan:Celgene Corporation: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Swern:Celgene: Employment. Sullivan:Celgene: Employment. Pashos:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Abstract 601 Background: Despite therapeutic advances and availability of novel agents, multiple myeloma (MM) remains an incurable malignant disorder and strategies to improve survival are being actively sought. One such approach is the use of maintenance therapy with lenalidomide (Revlimid®; R), which has shown PFS benefit, without conclusive evidence of OS benefit except in a selected population (CALGB100104). Shrinking resources with rising healthcare costs warrant careful assessment of the financial impact of expensive anticancer therapeutics in context with the true benefit to patients. Methods: This analysis was not supported or solicited by any pharmaceutical industry. For our pharmacoeconomic study we selected the MM-015 trial; a large (n=459) double-blind, randomized, placebo-controlled phase III study that investigated the efficacy of continuous R maintenance after initial therapy with melphalan/prednisone/lenalidomide (MPR) in a uniform cohort of patients (≥65 years, newly diagnosed MM, transplant ineligible). The three study arms were MP, MPR and MPR followed by R maintenance (MPR-R). The cost-effectiveness model included medical costs (drugs, office visits, laboratory tests) and costs of treatment-related adverse events (AEs) for an individual patient. Drug costs were calculated from the average wholesale price, using average US adult weight of 80kg. Office visit and laboratory test costs were obtained using Medicare reimbursement fees. Costs of AEs were obtained from peer-reviewed publications. Incidence of AEs was obtained from the published MM-015 trial. Costs were valued in 2011 US dollars. Cost calculations included: (1) computing distribution of the numbers of induction and maintenance courses completed by patients treated with each of these regimens; (2) computing the per-course probabilities of the occurrence of individual AEs during induction and maintenance for each of these toxicities; (3) combining these data with the treatment costs and costs of individual AEs to compute cumulative cost of treatment through 40 maintenance cycles and cumulative cost of treatment per progression-free survivor. Summary measures computed for each treatment: (1) average cumulative cost per patient (ACCP) treated; (2) average cumulative cost per progression free survivor (ACCPFS), representing the average cumulated cost/patient who is progression free at that time. The distribution of courses received was obtained from the MM-015 publication. Data on subsequent therapy at the time of disease progression was not available. Results: Median follow up reported in the published study was 30 months. Median PFS was 13 months (MP), 14 months (MPR) and 31 months (MPR-R) in the three arms. Table 1 summarizes the calculated ACCP and the ACCPFS of each regimen for induction and maintenance treatment. MPR-R was the most expensive of the three arms in terms of total cumulative costs, with an ACCP of $231,314, compared to $166,211 for MPR and $17,972 for MP. However, taking the efficacy of each regimen into account (ACCPFS), MPR greatly exceeds both MPR-R and MP ($1,540,139 vs. $516,322 vs. $309,346), while the difference between MPR-R and MP was less distinct. Figure 1 illustrates the exponential increase in ACCPFS of MPR, compared to MPR-R and MP. Conclusions: From a cost-effectiveness perspective, if MPR is used as the induction regimen, maintenance with R should be strongly considered, as MPR without maintenance does not confer any significant benefit over MP, while incurring a much higher cost. However, the overall cost of MPR-R is substantial with no reported OS benefit at present. In the absence of clear survival benefit the financial burden of prolonged treatment becomes an important factor to consider prior to adopting this therapeutic strategy in MM. As part of a global strategy for addressing healthcare costs, it is important to consider this in appropriate medical decision making for patients, and to include cost-effectiveness analyses as a part of large prospective clinical trial efforts. