ALBERT

Description: Abstract Marine Isotope Stage 11 from ~424 to 374 ka experienced peak interglacial warmth and highest global sea level ~ 410‐400 ka. MIS 11 has received extensive study on the causes of its long duration and warmer‐than‐Holocene climate, which is anomalous in the last half million years. However, a major geographic gap in MIS 11 proxy records exists in the Arctic Ocean where fragmentary evidence exists for a seasonally sea‐ice‐free summers and high sea‐surface temperatures (SST, ~ 8‐10 °C near the Mendeleev Ridge). We investigated MIS 11 in the western and central Arctic Ocean using twelve piston cores and several shorter cores using proxies for surface productivity (microfossil density), bottom‐water temperature (Mg/Ca ratios), the proportion of Arctic Ocean Deep Water (AODW) versus Arctic Intermediate Water (AIW) (key ostracode species), sea‐ice (epipelagic sea‐ice dwelling ostracode abundance), and SSTs (planktic foraminifers). We produced a new benthic foraminiferal δ18O curve, which signifies changes in global ice volume, Arctic Ocean bottom temperature, and perhaps local oceanographic changes. Results indicate that peak warmth occurred in the Amerasian Basin during the middle of MIS 11 roughly from 410 to 400 ka. Sea‐surface temperatures were as high as 8‐10 °C for peak interglacial warmth and sea‐ice was absent in summers. Evidence also exists for abrupt suborbital events punctuating the MIS 12‐MIS 11‐MIS 10 interval. These fluctuations in productivity, bottom‐water temperature, and deep and intermediate water masses (AODW and AIW) may represent Heinrich‐like events possibly involving extensive ice shelves extending off Laurentide and Fennoscandian Ice Sheets bordering the Arctic.

Description: Background:Allogeneic hematopoietic cell transplantation is a cornerstone of therapy for hematologic malignancies and often a patient's only curative intent treatment. Following development of post-transplant cyclophosphamide (PTCy) regimens, the use of haploidentical hematopoietic cell transplantation (haplo-HCT) has expanded. While overall outcomes for haploidentical transplantation appear to be excellent, its novel approach brings toxicities that are particular to its biological and clinical milieu. We recently described occurrence of severe cytokine release syndrome (CRS) after haplo-HCT. We further reported that severe CRS was associated with poor clinical outcomes, including transplant related mortality (TRM), overall survival (OS), and neutrophil engraftment (Abboud et al, BBMT, 2016). However, the factors predicting the occurrence of and long-term outcomes of patients who develop severe CRS after haplo-HCT is currently not known. Objective: To describe our clinical experience with CRS in an expanded cohort of haplo-HCT patients, its implication on clinical outcomes and elucidation of possible risk factors for the development of severe CRS. Patients and Methods: We performed a retrospective review of patients who had undergone peripheral blood T-Cell replete haplo-HCT with PTCy from July 2009 through March 2016 at our institution. A total of 137 patients were identified, 51% (74) were male, with a median age at transplant of 52 (19-73), a total of 40% (57) had active disease at the time of transplant. The most common diagnosis was AML (93 pts), followed by ALL (16 pts) and MDS (15 pts). Thirty-one percent (44 pts) had undergone prior transplant. In grading CRS, we used our approach modified from by Lee et al (Blood, 2014). Twenty-two patient, donor and disease characteristics were examined to identify predictors for the development of severe CRS. Results:One hundred and twenty-four (90%) of patients met criteria for CRS, and 26 (19%) suffered from severe (grade 3-4) CRS. Virtually all patients (99%) with CRS suffered from fevers. Patients with severe CRS had a significant delay in neutrophil (p 〈 0.0001) and platelet (p 〈 0.0001) engraftment compared to the patients who developed mild or no CRS (Figure 1A and 1B). Severe CRS was also associated with a high early transplant related mortality; the rate of death before post-transplant day 28 was 6.9 times higher for patients with grade 3-4 CRS compared with those with mild CRS (p 〈 0.0001, Figure 1C). Consistent with these findings, the development of severe CRS was associated with extremely poor survival. Median