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Climate change is accelerating gender inequality, as climate extremes amplify inequalities, vulnerabilities, negative gender norms, with Gender-Based Violence (GBV) rates increase during times of disaster. Yet the gendered experiences of climate change have to date been inadequately factored into climate law and policy-making, with the United Nations Framework Convention on Climate Change (UNFCCC) traditionally limiting its focus to ‘gender balance’ in representation within the regime. This article explores mainstreaming gender considerations within the UNFCCC by reflecting upon where we have come from, where we are now, and where we are going with respect with gender. While there was very little progress in the early days of the UNFCCC, this article shows that from 2001 to the present there have been a series of small gains, which this article will explain and critique. Much remains to be done, however, for gender within the UNFCCC. In recommending future actions, it draws particularly on lessons from the Pacific and Australian experiences.

Melanesia is becoming a region of many partners, expanding diplomatic options and a new sense of independence. The wider context of the new Melanesian assertiveness is one in which China is a rising power and Indonesia is forging closer links with the western Pacific. The impetus to Fiji's new assertiveness arose from the diplomatic isolation imposed upon it by Australia and New Zealand after the 2006 military coup. Papua New Guinea's new confidence is founded upon its liquefied natural gas boom. Even Solomon Islands is expanding diplomatic connections. Regionally, the change can be seen in the Melanesian Spearhead Group, which now counts Indonesia among its members, and in Fiji's push for its own vision of Pacific regionalism. Australia and New Zealand nevertheless remain the indispensable countries in the region. Australia's commitment to Melanesia remains constant but without the bold initiatives and interventionist enthusiasm of the early RAMSI years.

The proteasome inhibitor carfilzomib is highly effective in the treatment of multiple myeloma. It irreversibly binds the chymotrypsin-like active site in the β5 subunit of the 20S proteasome. Despite impressive response rates when carfilzomib is used in combination with immunomodulatory agents in newly diagnosed multiple myeloma patients; no biomarker exists to accurately predict response and clinical outcomes. We prospectively assessed the activity in peripheral blood of the chymotrypsin-like (CHYM), caspase-like (CASP) and trypsin-like (TRYP) proteolytic sites in 45 newly diagnosed multiple myeloma patients treated with eight cycles of carfilzomib, lenalidomide and dexamethasone (CRd) (NCT01402284). Samples were collected per protocol and proteasome activity measured through a fluorogenic assay. Median CHYM levels after one dose of carfilzomib decreased by >70%. CHYM and CASP activity decreased throughout treatment reaching a minimum after eight cycles of treatment. Higher levels of proteasome activity associated with higher disease burden (r>0.30; p

Angler surveys are reliant on the ability of anglers to accurately report various aspects of their fishing trips. Misidentification of sport fishes has been postulated as a source of error among angler surveys but has received little attention. We evaluated the overall ability of anglers to identify sport fishes common to Ohio and the potential impacts on catch estimates derived from angler surveys. During angler surveys conducted on lakes and reservoirs (2007, n = 34) and Ohio River tailwaters (2010, n = 3), anglers were presented with artist-rendered images of 18 different sport fishes common to these waters. Anglers (lake and reservoir, n = 2,442; Ohio River, n = 458) were asked to identify sport fish by their common name. On average, anglers correctly identified sport fishes 42% of the time, but accuracy varied widely among species (lake and reservoir, range = 4.4–85.1%; Ohio River, range = 9.4–71.8%), with greater accuracy exhibited for the most common species (e.g., largemouth bass Micropte...

Industrial concentration is broadly defined as a few firms controlling a substantial share of assets or sales of the market. In the multinational industrial sector, this paper shows that the largest 50 and 100 in the developing economies control substantial amounts of assets and sales, both foreign and total. Two well known indexes of concentration were used, the Herfindahl and Theil’s entropy, to check the levels of concentration between 1994 and 2003 for the top 50 and between 2004 and 2006 for the top 100. It was found that although the sizes of the multinationals in assets and sales increased during the period, the relative concentration remained somewhat static.

The focus of this paper is to evaluate similarities and differences between and within socio-economic samples of school attendance. Eight variables broadly classified by income, education, family background, and class size, are employed for this purpose. For each of the eight variables, the null hypothesis is that the means by various classifications (income, mother’s schooling, father’s schooling, math score, language score, 4th grade class size, number of 4th grade classes, 4th grade enrollment) are equal against an alternative hypothesis that at least one of the member group differs. The method employed for this purpose is one-way analysis of variance. In each of the classifications, samples were divided to reflect public schools, voucher private schools and unsubsidized private schools as well as the full sample. Furthermore, the full samples are employed to find whether differences between the three groups exist for the eight variables. The full sample is n = 3,776 schools. The results point to statistical significant differences for all of the variables.

The hypothesis is that the major source of concentration of arts in different regions is due to agglomeration effects of specialized talents, city size, income, and quality of life. Twenty-nine large metropolitan areas are ranked and assessed for enhancing the climate for arts activity. Data on metropolitan areas in the United States on cost of living, transportation, employment, education, climate, crime, health care, recreation, city size, and per capita income are used as explanations for predominance of art in the 29 metropolitan areas. The results indicate that cities with larger populations and higher per capita income have greater concentrations of artistic activity. Other explanatory variables include factors associated with the quality of life. (JEL RIO, R23)

This paper uses an index to measure the level of employment diversity at the state level of two periods spanning two decades. The index is based on aggregating employment at eight major sectors. The findings indicate a movement toward more specialization in the latter period (2000) as compared to an earlier period (1970s).

This paper examines the inequality characteristics for regional per capita personal income in metropolitan and nonmetropolian areas. Total inequality is disaggregated into between and within portions. The findings show no statistically significant differences between metro and nonmetro. For both metro and nonmetro during the early 1970s decade, there was a general trend toward equality whereby the nonmetro areas’ income approached the metro areas’ income but showed significant divergences thereafter. *** DIRECT SUPPORT *** A00DH021 00005

Mycobacterium avium causes disseminated infection in immunosuppressed individuals and lung infection in patients with chronic lung diseases. M. avium forms biofilm in the environment and possibly in human airways. Antibiotics with activity against the bacterium could inhibit biofilm formation. Clarithromycin inhibits biofilm formation but has no activity against established biofilm.