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3925 Introduction: CLL patients (pts) who relapse following purine-analog or bendamustine-based treatments have a poor prognosis. These pts have limited therapeutic options and novel agents with alternative mechanisms of action are needed. Several phase 1 and 2 trials in rel/ref CLL showed promising activity with escalating dose regimens of lenalidomide (LEN). In other phase II studies improved clinical responses to lenalidomide appeared to correlate with dose levels > 5mg/day. This phase 2 trial investigates the safety of LEN initiated at 3 different starting doses followed by a step-wise dose escalation as tolerated in rel/ref CLL. Methods: In this ongoing trial, eligible pts with rel/ref CLL who have received ≥ 1 prior treatment regimen containing purine-analog or bendamustine are being enrolled. The objectives of this study are to evaluate primarily the safety and secondarily the efficacy of different LEN dose regimens. Pts are randomized 1:1:1 to receive a double-blinded starting dose of 5 mg, 10 mg, or 15 mg oral LEN on days 1–28 of each 28-day cycle. In all 3 treatment arms, the dose is escalated by 5 mg increments every 28 days to reach a maximum dose of 25 mg/d, depending on tolerability. In instances of poor tolerability, dose reductions also occur in 5 mg steps. Pts are stratified by relapsed versus refractory status to their last purine-analog or bendamustine-based treatment regimen and according to age (< 65 vs ≥ 65 years). Tumor lysis syndrome (TLS) prophylaxis comprises of oral hydration and allopurinol 300 mg/day and is initiated ≥ 3 days prior to starting study drug and for a minimum of the first 3 treatment cycles. A total of 105 pts are planned for enrollment to the study. Per protocol, unblinded interim analyses were conducted by the independent Data Monitoring Committee (DMC) after 18 subjects completed 1 cycle and continue at 13-week intervals. Results: To date, 95 pts are enrolled at a median age of 64 years (range 32–81). Enrolled pts are primarily male (67%) and Caucasian (92%). Cytogenetic data are available for 73 pts; 21% have del(17p), 55% have del(13q), 25% have del(11q), and of 72 patients evaluable for trisomy 12, 11 patients (15%) tested positive. IGVH is unmutated in 77% of 77 evaluable pts and 44% of 84 evaluable pts are ZAP70-positive. Based on the Binet and Rai staging systems 9 (10%), 25 (26%) and 24 (25%) of subjects are stage A, B and C, respectively; 7 (7%), 12 (13%) and 16 (17%) subjects are low, intermediate or high-risk disease, respectively. For 2 (2%) subjects the Binet/Rai staging is currently unknown. Overall, 19 pts (20%) received prior bendamustine-containing treatment and 71 pts (75%) received prior fludarabine-based treatment. The median number of prior therapies was 3 (range 1–10). Most common hematological grade ≥ 3 AEs include neutropenia (62%) and thrombocytopenia (34%). At baseline, 19% of pts presented with grade 1–2 neutropenia. The most common non-hematological ≥ grade 3 AEs include pneumonia (13%), tumor flare (13%), and fatigue (11%). TLS was reported in 3 pts (3%): grade 1, 3, and 4. In total, 8 grade 5 events were reported, 3 of which were suspected to be related to LEN: 2 cases of pneumonia and 1 death for unknown cause. At the time of the cut-off, 59 pts (62%) have discontinued treatment. Most common reasons for treatment discontinuation include disease progression (n = 20) and AEs (n = 20). To date, 47 pts (49%) have dose escalated above their starting dose levels of which 12 patients escalated to the highest dose level (25 mg daily). 18 subjects have had no dose level reduction or escalations and 1 patient is still in the first cycle of the study. Average duration of treatment is 6.5 cycles, and median number of cycles is 4. Efficacy evaluations are completed monthly after 3 months of study drug treatment. At time of the data reporting, 5 pts were on study drug but did not reach the first assessment at cycle. For the 90 pts evaluable for response, the investigator's assessment indicates 2 pts (2%) reached CR, 36 (40%) achieved PR, 33 (37%) patients had SD, and 19 (21%) pts progressed. Conclusion: The independent DMC, as of 14 June, 2012 (N=95), recommended that accrual into all three treatment arms should continue as planned, suggesting all three starting doses were well tolerated. To date, the ORR is 42% and 49% of pts were dose escalated at least once. In this rel/ref CLL population LEN appears active, and completion of accrual will clarify the appropriate dose at which to initiate therapy. Disclosures: Wendtner: Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: use of lenalidomie in relapsed/refractory CLL. Hallek:Celgene Corporation: Consultancy, Honoraria, Research Funding. Hillmen:Celgene Corporation: Honoraria. Gregory:Celgene Corporation: Honoraria, Research Funding. Stilgenbauer:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. Kipps:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Purse:Celgene Corporation: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Mei:Celgene Corporation: Employment.