survival was 3 months for grade 3-4 CRS, 15 months for grade 1-2 CRS, and 13 months for no CRS. One-year OS was 4% for grade 3-4 CRS, 55% for grade 1-2 CRS, and 50% for no CRS (Figure 1D). There was no difference in the cumulative incidence of relapse, acute graft versus host disease, and chronic graft versus host disease (data not shown). A total of nine patients received Anti-IL-6 Therapy with tociluzimab (4 mg/kg of actual body weight), 4 of which suffered from severe CRS. In terms of predictive factors, the development of severe CRS was associated with disease risk index (p=0.037), HCT-CI score (p=0.005) and presence of a previous transplant (p=0.026) by univariate analysis. Risk and severity of CRS did not differ by age, ABO mismatch, age, CMV status of donor, donor sex, T-cell or CD34 cell dose. There was no difference in rates of CRS among patients in remission or with active disease at the time of transplant. Conclusions: Severe CRS after peripheral blood haplo-HCT is associated with high early TRM, poor OS and delayed neutrophil and platelet engraftment. Furthermore, patients with high DRI, high HCT-CI and prior HCT are at a higher risk for the development of severe CRS after haplo-HCT. We have previously shown the safety and potential efficacy of using anti-IL-6 therapy in these patients. Our current results suggest potential benefit to targeting this pathway prophylactically in patients at high risk for the development of severe CRS. Table Patient Characteristics Table. Patient Characteristics Figure CRS impacts neutrophil (A) and platelet (B) engraftment and is associated with high TRM (C) and poor OS (D). Figure. CRS impacts neutrophil (A) and platelet (B) engraftment and is associated with high TRM (C) and poor OS (D). Disclosures DiPersio: Incyte Corporation: Research Funding. Abboud:Gerson and Lehman Group: Consultancy; Merck: Research Funding; Teva: Research Funding, Speakers Bureau; Novartis: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Alexion: Honoraria; Baxalta: Honoraria; Pharmacyclics: Honoraria; Takeda: Honoraria; Cardinal: Honoraria. Fehniger:Affimed: Consultancy; Celgene: Research Funding; Fortress Biotech: Consultancy.

Description: Introduction: Allogeneic hematopoietic cell transplantation is a cornerstone of therapy for hematologic malignancies and often a patient's only curative intent treatment. Traditionally reserved for patients with an HLA-matched donor, advances in graft versus host disease (GVHD) prophylaxis utilizing post-transplant cyclophosphamide (PTCy) have expanded the use of haploidentical hematopoietic cell transplantation (haplo-HCT). While overall outcomes for haplo-HCT appear to be excellent, its novel approach brings toxicities that are particular to its biological and clinical milieu. The immediate post-transplant course in T cell replete haplo-HCT is often complicated by symptoms including fever, hypoxia, hypotension and organ dysfunction resembling the cytokine release syndrome (CRS) previously described in recipients of targeted cellular therapeutics such as CAR T-Cells. IL-6 is thought to be a key mediator of CRS in patients receiving novel T-cell engaging therapies, and tocilizumab has been used with success in this setting. Here we aim to describe the nature and incidence of CRS in haplo-HCT recipients, as well as its potential implications on clinical outcomes. Additionally, prospective analysis of cytokine profiles of haplo-HCT recipients and clinical responses to tocilizumab therapy are presented. Patients and Methods: We performed a retrospective review of patients who underwent haplo-HCT transplantation at our institution from July 2009 through April 2015. Patients were scored for symptoms of CRS based on established grading criteria (Lee et al, Blood 2014). Patients were stratified into three categories by grade of CRS experienced: none (grade 0), mild (grade 1-2) and severe (grade 3-4). Outcomes were assessed. A total of 84 patients were identified, 55% (46) were male, with a median age at transplant of 49 (19-73), and 49% (41) had active disease at the time of transplant. The most common diagnosis was AML (55 pts), followed by ALL (9 pts), MDS (5 pts) and NHL (2 pts). Among the patients, 26% (22 pts) had undergone prior transplant. In addition to the retrospective review, baseline and post- transplant