This paper examines proportionate contributions of states to total income dispersion among the states within the regions in the United States from 1929 to 1997. The criterion for equitable distribution is that each state receices a share of the total population comparable to its share of income. The coefficient of variation for each region on a yearly basis is employed. The results provide evidence for minor differences in contribution to regional income dispersion between component states.

The author offers a comparison of the history of slavery in South Africa and the United States in the eighteenth century.

Flow cytometry has increasing relevance for prognosis in myeloma and precursor disease (monoclonal gammopathy of unknown significance/smoldering myeloma), yet it has been reported that plasma cell enumeration by flow varies depending on the quality of marrow aspirate and field biopsied in patchy disease. We demonstrated increased sensitivity of flow over immunohistochemistry in abnormal-plasma cell detection in monoclonal gammopathy (n = 59)/smoldering myeloma (n = 87). We prospectively evaluated treatment-naïve smoldering myeloma (n = 9)/myeloma (n = 11) patients for the percentage of abnormal plasma cells/total plasma cell compartment, plasma cell viability/infiltration and flow immunophenotype depending on anticoagulant use, biopsy site and pull sequence in uni-and-bilateral bone marrow biopsies and aspirates. We found no statistical difference regarding the percentage of abnormal plasma cells, their immunophenotype or number/distribution in marrow samples even when obtained by different sequence in aspirates, or anticoagulants (p>0.05). Our results show that plasma cell enumeration and immunophenotyping by flow cytometry is consistent under different conditions in these populations.

This paper investigates the widening (divergence) or narrowing (convergence) of black income as well as black income proportionate to all income using median family income over the 1980s. Analysis is undertaken at the regional level using the coefficient of variation and analysis of variance, and at the city level using a linear model. The linear model, in addition to providing a measure for divergence or convergence, provides a measure of residual change which distinguishes city performance above or below expectation. At the regional level, the general result is divergence of black income born 1979 to 1989, while at the city level, the general results were divergence for black income, but a convergence in black income proportionate to all income.

There has been much discussion about whether population growth causes employment growth or vice versa. This study supplements the work of Mathur and Song by confirming that population growth causes employment growth in die Snowbelt and die reverse in die Sunbelt. Also, regional growth rates of population and employment alternated between convergence, divergence, and convergence during 1955-88.

Interstate and interregional income inequality are reported for each year from 1929 to 1990 using a measure that belongs to the entropy family. It was found that a substantial reduction in inequality occurred between the early 1930s and mid-J970s, followed by a slight increase thereafter for both interstate and interregion. In particular, interregional inequality as a percentage of total interstate was reduced from approximately 85% in the 1940s to approximately 55% in the mid-1980s, increasing thereafter to 61% in 1990.

Since the 1980s, Blacks have been overrepresented in the homeless population with respect to their share of the national population and the poverty population, but little research has emerged to explain why this over-representation exists. Previous researchers have suggested that residential segregation and a declining supply of affordable housing push low-income Blacks into homelessness and that greater access to homeless shelters pulls low-income Blacks into homelessness at greater rates than Whites. These hypotheses have not been tested, because longitudinal data linking housing characteristics, service accessibility, and the homeless population do not exist. For these reasons, the study in this article presents analyses of housed and homeless populations separately. The first set of analyses focuses on the segment of the housed population most at risk of becoming homeless: those living in inadequate and overcrowded housing. Using data from the 1990 and 2000 Decennial Censuses and the 1997 American Housing Survey, this study tests the relationship between residential segregation, affordable housing supply, and the extent to which Blacks live in inadequate and overcrowded housing. The study found that high rates of residential segregation and lower affordable housing supply were associated with inadequate housing quality and overcrowding in Black households. Working under the assumption that closer proximity to homeless services decreases migration for such services, in the second set of analyses, this study examines racial differences in migration for homeless services. Using data from the 1996 National Survey of Homeless Assistance Providers and Clients, this study reveals that Black homeless clients were less likely than White homeless clients to have migrated for homeless services. Black homeless clients were more likely than White homeless clients to both start their homeless spell in a large central-city location and end up using services in that location or in another large central city. Homeless spells were longer for Black homeless clients but were more transient for White homeless clients, who were more likely to stay in three or more towns during their spell. The study addresses implications for fair housing policy, affordable housing policy, and homeless-services provision; discusses limitations of the research; and proposes areas for future research.

This paper provides a profile of regional income inequality using a distributional criterion whereby a state's share of total income equals its share of total population. The results for 1929 to 1990 show that inequality persisted among regions with a substantial declining trend up to 1979 and a slight rise thereafter. On the other hand, equality among states within their regions is found to have been the condition since 1929.

