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Lenalidomide is an effective maintenance agent for patients with myeloma, prolonging first remission and, in transplant eligible patients, improving overall survival (OS) compared to observation. The 'Myeloma XI' trial, for newly diagnosed patients, aimed to evaluate whether the addition of the histone deacetylase inhibitor vorinostat to the lenalidomide maintenance backbone could improve outcomes further. Patients included in this analysis were randomised to maintenance therapy with lenalidomide alone (10 mg/day on days 1-21 of each 28-day cycle), or in combination with vorinostat (300 mg/day on day 1-7 and 15-21 of each 28-day cycle) with treatment continuing until unacceptable toxicity or progressive disease. There was no significant difference in median progression-free survival between those receiving lenalidomide-vorinostat or lenalidomide alone, 34 and 40 months respectively (hazard ratio [HR] 1.18, 95% confidence interval [CI] 0.96-1.44, p = 0.109). There was also no significant difference in median OS, not estimable and 75 months respectively (HR 0.99, 95% CI 0.76-1.29, p = 0.929). Subgroup analysis demonstrated no statistically significant heterogeneity in outcomes. Combination lenalidomide-vorinostat appeared to be poorly tolerated with more dose modifications, fewer cycles of maintenance therapy delivered and higher rates of discontinuation due to toxicity than lenalidomide alone. The trial did not meet its primary end-point, there was no benefit from the addition of vorinostat to lenalidomide maintenance.

Supplementary Tables: Supplementary table 1: Demographics of the 463 patients included in the Myeloma XI analysis Supplementary table 2: List of epigenetic modifier genes used to interrogate the list of mutations in the Myeloma XI dataset Supplementary table 3: Demographics of the 156 patients included in the UAMS dataset Supplementary table 4: List of epigenetic modifier genes sequenced in UAMS dataset Supplementary table 5: SIFT analysis of Histone 1 family gene mutations Supplementary table 6: Multivariate cox-regression model for overall survival in Myeloma XI patients Supplementary table 7: Percentage of patients with mutations in genes encoding epigenetic modifiers sequenced in both the MYXI and UAMS datasets (as shown in Supplementary table 4) - Supplementary Figures: Supplementary Figure 1: Epigenetic genes mutated in {greater than or equal to}5/463 patients (>1%) in Myeloma XI dataset - location of mutation with respect to protein functional domains Supplementary Figure 2: Translocation subgroup distribution by presence or absence of epigenetic modifier mutation in the Myeloma XI dataset Supplementary Figure 3: Survival curves for Histone 1 mutations in Myeloma XI dataset Supplementary Figure 4: A comparison of the variant allele frequency between the MyXI and UAMS mutations Supplementary Figure 5: The distribution of mutations in epigenetic modifiers in previously treated patients by GEP70 risk score Supplementary Figure 6: A comparison of the UAMS molecular subgroup distribution by presence of epigenetic modifier mutations in previously treated patients

Purpose: Epigenetic dysregulation is known to be an important contributor to myeloma pathogenesis but, unlike other B-cell malignancies, the full spectrum of somatic mutations in epigenetic modifiers has not been reported previously. We sought to address this using the results from whole-exome sequencing in the context of a large prospective clinical trial of newly diagnosed patients and targeted sequencing in a cohort of previously treated patients for comparison.Experimental Design: Whole-exome sequencing analysis of 463 presenting myeloma cases entered in the UK NCRI Myeloma XI study and targeted sequencing analysis of 156 previously treated cases from the University of Arkansas for Medical Sciences (Little Rock, AR). We correlated the presence of mutations with clinical outcome from diagnosis and compared the mutations found at diagnosis with later stages of disease.Results: In diagnostic myeloma patient samples, we identify significant mutations in genes encoding the histone 1 linker protein, previously identified in other B-cell malignancies. Our data suggest an adverse prognostic impact from the presence of lesions in genes encoding DNA methylation modifiers and the histone demethylase KDM6A/UTX. The frequency of mutations in epigenetic modifiers appears to increase following treatment most notably in genes encoding histone methyltransferases and DNA methylation modifiers.Conclusions: Numerous mutations identified raise the possibility of targeted treatment strategies for patients either at diagnosis or relapse supporting the use of sequencing-based diagnostics in myeloma to help guide therapy as more epigenetic targeted agents become available. Clin Cancer Res; 22(23); 5783–94. ©2016 AACR.

Impoundments in the midcontinent region of the United States provide the beneficial services of lentic waters. These impoundments were constructed long after intensified agriculture was established...

Autologous stem cell transplant (ASCT) remains the standard of care for consolidation after induction therapy for eligible patients with newly diagnosed myeloma. In recent clinical trials comparing ASCT to delayed ASCT, patients aged over 65 were excluded. In real-world practice stem cell transplants are not restricted to those aged under 65 and clinicians decide on transplant eligibility based on a patient’s fitness rather than a strict age cut-off. Data from the UK NCRI Myeloma XI trial, a large phase III randomized controlled trial with pathways for transplant-eligible and -ineligible patients, were used in an exploratory analysis to examine the efficacy and toxicity of ASCT in older patients including an analysis using an age-matched population to compare outcomes for patients receiving similar induction therapy with or without ASCT. Older patients within the transplant-eligible pathway were less likely to undergo stem cell harvest at the end of induction than younger patients and of those patients undergoing ASCT there was a reduction in progression-free survival associated with increasing age. ASCT in older patients was well tolerated with no difference in morbidity or mortality between patients aged

Background The most common cause of severe renal impairment in myeloma (MM) is the direct effect of a high concentration of nephrotoxic monoclonal free light chains (LC) leading to MM cast nephropathy. Decreasing LC and therefore improving renal function is important for long term outcome. In the UK NCRI Myeloma XI trial the addition of the second generation PI carfilzomib (K) to the immunomodulatory agent (IMiD) lenalidomide, cyclophosphamide and dexamethasone (Rdc) improved progression-free survival (PFS) in newly diagnosed MM patients (NDMM) eligible for autologous stem cell transplant (ASCT) (median PFS KRdc not reached (NR) v Rdc 36 months HR 0.66 (95% CI 0.52, 0.83, P=0.0004). This exploratory subgroup analysis compares PFS and renal recovery between patients receiving KRdc and Rdc within renal function subgroups. Methods Myeloma XI is a phase III, randomized controlled trial with an adaptive design for symptomatic NDMM patients of all ages. This renal analysis is of the transplant eligible (TE) pathway and compares induction treatment with the quadruplet KRdc to triplet Rdc. Patients were randomized contemporaneously 2:1. All patients were randomized to post-ASCT R maintenance or observation. For further exploratory analysis patients randomized earlier in the study to Rdc were also included. Relevant exclusion criteria were acute renal failure non-responsive to 72 hours rehydration (creatinine >500umol/L, urine output =60 ml/min/1.73m2, moderately impaired 30-59 or severely impaired =500mg/L between the involved and uninvolved (dFLC). Renal recovery was defined as an improvement in eGFR of ≥25% at the end of induction therapy. Results 1547 patients were randomized to KRdc n=526 or Rdc n=1021 (265 contemporaneous, 756 not). In the contemporaneous group baseline renal function was normal in 609/791 (77.0%), moderately impaired in 141/791 (17.8%) and severely impaired in 40/791 (5.1%) (data n/a in 1 patient). Patients with moderately or severely impaired renal function had shorter PFS compared to those with normal renal function. Subgroup analysis showed consistent outcomes for KRdc compared to Rdc across all renal subgroups with no evidence of significant heterogeneity (Figure 1, Phet=0.9354). Further exploratory analysis combined patients with moderate or severe renal impairment into one group. Difference in PFS and renal recovery between patients with normal or impaired renal function and high (>=500) or low ( Within the group of patients with normal renal function at baseline those with high dFLC had shorter PFS than those with low dFLC. KRdc was associated with improved PFS irrespective of LC level: high dFLC KRdc median PFS NR (95% CI 39, NR) v Rdc 34 months (30, 39) and low dFLC KRdc NR (44, NR) v Rdc 41 (37, 47). In the group of patients with renal impairment at baseline KRdc was also associated with an improved PFS irrespective of LC level: high dFLC KRdc median PFS NR (95% CI 29, NR) v Rdc 32 months (28, 42) and low dFLC KRdc 37 (25, NR) v Rdc 27 (24, 33). In contrast to those with normal renal function, however, patients with renal impairment and high dFLC had a longer PFS than those with low dFLC. This observation was apparent whether patients received KRdc or Rdc and suggests that patients with high dFLC may have had reversible renal impairment, improving their ultimate outcomes. Supporting this hypothesis, measurable renal recovery in the renal impaired group at the end of induction was more common in patients with high dFLC (dFLC>=500 68.6% v dFLC Conclusions KRdc was associated with improved PFS compared to Rdc in NDMM patients across all renal subgroups. Irrespective of treatment, renal function is more likely to improve if attributable to nephrotoxic LC. Disclosures Pawlyn: Janssen: Honoraria, Other: Travel expenses; Celgene: Consultancy, Honoraria, Other: Travel expenses; Amgen: Consultancy, Other: Travel expenses; Takeda: Consultancy, Other: Travel expenses. Menzies:Celgene, Amgen, Merck: Research Funding. Davies:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotech: Honoraria; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cook:Celgene, Janssen, Takeda: Research Funding; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda, Roche, Sanofi: Honoraria; Karyopharm: Honoraria. Gregory:Celgene, Amgen, Merck: Research Funding; Janssen: Honoraria; Celgene: Consultancy. Jenner:Amgen, Janssen, Celgene, Takeda, Novartis, Sanofi, GSK: Consultancy; Janssen, Takeda, Amgen, Celgene, Novartis: Honoraria; Janssen, Celgene: Research Funding; Janssen, Takeda, Amgen: Other: Travel expenses. Jones:Celgene: Honoraria, Research Funding. Kaiser:Bristol-Myers Squibb/Celgene, Janssen, Karyopharm: Research Funding; Bristol-Myers Squibb, Chugai, Janssen, Amgen, Takeda, Celgene, AbbVie, Karyopharm, GlaxoSmithKline: Consultancy; Janssen, Amgen, Celgene, Bristol-Myers Squibb, Takeda: Honoraria; Bristol-Myers Squibb, Takeda: Other: Travel expenses. Owen:Takeda: Honoraria, Other: Travel expenses; Janssen: Consultancy, Other: Travel expenses; Celgene: Consultancy, Honoraria, Research Funding. Morgan:Karyopharm: Consultancy, Honoraria; Janssen: Research Funding; GSK: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Jackson:Takeda: Honoraria, Research Funding, Speakers Bureau; Gsk: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Cairns:Celgene, Amgen, Merck: Research Funding; Celgene: Other: Travel Support. OffLabel Disclosure: Carfilzomib, lenalidomide, dexamethasone and cyclophosphamide combination induction therapy for newly diagnosed myeloma