cytokine levels were prospectively drawn in 10 patients who underwent haplo-HCT. A total of 7 additional patients who met criteria for CRS were treated prospectively with tocilizumab (dose: 4mg/kg-bw) and clinical responses were recorded. We recorded CRP levels in selected patients as part of clinical monitoring. Results: We found a high incidence, 85%, of CRS in our haplo-HCT patients. Among a total of 84 patients, 12 (14%) experienced severe CRS, 60 (72%) had mild CRS, and 12 (14%) patients had no evidence of CRS. The most common manifestations of severe CRS included: fever (100%), respiratory failure (75%), hypotension (83.3%), hepatic failure (25%) and renal failure (33.3%). The median maximum CRP (during post-transplant days 0 to 8) in all patients suffering from CRS was 155 mg/L. Of the twelve patients who suffered from severe CRS, nine (75%) died. Predicted median survival was 0.72 months for severe CRS, 12.7 months for patients with no CRS and was not reached for patients with mild CRS (fig 1). Rates of acute and chronic graft-versus-host disease did not differ by CRS status. The incidence of mild and severe CRS did not differ by ABO mismatch, age, CMV status, donor sex, T-cell or CD34 cell dose. There was no difference in rates of CRS for patients in remission versus active disease at time of transplant. There were no differences in engraftment. Cytokine profiles in haplo-HCT recipients showed significant elevation in serum IL-6 levels, most significant in patients who suffered from severe CRS (fig 2). We administered tocilizumab to 7 patients with severe CRS symptoms early after haplo-HCT (median day of treatment was day +3) resulting in the resolution of their CRS symptoms within 48-72 hours. Over the same time period CRP levels dropped below 50% of the peak value. Summary: CRS is common after T-cell replete haplo-HCT and severe CRS is potentially associated with high risk of early mortality after transplant. Cytokine profiles suggest IL-6 is a key mediator of CRS in haplo-HCT patients. Tocilizumab appears to be an effective treatment for patients who develop severe CRS early after T-cell replete haplo-HCT. Future prospective studies are warranted in studying the role of tocilizumab in the treatment and potentially prevention of severe CRS in haplo-HCT patients. Disclosures Fehniger: Celgene: Research Funding. Uy:Novartis: Research Funding. Abboud:Teva Pharmaceuticals: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Pfizer: Research Funding; Merck: Research Funding; Gerson Lehman Group: Consultancy.

Description: Background: Black patients with multiple myeloma (MM) have poorer outcomes than their white counterparts. This has largely been attributed to reduced access to health care; however, little data exists comparing the disease and overall health status at MM presentation between the two races. More severe disease burden, symptom burden, or comorbidities could also explain the differences in outcome. Objective: To compare disease burden, symptom burden, and comorbidities between black and white patients with MM. Methods: Two datasets were analyzed: 1) the Multiple Myeloma Research Foundation (MMRF) CoMMpass study interim analysis 6, and 2) the Surveillance, Epidemiology, and End Results-Medicare Health Outcomes Survey (SEER-MHOS) 2015 dataset (SEER years 1973-2011; MHOS years 1998-2013). The CoMMpass dataset included 625 patients who completed the EORTC QLQ-C30 and QLQ-MY20 at MM diagnosis. The SEER-MHOS dataset included 377 patients who completed the HOS survey the year of or year prior to MM diagnosis. All patients identified as a race other than white or black/African American were excluded. Data was analyzed using SPSS 21. Categorical variables were compared using χ2, continuous with the Mann-Whitney U test. Results: CoMMpass: 585 patients were eligible for analysis. 477 (82%) were white, 108 (19%) were black. Whites and blacks were similar in median age, but a significantly higher percentage of white patients were female (p=0.027). Overall, black patients were more likely to be stage III (p=0.041), have higher LDH (p=0.006) and creatinine (p=0.001), and lower hemoglobin (p