IMPORTANCE: Carfilzomib-lenalidomide-dexamethasone therapy yields deep responses in patients with newly diagnosed multiple myeloma (NDMM). It is important to gain an understanding of this combination’s tolerability and impact on minimal residual disease (MRD) negativity because this end point has been associated with improved survival. OBJECTIVE: To assess the safety and efficacy of carfilzomib-lenalidomide-dexamethasone therapy in NDMM and high-risk smoldering multiple myeloma (SMM). DESIGN, SETTING, AND PARTICIPANTS: Clinical and correlative pilot study at the National Institutes of Health Clinical Center. Patients with NDMM or high-risk SMM were enrolled between July 11, 2011, and October 9, 2013. Median follow-up was 17.3 (NDMM) and 15.9 months (SMM). INTERVENTIONS: Eight 28-day cycles were composed of carfilzomib 20/36 mg/m(2) on days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg on days 1 through 21; and dexamethasone 20/10 mg (cycles 1-4/5-8) on days 1, 2, 8, 9, 15, 16, 22, and 23. Patients who achieved at least stable disease subsequently received 24 cycles of lenalidomide extended dosing. MAIN OUTCOMES AND MEASURES: Primary end points were neuropathy of grade 3 or greater (NDMM) and at least very good partial response rates (SMM). Minimal residual disease was also assessed. RESULTS: Of 45 patients with NDMM, none had neuropathy of grade 3 or greater. Of 12 patients with high-risk SMM, the most common of any-grade adverse events were lymphopenia (12 [100%]) and gastrointestinal disorders (11 [92%]). All patients with SMM achieved at least a very good partial response during the study period. Among the 28 patients with NDMM and the 12 with SMM achieving at least a near-complete response, MRD negativity was found in 28 of 28 (100% [95% CI, 88%-100%]), 11 of 12 (92% [95% CI, 62%-100%]) (multiparametric flow cytometry), 14 of 21 (67% [95% CI, 43%-85%]), and 9 of 12 (75% [95% CI, 43%-94%]) (next-generation sequencing), respectively. In patients with NDMM, 12-month progression-free survival for MRD-negative vs MRD-positive status by flow cytometry and next-generation sequencing was 100% vs 79% (95% CI, 47%-94%; P < .001) and 100% vs 95% (95% CI, 75%-99%; P = .02), respectively. CONCLUSIONS AND RELEVANCE: Carfilzomib-lenalidomide-dexamethasone therapy is tolerable and demonstrates high rates of MRD negativity in NDMM, translating into longer progression-free survival in patients achieving MRD negativity. Carfilzomib-lenalidomide-dexamethasone therapy also demonstrates efficacy in high-risk SMM.

Mycobacterium avium is an environmental organism encountered in natural and urban water sources as well as soil. M. avium biofilm has recently been identified on sauna walls and in city water pipes and might have a role in the survival of virulent strains in the environment and in the host. To characterize the M. avium biofilm, an in vitro model was adapted wherein biofilm develops on a PVC surface. Biofilm was detected by staining with crystal violet and visualization by optical microscopy and quantified by A(570). M. avium strains MAC 101, MAC 100, MAC 104, MAC 109, MAC A5 and MAC 5501 (all isolated from the blood of AIDS patients) were used in the assays. Biofilm formation was dependent on the presence of Ca(2+), Mg(2+) or Zn(2+) ions in the water, with the maximal effect seen at a concentration of 1 micro M. The presence of 2 % glucose and peptone as sources of carbon increased the formation of biofilm, while this was partially inhibited by humic acid. Since sliding motility has been associated with the amount of glycopeptidolipid (GPL), TLC was used to determine the presence of GPL. The supernatant of a biofilm-forming culture induced formation of a stable biofilm and amikacin blocked the establishment of biofilm by M. avium strains at subinhibitory concentrations. Bacteria in the biofilm were more resistant to chlorine as well as to exposure to potassium monopersulfate and chloroheximide acetate than were planktonic bacteria. Identification of M. avium genes involved in biofilm formation and further studies of the effect of antimicrobials on the establishment of biofilm may identify approaches for inhibiting M. avium biofilm formation and colonization.

Decapsulation of plastic packaged components is frequently necessary for failure analysis or product development. Conventional techniques utilize an acid etch process, which is not compatible with copper and other acid-sensitive materials. There is limited ability to alter etch geometry or selectively decapsulate individual circuit elements. Laser ablation using a raster scanned Nd:YAG laser was used for selective decapsulation of temperature sensitive passive components in a PDIP packaged DC-DC converter. Copper welds, nylon insulated ferrite, and polyesterimide insulated magnet wire were decapsulated without damage, allowing failure analysis of a miniature transformer and its associated welded leads.

Utilizing a distance index, state-level pollution data extracted from List and McHone (2000b ), states, and regions of the United States are ranked for their air, river, lake, composite water (lake and river), and overall composite (water and air) environmental degradation outputs. For the composite water index, the New England region is ranked first and the Far West region is ranked last. For the overall composite index, the Rocky Mountain region is ranked first and the Mideast region is ranked last.