Newly diagnosed multiple myeloma (NDMM) patients treated with immunomodulatory drugs are at high risk of venous thromboembolism (VTE), but data are lacking from large prospective cohorts. We present thrombosis outcome data from Myeloma IX (n = 1936) and Myeloma XI (n = 4358) phase 3 randomized controlled trials for NDMM that treated transplant-eligible and transplant-ineligible patients before and after publication of thrombosis prevention guidelines. In Myeloma IX, transplant-eligible patients randomly assigned to cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) induction had higher risk of VTE compared with patients treated with cyclophosphamide, thalidomide, and dexamethasone (CTD) (22.5% [n = 121 of 538] vs 16.1% [n = 89 of 554]; adjusted hazard ratio [aHR],1.46; 95% confidence interval [95% CI], 1.11-1.93). For transplant-ineligible patients, those randomly assigned to attenuated CTD (CTDa) induction had a higher risk of VTE compared with those treated with melphalan and prednisolone (MP) (16.0% [n = 68 of 425] vs 4.1% [n = 17 of 419]; aHR, 4.25; 95% CI, 2.50-7.20). In Myeloma XI, there was no difference in risk of VTE (12.2% [n = 124 of 1014] vs 13.2% [n = 133 of 1008]; aHR, 0.92; 95% CI, 0.72-1.18) or arterial thrombosis (1.2% [n = 12 of 1014] vs 1.5% [n = 15 of 1008]; aHR, 0.80; 95% CI, 0.37-1.70) between transplant-eligible pathways for patients treated with cyclophosphamide, lenalidomide, and dexamethasone (CRD) or CTD. For transplant-ineligible patients, there was no difference in VTEs between attenuated CRD (CRDa) and CTDa (10.4% [n = 95 of 916] vs 10.7% [n = 97 of 910]; aHR, 0.97; 95% CI, 0.73-1.29). However, arterial risk was higher with CRDa than with CTDa (3.1% [n = 28 of 916] vs 1.6% [n = 15 of 910]; aHR, 1.91; 95% CI, 1.02-3.57). Thrombotic events occurred almost entirely within 6 months of treatment initiation. Thrombosis was not associated with inferior progression-free survival (PFS) or overall survival (OS), apart from inferior OS for patients with arterial events (aHR, 1.53; 95% CI, 1.12-2.08) in Myeloma XI. The Myeloma XI trial protocol incorporated International Myeloma Working Group (IMWG) thrombosis prevention recommendations and compared with Myeloma IX, more patients received thromboprophylaxis (80.5% vs 22.3%) with lower rates of VTE for identical regimens (CTD, 13.2% vs 16.1%; CTDa, 10.7% vs 16.0%). However, thrombosis remained frequent in spite of IMWG-guided thromboprophylaxis, suggesting that new approaches are needed.

A growing body of research supports the validity of the Personality Inventory for DSM-5 (PID-5) in evaluating community and psychiatric samples. Although maladaptive personality also has significant relevance in primary care settings, research on the PID-5 in primary care samples is limited. In this study, the authors examined the intercorrelations, convergent validity, and discriminant validity of the brief form of the PID-5 (PID-5-BF) in 100 primary care outpatients. Results are consistent with findings in other samples in suggesting that PID-5 domains are moderately intercorrelated and associated with a variety of mental health variables. Smaller associations with physical health variables support the discriminant validity of the instrument. Overall, results suggest that the PID-5-BF can provide a useful psychiatric screening tool in primary care settings.

Personalised medicine (PM) is becoming increasingly integrated into standard clinical practice for treating numerous diseases, including cancer. Implementing PM into healthcare systems will only be successful with the acceptance and input of both patients’ and public opinion. This review, therefore, aimed to identify both patients’ and public understanding, and perceived benefits and concerns of PM in cancer treatment. A literature search was conducted using MEDLINE, EMBASE, PsycINFO and CINAHL databases. The eligibility criteria specified that papers must explore the public or patients’ understanding of PM or pharmacogenomic (PGx) testing in relation to cancer treatment. Patients have a greater understanding of, and trust in, PM compared with members of the public, but often misunderstand how genomic testing in PM works. Key areas that can be targeted to inform future health literacy interventions include genetic literacy for the public and understanding of how PM testing and treatment works for patients.

Myeloma is the second most common hematological cancer, with 5800 cases per year diagnosed in the UK. Despite improved treatment it is still considered non-curable, although the median survival has increased from 3 to 8 years over the past 20 years. Treatment involves the use of induction therapy and consolidation with autologous stem cell transplant (ASCT) in patients deemed fit enough. Further attempts to improve outcomes include the use of maintenance therapy.\ud \ud This review details all trials in which lenalidomide has been used as maintenance following ASCT. PubMed searches included randomized control trials, observational cohort, reviews, and meta-analysis.\ud \ud Lenalidomide is a well-tolerated, oral agent that is associated with increased overall and progression free survival when used as maintenance following ASCT. Its use in this setting is FDA and EMA approved and is standard of care in Europe and North America. The early link between lenalidomide and second hematological cancers appears to be associated with use in combination with melphalan. There is an increase in non-melanoma skin cancers and solid tumors in the elderly but this has minimal impact on mortality. Lenalidomide use as part of combination maintenance is underway and may further improve outcomes.

