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Item does not contain fulltext BACKGROUND: Current methods do not allow a thorough assessment of causes associated with limited exercise capacity in patients with chronic obstructive pulmonary disease (COPD). METHODS: Twenty patients with COPD and 20 matched control subjects were assessed using combined cardiopulmonary and stress echocardiographic testing. Various echocardiographic parameters (left ventricular [LV] volumes, right ventricular [RV] area, ejection fraction, stroke volume, S', and E/e' ratio) and ventilatory parameters (peak oxygen consumption [Vo(2)] and A-Vo(2) difference) were measured to evaluate LV and RV function, hemodynamics, and peripheral oxygen extraction (A-VO(2) difference). RESULTS: Significant differences (both between groups and for group-by-time interaction) were seen in exercise responses (LV volume, RV area, LV volume/RV area ratio, S', E/e' ratio, tricuspid regurgitation grade, heart rate, stroke volume, and Vo(2)). The major mechanisms of reduced exercise tolerance in patients with COPD were bowing of the septum to the left in 12 (60%), abnormal increases in E/e' ratio in 12 (60%), abnormal stroke volume reserve in 16 (80%), low peak A-Vo(2) difference in 10 (50%), chronotropic incompetence in 13 (65%), or a combination of several mechanisms. Patients with COPD and poor exercise tolerance showed attenuated increases in stroke volume, heart rate, and A-Vo(2) difference and exaggerated changes in LV/RV ratio and LV compliance (ratio of LV volume to E/e' ratio) compared with patients with COPD with good exercise tolerance. CONCLUSIONS: Combined cardiopulmonary and stress echocardiographic testing can be helpful in determining individual mechanisms of exercise intolerance in patients with COPD. In patients with COPD, exercise intolerance is predominantly the result of chronotropic incompetence, limited stroke volume reserve, exercise-induced elevation in left filling pressure, and peripheral factors and not simply obstructive lung function. Limited stroke volume is related to abnormal RV contractile reserve and reduced LV compliance introduced through septal flattening and direct ventricular interaction.

Objective To evaluate the efficacy and safety of elotuzumab and dexamethasone (Ed) for relapsed or refractory multiple myeloma (RRMM) patients. Method This retrospective study evaluated the efficacy and safety of (Ed) treatment for 21 RRMM patients, 11 of whom were considered lenalidomide-refractory, and all of whom had progressed on at least 1 prior steroid-containing regimen. We also evaluated the efficacy of adding lenalidomide to a subset of patients following progression from Ed. Results The overall response rate (ORR) and clinical benefit rate (CBR) of Ed were 10% and 19%, respectively. An additional 52% of patients demonstrated stable disease as their best response. The median PFS was 1.8 months on Ed for all patients. Fifteen patients received ERd following progression on Ed, and 60% of these patients were lenalidomide-refractory. The ORR and CBR were 20% and 33%, respectively, and the median PFS was 3.4 months. Conclusion Our results suggest that some patients can benefit from Ed without an accompanying immunomodulatory agent and that efficacy can be achieved with the addition of lenalidomide at the time of progression. No new safety signals were detected, except for thrombocytopenia in 1 patient on Ed. This article is protected by copyright. All rights reserved.

Background Right ventricular (RV) dysfunction and tricuspid regurgitation (TR) may coexist with aortic stenosis. The aim of this study was to assess the association between RV dysfunction, TR, associated comorbidities, and outcomes following transcatheter aortic valve replacement (TAVR). Methods A retrospective analysis was conducted of baseline and 6-month clinical and echocardiographic parameters, including TR grade, RV size (grade, end-diastolic and end-systolic areas, annular diameter), and function (grade, tricuspid annular plane systolic excursion [TAPSE], fractional area change, Tei index), in 519 consecutive TAVR patients. Results The prevalence of moderate or greater TR was 11% ( n = 59). Although TR was associated with increased mortality ( P = .02) in unadjusted analysis, it did not demonstrate an independent association with outcome when adjusted for RV dysfunction (TAPSE; P = .30) or multiple clinical parameters ( P ≥ .20). RV parameters associated with poor outcomes included TAPSE ( P = .006) and Tei index ( P = .005). TAPSE was associated with lower survival even when adjusted for TR ( P = .009) and all clinical parameters ( P = .01). Persistence of moderate or greater TR 6 months after TAVR seemed to be associated with lower survival ( P = .02), even when adjusted for clinical and RV parameters ( P = .07). Conclusions TR in association with aortic stenosis is frequently progressive despite TAVR but is not independently associated with outcomes. RV function is a stronger driver of adverse outcomes compared with TR itself, and RV quantitative rather than qualitative evaluation is the key to stratify these patients.