*Equally Contributed Introduction: Recent studies show better progression-free (PFS) and overall survival (OS) for newly diagnosed multiple myeloma (NDMM) pts achieving MRD negativity by multicolor flow cytometry (MFC) or next-generation sequencing (NGS). Here, we report on the comprehensive assessment of MRD in a uniformly treated cohort of 45 MM patients (Korde et al. ASH 2013). Methods: 45 NDMM pts were treated with 8 cycles of combination therapy (carfilzomib, lenalidomide and dexamethasone) followed by 2 years of maintenance lenalidomide. Median potential follow-up was 17.3 mos. All patients were evaluated by NGS by LymphoSIGHT™ method. Briefly, using universal primer sets, we amplified immunoglobulin heavy and kappa chain (IGH and IGK) variable, diversity, and joining (VDJ) gene segments from genomic DNA obtained from CD138+ BM cell lysate or cell free bone marrow (BM) aspirate at baseline. A MM clonotype was defined as an immunoglobulin rearrangement identified by NGS at a frequency >=5%. MRD assessment by NGS, MFC and PET was repeated when patients achieved a complete response (CR) or completed 8 cycles of therapy. In a subset of patients, we performed NGS in peripheral blood (plasma) at baseline and after 2 cycles of treatment. Results: 40/45 (89%) of pts achieved VGPR or better after combination therapy. At least one clonal rearrangement was identified in 31/34 (91%) of BM CD138+ cell samples and in 34/45 (76%) of cell free BM aspirates; overall clonal rearrangement was detected in 37/45 (82%) bone marrow aspirates at baseline. Repeat MRD assessment at CR or the completion of 8 cycles in 32 pts show residual disease in cell free BM aspirates by NGS in 18 (56% of pts tested and 40% of the total study population). Estimated 12-mo and 18-mo PFS for MRD neg vs. pos by NGS was 100% vs 94% and 100% vs 84%, respectively (p=0.025). MFC testing for MRD was feasible in 43/44 pts (98%). PFS probabilities at 12-mo and 18-mo for flow neg vs pos was 100% vs 79% and 100% vs 63%, respectively (p=0.0022). Among pts assessed by both MRD methods (n=31), 23 samples were concordant (9 pos and 14 neg); among 8 discordant cases, all were positive by sequencing and negative by flow (p=0.0078). Abnormal PET scans were noted in 38/45 (84%) of pts at baseline. 24/43 (56%) pts at CR or after 8 cycles of CRd had a neg/dec PET response and 19/43 (44%) pts had a pos/partial PET response. At 12-mo and 18-mo, PFS by a neg/dec PET response vs pos/partial PET response was 100% vs 89% and 92% vs 89%, respectively (p=0.54). Furthermore, in 14 pts, we performed NGS in peripheral blood samples collected at baseline. At least one MM clonotype identified in baseline BM was detectable in corresponding plasma sample in 13/14 pts. Number of myeloma-specific molecules per million diploid genomes in the plasma was 3-log fold lower than in the BM (median 252 vs 730,950 MM specific clonal molecules per million diploid genomes). After 2 cycles of CRd treatment, 12/13 pts were still pos by serum electrophoresis and/or immunofixation while only 1 had detectable myeloma clonotypes in the plasma. Conclusions: This prospective evaluation of MRD testing in MM has several key findings: 1. Detection of myeloma-specific clonotypes by NGS of the Immunoglobulin VDJ segments in the BM is feasible in majority of pts with NDMM. 2. MRD detection by NGS compares favorably to MFC since all pts with residual disease by MFC are also MRD positive by sequencing; an additional 8 pts who were MRD negative by flow MFC were MRD positive by sequencing. 3. MRD negativity by MFC and NGS are both associated with significantly better PFS. 4. Detection of myeloma-specific clonotypes by NGS of the immunoglobulin VDJ segments (i.e. cell free DNA) in the peripheral blood plasma is feasible in NDMM pts at diagnosis; however, since tumor load in the plasma is >2000-fold lower than in the BM; using standard volumes of peripheral blood (plasma), the levels of myeloma-specific clonotypes were too low to be quantified already after 2 cycles of combination therapy. This was true despite presence of positive serum electrophoresis and/or immunofixation. Additional studies to understand the dynamics of the myeloma clonotype level in peripheral blood plasma are necessary to determine optimal MRD testing regimen. Disclosures Faham: Sequenta, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Moorhead:Sequenta, Inc.: Employment.

BACKGROUND: Early treatment with lenalidomide and dexamethasone delays progression and increases overall survival in patients with high-risk smoldering multiple myeloma. The addition of the selective proteasome inhibitor carfilzomib to a lenalidomide and dexamethasone backbone has proven effective in patients with newly-diagnosed multiple myeloma; this combination may allow patients with high-risk smoldering multiple myeloma to obtain deep and durable responses. METHODS: In this phase 2 pilot study, patients with high-risk smoldering multiple myeloma received eight 28-day cycles of induction therapy with carfilzomib (at a dose of 20/36 mg per square meter on days 1, 2, 8, 9, 15, and 16), lenalidomide (at a dose of 25 mg on days 1–21), and dexamethasone (at a dose of 10 or 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23). Patients achieving stable disease or better after combination therapy received 2 years of maintenance therapy with lenalidomide. Minimal residual disease was assessed with multi-color flow cytometry, next-generation sequencing by the LymphoSIGHT method, and fluorodeoxyglucose-positron emission tomography-computed tomography (FDG-PET/CT). Myeloma clonotypes were identified in genomic DNA obtained from CD138+ bone marrow cell lysate or cell-free bone marrow aspirate at baseline for each patient based on their high frequency within the B-cell repertoire. Per study protocol, minimal residual disease assessment by next-generation sequencing, multi-color flow cytometry and FDG-PET/CT was repeated when patients achieved a complete response or completed 8 cycles of induction treatment. A sample size of 12 evaluable patients was calculated as being minimally necessary based on the following probability calculations: If the true probability of a very good partial response was 20% or 50%, we calculated that there would be a 7.3% or 80.6% probability, respectively, if 5 or more patients exhibiting a very good partial response (VGPR). Thus, if 5 or more patients out of 12 achieved a very good partial response, there would be strong evidence that the true probability of a VGPR was 50% or more. RESULTS: Twelve patients were enrolled. All 11 patients (100%) who completed 8 cycles of combination therapy obtained VGPR or better (primary end point). Minimal residual disease assessment by next-generation sequencing was performed on bone marrow supernatant to detect cell-free myeloma clonotypes, while flow cytometry analysis utilized bone marrow cells. Overall (N=12), 100% of patients achieved a complete response or better over the study period, including 11 patients (92%) negative for minimal residual disease based on multi-color flow cytometry. Based on next-generation sequencing, two of the 12 patients were positive for minimal residual disease in the bone marrow supernatant; one of these two patients was also positive for minimal residual disease based on multi-color flow cytometry in the bone marrow cells. Information regarding longitudinal minimal residual disease status will be available and presented at the meeting. Adverse events were manageable. CONCLUSIONS: Early treatment with carfilzomib, lenalidomide, and dexamethasone was associated with high rates of complete response and minimal residual disease negativity by multi-color flow cytometry, next-generation sequencing, and FDG-PET/CT in patients with high-risk smoldering multiple myeloma. Disclosures Landgren: Onyx Pharmaceuticals: Consultancy; Medscape: Consultancy; Millennium Pharmaceuticals: Independent Data Monitoring Committee (IDMC), Independent Data Monitoring Committee (IDMC) Other. Off Label Use: Carfilzomib and lenalidomide for high-risk smoldering multiple myeloma.