The concentration of dissolved oxygen in aquatic systems helps to regulate biodiversity1,2, nutrient biogeochemistry3, greenhouse gas emissions4, and the quality of drinking water5. The long-term declines in dissolved oxygen concentrations in coastal and ocean waters have been linked to climate warming and human activity6,7, but little is known about the changes in dissolved oxygen concentrations in lakes. Although the solubility of dissolved oxygen decreases with increasing water temperatures, long-term lake trajectories are difficult to predict. Oxygen losses in warming lakes may be amplified by enhanced decomposition and stronger thermal stratification8,9 or oxygen may increase as a result of enhanced primary production10. Here we analyse a combined total of 45,148 dissolved oxygen and temperature profiles and calculate trends for 393 temperate lakes that span 1941 to 2017. We find that a decline in dissolved oxygen is widespread in surface and deep-water habitats. The decline in surface waters is primarily associated with reduced solubility under warmer water temperatures, although dissolved oxygen in surface waters increased in a subset of highly productive warming lakes, probably owing to increasing production of phytoplankton. By contrast, the decline in deep waters is associated with stronger thermal stratification and loss of water clarity, but not with changes in gas solubility. Our results suggest that climate change and declining water clarity have altered the physical and chemical environment of lakes. Declines in dissolved oxygen in freshwater are 2.75 to 9.3 times greater than observed in the world’s oceans6,7 and could threaten essential lake ecosystem services2,3,5,11., The concentration of dissolved oxygen in aquatic systems helps to regulate biodiversity, nutrient biogeochemistry, greenhouse gas emissions, and the quality of drinking water. The long-term declines in dissolved oxygen concentrations in coastal and ocean waters have been linked to climate warming and human activity, but little is known about the changes in dissolved oxygen concentrations in lakes. Although the solubility of dissolved oxygen decreases with increasing water temperatures, long-term lake trajectories are difficult to predict. Oxygen losses in warming lakes may be amplified by enhanced decomposition and stronger thermal stratification8,9 or oxygen may increase as a result of enhanced primary production10. Here we analyse a combined total of 45,148 dissolved oxygen and temperature profiles and calculate trends for 393 temperate lakes that span 1941 to 2017. We find that a decline in dissolved oxygen is widespread in surface and deep-water habitats. The decline in surface waters is primarily associated with reduced solubility under warmer water temperatures, although dissolved oxygen in surface waters increased in a subset of highly productive warming lakes, probably owing to increasing production of phytoplankton. By contrast, the decline in deep waters is associated with stronger thermal stratification and loss of water clarity, but not with changes in gas solubility. Our results suggest that climate change and declining water clarity have altered the physical and chemical environment of lakes. Declines in dissolved oxygen in freshwater are 2.75 to 9.3 times greater than observed in the world’s oceans and could threaten essential lake ecosystem services.

Respiratory motion degrades quantitative and qualitative analysis of medical images. Estimation and, hence, correction of motion commonly uses static correspondence models between an external surrogate signal and internal motion. This paper presents a patient specific respiratory motion model with the ability to adapt in the presence of irregular motion via a Kalman filter with expectation maximization for parameter estimation. The adaptive approach introduces generalizability allowing the model to account for a broader variety of motion. This may be required in the presence of irregular breathing and with different sensors monitoring the external surrogate signal. The motion model framework utilizing an adaptive Kalman filter approach is tested on dynamic magnetic resonance imaging data of nine volunteers and compared to a state-of-the-art static total least squares approach. Results demonstrate the framework is capable of reducing motion to the order of ${p} ) more effective in the presence of irregular motion, assessed using the ${F}$ -test for model comparison. Utilizing the total sum of squares of estimated vector field error from the calculated ground truth, we observe approximately a fifty percent reduction in root mean square error and thirty percent reduction in standard deviation utilizing the Kalman model (EKF) in comparison to a static counterpart.

This is one of few studies to comprehensively examine seasonality and phytoplankton nutrient deficiency in sub-tropical lakes over multiple years, to our knowledge. We tested whether phytoplankton communities in two sub-tropical impoundments in the mid-hills of Nepal were nitrogen (N)-, phosphorus (P)-, or co-deficient in N and P across pre-monsoon, monsoon, and post-monsoon seasons spanning a decade. Nutrient limitation to phytoplankton growth was assessed via in situ stoichiometry of N and P (N:P ratios) and nutrient stimulation experiments (NSEs). The experiments indicated co-deficiency of N and P in 97–100% of NSEs in all seasons. N-deficiency was common (> 60% of N:P ratios and ~ 90% of NSEs) during the rainy monsoon, but P-deficiency occurred twice as often as N-deficiency during drier seasons (pre- and post-monsoon). These findings provide perspective for the ongoing debate over N and P as limiting nutrients in freshwater ecosystems by incorporating seasonality and corresponding hydrology. We also re-visit long-standing assumptions regarding the nutrient status of sub-tropical lakes. The warm, stratified season does not fully illustrate lake processes, and more research during dry periods will inform how seasonality affects phytoplankton nutrient deficiencies across aquatic systems.

The elemental composition of seston provide insights into the functioning of lake food webs and how nutrients cycle through the environment. Here, we describe a Bayesian network model that simultaneously estimates relationships between dissolved and particulate nutrients, suspended volatile and non-volatile sediments, and algal chlorophyll. The model provides direct estimates of the phosphorus and nitrogen content of phytoplankton, suspended non-living organic matter, and suspended inorganic sediment. We apply this model to data collected from reservoirs in Missouri, USA to test the validity of our assumed relationships. The results indicate that, on average among all samples, the ratio of nitrogen to phosphorus (N:P) in phytoplankton and non-living organic matter in these reservoirs were similar, although under nutrient replete conditions, N:P in phytoplankton decreased. Phosphorus content of inorganic sediment was lower than in phytoplankton and non-living organic matter. The analysis also provided a means of tracking changes in the composition of whole seston over time. In addition to informing questions regarding seston stoichiometry, this modeling approach may inform efforts to manage lake eutrophication because it can improve traditional models of relationships between nutrients and chlorophyll in lakes.

Creutzfeldt-Jakob disease (CJD) is a rapidly progressive fatal neurodegenerative disorder. We report an unusual case of pathologically confirmed sporadic CJD developing in a HIV-positive patient but presenting with clinical and radiological features suggestive of variant CJD. A 63-year-old man with chronic stable HIV developed progressive difficulties with decision-making, obsessive compulsive disorder and visual hallucinations over 3 months. CSF examination detected a weakly positive 14-3-3 protein, elevated S-100 protein, and siginificantly elevated total-Tau protein. Brain MRI revealed bilateral abnormal signal within the posterolateral thalami compatible with pulvinar sign. Further investigations revealed a negative tonsillar biospy and positive blood test consistent with variant CJD. However, prion protein genotyping detected MV heterozygosity at codon 129 and post-mortem histopathological examination was consistent with sporadic CJD. Although MRI findings were suggestive of variant CJD, the short residence in the UK and MV heterozygosity are aytpical, and the histopathological examination was consistent with sporadic CJD. With only two cases of HIV and sporadic CJD reported so far, the association of CJD with HIV remains unclear.

Study region The Geum River Basin, South Korea. Study focus In-stream structures potentially amplify harmful algal blooms (HABs) by increasing water residence time and deteriorating water quality. Removal or gate control of in-stream structures is considered a management tool to reduce HAB occurrence. Prior evaluation, however, is necessary to assess the effect of structural modifications to control HABs. This study focused on factors affecting HAB occurrence relative to the operation of 3 in-stream weirs using a 3-dimensional hydrodynamic and water quality model. New hydrological insights for the study region Physical changes due to gate opening could not guarantee an improvement in water quality and reduction in cyanobacterial biomass. Cyanobacteria, a major component of HABs, decreased in the upstream reach but conditions deteriorated downstream during summer. Maximum cyanobacteria concentrations in the downstream reach almost doubled during summer with the open-gate scenario. Although the open-gate flow allowed less time for algal growth, (1) increased light availability with decreased water depth and (2) dissolved phosphorus, which was not depleted upstream, promoted cyanobacterial growth. Consequently, the proliferation of cyanobacterial blooms downstream was due to conditions that enhanced algal growth, despite reduced hydraulic residence time under the open-gate scenario. This analysis indicates that hydrologic regulation may not improve water quality and also may affect spatial and temporal distribution of cyanobacteria in the system. Reducing HABs will likely require a reduction in the pollution load.