Abstract Abstract 728 Background: LM, an antibody-drug conjugate (ADC), is designed to specifically kill CD56+ cancer cells and contains a potent maytansinoid cytotoxic agent (DM1) attached to a CD56-targeting antibody. MM shows CD56 expression in >70% of cases. LM has demonstrated single agent clinical activity and an acceptable safety profile in relapsed/refractory (rel/ref) MM patients. Preclinical studies showed enhanced anti-MM activity when LM was combined with Len/Dex. To further study the safety and efficacy of LM in combination with Len/Dex, a phase I study was conducted in rel/ref patients. This abstract reports updated results on the safety and efficacy of LM/Len/Dex and preliminary results on the pharmacokinetics (PK) and immunogenicity studies. Methods: Primary study objectives were to determine the safety, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), anti-MM activity and PK of LM in combination with standard oral (PO) doses of Len (25 mg po, daily on days 1–21) and Dex (40 mg po on D 1, 8, 15, and 22) in CD56+ rel/ref MM patients who have received at least 1 prior therapy. LM was given intravenously (IV) on D 1, 8, and 15 on a 28-day cycle. Dose escalation was conducted in new cohorts of patients to define the MTD, which was then further evaluated in a dose-expansion cohort. Adverse events (AEs) were assessed using CTCAEv3 criteria, and dose-limiting toxicity (DLT) determination was based on the occurrence of AEs that were probably or definitely attributed to the study regimen. Efficacy was assessed using the International Myeloma Working Group (IMWG) criteria. Enrollment has completed and 16 patients remain on study. Results: Forty-four patients were enrolled, 41 are currently evaluable for safety and 32 are evaluable for efficacy. The median number of prior therapies was 2 (range 1–11), 62% of patients had prior Len exposure and 33% were Len refractory. LM doses of 75 (N = 11), 90 (N=4), and 112 (N =6) mg/m2 were evaluated in the dose-escalation phase. The most common AE was peripheral neuropathy (PN), which occurred more frequently at higher LM doses (55% at 75 mg/m2 and 100% at 90 and 112 mg/m2); Grade 3 PN was seen only in patients treated at 90 mg/m2 or above. PN emerged, in most cases, in cycles >3 and was manageable with LM dose modification. During dose escalation, 1 patient experienced Grade 4 neutropenia and hyperuricemia. The 75 mg/m2 LM dose was considered the MTD based on overall tolerability and the lower incidence of PN observed, and was further tested to determine its suitability as the RP2D in the dose expansion portion of the study (N=23 patients, 19 patients available for safety evaluation). Grade 1–2 PN occurred in 8 patients (42%) and grade 3 PN was observed only in 1 pt in the dose-expansion cohort. Two patients developed grade 3 tumor lysis syndrome (TLS). Other grade 3 AEs reported in 1 patient each (5%) in the dose-expansion cohort consisted of neutropenia, thrombocytopenia, anemia, hemolytic anemia, and LDH increase. Efficacy was observed across all dose levels and the overall response rate (ORR) was 59%, including 1 patient each with stringent complete response (sCR) and complete response (CR), 8 patients with very good partial remission (VGPR), and 9 patients with partial remission (PR). No immunogenicity against the antibody (HAHA) or DM1 component (HADA) of LM was detected. PK results from 18 patients treated at 75 mg/m2 indicate LM Cmax and exposure in this combination regimen is consistent with LM monotherapy. Conclusions: Based on all available safety data, 75 mg/m2 was considered the RP2D. LM at 75mg/m2 in combination with Len and Dex has shown objective evidence of clinical activity with an acceptable safety profile. Disclosures: Off Label Use: Lorvotusumab mertansine is not FDA approved for treatment of multiple myeloma alone or in combination with lenalidomide and dexamethasone as is investigated in this trial. Running:ImmunoGen, Inc.: Employment. Murphy:ImmunoGen, Inc.: Employment. Guild:ImmunoGen, Inc.: Employment. Carrigan:ImmunoGen, Inc: Employment. Ladd:ImmunoGen, Inc.: Employment. Wolf:ImmunoGen, Inc.: Employment, Equity Ownership. O'Leary:ImmunoGen, Inc.: Employment. Ailawadhi:Millenium Pharmaceuticals: Speakers Bureau.