Background Carfilzomib (Cz) is an irreversible proteasome inhibitor with potent anti-myeloma effects resulting in deep clinical responses and durable remissions in the majority of patients. In our two-stage phase II trial of 45 newly diagnosed multiple myeloma (MM) patients using carfilzomib (Cz), lenalidomide (Ln), and dexamethasone (Dx) combination therapy followed by 2 years of Ln maintenance, best responses after a median of 9 completed cycles (range 2-20), included 17-stringent-(s)-complete response-(CR)/1-CR/6-near-(n)-CR (63%), 10-very good partial response (VGPR) (26%), 3-partial response (PR) (8%), and 1-stable disease (SD) (3%) (reported in a separate abstract). In this pre-planned correlative sub-study based on our ongoing clinical CRd trial for newly diagnosed MM patients, we conducted a prospective flow cytometric study designed to characterize pretreatment levels of proteasomes and aggresomes in plasma cells in relation to response to therapy. Methods Bone marrow aspirates were collected at baseline and C1D2 (single agent Cz exposed). Permeabilized CD138 and CD38 positive plasma cells were tested using anti-19S proteasome subunit antibodies (Abcam, Cambridge, UK). In parallel, cells were labeled with ProteoStat Aggresome Detection Reagent (Enzo Life Sciences, Farmingdale, NY). Multicolor flow cytometric acquisition and analysis was performed using BD FACS CANTO and DIVA software. Data was expressed as mean fluorescence intensity (MFI) ratio using isotype-matched controls. Patients’ best responses to therapy after minimum of 4 cycles were correlated to the acquired proteasome and aggresome data. Statistical analysis was performed using DataPrism software. Statistical significance was considered as p-value Results Total of 21 patients were assessed: 14 achieved CR (CR group), 4-VGPR, 2-PR and 1-SD (non-CR group). The median plasma cell 19S MFI ratio in the CR group was 20.21 (range 5.21-84.27), and in the non-CR group 6.19 (range 2.88-11.68), p Conclusions We found the pretreatment florescence intensity (MFI) ratio of 19S proteasome subunit in plasma cells to be significantly higher in MM patients who obtained CR (versus non-CR) when treated with CRd treatment. None of the patients with pretreatment 19S MFI ratio of less than 5 achieved CR; conversely, all patients with pretreatment 19S MFI ratio of over 12 achieved CR. After a single dose of carfilzomib, 90% of CR patients had decreased 19S MFI and increased aggresomes MFI ratio, while 80% of non-CR patients showed opposite changes: increased 19S MFI and unchanged/decreased aggresomes MFI ratio. We conclude that pretreatment plasma cell proteasome levels predict response to the CRd treatment in newly diagnosed MM patients. Disclosures: No relevant conflicts of interest to declare.

Background The proteasome inhibitor carfilzomib is highly effective in the treatment of multiple myeloma (MM). It selectively and irreversibly binds the chymotrypsin-like (CHYM) active site in the β5 subunit of the proteasome. One prior retrospective study based on 50 NDMM patients found maintained elevated total cProt levels post therapy to be associated with poorer response to therapy and shorter overall survival (PMID: 17095627). We conducted a study based on NDMM patients treated with carfilzomib, lenalidomide and dexamethasone (CRd). The aim of this investigation was to assess the role of specific enzymatic activities of plasma cProt in relation to treatment responses. Methods We assessed 37 newly diagnosed MM patients from our ongoing clinical trial using CRd therapy (NCT01402284). Baseline demographic, clinical and laboratory parameters were collected. Plasma samples were collected at time intervals as specified in the protocol [C1D1 (baseline), C1D2 (post single dose carfilzomib), C2D1, C4D1 and C8D1] and frozen to -80ºC. Patient responses were assessed per current IMWG guidelines. CHYM, caspase-like (CASP), and trypsin-like (TRYP) activities from cProt were assayed by continuously monitoring the production of 7-amino-4-methylcoumarin (AMC) from fluorogenic peptides in plasma. Briefly, plasma samples were activated with SDS (for chymotrypsin-like and caspase-like) or 10% Tween-20 (for trypsin-like). The reaction wells contained 30 μL assay buffer (25 mmol/L HEPES), 10 μL activated sample, and 10 μL of the prospective fluorogenic peptide-AMC substrate. To measure the fluorescence release of free AMC with time, the SpectraMax M5 (Molecular Devices) instrument was used with a read interval of 1 min during 30 min at 37ºC. Samples were analyzed per triplicate. Enzymatic activities were quantified (pmol AMC/s/mL plasma) by generating a standard curve of AMC. A two tailed Wilcoxon signed rank test was used for comparisons across matched cProt values. The Mann Whitney Test was used to compare differences between two independent groups of cProt values. Spearman’s rank correlation was used for correlation between cProt levels and clinical parameters. All p-values are two-tailed. Results Patients had a median age of 61 years (range 40-86; 57% males). Median M-spike was 2.7 (0.8-7.1) g/dL, isotypes included IgG (n=26), IgA (n=6), kappa (n=4) and lambda (n=1); International Staging System (ISS) Stage I (n=19) and II (n=18). Median C1D1 levels of chymotrypsin-like, caspase-like and trypsin-like activity for all patients were 0.84 (0.12-3.89), 0.85 (0.31-2.28) and 2.95 (1.4-7.39) pmol AMC/s/ml plasma, respectively. CHYM and CASP C1D1 levels correlated with the levels of baseline IgG (r=0.42, CHYM; r=0.38 CASP) and the levels of baseline β2-microglobulin (r=0.37, CHYM; r=0.45, CASP). Additionally, CHYM correlated with levels of free kappa (r=0.33) and levels of serum M-protein (r=0.34); and CASP correlated with the percentage of plasma cell infiltration in core bone marrow biopsy (r=0.36). Baseline TRYP levels did not correlate with clinical parameters. Median CHYM (1.3 versus 0.7 pmol AMC/s/ml plasma) and CASP (1.0 versus 0.7 pmol AMC/s/ml plasma) levels, but not TRYP levels, were were non-significantly elevated in Stage II ISS compared to Stage I patients. CHYM levels after an initial single dose of carfilzomib were reduced by a median of 68.2% (p0.05) and 0.4% (p>0.05), respectively. CASP and TRYP levels measured at C2D1, C4D1 and C8D1 remained stable throughout treatment cycles. When compared to baseline, median CHYM levels decreased significantly at C1D2 (after one dose of carfilzomib), then increased at C2D1 and steadily decreased again throughout treatment at the C4D1 and C8D1 time intervals. Conclusions In newly diagnosed MM patients, pre-treatment CHYM and CASP plasma activity levels were non-significantly higher among patients with higher ISS stage. Peripheral blood collected 24 hours after a single dose carfilzomib showed reduced CHYM levels by >60% in most patients. Fluctuations in CHYM, CASP and TRYP levels were noted throughout CRd treatment; no consistent patterns were observed in relation to response to therapy. Disclosures: No relevant conflicts of interest to declare.