Background Sex differences in the incidence and outcomes of several cancers are well established. Multiple myeloma (MM) is a malignant plasma cell dyscrasia accounting for 2% of all new cancer cases in the UK. There is a clear sex disparity in MM incidence, with 57% of cases in males and 43% in females. The mechanisms behind this are not well understood and the impact of sex on patient outcomes has not been thoroughly explored. Patients and Methods We investigated the association of sex with baseline disease characteristics and outcome in 3894 patients recruited to the phase III UK NCRI Myeloma XI trial, in which treatment exposure to lenalidomide predominated. Results Females were significantly more likely to have the molecular lesions t(14;16) and del(17p) and were more likely to meet the cytogenetic classification of high-risk (HiR) or ultra-high-risk disease (UHiR). There was no difference in progression-free survival (PFS) or overall survival (OS) between the sexes in the overall population. Conclusion Our data suggest that the genetic lesions involved in the initiation and progression of MM may be different between the sexes. Although females were more likely to have the poor prognosis lesions t(14;16) and del(17p), and were more likely to be assessed as having HiR or UHiR disease, this was not associated with reduced PFS or OS. In female patients the trial treatment may have been able to overcome some of the adverse effects of high-risk cytogenetic lesions. MicroAbstract Multiple myeloma (MM) is more common in males compared to females but the reasons behind this are not well understood and the impact of sex on patient outcomes is unclear. This study demonstrates fundamental differences in genetic lesions underlying the biology of MM between males and females. However, we found that progression-free survival and overall survival were the same in both sexes.

Severe cases of COVID‐19, caused by novel coronavirus SARS‐CoV‐2, have been associated with a hyperinflammatory state.(Huang, Wang et al. 2020) This has been described as a form of secondary haemophagocytic lymphohistiocytosis (sHLH)(Bergsten, Horne et al. 2017) that may contribute to increased mortality.(Ramos‐Casals, Brito‐Zeron et al. 2014) Screening with the HScore(Fardet, Galicier et al. 2014) to identify cases has been recommended to guide immunosuppressive therapy(Mehta, McAuley et al. 2020).

The empirical relationship between total phosphorus and chlorophyll has guided lake management decisions for decades, but imprecision in this relationship in individual lakes limits the utility of these models. Many environmental factors that potentially affect the total phosphorus-chlorophyll relationship have been studied, but here we hypothesize that imprecision can be reduced by considering differences in the proportions of phosphorus bound to three different "compartments" in the water column: phosphorus bound in phytoplankton, phosphorus bound to suspended sediment that is not associated with phytoplankton, and dissolved phosphorus. We specify a hierarchical Bayesian network model that estimates phosphorus associated with each compartment using field measurements of chlorophyll, total suspended solids, and total phosphorus collected from reservoirs in Missouri, USA. We then demonstrate that accounting for these different compartments yields accurate predictions of total phosphorus in individual lakes. Results from this model also yield insights into the mechanisms by which lake morphometric and watershed characteristics affect observed relationships between total phosphorus and chlorophyll.

Second-generation immunomodulatory agents, such as lenalidomide, have a more favourable side-effect profile than the first-generation thalidomide, but their optimum combination and duration for patients with newly diagnosed transplant-ineligible myeloma (ND-TNE-MM) has not been defined. The most appropriate delivery and dosing regimens of these therapies for patients at advanced age and frailty status is also unclear. The Myeloma XI study compared cyclophosphamide, thalidomide and dexamethasone (CTDa) to cyclophosphamide, lenalidomide and dexamethasone (CRDa) as induction therapy, followed by a maintenance randomisation between ongoing therapy with lenalidomide or observation for patients with ND-TNE-MM. CRDa deepened response but did not improve progression-free (PFS) or overall survival (OS) compared to CTDa. However, analysis by age group highlighted significant differences in tolerability in older, frailer patients that may have limited treatment delivery and impacted outcome. Deeper responses and PFS and OS benefits with CRDa over CTDs were seen in patients aged ≤70 years, with an increase in toxicity and discontinuation observed in older patients. Our results highlight the importance of considering age and frailty in the approach to therapy for patients with ND-TNE-MM, highlighting the need for prospective validation of frailty adapted therapy approaches, which may improve outcomes by tailoring treatment to the individual.

The optimal way to use immunomodulatory drugs as components of induction and maintenance therapy for multiple myeloma is unresolved. We addressed this question in a large phase III randomized trial, Myeloma XI. Patients with newly diagnosed multiple myeloma (n = 2042) were randomized to induction therapy with cyclophosphamide, thalidomide, and dexamethasone (CTD) or cyclophosphamide, lenalidomide, and dexamethasone (CRD). Additional intensification therapy with cyclophosphamide, bortezomib and dexamethasone (CVD) was administered before ASCT to patients with a suboptimal response to induction therapy using a response-adapted approach. After receiving high-dose melphalan with autologous stem cell transplantation (ASCT), eligible patients were further randomized to receive either lenalidomide alone or observation alone. Co-primary endpoints were progression-free survival (PFS) and overall survival (OS). The CRD regimen was associated with significantly longer PFS (median: 36 vs. 33 months; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.75-0.96; P = 0.0116) and OS (3-year OS: 82.9% vs. 77.0%; HR, 0.77; 95% CI, 0.63-0.93; P = 0.0072) compared with CTD. The PFS and OS results favored CRD over CTD across all subgroups, including patients with International Staging System stage III disease (HR for PFS, 0.73; 95% CI, 0.58-0.93; HR for OS, 0.78; 95% CI, 0.56-1.09), high-risk cytogenetics (HR for PFS, 0.60; 95% CI, 0.43-0.84; HR for OS, 0.70; 95% CI, 0.42-1.15) and ultra high-risk cytogenetics (HR for PFS, 0.67; 95% CI, 0.41-1.11; HR for OS, 0.65; 95% CI, 0.34-1.25). Among patients randomized to lenalidomide maintenance (n = 451) or observation (n = 377), maintenance therapy improved PFS (median: 50 vs. 28 months; HR, 0.47; 95% CI, 0.37-0.60; P < 0.0001). Optimal results for PFS and OS were achieved in the patients who received CRD induction and lenalidomide maintenance. The trial was registered with the EU Clinical Trials Register (EudraCT 2009-010956-93) and ISRCTN49407852.