Aim To assess the impact of left ventricular (LV) filling parameters on outcomes following trans-catheter aortic valve replacement (TAVR). Methods and results A total of 526 TAVR patients were compared with 300 patients with severe aortic stenosis (AS) treated conservatively. Clinical variables were collected along with echocardiographic data at baseline, 1 month, and 6 months after study entry. End points included all-cause mortality and the combination of death and heart failure admission. LV filling parameters associated with mortality included reduced A wave velocity ( P = 0.005) and shorter deceleration time (DT) ( P = 0.0005). DT was superior to all other parameters ( P = 0.05) apart from patients with atrial fibrillation in whom E/e′ was better. Short DT (

Introduction: A hallmark of multiple myeloma (MM) is the low levels of uninvolved immunoglobulin (Ig) levels. B-cell maturation antigen (BCMA) is a receptor expressed in mature non-malignant and malignant B lymphocytes, including plasma cells. Its ligands are B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL). We previously demonstrated that BCMA is present in the serum of MM patients (pts) and that its levels predict survival (Sanchez et al. Br J Haematol 2012). We hypothesized that circulating BCMA binds it ligands, preventing normal plasma cell development in MM patients which may explain their reduction in uninvolved Ig levels. Methods: BCMA-Fc and control Ig were obtained and reconstituted in PBS (R&D Systems). Retro-orbital bleeds were performed on C57 Bl/6 and SCID mice implanted with the human MM xenografts LAGλ-1, LAGk-1A or LAGk-2. Human BCMA and mouse BAFF, IgM, IgA and IgG levels were measured with ELISA (R&D Systems & Bethyl Laboratories). The Raji B-cell line was obtained from the American Type Culture Collection (Rockville, MD, USA). Human IgA and IgG levels were determined in MM patients using nephelometry (Immage 800, Beckman Coulter). Hevylite® Assays (Binding Site) were used to quantify the levels of heavy-light chain isoform pairs in MM patients. Results: We determined if mBAFF formed complexes with human BCMA (hBCMA) in the plasma from SCID mice implanted with LAGλ-1, LAGκ-2 or LAGκ-1A, and were able to identify mBAFF-hBCMA complexes in plasma samples from these mice. To determine what effect human BCMA had on Ig levels in immune competent mice, rhBCMA-Fc or control Ig-Fc (100 mg) was injected into C57 Bl/6 mice, and plasma IgA, IgM and IgG levels were measured. Decreases in IgA levels were observed following BCMA treatment when compared to baseline plasma IgA on days 4 and 6 (P = 0.0031 and P = 0.0064, respectively), and the control group (P = 0.0087 and P = 0.0221). Samples were also analyzed for mouse IgM levels with similar marked reductions when compared to the untreated (P = 0.0001) and Ig-Fc (P = 0.0088) groups. For plasma IgG levels, a marked decrease was observed on day 6 following rhBCMA-Fc administration when compared to its baseline levels (P = 0.0023), and also when compared to the Ig-Fc control protein (P = 0.0014) and the untreated control (P = 0.0129) groups. We then set out to determine if sera from MM patients contained BCMA-BAFF complexes, using ELISA plates coated with an anti-human BAFF antibody followed by exposure to a polyclonal anti-human BCMA antibody. A strong absorbance indicating the presence of BCMA-BAFF complexes was detected in serum samples from MM patients, whereas no antibody cross reactivity was observed in control samples. We also determined whether human MM serum or rhBCMA-Fc blocked BAFF from binding to Raji B-cells. Raji cells (B-cell line) were incubated with serum from a MM patient containing hBCMA (0.75μg/ml) or rhBCMA-Fc (3 μg/ml) in the presence of rhBAFF (500 ng/ml). Myeloma serum and rhBCMA-Fc decreased rhBAFF binding to Raji cells by 71% (from 96.8 to 25.6 %) and 74% (from 96.8 to 22.9 %), respectively. Next, we determined whether serum BCMA levels inversely correlated with uninvolved Ig levels in MM pts. For pts with IgA (n = 134) or IgG (n = 313) MM, higher BCMA levels (> 100 ng/ml) correlated with below normal levels of uninvolved IgG in IgA MM and uninvolved IgA in IgG MM, whereas lower BCMA levels (< 100 ng/ml) correlated with normal uninvolved levels (P < 0.0001). Using the Hevylite Assay, similar results were observed for the levels of BCMA compared to uninvolved IgG isoforms in both pts with involved IgG lambda (n = 62, P = 0.0006) and IgG kappa (n = 117, P < 0.0001) MM. Conclusions: Our laboratory previously has reported that serum levels of BCMA are increased in the serum of MM patients, and correlates with response to treatment and predicts survival. We now demonstrate 1) the formation of complexes of BCMA with its B-cell ligand BAFF in the plasma of MM xenografts and sera of MM patients, 2) show that rhBCMA and MM patient serum blocks the binding of BAFF to human B-cells, 3) administration of rhBCMA to normal mice results in marked reductions in their antibody levels, and 4) show that BCMA levels inversely correlate with uninvolved Ig levels in MM pts. Thus, the lack of normal antibody production in MM pts results, in part, from circulating BCMA binding its ligands, preventing production of normal antibody-producing cells. Disclosures No relevant conflicts of interest to declare.