Abstract Abstract 4034 Through literature review we identified 376 pre-clinical studies in which a small molecule or antibody has been demonstrated to be cytotoxic to multiple myeloma (MM) cells either as cell lines, primary tumor samples or in mouse models. Indeed it seems there is no limit to the number of compounds that are cytotoxic to MM cell lines at high enough concentration. Since the pipeline to clinical trials is then large the utility of such assays in predicting future clinical value is debatable. We therefore sought to examine the utility of applying very early Phase I or Phase II trial experiences to predict for future clinical adoption. Using Pubmed, ASCO, ASH, EHA and IMWG abstracts we identified 117 drugs explored as single agents in 211 early stage clinical MM trials between 1961 and 2012 involving 7,166 patients. As definitions have changed over time, our analysis used partial responses (PR) or better as a response. When multiple trials were reported with a single drug, the average and the highest response rate for that agent was identified. Results were considered regardless of whether single or multi center trial, elderly or younger patients, stage of disease, targeted or non targeted therapy. High dose therapies requiring autologous stem cell support (eg. melphalan and etoposide), trials with less then 5 patients (e.g. siltuximab) or trials with concomitant steroid application which obscure single agent activity (e.g. pomalidomide, marizomib or daratumumab) were excluded in the analysis. Results: 17 drugs (14.5%) showed a best result of PR in more than 20% of patients, but when average response across all reported trials is considered, doxorubicin, arsenic trioxide and idarubicin drop out leaving 14 active drugs. Twelve drugs (10.3%) report as a best result PR in 10–20% of patients. 88 drugs (75.2%) reported a PR response in less than 10% of patients, 68 of which (58.1%) had no reported activity. A striking finding of our study is that all drugs approved for, or commonly used in clinical practice (prednisone, dexamethasone, cyclophosphamide, melphalan, bendamustine, thalidomide, lenalidomide, bortezomib, carfilzomib) have an average single agent PR response of at least 20%. Pomalidomide, although not approved, meets this threshold in Phase I testing. Older agents including teniposide, fotemustine, paclitaxel, and interferon also appear active by this criteria but have fallen from favor or were never adopted due to perceived toxicity. Of note, a number of newer agents which are in, or which recently completed Phase 3 testing, such MLN9708, elotuzumab, panobinostat, vorinostat or perifosine show little single agent activity. A weakness in this approach is that changes in measurement of response over time might bias the results, especially in favor of older studies. Furthermore, the chance of responding to a new drug has likely slowly declined as therapies have improved and patients have entered such trials at increasingly late stages of disease. It also does not rule out the possibility of synergistic activity or clinical benefit from a cytostatic drug. Nevertheless, our analysis suggests that a cut off of 20% single agent partial response activity averaged across all trials with that agent is highly predictive of future clinical success. If best reported response over 20% is considered no drug except vincristine has yet reached the clinic and has subsequently fallen from favor. Thus only drugs with 20% PR activity are in widespread use and thus this benchmark provides a framework for guiding choice of drugs for late stage clinical testing. Disclosures: Jimenez-Zepeda: MMRF: Research Funding; Jansenn Ortho: Honoraria. Fonseca:Onyx: Consultancy, Research Funding; Cylene: Research Funding; Medtronic: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Genzyme: Consultancy; BMS: Consultancy; Lilly: Consultancy; Binding Site: Consultancy; Millenium: Consultancy; AMGEN: Consultancy; Mayo Clinic: Patents & Royalties. Stewart:Millenium: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy.