Background Although the median age of patients with newly diagnosed multiple myeloma (MM) is 70-74 years, recruitment of frail older patients to clinical trials is poor. The International Myeloma Working Group (IMWG) frailty score predicts survival, adverse events and treatment tolerability using age, the Katz Activity of Daily Living, the Lawton Instrumental Activity of Daily Living, and the Charlson Comorbidity Index, rather than age alone. Despite IMWG score prognostic biomarker capability, to date no evidence exists of its predictive biomarker potential. The UK-MRA Myeloma Risk Profile (MRP) has also been shown in both clinical trial and real-world populations to be a prognostic biomarker in transplant ineligible patients but prospective comparisons of the two scores have not been previously conducted. Study Design/Methods The FiTNEss trial (Myeloma XIV, NCT03720041, Figure 1A) is a UK-MRA phase III, multi-centre, randomised controlled trial for newly diagnosed MM patients not suitable for stem cell transplant. The primary objectives are 1) to compare early treatment cessation ( 2) to compare progression free survival for maintenance lenalidomide plus placebo (R) and lenalidomide plus ixazomib (IR). The FiTNEss trial is designed as an all-comers study with few exclusion criteria other than necessary for safety including some haematological and biochemical parameters, but there is no exclusion based on renal function. Patients with grade 2 or greater baseline peripheral neuropathy, current systemic infection or recent surgery or other cancer are excluded. Here we report the demographics for the first patients recruited, including IMWG frailty assessments and MRP to demonstrate the feasibility of recruiting frail patients to randomised phase III clinical trials. Results The FiTNEss trial opened on 04/08/2020 during the second wave of the COVID-19 pandemic in the UK. At the time of data cut off (14/07/2021) recruitment is active at 84 sites, with 180 patients randomised. Baseline characteristics for the randomised patients are shown in Figure 1B. The median age of patients is 77 years (range 64, 93) with 36.1% aged 76-80 and 26.1% over 80. In keeping with the older patient population 26.6% have an ECOG performance status of 2 or 3 and 31.7% ISS stage III. The IMWG frailty classification at baseline is FIT 43/180 (23.9%), UNFIT 53/180 (29.4%) and FRAIL 84/180 (46.7%). The effect of using age groups on the definition of patient frailty was explored. The IMWG frailty score defines all patients over 80 as FRAIL whilst an age of 76-80 contributes one point to the score. An analysis of patients' frailty was repeated with the contribution of age removed. For those aged over 80 years (n=47, 100% FRAIL) we found that 20 (42.6%) would have been re-classified as FIT and 18 (38.3%) as UNFIT, with only 9 (19.2%) retaining the FRAIL category. For those aged 76-80 (n=65, 53.8% UNFIT, 46.2% FRAIL) all 35 patients previously classified as UNFIT became FIT (53.8%) whilst 19 (29.2%) classed as FRAIL became UNFIT with 11 (16.9%) remaining FRAIL. The MRP classification, using age as a continuous variable, was Low-risk 45/180 (25.0%), Medium-risk 46/180 (25.6%), High-risk 75/180 (41.7%) and not available for 14/180 (7.8%) patients. Concordance between the IMWG frailty score and the MRP occurred in 48.9% of patients (88/180). 37.2% of FIT patients were classified as MRP Low-risk, 32.1% of UNFIT patients as MRP Medium-risk and 65.5% of FRAIL patients as MRP High-risk. Discussion The FiTNEss trial demonstrates the feasibility of recruiting older, less fit patients to clinical trials. Recruitment of patients classified as FRAIL was very high despite the COVID pandemic, likely due to the all-oral nature of the regimen under investigation enabling patients to avoid attendance at hospital day units for treatment and associated exposure risk. In the population recruited to date we found age to be a key contributor to the FRAIL category of the IMWG frailty score. Concordance between IMWG frailty score and MRP was highest in FRAIL/High-risk patients. The first interim analysis of the primary objectives is planned when 50% of required participants for R1 have reached 60 days post R1, which is anticipated in Q2 of 2022. Figure 1 Figure 1. Disclosures Cook: Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Pawlyn: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. Royle: BMS: Research Funding; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Coulson: BMS / Celgene: Honoraria; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Jenner: BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy. Kishore: Sanofi: Other: Attending fees; Celgene: Other: Attending fees; Takeda: Other: Attending fees; Jannsen: Other: Attending fees. Rabin: BMS / Celgene: Consultancy, Honoraria, Other: Travel support for meetings; Takeda: Consultancy, Honoraria, Other: Travel support for meetings; Janssen: Consultancy, Honoraria, Other: Travel support for meetings. Best: BMS/Celgene: Research Funding; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Gillson: BMS / Celgene: Research Funding; Meck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Henderson: Takeda: Research Funding; Amgen: Research Funding; Merck Sharpe and Dohme: Research Funding; BMS / Celgene: Research Funding. Olivier: Merck Sharpe and Dohme: Research Funding; Takeda: Research Funding; Amgen: Research Funding; Celgene / BMS: Research Funding. Kaiser: AbbVie: Consultancy; GSK: Consultancy; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy; Takeda: Consultancy, Other: Educational support; Janssen: Consultancy, Other: Educational support, Research Funding; BMS/Celgene: Consultancy, Other: Travel support, Research Funding. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jones: Janssen: Honoraria; BMS/Celgene: Other: Conference fees. Cairns: Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Jackson: celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; J and J: Consultancy, Honoraria, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. OffLabel Disclosure: Frailty-score adapted dosing strategies

Introduction Despite efficacious modern induction combination therapies a subset of myeloma patients have high-risk disease which manifests as either primary refractory disease or early relapse following initial response. The presence of known molecular high-risk lesions explain the majority of these cases but understanding the factors influencing the poor phenotypic outcome for the remainder will help us improve outcomes further. This exploratory analysis of the Myeloma XI+ trial aimed to understand the population of patients with phenotypic high-disease in the context of carfilzomib and lenalidomide induction therapy. Methods The UK NCRI Myeloma XI trial is a phase III randomised controlled trial that recruited 2568 newly diagnosed transplant eligible patients, of which 526 were randomised to receive the induction combination KRdc comprising carfilzomib (K, 36mg/m2 IV d1-2, 8-9,15-16 (20mg/m2 #1d1-2)), lenalidomide (R, 25mg PO d1-21), dexamethasone (d, 40mg PO d1-4,8-9,15-16) and cyclophosphamide (c, 500mg PO d1,8) as part of an adaptive trial design. Induction therapy was planned for a minimum of 4 cycles or to maximum response prior to autologous stem cell transplant (ASCT). There was a subsequent randomisation to lenalidomide maintenance or observation at 3 months post ASCT. Primary refractory disease was defined as not achieving at least a minimal response (MR) at maximum response after at least 4 cycles of induction therapy or progression at any time during induction regardless of initial response. Early relapse (ER) after ASCT was defined as progression within 12 months of ASCT. Molecular risk was defined as the presence of one (high risk) or more than one (ultra-high risk) of the following lesions: del(17p), gain(1q), t(4,14), t(14;16) or t(14;20). Results The incidence of primary refractory disease with the KRdc combination was very low. Only 8/526 (1.5%) patients were primary refractory, all having progression during induction therapy with a median progression free survival of only 126 days. The number of patients is too small to draw any firm conclusions regarding the characteristics associated with primary refractory disease. 401/526 (76%) of patients underwent high dose melphalan and ASCT on trial after KRdc induction. Those that did not proceed to ASCT on trial were either ineligible, mostly due to not completing the minimum required induction therapy, or were deemed not fit to undergo the procedure based on patient/clinician decision. Of those patients who underwent ASCT, 36/401 (9.0%) relapsed within 12 months (ER). These ER patients had both a shorter PFS2 and second PFS suggesting a continued association with adverse outcome beyond first line therapy. Patients in the ER group were compared with those patients not relapsing until beyond 12 months after ASCT (nER). There was no difference in the sex, age or paraprotein or light chain sub-type of patients. There was evidence of a greater impact of bone marrow disease burden in the ER group with a lower haemoglobin (median 99 g/L vs 115, p = 0.0216), lymphocyte count (1.3 x10^9/L vs 1.8, p = 0.0012) and platelet count (187 x10^9/L vs 252, p = 0.0049) at baseline. Median bone marrow aspirate plasma cell infiltration was ER 33% vs nER 23%. There were no significant differences in ISS stage (ER ISS I 19%, II 50%, III 22%, nER ISS I 35%, II 36%, III 22%, p = 0.1434), lactate dehydrogenase, albumin or beta-2 microglobulin. Patients in the ER group were less likely to have received lenalidomide maintenance (ER 12/36 [33%] vs nER 222/365 [61%]). For some (4/36) not receiving lenalidomide was due to relapse occurring prior to reaching the maintenance randomisation point (100 days post-ASCT). For those with available data 75% of patients in the ER group had molecular high (50%) or ultra-high (25%) risk disease, whilst 25% had standard risk using the trial definition. The individual lesions accounting for high-risk status were: gain(1q) in ER 42% vs nER 35%; t(4;14) ER 50% vs nER 10%; del(17p) ER 8% vs nER 7%. Discussion The combination of a second-generation immunomodulatory agent and proteasome inhibitor in the KRdc induction regimen is associated with deep responses and only a very small proportion of patients have primary refractory disease. Early relapse after KRdc and ASCT occurred in 9% of patients and was associated with high bone marrow disease burden and molecular high-risk features. Disclosures Pawlyn: Amgen: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Davies: Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Menzies: Celgene / BMS: Research Funding; Amgen: Research Funding; Merck Sharpe and Dohme: Research Funding. Henderson: BMS / Celgene: Research Funding; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Cook: Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Jenner: BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy. Jones: Janssen: Honoraria; BMS/Celgene: Other: Conference fees. Kaiser: AbbVie: Consultancy; Takeda: Consultancy, Other: Educational support; Seattle Genetics: Consultancy; Amgen: Honoraria; Pfizer: Consultancy; Karyopharm: Consultancy, Research Funding; GSK: Consultancy; Janssen: Consultancy, Other: Educational support, Research Funding; BMS/Celgene: Consultancy, Other: Travel support, Research Funding. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Cairns: Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Jackson: celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; J and J: Consultancy, Honoraria, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. OffLabel Disclosure: The KRdc combination is off label