Introduction: The levels of serum monoclonal immunoglobulins (M-Igs) are used to monitor multiple myeloma (MM) patients. However, these assessments do not discriminate between normal polyclonal immunoglobulins (uninvolved) and M-Igs since they cannot determine the type of light chain associated with each immunoglobulin class (i.e. IgGκ, IgGλ, IgAκ, IgAλ, IgMκ, and IgMλ). The HevyLite® +(HLC) assays are able to accomplish this but the usefulness of these results for MM patients needs to be further established. We evaluated the levels of involved and uninvolved HLC levels, their ratios and differences and their relationship to outcomes among MM patients. Materials and Methods: Serum samples (n=189) from MM patients were analyzed using the HLC assays. Manufacturer’s HLC normal reference ranges were used. HLC results were correlated with clinical status as determined at the time of sampling and divided into groups according to clinical status (complete response (CR), ≥ partial response (PR) , < partial response, and progressive disease (PD)). Normality was assessed using the D’Agostino-Pearson omnibus normality test. Statistical comparisons were made using t-student’s or Mann-Whitney tests as appropriate as well as Fisher’s test. Progression-free survival (PFS) was calculated using Kaplan--Meier analysis for specific regimens received during the time the samples were taken. All tests were double-tailed and p-values lower than 0.05 were considered to be statistically significant. Results: All MM serum samples analyzed had IgG (62%) or IgA (38%) isotypes. Results from the involved HLC/uninvolved HLC ratios and their differences demonstrated that samples from patients with PD had significantly both higher ratios and differences (P PR compared with those with < PR so that patients in > PR were more likely to have normal uninvolved HLC levels than among patient with Conclusion: This study shows that involved HLC/uninvolved HLC ratios, differences between the involved and uninvolved HLCs, higher absolute levels of involved HLC, and lower levels of uninvolved HLC correlate with clinical status for MM patients. In addition, MM patients with normal uninvolved HLC levels have a longer PFS whereas those with involved HLC levels above the normal range show a shorter PFS. These results demonstrate the usefulness of the HLC assay for determining outcome for multiple myeloma patients. Disclosures No relevant conflicts of interest to declare.

Introduction:B-cell maturation antigen (BCMA) is a tumor necrosis factor receptor family member that is expressed on normal and malignant B-cells, including those from patients (pts) with multiple myeloma (MM). Our group has recently shown that this protein is present in the serum of MM pts, and preliminary findings from our group suggested that its levels may correlate with their clinical status and overall survival (OS; Sanchez et al. Brit J Haematol 2012). We now have analyzed the relationship between serum BCMA levels and monoclonal (M)-protein levels as well as the relationship of BCMA to response status, progression-free survival (PFS) and OS in a large cohort of MM pts including those with nonsecretory disease (NSD). Methods:Two hundred fifty-two MM pts were evaluated. Enzyme-linked immunosorbent assay (ELISA) was used to determine serum BCMA levels (R&D Systems). The Kruskal-Wallis Test was used to assess the correlation between serum BCMA levels and clinical status, and Dunn’s posttest was used to assess differences between clinical status groups. Kaplan-Meier analysis and multivariate Cox regression models were also used. Kaplan-Meier survival of MM pts was determined from the time of initial serum BCMA measurement to death or the date of last follow-up. PFS of MM pts was evaluated from the time of initial serum BCMA measurement to date of first disease progression. Cox-proportional hazards regression was utilized to determine the predictive influence of serum BCMA and various other factors including age, creatinine, hemoglobin, ISS stage, and bone disease on OS and PFS. P-values less than .05 were considered statistically significant. Changes in serum BCMA levels were correlated with serum M-protein levels for 44 consecutive MM pts during their course of disease. Similarly, BCMA was correlated with bone marrow and PET scan findings for NSD pts. Results: Serum BCMA levels correlated with the patient’s clinical status at the time of its determination (p PR had significantly lower serum BCMA levels (median, 11.69 ng/mL) than those with stable and progressive disease (median, 64.17 ng/mL; p30-140 ng/mL) and Stage 3 (n=55; > 140 ng/mL). Pts in Stage 1 had a longer OS (5-year, 95%) compared to pts in Stage 2 (5-year, 72%; p < 0.0002) while pts in Stage 2 had a longer OS than pts in Stage 3 (5-year, 60%; p < 0.0109). We determined the relationship of OS to serum BCMA level, age, serum creatinine, hemoglobin, ISS stage, and bone disease through Cox proportional-hazards regression. In the multivariate regression analyses, serum BCMA levels significantly correlated with only OS (p Conclusion:The results of this study demonstrate that BCMA is a novel serum marker that can be used to follow the course of disease for MM pts. The level of this serum protein is also correlated with clinical status and predicts their PFS and OS. It also provides MM pts with NSD a new potential way to follow their disease course, which currently requires frequent PET scans and bone marrow exams. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction: A hallmark of multiple myeloma (MM) is the low levels of uninvolved immunoglobulin (Ig) levels. B-cell maturation antigen (BCMA) is a receptor expressed in mature non-malignant and malignant B lymphocytes, including plasma cells. Its ligands are BAFF (B-cell activating factor) and APRIL (a proliferation inducing ligand). We previously demonstrated that BCMA is present in the serum of MM patients (pts) and that its levels predict survival (Sanchez et al. Br J Haematol 2012). We hypothesized that circulating BCMA binds it ligands, preventing normal plasma cell development in MM patients which may explain their reduction in uninvolved Ig levels. Methods: BCMA-Fc and control Ig were obtained and reconstituted in PBS (R&D Systems). Retro-orbital bleeds were performed on SCID mice implanted with the human xenografts LAGλ-1, LAGk-1A or LAGk-2 following BCMA treatment. Human BCMA and mouse BAFF, IgM and IgA levels were measured with ELISA (R&D Systems & Bethyl Laboratories). Human IgA and IgG levels were determined in MM patients using nephelometry (Immage 800, Beckman Coulter). Hevylite® Assays (Binding Site) were used to quantify the levels of heavy-light chain isoform pairs in MM patients. Results: Recombinant mouse BAFF (rmBAFF) was mixed with recombinant human BCMA (rhBCMA) and incubated on plates coated with anti-mouse BAFF antibody (Ab). An anti-BCMA detection Ab was added, and BCMA-BAFF complexes were easily detected at concentrations of human BCMA and BAFF present in MM pts. We determined if mBAFF from SCID mice would also bind rhBCMA. SCID mice were bled; their plasma isolated and incubated with rhBCMA, and showed that rhBCMA formed complexes with mBAFF. To determine what effect human BCMA had on Ig levels in immune competent mice, rhBCMA-Fc or control Ig-Fc (100 mg) was injected into C57 Bl and Balb/c mice, and plasma IgA and IgM levels were measured. Following rhBCMA-Fc injection, a marked decrease in both antibody classes was observed in both mouse strains. Decreases in IgA levels were observed following BCMA treatment when compared to baseline plasma IgA on days 4 and 6 (P = 0.0031 and P = 0.0064, respectively), and the control groups (P = 0.0087 and P = 0.0221). Samples were also analyzed for mouse IgM levels with similar marked reductions when compared to the untreated (P = 0.0001) and Ig-Fc (P = 0.0088) groups. To determine if rhBCMA-mBAFF complexes formed in vivo, an ELISA was performed. Plates were pre-coated with a monoclonal mouse anti-BAFF capture Ab. Plasma samples were incubated and an anti-human-BCMA detection Ab was added. rhBCMA-mBAFF complexes were detected at high levels in plasma samples from mice dosed 4 and 6 days previously with BCMA-Fc whereas no complexes were found in samples in control Ig-Fc or untreated mice. We evaluated mBAFF levels in SCID mice with and without human MM. We have previously shown high levels of human BCMA in the plasma of MM tumor-bearing mice (Sanchez et al. Br J Haematol 2012). On days 14, 21 and 28 post-tumor implantation, mice implanted with LAGλ-1 had markedly lower plasma levels of mBAFF (P = 0.0143, P = 0.0002 and P = 0.0008, respectively) when compared to age and sex-matched mice not bearing any tumors. We obtained similar results using two additional human MM xenograft models (LAGk-1A and LAGk-2). Next, we determined whether serum BCMA levels inversely correlated with uninvolved Ig levels in MM pts. For pts with IgA (n = 134) or IgG (n = 313) MM, higher BCMA levels (> 100 ng/ml) correlated with below normal levels of uninvolved IgG in IgA MM and uninvolved IgA in IgG MM, whereas lower BCMA levels (< 100 ng/ml) correlated with normal uninvolved levels (P < 0.0001). Using the Hevylite Assay, similar results were observed for the levels of BCMA compared to uninvolved IgG isoforms in both pts with involved IgG lambda (n = 62, P = 0.0006) and IgG kappa (n = 117, P < 0.0001) MM. Conclusions: Our laboratory previously reported that BCMA is present in the serum of MM patients, correlates with response to treatment and predicts survival. We now demonstrate the formation of circulating BCMA-BAFF complexes in MM, and administration of recombinant BCMA to normal mice results in marked reductions in their antibody levels. We also show that BCMA levels inversely correlate with uninvolved Ig levels in MM pts. Thus, the lack of normal antibody production in MM pts results in part from circulating BCMA binding its ligands, preventing production of normal antibody-producing cells. Disclosures No relevant conflicts of interest to declare.