Background An irreversible proteasome inhibitor with decreased peripheral neuropathy compared to bortezomib, Carfilzomib (Cz) has potent anti-MM effects resulting in deep clinical responses and durable remissions. In this two-stage phase II trial of 45 planned patients, we treat newly diagnosed MM patients with Cz, lenalidomide(Ln), and dexamethasone (Dx) followed by 2 years of Ln maintenance. Methods Eight 28-day cycles of combination therapy comprises: Cz IV 20/36 mg/m2 on days 1, 2, 8, 9, 15, 16; Ln oral 25 mg days 1-21; and Dx IV or oral 20/10 mg (C1-4/5-8) on days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients undergo stem cell collection after 4 cycles of CRd and continue with treatment. After 8 cycles of combination therapy, patients with SD or better receive up to 24 cycles of Ln extended dosing 10 mg days 1-21. Primary endpoint is ≥ grade 3 neuropathy. Bone marrow samples are collected at baseline, C1D2 (single agent Cz exposed), CR/end of cycle 8 (cycles 1-8), CR/end of cycle 20 (cycles 9-20), and CR/end of cycle 32/treatment termination (cycles 21-32). Patients are evaluated for clinical biomarkers, FDG-PET CT, and MRD studies (flow cytometry and PCR) at regular time points. Flow cytometry utilizes 8-color flow panel and analyzes ≥ 3 x 106 events (sensitivity 1 x 10-5). Results Forty-one patients meeting eligibility criteria have been enrolled (24 male, 17 female; median age 60; range 40-88). Among patients enrolled, median M-spike is 2.9 (1.0-7.6 g/dL) and isotypes included 26-IgG, 10 – IgA, 4 – free kappa, and 1 – free lambda. Thirty-eight patients are evaluable for response and toxicity. No patients have had ≥ grade 3 neuropathy. The mean decline in serum M-protein (n=33) was 72% after 1 cycle of CRd received. Best responses after a median of 9 cycles (range 2-20) completed, include 17–sCR/1-CR/6-nCR (63%), 10-VGPR (26%), 3-PR (8%), and 1-SD (3%). Among 18/38 (47%), median time to sCR/CR was 5 cycles. Among 14 CR/sCR + 3 nCR patients who underwent MRD assessment, all were negative. Among patients with ≤ VGPR at the end of 8 cycles of CRd, 5/8 (63%) had evidence of immunophenotypically abnormal plasma cells defined by flow cytometry, and 3 patients had undetectable abnormal plasma cells (1 achieved sCR after 8 additional Ln cycles). After median follow-up of 10 months (3-22), PFS rate was 83.3%. Twenty-five patients have completed 8 cycles of CRd, while 24/25 continued to Ln extension and 1 patient opted to exit study after CRd. Patients with non-hematologic toxicity events (≥ grade 3) include: electrolyte disturbances - 7(18%), LFT elevation - 5(13%), rash/pruritus – 4(11%), fatigue – 4(11%), cardiovascular – 3(8%), dyspnea/respiratory – 3(8%), constitutional symptoms – 2(5%), infections – 2(5%), VTE - 2(5%), and anxiety – 1(3%). Patients with hematologic toxicity events (≥ grade 3) include: lymphopenia –24(63%), anemia – 6(16%), leukopenia - 5(13%), and thrombocytopenia - 4(11%). All patients with baseline FDG avid lesions or extramedullary disease showed decrease or resolution of FDG avidity at MRD assessment time points. Conclusions Beyond traditional clinical response criteria, using a functional imaging and highly sensitive MRD assays, we consistently show high rates of deep remission and MRD negativity among newly diagnosed MM patients treated with carfilzomib, revlimid, dexamethasone (CRd) combination therapy. The results were very similar across age-groups and the oldest patient on this trial was 88 years old. If deep remissions are maintained with a delayed ASCT strategy incorporating extended dosing revlimid therapy, this may be a future strategy available to all patients irrespective of age. Disclosures: Off Label Use: Abstract is in newly diagnosed Multiple Myeloma patients. Carfilzomib is approved for relapsed/refractory patients.