Introduction In Multiple Myeloma (MM) the emergence of treatment resistant clones is a characteristic feature of relapse and this is particularly so for high-risk cases. A key driver event mediating progression, risk status and relapse is gain(1q) (1q+). We report on the impact of 1q+ on the genetic profile seen at first relapse in a uniformly treated, newly diagnosed series of 56 patients enrolled to the NCRI Myeloma XI Trial. Methods We included 56 high risk patients, defined as relapse within 30 months of maintenance randomisation (median 19 months, range 8-51). Of the 56 patients, 30 received lenalidomide maintenance and 26 were observed. Whole exome sequencing was conducted at presentation and relapse to a median depth of 122x for tumour samples and 58x for controls. Libraries were prepared using the SureSelectQXT sample prep kit and SureSelect Clinical Research Exome kit. MuTect was used to determine gene variants and SciClone clustering was undertaken to map mutation variant allele frequencies. MANTA was used to determine translocations and Sequenza for copy number aberrations. Clonal structure and mechanisms of clonal evolution were assessed using kernel density estimation of the cancer clonal fraction for all mutations. Wilcoxon matched-pairs signed rank tests (2-sided) were used to determine the significance between paired data sets, including mutational load. Fishers exact test was used to determine the difference between two nominal variables. Results We looked at mutational, structural and clonal evolution events in all patients based on 1q+ status at relapse. At diagnosis, 34% (19/56) patients had evidence of 1q+, increasing to 46% (26/56) at relapse, with all patients harbouring 1q+ at presentation having the lesion at relapse. There was a significantly higher non-synonymous mutational load at relapse in patients with 1q+, 107 vs 126 (p=0.047), compared to those without 1q+, 36 vs 44 (p=0.140). Twenty two genes known to be significant in MM and mutations within the genes known to be important in IMiD mechanism of action were reviewed. Of the patients with 1q+, 92% (24/26) had at least one mutation during the course of the disease, compared to 77% in those without 1q+ (p=0.15). The impact on tumour suppressor gene regions including deletions of chromosome 1p, 13, 14 and 17p was analyzed. Of the patients with 1q+, 77% (20/26) of patients had a deletion of one of these regions during the disease course, compared to 57% (17/30) of patients without 1q+ (p=0.16). At relapse a change in the profile of these lesions was noted in 23% (6/26) patients with 1q+, compared to 20% (6/30) patients without 1q+ (p=1). Translocations involving MYC (t MYC) were also determined and found in 27% (7/26) of patients with 1q+ and 27% (8/30) of patients without (p=1). As with 1q+, t MYC was always preserved at relapse. Mechanisms of evolution leading to relapse were established for all patients. Branching and linear evolution predominated, noted to be the mechanism leading to relapse in 88% (23/26) patients with 1q+ and 83% (25/30) without (p0.71). Stable evolution was noted in the remaining patients. 1q+ occurring as a new event at relapse was associated with branching or linear evolution in all patients (n=7), consistent with a change in clonal structure. Conclusion These data reveal that 1q+ is conserved throughout the disease course, suggesting it imparts a survival advantage and treatment resistant phenotype to the clone(s) containing it. The presence of 1q+ is associated with a significant increase in mutational load at relapse and a greater incidence of tumour suppressor gene structural deletions, mechanisms that may contribute to clonal evolution and therapeutic escape. Disclosures Jones: BMS/Celgene: Other: Conference fees; Janssen: Honoraria. Pawlyn: Celgene / BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Weinhold: Sanofi: Honoraria. Walker: Sanofi: Speakers Bureau; Bristol Myers Squibb: Research Funding. Cairns: Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Kaiser: AbbVie: Consultancy; Seattle Genetics: Consultancy; BMS/Celgene: Consultancy, Other: Travel support, Research Funding; Amgen: Honoraria; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Janssen: Consultancy, Other: Educational support, Research Funding; GSK: Consultancy; Takeda: Consultancy, Other: Educational support. Cook: Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jackson: oncopeptides: Consultancy; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; J and J: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Davies: BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees.

Introduction In traditional analysis of cancer clinical trials, key endpoints such as progression-free survival (PFS) and overall survival (OS) are often analysed separately. Using multistate models (MSMs) we can model these events simultaneously to holistically analyse the disease-treatment pathway. This provides meaningful estimates for the probability of disease progression and death at any point in the disease course, incorporating treatment and prognostic factors of interest. MSMs are also a useful tool to assess the relationship between how the time spent in one state affects the risk of transitioning to future states. In the context of myeloma (MM), this can be used to determine patient prognosis based on the time for which they remain in 1 st remission after initial treatment. Methods In the largest randomised trial of MM patients undertaken to date (NCRI Myeloma XI), newly diagnosed MM patients eligible for ASCT (NDMM TE) were randomised to induction, intensification and maintenance treatments. Maintenance randomisation, at ASCT+3 months, was to lenalidomide (R), lenalidomide plus vorinostat (RZ) or observation. Co-primary endpoints were PFS and OS analysed by Cox regression. An MSM was used for exploratory analysis of 1074 TE patients randomised to maintenance. Patients transitioned irreversibly between 4 states: 1 st remission, alive and in remission after 1 st progressive disease (PD1), alive and in remission after 2 nd PD (PD2) and dead (Figure 1). Time in 1 st remission was included as a covariate to assess the effect of early disease progression on subsequent state transitions ( Results The median follow-up from randomisation was 57m (interquartile range: 43-72m). MSM analysis found that a 1 st remission of At a snapshot at 5 years post-randomisation, those with a 1 st remission ≥18m had a 24.9% chance of being in the PD1 state, compared to just 6.4% and 1.1% in those with 1 st remissions of 12-18m and MSM analysis also found R and RZ were associated with a reduced risk of transition from 1 st remission to PD1 vs. observation (R HR 0.51, 95%CI 0.42-0.60; RZ HR 0.68, 95%CI 0.55-0.88), reflecting the results of the primary trial analysis of PFS. Primary trial analysis of OS found that R was associated with significantly longer OS than observation. However, MSM analysis found R was associated with an increased risk of death following both PD1 (HR 1.60, 95%CI 1.06-2.41) and PD2 (HR 1.46, 95%CI 1.03-2.07) vs. observation. This suggests that the OS benefit of R is gained by extending the time in 1 st remission. RZ was associated with increased risk of death without PD (HR 3.07, 95%CI 1.05-9.03) and death following PD2 (HR 1.49, 95%CI 0.99-2.26) vs. observation. The MSM also found that the expected duration in 1 st remission was longest for R and shortest for observation (R 56.7m, RZ 47.7m and obs. 38.6m). However, in the PD1 state (R 12.8m, RZ 15.7m and obs. 21.9m) and PD2 state (R 5.4m, RZ 7.3m and obs. 11.0m) this order was reversed, although the difference between the groups was reduced for later states. Discussion MSMs are a powerful tool for exploring the myeloma disease pathway, identifying associations between states and providing transition probabilities which can be easily interpreted to gain further insights to those obtained via traditional methods. MSMs are an effective method to visualise data, clearly demonstrating the association between early relapse post-ASCT and poor prognosis in NDMM. This work has expanded on the primary analysis of the maintenance randomised treatments in Myeloma XI, corroborating results previously observed and highlighting the potential effects of maintenance treatment on each stage of the disease pathway. Figure 1 Figure 1. Disclosures Craig: Celgene: Research Funding; Merck Sharpe & Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Pawlyn: Amgen: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kaiser: AbbVie: Consultancy; BMS/Celgene: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Educational support, Research Funding; GSK: Consultancy; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Other: Educational support; Pfizer: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy. Olivier: Celgene / BMS: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Merck Sharpe and Dohme: Research Funding. Jones: Janssen: Honoraria; BMS/Celgene: Other: Conference fees. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jenner: Takeda: Consultancy; Pfizer: Consultancy; Janssen: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau. Cook: Amgen: Consultancy; BMS/Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Karyopharm: Consultancy. Davies: BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Jackson: J and J: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. Cairns: Celgene / BMS: Other: travel support, Research Funding; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding.