Description: Background: The clinical presentation of multiple myeloma (MM) varies greatly but often includes bone pain, anemia, renal dysfunction, hypercalcaemia, and/or constitutional symptoms. There are no signs or symptoms that are disease specific. The earliest staging system for MM, the Durie-Salmon (DS), associated disease and symptom burden with prognosis; however, it has been largely replaced by the International Staging System (ISS), which is easier to compute and better identifies patients with the poorest prognosis. It is unclear if ISS stage, like DS, is associated with disease or symptom burden. Objective: To compare disease and symptom burden of patients with newly diagnosed MM by ISS Stage. Methods: Data was extracted from the open-access Multiple Myeloma Research Foundation (MMRF) Researcher Gateway corresponding with interim analysis 6 from the CoMMpass study. The CoMMpass study is enrolling 1000 newly diagnosed MM patients who will be tracked longitudinally for 5 years. CoMMpass collects relevant clinical data and patient reported quality of life (EORTC QLQ-C30 and QLQ-MY20), as well as sequential tissue samples. Eligibility requirements for CoMMpass include: symptomatic MM with measureable disease by SPEP (≥1.0g/dL), UPEP (≥200mg/24 hours), or SFLC (≥10mg/dL); receiving an immunomodulator and/or a proteasome inhibitor for initial MM treatment; and no prior malignancies in the past 5 years. All clinical data was reported by trained data analysts at the enrolling center with the exception of flow cytometry which was performed centrally; raw lab values for beta-2 microglobulin and albumin were entered and stage was subsequently calculated by the analysts for this study according to the ISS (Greipp et al, JCO 2005). Twenty-six patients with unknown ISS were excluded from the analysis. Data was analyzed using SPSS 21. Categorical variables were compared using χ2, continuous with one-way ANOVA tests. Results: 599 patients were eligible for analysis. Sex, race, and heavy and light chain isotypes were all evenly distributed among the ISS stages; however, median age for ISS stage III was 67, 65 for stage II and 62 for stage I (p

Description: Background: Bone lesions and extramedullary plasmacytomas, present in ~70% and ~15% of multiple myeloma (MM) patients at diagnosis, respectively, are a major source of morbidity. Extensive bone or extramedullary disease is often associated with severe pain, fracture, or spinal cord compression requiring immediate medical attention. Palliative radiation to the afflicted area(s) can provide relief or reduction of the associated symptoms. The presence of bone lesions or extramedullary plasmacytomas at MM diagnosis have been linked to poorer prognosis, but to date, the prognosis of patients with extensive bone or extramedullary disease requiring radiotherapy during front-line treatment is unclear. In a single institution retrospective study of 162 newly diagnosed MM patient’s, including 87 who received front-line radiotherapy, Yaneva, et al (J Buon, 2006) found no survival difference between patients who received radiotherapy during front-line treatment and those who did not. Methods: Using the SEERStat software, we extracted the case listings of 85,115 patients diagnosed with MM from 1973 through 2010 in Surveillance Epidemiology and End Results (SEER)-18 registries database based on the November 2012 submission. Children (under 18 years old) were excluded. Autopsy or death certificate only cases were excluded. As non-black minorities have been historically underrepresented in the SEER databases, patients identified as any race other than white or black were excluded. Patients were followed for OS through December 2011. Disease-specific-survival was defined as death from myeloma. Patients were classified as having radiotherapy during front-line treatment or not. Patients who refused radiotherapy (n = 184) or for whom radiotherapy status was unknown (n = 973) were excluded. Results: 77,714 patients were eligible for analysis. The median age at diagnosis was 70 years (range 18-85+); 54% were male; 19% were black. The median follow-up was 22 months (range 0-441). 