Background Multiple myeloma (MM) consistently has a precursor state. High risk smoldering myeloma (SMM) or “early myeloma” has a 72-76% risk of progression at 5 years. In this phase II single arm pilot study, we report the results based on the completed enrollment of high risk (Mayo clinic or PETHEMA models) SMM patients treated with CRd (carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (DEX) followed by 2 years of Ln extended dosing. Methods This phase II single arm study treats high risk (Mayo clinic or PETHEMA models) SMM patients ≥18 years old with 8 cycles of CRd therapy. Dosing schedule consists of 28-day cycles of CFZ 20/36 mg/m2 IV on days 1, 2, 8, 9, 15, 16; LEN 25 mg PO daily on days 1-21; and DEX 20/10 mg IV/PO on days 1, 2, 8, 9, 15, 16, 22, 23. After 8 cycles of induction, patients with SD or better response receive LEN extension at 10 mg daily on days 1-21 for 2 years. The primary endpoint is response rate with the secondary endpoints of progression free survival, duration of response, and correlative assays focusing on minimal residual disease (MRD). Patients are evaluated for clinical biomarkers, FDG-PET CT, and MRD studies (flow cytometry and VDJ sequencing of bone marrow aspirates) at regular intervals. Flow cytometry utilizes an 8-color flow panel and analyzes ≥3 x 106 events (sensitivity detection rate of 1 x 10-5). Results Twelve patients (42% males; median age 58, range 48-65) meeting eligibility criteria have been enrolled onto study and are evaluable for toxicity and response. Eleven patients met high risk SMM criteria by PETHEMA model alone, and one patient met criteria for both PETHEMA and Mayo Clinic models. Mean baseline serum M-protein was 2.1 g/dL (1.1-3.3). Best responses (n=12) after a median of 6 cycles of CRd-R delivered (range 2-14 cycles) are 5-sCR/2-CR/2-nCR (75%) and 3-VGPR (25%). Among the 7/12 (58%) that reached CR/sCR, median time to CR/sCR was 5 cycles. Nine patients have completed 4 cycles of CRd therapy with all 9/9 (100%) reaching at least VGPR or better response. Non-hematologic toxicities ≥ grade 3 include: rash 2(17%), CHF 1(8%), dyspnea 1(8%), LFT elevation 1(8%), creatinine increase 1(8%), and hyperglycemia 1(8%). Hematologic toxicities include lymphopenia 4(33%), thrombocytopenia 1(8%), leukopenia 1(8%), neutropenia 1(8%), and anemia 1(8%). All patients have thus far maintained their best responses and none have progressed to clinical symptomatic multiple myeloma. Overall the treatment regimen has been well tolerated with manageable toxicities; one patient discontinued after 6 cycles due to CHF. Among 7 CR/sCR patients, 6/7 (86%) are MRD negative based on high-quality 8-color flow cytometry (sensitivity detection rate of 1 x 10-5) of bone marrow aspirates. In addition, one nCR patient does not demonstrate evidence of abnormally immunophenotypic plasma cells using multi-parameter flow cytometry (post 8 cycles of CRd). Conclusions Among patients completing 4 cycles of CRd therapy, 100% have achieved a VGPR or better. High risk SMM or “early myeloma” may represent a key interventional time point before the development of debilitating complications including onset of end-organ damage. The enrollment for this pilot study has been completed; an expansion cohort for additional 16 patients just opened for enrollment. Updated results will be presented at the meeting. Larger clinical studies are needed to replicate and expand on these promising results. Disclosures: Off Label Use: The abstract discussess off-label use of carfilzomib and lenalidomide.

Background Effective anti-myeloma combination therapies including carfilzomib and lenaldiomide (Ln) induce deep clinical responses and durable remissions. Attainment of stringent (s)- complete response (CR), as well as negative minimal residual disease (MRD) by sensitive molecular techniques and multiparameter flowcytometry (MFC) in bone marrow is predictive of improved outcome. Here we report the association of HLC, FLC, and other prognostic factors to predict early CR and MRD in our ongoing prospective clinical CRd trials for multiple myeloma (MM) and high risk smoldering MM (SMM) patients. Methods Treatment consisted of 8 cycles of CRd combination, followed by 24 cycles of Ln maintenance; the treatment schedule for SMM and MM was the same. Serum FLC, and immunoglobulin HLC pairs were determined using the Freelite and Hevylite assay (Binding Site, Birmingham, UK). The clonal FLC and HLC burden was measured as the difference between involved and uninvolved FLC (FLC-diff) and involved and uninvolved HLC pair (HLC-diff), as well as FLC κ to λ ratio (FLC ratio; normal range 0.26 to 1.65), and HLC ratios IgGκ/IgGλ and IgAκ/IgAλ; normal ranges, 1.12 to 3.21 and 0.78 to 1.94, respectively. Patients were evaluated for clinical responses by standard criteria and for MRD by sensitive MFC. Patients with any type of CR (CR, near(n)CR or sCR) were divided into groups according to whether their best response occurred in cycles 1-4, 5-8 or 9+, or 1-4 vs. 5+. Dichotomous parameters were compared using Fisher’s exact test. The associations between cycle categories and dichotomous parameters were determined using a Cochran-Armitage test. Continuous parameters were compared between two groups using an exact Wilcoxon rank sum test, while continuous categories were compared across cycle categories using a Jonckheere-Terpstra test for trend. Logistic regression analysis was used to predict if any type of CR would occur within 1-4 cycles. All p-values are two-tailed and reported without formal adjustment for multiple comparisons. Results We included 38 MM and 12 SMM patients (27 male, 23 female; median age 59.5; range 40–88). Among these patients, median M-spike was 2.5g/dL, median FLC-diff was 28.94mg/dL (range -0.06–1619.87); isotypes included 37–IgG, 7–IgA, 5–κ, and 1–λ; immunoparesis was present in 46 (92%); and abnormal FLC ratio in 47 (94%). Six patients with light chain only disease were excluded from HLC analyses; among 43 analyzed, all had abnormal HLC ratio, and median HLC-diff was 22.14 g/L (range 1.85–109.13). Of 8 patients, in whom M spike could not be precisely evaluated due to migration in beta region, accurate HLC pair analysis was possible in 7. A total of 33 patients achieved CR: 22–sCR, 3–CR, and 8–nCR (66%). The number of CRd cycles administered to first CR of any type was 1-4 in 15 patients, 5-8 in 12, and 9-17 in 6; median number of cycles was 6. Among patients who achieved CR, 23 CR/sCR + 4 nCR patients underwent MRD assessment, and all were negative. There was a strong trend of an association between a normalized FLC ratio after 1 cycle of CRd and all types of CR (p= 0.003) obtained in first 4 cycles. Similarly normalization of the HLC ratio after 2 cycles of CRd was significantly associated with obtaining a nCR/CR/sCR (p=0.0098) or sCR (p=0.001) in 1-4 cycles; CR was reached in 1-4 cycles in 7/9 (78%) patients who normalized their HLC ratios after 2 cycles, as compared with 4/15 (27%) among those who did not. In a univariate analysis, FLC-diff after 1 cycle of CRd (p=0.0035), and HLC-diff after 2 cycles of CRd (p=0.0092) was associated with a significant trend to achieving nCR/CR/sCR in 1-4 vs.5-8 vs.9+ cycles. In a multivariate model that initially included M spike, FLC-diff, normalized FLC ratio, HLC-diff, as well as normalized HLC ratio, only HLC-diff after 2 cycles of CRd ( Conclusions Early monitoring (after 2 cycles) of HLC patterns is an independent predictor of rapid response among high risk SMM and newly diagnosed MM patients treated with CRd therapy. Biomarkers predictive of rapid responses to therapy have a major clinical potential as they will allow better tailoring of treatment with the goal to maximize survival and minimize toxicities. Disclosures: Off Label Use: Treatment of smoldering multiple myeloma- carfilzomib and lenalidomide.