TO THE EDITOR: The key event in the pathogenesis of systemic light chain amyloidosis (AL) is an unstable misfolded secondary or tertiary structure of a monoclonal immunoglobulin (IG) light chain that precipitates in the extracellular compartments.[1][1] The plasma cell disorder underlying AL is

Background: Immunomodulatory drugs (IMiDs) are the current backbone of standard and experimental combination myeloma therapies at all stages of disease, but the majority of patients eventually relapse. The mechanisms driving IMiD resistance are poorly understood. Previous studies looking for genetic drivers of resistance have looked at core members of the CRL4CRBN E3-ubiquitin ligase complex (CUL4-RBX1-DDB1-CRBN) and identified infrequent mutations and deletions in cereblon (CRBN), but at a rate that cannot account for resistance in the majority of patients. More recently several in vitro studies have identified novel regulators of cereblon activity including the COP9 signalosome, E2 ubiquitin conjugating enzymes, neddylation modifiers and additional IMiD neosubstrates. In this study paired presentation/relapse samples from newly diagnosed patients recruited to a clinical trial (UK NCRI Myeloma XI trial: NCT01554852) of largely IMiD-based therapies were used to investigate the role of mutations and deletions in all genes implicated in IMiD activity. For comparison, cell line models of resistance were generated in vitro. Methods: 56 patients who received IMiD induction therapy followed by either lenalidomide maintenance (n=30) or observation (n=26), and subsequently relapsed, underwent whole exome sequencing (WES) of CD138+ cells, median depth 122x for tumour samples and 58x for paired germline controls. Non-synonymous mutations and deletions present in tumour but not germline controls were considered. Cell line models were generated using the IMiD sensitive MM1s cell line. Cells were cultured in 10xGI50 concentrations of lenalidomide/pomalidomide alongside a control exposed to the same %DMSO. WES was carried out and non-synonymous mutations identified. Mutations present in the lenalidomide resistant (Len-R) and pomalidomide resistant (Pom-R) but not their relevant DMSO exposed control were considered. From recent publications a list of 42 genes (Figure 1) involved in cereblon pathway regulation and IMiD response was curated, termed "CRBN/IMiD genes". Mutations in CRBN/IMiD genes in the patient dataset and cell line models were examined. Results: In the patient data set 12/42 (28.6%) of the CRBN/IMiD genes were found to be mutated, with a total of 17 mutations in 14/56 (25%) patients identified. 9/17 (53%) were identified in patients who had received lenalidomide maintenance and 8/17 (47%) in the observation group. Importantly, in the patients receiving lenalidomide maintenance, 6 of the 9 (66.7%) mutations had a higher cancer clonal fraction (CCF) at relapse, suggesting they may have been selected for by exposure to treatment. Comparatively, in mutations identified in patients undergoing observation, only 3 of the 8 (37.5%) mutations had a higher CCF at relapse compared with presentation. The only deletion in CRBN/IMiD genes was in SETX, in one patient at relapse. Only one mutation or deletion was identified in CRBN itself, a missense mutation at relapse at g.3:3195148A>C, encoding a Cys326Gly sequence modification at the protein level. Interestingly, Cys326 is one of 4 cysteines in CRBN coordinating a single zinc ion to form a Zn finger motif, which stabilises the Thalidomide Binding Domain (TBD) of the protein, suggesting this mutation may have had functional significance. In the cell line models full resistance up to 100xGI50 concentrations was established by 12 weeks. The resistant cell lines had cross-resistance to the other IMiDs and comparable morphology, growth rates and responses to non-IMiD drugs as their sensitive counterpart. Resistant cells had reduced levels of CRBN mRNA and protein expression. Functional assays demonstrated that well characterised downstream effects of IMiD treatment were abrogated: transcription factors Ikaros and Aiolos not degraded and no downregulation of IRF4 mRNA. The Pom-R cell line had a mutation affecting a CRBN splice site 5' of exon 8. No other mutations or deletions in the 42 IMiD pathway genes were identified in either the Len-R or Pom-R lines. Conclusions: CRBN and other genes in the IMiD response pathway were mutated or deleted in around 25% of patients suggesting other mechanisms, for example epigenetic alterations, underlie resistance acquisition in a significant proportion. Models for both CRBN/IMiD gene mutated and unmutated resistant states have been generated and will be used to study mechanisms of IMiD resistance. Figure Disclosures Jones: Celgene: Honoraria, Research Funding. Che:Monte Rosa Therapeutics: Research Funding. Le Bihan:Monte Rosa Therapeutics: Research Funding. Wang:Monte Rosa Therapeutics: Research Funding. Kaiser:Bristol-Myers Squibb, Chugai, Janssen, Amgen, Takeda, Celgene, AbbVie, Karyopharm, GlaxoSmithKline: Consultancy; Janssen, Amgen, Celgene, Bristol-Myers Squibb, Takeda: Honoraria; Bristol-Myers Squibb/Celgene, Janssen, Karyopharm: Research Funding; Bristol-Myers Squibb, Takeda: Other: Travel expenses. Jackson:Takeda: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Gsk: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Davies:Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotech: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chopra:Apple Tree Life Sciences: Current Employment; Monte Rosa Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Research Funding. Morgan:GSK: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Pawlyn:Takeda: Consultancy, Other: Travel expenses; Celgene: Consultancy, Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Amgen: Consultancy, Other: Travel expenses.

The United States (U.S.) has faced major environmental changes in recent decades, including agricultural intensification and urban expansion, as well as changes in atmospheric deposition and climate—all of which may influence eutrophication of freshwaters. However, it is unclear whether or how water quality in lakes across diverse ecological settings has responded to environmental change. We quantified water quality trends in 2913 lakes using nutrient and chlorophyll (Chl) observations from the Lake Multi-Scaled Geospatial and Temporal Database of the Northeast U.S. (LAGOS-NE), a collection of preexisting lake data mostly from state agencies. LAGOS-NE was used to quantify whether lake water quality has changed from 1990 to 2013, and whether lake-specific or regional geophysical factors were related to the observed changes. We modeled change through time using hierarchical linear models for total nitrogen (TN), total phosphorus (TP), stoichiometry (TN:TP), and Chl. Both the slopes (percent change per year) and intercepts (value in 1990) were allowed to vary by lake and region. Across all lakes, TN declined at a rate of 1.1% year−1, while TP, TN:TP, and Chl did not change. A minority (7%–16%) of individual lakes had changing nutrients, stoichiometry, or Chl. Of those lakes that changed, we found differences in the geospatial variables that were most related to the observed change in the response variables. For example, TN and TN:TP trends were related to region-level drivers associated with atmospheric deposition of N; TP trends were related to both lake and region-level drivers associated with climate and land use; and Chl trends were found in regions with high air temperature at the beginning of the study period. We conclude that despite large environmental change and management efforts over recent decades, water quality of lakes in the Midwest and Northeast U.S. has not overwhelmingly degraded or improved.

Production in many ecosystems is co-limited by multiple elements. While a known suite of drivers associated with nutrient sources, nutrient transport, and internal processing controls concentrations of phosphorus (P) and nitrogen (N) in lakes, much less is known about whether the drivers of single nutrient concentrations can also explain spatial or temporal variation in lake N:P stoichiometry. Predicting stoichiometry might be more complex than predicting concentrations of individual elements because some drivers have similar relationships with N and P, leading to a weak relationship with their ratio. Further, the dominant controls on elemental concentrations likely vary across regions, resulting in context dependent relationships between drivers, lake nutrients and their ratios. Here, we examine whether known drivers of N and P concentrations can explain variation in N:P stoichiometry, and whether explaining variation in stoichiometry differs across regions. We examined drivers of N:P in ~2,700 lakes at a sub-continental scale and two large regions nested within the sub-continental study area that have contrasting ecological context, including differences in the dominant type of land cover (agriculture vs. forest). At the sub-continental scale, lake nutrient concentrations were correlated with nutrient loading and lake internal processing, but stoichiometry was only weakly correlated to drivers of lake nutrients. At the regional scale, drivers that explained variation in nutrients and stoichiometry differed between regions. In the Midwestern U.S. region, dominated by agricultural land use, lake depth and the percentage of row crop agriculture were strong predictors of stoichiometry because only phosphorus was related to lake depth and only nitrogen was related to the percentage of row crop agriculture. In contrast, all drivers were related to N and P in similar ways in the Northeastern U.S. region, leading to weak relationships between drivers and stoichiometry. Our results suggest ecological context mediates controls on lake nutrients and stoichiometry. Predicting stoichiometry was generally more difficult than predicting nutrient concentrations, but human activity may decouple N and P, leading to better prediction of N:P stoichiometry in regions with high anthropogenic activity.