Abstract Abstract 132 Multiple myeloma (MM), an incurable neoplasia of terminally differentiated plasma cells, are critically dependent on their interactions with bone marrow stromal cells (BMSC) for essential survival signals, growth and immunosuppressive factors. Very little is known about the specific BM cell type or the molecular elements in these interactions, an understanding of which could provide novel targets that could be interdicted to enhance conventional chemotherapy. A potential MM surface protein that could be involved in these interactions is CD28, based on its known pro-survival role in T cells. Clinical studies have shown that expression of CD28 in multiple myeloma highly correlates (p=0.006) with myeloma tumoral expansion. Moreover, CD28+ MM cells invariably express the CD28 ligand CD86. A survival role for MM-CD28 might involve interactions with BM cells that express B7 (CD80/CD86) such as dendritic cells (DCs, that are known to be closely associated with MM cells in the BM) or with CD86+ MM cells themselves. We had previously shown (ASH2008, #I-769) that blocking CD28-CD86 interactions between myeloma cells with high affinity B7 ligand CTLA4Ig (Abatacept®) sensitized myeloma cells to chemotherapy. Now we show that myeloma cells co-cultured with myeloid DCs in vitro derive both direct and indirect survival signals from DCs, and this can be partially blocked by commercially available reagents. Our data show that flow cytometric analysis of mononuclear cells (MNC) from BM aspirates of myeloma patients with increased CD138+ plasma cell populations (9-58%), show an increased CD11b+ (myeloid) population (20-37%) as well, which is in contrast to healthy transplant donor controls (12-15% CD11b+, 4–6% CD138+). Moreover, a larger fraction (11-47%) of the myeloma CD138+ plasma cells expressed CD28 compared to healthy control (3.3-7.7%). Also, when we analyzed gene expression datasets (NCBI #GSE5900 and GSE4204) from plasma cells (PC) of normal donors, monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SM) and newly diagnosed multiple myeloma (MM), we found a progressive increase in patients showing CD28 expression with increasing severity of disease (normal<MGUS<SM<MM) (Fig 1A). When we sorted the highest scoring MM group (n=538) into 8 genetic subgroups as defined earlier, CD28 expression was found to peak in the MF subgroup (typically associated with poor survival in myeloma patients) (Zhan et al. 2006, Blood 108, pp. 2020) relative to total population (p<0.0001) (Fig 1B). Antibody mediated activation of MM-CD28 over 48 hrs increased viability of myeloma cell line MM.1S cultured under serum starvation (3.7%) or with drugs ATO (1.9%), melphalan (18%) or dexamethasone (3.3%) to 66%, 21%, 33% and 11% respectively. Viability of MM.1S cells or primary CD138+ plasma cells (isolated from myeloma BM aspirates) cultured under serum starvation was enhanced >3 fold (p<0.001) when co-cultured with monocyte derived DCs, and in MM.1S this was partially reversed when either MM-CD28 or DC-B7 was blocked (Fig 2). Similar protection of MM.1S was also observed against a gradient of dexamethasone or melphalan. CD28 activation was accompanied by rapid tyrosine phosphorylation of CD28, association of p85 (PI3K), activation of Vav-1 and increase in CD28 associated tyrosine kinase activity, as shown by immunoprecipitation, western and kinase activity assays. We had previously shown that MM-CD28 interaction drive DC production of pro-survival factor IL-6 and immunosuppressive factor IDO via DC-B7 “backsignaling” (ASH2008 #I-769). Now we show that MM induced DC production of IL-6 (8 ng/ml) was partially inhibited in presence of CD28 blocking αCD28(Fab) fragments (3 ng/ml) or with protein kinase C (PKC) inhibitor Bisindolylmaleimide-I (2.1ng/ml). Activity of the immunosuppressive enzyme IDO in these co-cultures was completely inhibited in the presence of a novel IDO inhibitor from Incyte corporation, and this helped partially reverse IDO mediated suppression of T-cell proliferation in proliferation assays using co-culture supernatants. In conclusion, our data characterizes CD28-B7 pathway and DCs in the BM as vital for myeloma survival and also as possible targets to include in future strategies in the treatment of myeloma. FIGURE 1 FIGURE 1. FIGURE 2 FIGURE 2. Disclosures: Boise: University of Chicago: Patents & Royalties.