25% (n = 19,295) of patients received radiotherapy during front-line treatment. Radiotherapy during front-line treatment was more common among patients under the age of 60 at diagnosis (30.9% vs 21.4%; p 〈 0.001), white patients (25.5% vs 21.8%; p 〈 0.001), and male patients (26.2% vs 23.2%; p 〈 0.001). The frequency of radiotherapy during front-line treatment decreased in the most recent decade (22.8% vs 27.3%; p 〈 0.001). Patients who received radiotherapy during front-line treatment had an estimated median disease-specific-survival of 38 months compared to 46 months for patients without (p 〈 0.001). In a multivariate cox regression model of age, race, sex, and radiotherapy during front-line treatment, all four variables were independently significant (Table 1). Radiotherapy was associated with a 17% (95% CI 15-20) increase in disease-specific mortality. The impact of radiotherapy was relatively stable over the time frame studied (Table 2). Conclusions: Radiotherapy during front-line treatment, a surrogate for extensive bone or extramedullary disease at MM diagnosis, is independently associated with increased disease-specific mortality. It has remained a relatively stable predictor of poorer prognosis throughout the timeframe tested, suggesting that MM treatment advances have not overcome the poor prognosis associated with extensive bone lesions or extramedullary disease at MM diagnosis. Table 1 Multivariate Overall Survival Analysis Overall Age HR1 (95% CI) p value

Description: Background: The use of autologous stem cell transplants (ASCT) for multiple myeloma (MM) has greatly improved overall survival (OS), however, not all patients have benefited equally. Several studies have indicated that patients over the age of 65 or 70 at diagnosis had no immediate improvement in OS following the use of ASCT for MM, which is intuitive as ASCT was not covered by Medicare until 2001 and today is still often reserved for patients under 70. In addition, Waxman, et al (Blood, 2010) reported that ASCT for MM, resulted in nearly a two-fold improvement in OS in white patients compared to black patients. This suggests that white patients had better access to ASCT as retrospective studies of MM patients who undergo ASCT have failed to show an OS difference between the two races. Disparities in the OS benefit of ASCT among patients of different socioeconomic groups have not been reported on to date. It is also unclear if these disproportional improvements in outcomes have continued following the approvals of bortezomib and lenalidomide. Methods: Using the SEERStat software, we extracted the case listings of 85,115 patients diagnosed with MM from 1973 through 2010 in Surveillance Epidemiology and End Results (SEER)-18 registries database based on the November 2012 submission. Children (under 18 years old) were excluded. Autopsy or death certificate only cases were excluded. Patients identified as any race other than white or black were excluded. Patients were followed for OS through December 2011. Patients were divided into three cohorts based on the year of diagnosis, era 1 those diagnosed from 1973 to 1994, era 2 those diagnosed from 1995-2002 (to coincide with ASCT), and era 3 those diagnosed from 2003-2010 (to coincide with bortezomib’s approval). Socioeconomic status (SES) was approximated by median household income (MHI) of each patient’s county of residence from the 1990 US census; patients were divided into tertiles within their era of diagnosis based on MHI and classified as low-SES, middle-SES, or high-SES. Results: 78,681 patients were eligible for analysis. The median age at diagnosis was 70 years (range 18-85+); 54% were male; 18% were black. The median follow-up was 22 months (range 0-441). The OS of white patients increased from 23 months in the era 1 to 27 months in era 2, to 36 months in the era 3 (p

Description: Background: Performance Status (PS) is often used to assess the functional status of cancer patients. One of the most commonly used scales is the Eastern Cooperative Oncology Group (ECOG) PS. Using the ECOG PS scale, the oncologist assigns a score ranging from 0 (Fully active, able to carry on all pre-disease performance without restriction) to 4 (completely disabled; cannot carry on any selfcare; totally confined to bed or chair). In multiple myeloma (MM), a PS 〉 2 has been associated with a 35% increased risk of death following autologous stem cell transplant (ASCT) (Turesson et al, Br J Haematol, 1999), and therefore a PS ≤ 2 is generally required for ASCT and for eligibility in clinical trials. PS is often seen as a surrogate for health-related quality of life (HRQOL), which are patient reported measure(s) of well-being; however, they