Introduction: Despite the advances for treating multiple myeloma (MM) patients (pts), it remains an incurable B-cell malignancy. Thus, the objective for treating these pts is to prolong overall survival (OS) and preserve quality of life. New classes of drugs in the past decade have improved OS for MM pts; however, most of the studies conducted to predict outcome and predict factors that determine OS have relied on older data sets derived from large institutions including pts not receiving treatment there and lacking accurate follow up of pts as well as information from centers in which therapeutic choices are limited. These studies have suggested that depth of response, specifically complete response (CR), and lower International Staging System (ISS) staging at diagnosis predict improved OS. We have now analyzed data on all MM pts who have received treatment in a single clinic specializing in MM. Methods: Data was obtained from all MM pts who received treatment in a single clinic specializing in MM that was established 10 years ago. Kaplan-Meier analysis was used to generate all survival curves and the log-rank test was used to measure difference between curves, with P Results: Two hundred sixty-three MM patients (161 male, 102 female) with a median follow-up of 52 months were analyzed in this study. The median age at diagnosis was 63 years (range, 31 to 88). Thirty-seven pts (14%) had smoldering MM (SMM) while the remainder (n=225 [86%]) were diagnosed with active MM. For pts with active disease, ISS staging at diagnosis (n=156) included 68 (44%), 46 (29%) and 42 (27%) pts with ISS Stages I, II and III. The median OS of all patients was 118 months with a 5-year survival of 77%. The 5-year OS of SMM pts was 88% compared to 76% for those with active disease. There were no significant differences in OS between pts with different ISS stages at the time of diagnosis. Specifically, the median 5-year survival of pts with ISS Stage I, II and III disease at diagnosis were 79, 91 and 84 months, respectively. We also analyzed OS of MM pts according to the depth of response from treatment. There were no significant differences in OS between pts who attained a CR during their first treatment regimen compared to those who achieved their first CR during subsequent regimens or those who never attained a CR. During their first treatment, pts with stable disease (SD; n=28) showed no difference in OS compared to those achieving > minimal response (MR; n=135), > partial response (PR; n=107), PR (n=72), or CR (n=35). The OS of pts who had achieved a CR with at least one regimen (n=83 [38% of pts]) was not different than among pts never achieving CR (n=135 [62% of pts]; P=0.1173). In order to further determine whether depth of response predicts OS during the patient’s course of disease, OS was determined based on the best response ever achieved to any anti-myeloma regimen. There was no significant difference in OS between patients who achieved a CR (n=84) with any treatment regimen compared to those who attained an MR or PR (n=108), PR (n=73), MR (n=35) or those who had achieved only an SD (n=11). However, OS among pts who achieved CR, > PR, ≥ MR, or > SD (SD+MR+PR+CR) was better than among those who had only demonstrated PD during their course of disease (P In order to determine whether the initial treatment regimen predicted OS, we also analyzed survival of pts who received bortezomib-based therapy compared to those who received an IMiD or both drugs together as their initial treatment, and showed there was no significant differences in OS between these three upfront treatment approaches. Conclusion: Results from an analysis of a large cohort of MM pts from a single clinic specializing in MM show that the median survival has greatly improved to nearly 10 years due to the availability of many new treatment options. Although previous studies have suggested that ISS staging at diagnosis and depth of response to anti-MM regimens predict OS for MM pts, results from our study involving analysis of a large cohort of MM pts from a single clinic specializing in MM show that these prognostic factors do not predict OS for pts with this B-cell malignancy. Differences in our results compared to other previous studies may reflect the many treatment options available in the clinical setting used to obtain our results. Disclosures No relevant conflicts of interest to declare.