INTRODUCTION: Options to treat medically refractory gastroparesis are limited. Gastric peroral endoscopic myotomy (G-POEM) is a novel minimally invasive technique in endosurgery that has shown promising results. Data is limited as to its efficacy, safety, predictive factors and its comparability to surgical pyloroplasty. The aim of our study was to synthesize and analyze the clinical outcomes of GPOEM by meta-analysis methods. METHODS: We searched multiple databases from inception through March 2019 to identify studies that reported on G-POEM and surgical pyloroplasty in gastroparesis. Our primary outcome was to analyze the pooled rates of gastroparesis cardinal symptom index (GCSI) score and 4-hr gastric emptying study (GES) results, with G-POEM. Similar outcomes with surgical pyloroplasty was used as a comparator group. RESULTS: 332 and 375 patients underwent G-POEM (11studies) and pyloroplasty (7studies), respectively. The pooled rate of clinical success, based on the GCSI score, with G-POEM was 75.8% (95% CI 68.1-82.1, I 2 = 50) and with pyloroplasty was 77.3% (95% CI 66.4-85.4, I 2 = 0), with no significance, P = 0.81. The pooled rate of clinical success, based on the 4-hour GES results, with GPOEM was 85.1% (95% CI 68.9-93.7, I 2 = 74) and with pyloroplasty was 84% (95% CI 64.4-93.8, I 2 = 81), with no significance, P = 0.91. The pooled rate of mean pre-G-POEM GCSI score was 3.4 (95% CI 3.1-3.7, I 2 = 89) and post-G-POEM GCSI score was 1.8 (95% CI 1.4-2.1, I 2 = 89), with statistical significance ( P = 0.001). The pooled pre-G-POEM 4-hr GES was 49.9% (95% CI 41.6-58.3, I 2 = 94) and post-G-POEM 4-hr GES was 20.6% (95% CI 12.3-28.8, I 2 = 77), with statistical significance ( P = 0.001). The pre and post pyloroplasty 4-hr GES results were 36% (95% CI 32.7-39.3, I 2 = 88) and 3.9% (95% CI 2.3-5.5, I 2 = 43), respectively ( P = 0.001). The pre and post pyloroplasty GCSI score was not analyzed due to paucity in data. The overall adverse events were comparable (11%, 5.9-19.8, I 2 = 66 vs 11.4%, 5-24, I 2 = 69, P = 0.95). Based on meta-regression analysis, idiopathic-gastroparesis, prior treatment with botulinum toxin and gastric-stimulator seemed to predict clinical success with G-POEM. CONCLUSION: G-POEM demonstrates clinical success in treating refractory gastroparesis with comparable outcomes to pyloroplasty. Idiopathic gastroparesis, prior treatment with botulinum injection and gastric stimulator appear to have positive predictive effects on the 4-hr GES results after G-POEM.

Background Current treatment guidelines strongly recommend statin therapy for secondary prevention. However, it remains unclear whether patients’ perceptions of cardiovascular risk, beliefs on cholesterol, or the intensity of prescribed statin therapy differs for patients with coronary artery disease ( CAD ) versus cerebrovascular disease (Ce VD ) versus both CAD and Ce VD ( CAD &Ce VD ). Methods and Results The PALM (Patient and Provider Assessment of Lipid Management) registry collected data on statin use, intensity, and core laboratory low‐density lipoprotein cholesterol levels for 3232 secondary prevention patients treated at 133 US clinics. Among individuals with Ce VD only (n=403), CAD only (n=2202), and Ce VD & CAD (n=627), no significant differences were observed in patient‐perceived cardiovascular disease risk, beliefs on cholesterol lowering, or perceived effectiveness and safety of statin therapy. However, patients with Ce VD only were less likely to receive any statin therapy (76.2% versus 86.2%; adjusted odds ratio 0.64, 95% CI 0.45–0.91), or guideline‐recommended statin intensity (34.6% versus 50.4%; adjusted odds ratio 0.60, 95% CI 0.45–0.81) than those with CAD only. Individuals with Ce VD only were also less likely to achieve low‐density lipoprotein cholesterol <100 mg/ dL (59.2% versus 69.7%; adjusted odds ratio 0.79, 95% CI 0.64–0.99) than individuals with CAD alone. There were no significant differences in the use of any statin therapy or guideline‐recommended statin intensity between individuals with CAD &Ce VD and those with CAD only. Conclusions Despite lack of significant differences in patient‐perceived cardiovascular risk or statin beliefs, patients with Ce VD were significantly less likely to receive higher intensity statin or achieve low‐density lipoprotein cholesterol <100 mg/ dL than those with CAD only.