are separate constructs. While poorer PS has been associated with a decrease in HRQOL, it is unclear how much of the variance in HRQOL is explained by PS. Objectives: 1) To determine the association between PS and HRQOL; 2) to determine how much variance in HRQOL is explained by PS. Methods: Data was extracted from the open-access Multiple Myeloma Research Foundation (MMRF) Researcher Gateway corresponding with interim analysis 6 from the CoMMpass study. The CoMMpass study dataset included 562 patients who completed the EORTC QLQ-C30 and EORTC QLQ-MY20 at MM diagnosis. The range of scores for these HRQOL measures is 0-100, with higher scores indicating higher values. Data was analyzed using SPSS 21. The association between PS and HRQOL was assessed by one-way ANOVA tests; the amount of variance in HRQOL explained by PS was assessed by linear regression modeling. Results: PS was associated with all 9 HRQOL scales analyzed (p

Description: Background: Multiple myeloma (MM) is a disease of older adults, with a median age of diagnosis in the late 60s. While treatment advances have prolonged overall survival (OS) in MM, improvements have been modest among older MM patients. Symptom burden and quality of life are concerns for older patients, as they are more susceptible to treatment intolerance and dose reduction or treatment cessation. Older patients are often under-represented in clinical trials, and less information is available regarding their presenting clinical characteristics and treatment course. The Multiple Myeloma Research Foundation (MMRF) CoMMpass study, is a multicenter study in newly diagnosed multiple myeloma. It collects clinical-molecular data and patient reported health-related quality of life measures (EORTC QLQ-C30 and EORTC QLQ-MY20). In this study, we analyzed data from the CoMMpass study and compared presenting clinical characteristics, symptom burden and genetic features of newly diagnosed MM patients ≥ 75 years of age and those 〈 75 years of age. An additional analysis of t(4;14) was performed among those aged 75 years to confirm prior observations that the incidence of t(4;14) decreases with age (Avet-Loiseau et al. 2013). Methods: Clinical data from the interim analysis 6 of the CoMMpass study was extracted via the MMRF Researcher Gateway. CoMMpass eligibility requirements include: symptomatic MM with measureable disease by SPEP (≥1.0g/dL), UPEP (≥200mg/24 hours), or SFLC (≥10mg/dL); receiving an immunomodulator and/or a proteasome inhibitor for initial MM treatment; and no prior malignancies in the past 5 years.Enrollment began in July 2011. Clinical data is recorded at enrolling centers by data analysts. Analysis was with STATA 12.0. Categorical variables were compared withχ2; continuous variables were compared with student's t-tests and Wilcoxon rank-sum tests. Results: 625 patients were eligible for analysis. 92 patients were ≥ 75 years of age, and 533 were 〈 75 years of age. Median ages were 80 years (range 75-93) and 63 years (range 27-74). Distribution of sex and race were evenly divided. Older patients had higher rates of International staging system (ISS), stage III disease at presentation. Baseline measurements of creatinine, platelet counts and hemoglobin were worse for older patients. On symptom and quality of life assessment, older patients were more likely to have difficulties with physical functioning, and were less likely to have difficulties with emotional functioning or finances. Subset analysis of those aged 〈 65 years, 65-75 years and 〉 75 years showed a trend towards decreasing rates of t(4;14).Results are summarized in Table 1. Conclusion: Older patients in this study had higher ISS stage at diagnosis and worse ECOG performance status scores. Baseline labs showed inferior renal function and lower platelet and hemoglobin levels. Emotional and financial status was rated higher than younger patients, while physical functioning was worse. A trend towards decreased incidence of t(4;14) was appreciated by age. Table 1. Clinical Characteristics ≥ 75 years (n=92) 〈 75 years (n=533) P Demographics Median age in years 80 63 Sex % NS Male 63 60 Female 37 40 Race % NS White 81 79 Black 19 18 Other 0 3 Heavy Chain % NS IgG 83 77 IgA 17 23 Light Chain % NS Kappa 65 62 Lambda 33 37 Biclonal 2 1 Disease Burden ISS Stage % 75 years 65-75 years