The long-run equilibrium of the competitive model of the economy predicts that per capita income across industries and regions becomes equalized over time. Since earnings constitute a substantial part of income, that model predicts that earnings per person also equalizes over time. During the 1980s, state and regional income in the United States diverged. thereby contradicting the competitive model hypothesis as well as Simon Kuznets’s hypothesis of income equality varying directly with economic development. This paper examines earnings growth rates of 10 industrial sectors by using actual state data for 1969-88 and projected state data for 1988-2000. Even though the findings indicate overall convergence in growth rates based on state data, continued average inequality between regions persists.

Abstract 2944 Emerging evidence suggests multiple myeloma (MM) may be susceptible to components of the innate immune system including natural killer (NK) cells. In vitro studies have shown that allogeneic and autologous NK cells have the ability to kill CD138-purified primary MM cells. A recent study focusing on allogeneic hematopoietic stem cell transplantation for MM showed recipients who lacked MHC class I ligands for donor KIR (so called KIR incompatible transplants) had markedly reduced relapse rates, indicating NK cell KIR may exert significant control over clinical NK cell-mediated anti-MM responses. In this two-stage phase II study, we evaluated the response rate, toxicity, pharmacokinetic parameters and biological activity of IPH2101 in smoldering myeloma (SMM). IPH2101 is a fully human IgG4 monoclonal antibody (mAb) that facilitates natural killer (NK) cell-mediated killing of myeloma cells by blocking the interaction of inhibitory killer cell immunoglobin (Ig)-like receptor (KIR) 2D on NK cells with their human leukocyte antigen-C (HLA-C) ligands on target cells. This interim analysis was planned when all patients in the first stage (n=9/21) were recruited. Nine SMM patients meeting eligibility criteria were prospectively enrolled (median 59 yrs; 8 males and 1 female). Patients received a single dose of IPH2101 1mg/kg by intravenous route every other month (for a total of 6 cycles). A pre-treatment bone marrow biopsy was obtained for confirmation of diagnosis and for correlative studies. Peripheral blood mononuclear cells were obtained on days 1, 8, 18, 22 for cycle one then monthly thereafter for subsequent cycles for correlative studies to assess KIR 2D blockade and the effects of mAb therapy on NK cytotoxic function against K562 cells and MM cells matched for recipient KIR ligands. Routine blood work, serum/urine protein electrophoresis and immunofixation, and serum free light chain assays were conducted monthly. At the end of study, a post-treatment bone marrow biopsy will be obtained for clinical evaluation and correlative studies. To date, of the 9 patients enrolled on trial, 1 patient has received 5 cycles, 2 patients have received 4 cycles, and 4 patients have received 2 cycles. After an average of 3 (range 2–5) cycles of IPH2101, no patients have yet achieved a 50% reduction of their baseline M-spike (target for the study). Toxicities have been minimal and no grade 3–4 toxicities have been observed to date. Occupancy of KIR2D by IPH2101 has been assessed on peripheral blood NK cells taken at baseline, 24 hrs after the first infusion, and prior to each subsequent infusion using a flow based KIR occupancy assay that measures the binding of a labeled immunofluorescent anti-KIR relative to standard fluorescent beads. The interim results are consistent with a very high KIR occupancy of >90% at 24 hr post the first infusion and the maintenance of a high level of occupancy of available IPH2101 binding sites at 2 months post-infusion. In vitro studies measuring the cytotoxic function of patient's NK cells against K562 cells and KIR ligand matched myeloma cells before and after IPH2101 treatment are ongoing and will be reported at the meeting. In conclusion, this first interim analysis based on 9 SMM patients treated with IPH2101 are consistent with a very high KIR2D occupancy on NK cells by this mAb up to 2 months post-infusion. To date, none of the patients treated have had 50% reduction of their baseline M-spike. mAb infusions have been well tolerated with no grade 3–4 toxicities observed to date. Updated clinical data and functional in vitro studies measuring the cytotoxic function of patient's NK cells before and after mAb therapy will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

A helmet display that has the ability to present imageiy from both NVGand FLIR sensors provides the best visual performance under a wide range of operating conditions from daylight to total darkness, because it combines the complementary advantages of the two different types of sensor. The pilot can select his sensor and operating mode to maintain imagery during natural conditions such as high humidity, thermal gradients or total darkness that would otherwise result in poor or unuseable display contrast. Design requirements for a multi image source helmet mounted display needed for this approach are severe, since aircrew expect no compromises in image quality or physiological protection, despite the extra hardware compared with a simpler HMD or NVG. The system advantages are significant however, and a new helmet display that presents both intensifier and CRT imagery is being designed for both fixed and rotary wing applications.

Helmet mounted displays are exercising the ingenuity of optical and mechanical designers more than any other type of display in attempting to meet essential criteria with currently available technology. The inevitable result is that a wide range of design options and attendant compromises are available to the crew station designer. This paper offers some guidelines on the implications of selecting key helmet display parameters, and describes a unique solution to the problem.© (1990) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.