Background Carfilzomib is a second-generation irreversible proteasome inhibitor that is efficacious in the treatment of myeloma and carries less risk of peripheral neuropathy than first-generation proteasome inhibitors, making it more amenable to combination therapy. Methods and findings The Myeloma XI+ trial recruited patients from 88 sites across the UK between 5 December 2013 and 20 April 2016. Patients with newly diagnosed multiple myeloma eligible for transplantation were randomly assigned to receive the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) or a triplet of lenalidomide, dexamethasone, and cyclophosphamide (Rdc) or thalidomide, dexamethasone, and cyclophosphamide (Tdc). All patients were planned to receive an autologous stem cell transplantation (ASCT) prior to a randomisation between lenalidomide maintenance and observation. Eligible patients were aged over 18 years and had symptomatic myeloma. The co-primary endpoints for the study were progression-free survival (PFS) and overall survival (OS) for KRdc versus the Tdc/Rdc control group by intention to treat. PFS, response, and safety outcomes are reported following a planned interim analysis. The trial is registered (ISRCTN49407852) and has completed recruitment. In total, 1,056 patients (median age 61 years, range 33 to 75, 39.1% female) underwent induction randomisation to KRdc (n = 526) or control (Tdc/Rdc, n = 530). After a median follow-up of 34.5 months, KRdc was associated with a significantly longer PFS than the triplet control group (hazard ratio 0.63, 95% CI 0.51–0.76). The median PFS for patients receiving KRdc is not yet estimable, versus 36.2 months for the triplet control group (p < 0.001). Improved PFS was consistent across subgroups of patients including those with genetically high-risk disease. At the end of induction, the percentage of patients achieving at least a very good partial response was 82.3% in the KRdc group versus 58.9% in the control group (odds ratio 4.35, 95% CI 3.19–5.94, p < 0.001). Minimal residual disease negativity (cutoff 4 × 10−5 bone marrow leucocytes) was achieved in 55% of patients tested in the KRdc group at the end of induction, increasing to 75% of those tested after ASCT. The most common adverse events were haematological, with a low incidence of cardiac events. The trial continues to follow up patients to the co-primary endpoint of OS and for planned long-term follow-up analysis. Limitations of the study include a lack of blinding to treatment regimen and that the triplet control regimen did not include a proteasome inhibitor for all patients, which would be considered a current standard of care in many parts of the world. Conclusions The KRdc combination was well tolerated and was associated with both an increased percentage of patients achieving at least a very good partial response and a significant PFS benefit compared to immunomodulatory-agent-based triplet therapy. Trial registration ClinicalTrials.gov ISRCTN49407852., Graham Jackson and co-workers study a combination induction treatment including carfilzomib for patients with transplant-eligible myeloma., Author summary Why was this study done? Although outcomes for myeloma patients have improved over recent decades, many patients will eventually relapse, and finding new treatment regimens that keep patients in first remission for longer is imperative. Treatment combinations aim to target myeloma using different mechanisms of action. This aims to prevent resistant cells remaining and leading to relapse. Carfilzomib has been shown to be effective in the treatment of relapsed myeloma when given in combination with lenalidomide. We performed this study to compare the outcomes of newly diagnosed myeloma patients treated with the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) to those of patients treated with immunomodulatory-agent-based triplet control combinations. What did the researchers do and find? A total of 1,056 patients with newly diagnosed myeloma were randomised between KRdc and control. Patients receiving the quadruplet KRdc combination were more likely to achieve at least a very good partial response and had longer progression-free survival than patients receiving control treatments. Side effects were not significantly increased with the quadruplet combination compared to control. What do the findings mean? The results suggest that KRdc can elicit deep responses and long periods of progression-free survival with tolerable side effects in newly diagnosed myeloma patients. Further studies are needed to compare KRdc to combinations of other new agents for the treatment of newly diagnosed myeloma patients.

Evidence suggests that lakes are important sites for atmospheric CO 2 exchange and so play a substantial role in the global carbon budget. Previous research has 2 weaknesses: (1) most data have been collected only during the open-water or summer seasons, and (2) data are concentrated principally on natural lakes in northern latitudes. Here, we report on the full annual cycle of atmospheric CO 2 exchanges of 15 oligotrophic to eutrophic reservoirs in the Glacial Till Plains of the United States. With one exception, these reservoirs showed an overall loss of CO 2 during the year, with most values within the lower range reported for temperate lakes. There was a strong cross-system seasonal pattern: an average of 70% of total annual CO 2 efflux occurred by the end of spring mixis; some 20% of annual flux was reabsorbed during summer stratification; and the remaining 50% of efflux was lost during autumnal mixing. Net annual flux was negatively correlated with depth and positively correlated with both water residence time and DOC, with the smallest annual CO 2 efflux measured in shallow fertile impoundments. Strong correlations yield relationships allowing regional up-scaling of CO 2 evasion. Understanding lacustrine CO 2 uptake and evasion requires seasonal analyses across the full range of lake trophic states and morphometric attributes.

Lentic ecosystems are important agents of local and global carbon cycling, but their contribution varies along gradients of dissolved organic matter (DOM) and productivity. We investigated how contrasting summer and autumn precipitation can shape annual and inter-annual variation in ecosystem carbon (C) flux (gross primary production (GPP), ecosystem respiration (ER), and CO2 efflux) in two subtropical lakes differing substantially in trophic state and water color. Instrumented buoys recorded time series of free-water DO, terrestrial DOM (tDOM), chlorophyll a, water temperature profiles, and meteorological measurements over five years (2009–2011 and 2014–2015). Reduced precipitation caused immediate and prolonged effects on C flux in both lakes. During the drought year (2014) GPP and ER declined by 60 to 80% and both lakes were either CO2 sinks or neutral. In the subsequent wet year (2015), GPP and ER increased by 40 to 110%, and both lakes shifted to strong net CO2 emitters. Higher ecosystem R resulted from larger GPP while higher tDOM contributed to a dramatic increase in dissolved inorganic carbon, which intensified CO2 emission in both lakes. C flux was more responsive in the clear mesotrophic lake, declining by approximately 40% in the cumulative GPP and ER, and increasing by >400% in CO2 efflux whereas changes in the oligotrophic colored lake were more modest (approximately 30% and 300% for metabolic declines and efflux increases, respectively). Temporal variation and magnitude of C flux were governed by tDOM-mediated changes in epilimnetic nutrient levels and hypolimnetic light availability. This study demonstrated terrestrial loads of DOM strongly influence the inter-annual response and sensitivity of ecosystem C flux to variation in inter-annual precipitation. Our findings have important implications for predicting the trend, magnitude, duration, and sensitivity of the response of C flux in subtropical lakes/reservoirs to future changes in precipitation patterns under altered climatic conditions.

The emergence of treatment resistant sub-clones is a key feature of relapse in multiple myeloma. Therapeutic attempts to extend remission and prevent relapse include maximizing response and the use of maintenance therapy. We used whole exome sequencing to study the genetics of paired samples taken at presentation and at relapse from 56 newly diagnosed patients, following induction therapy, randomized to receive either lenalidomide maintenance or observation as part of the Myeloma XI trial. Patients included were considered high risk, relapsing within 30 months of maintenance randomization. Patients achieving a complete response had predominantly branching evolutionary patterns leading to relapse, characterized by a greater mutational burden, an altered mutational profile, bi-allelic inactivation of tumor suppressor genes, and acquired structural aberrations. Conversely, in patients achieving a partial response, the evolutionary features were predominantly stable with a similar mutational and structural profile seen at both time points. There were no significant differences between patients relapsing after lenalidomide maintenance versus observation. This study shows that the depth of response is a key determinant of the evolutionary patterns seen at relapse. This trial is registered at clinicaltrials.gov identifier: 01554852.

Introduction: Multiple myeloma (MM) is more common in men than women but the mechanism(s) driving this are not understood. In our previous study (Myeloma IX) we found sex disparities in the cytogenetic lesions present in myeloma cells at the time of diagnosis and that female sex was associated with reduced overall survival in the context of treatment with traditional chemotherapy (CVAMP/MP) and thalidomide combinations. Here, we evaluate sex differences in almost 4000 patients recruited to the UK NCRI Myeloma XI trial, in which treatment exposure to lenalidomide predominated. Methods: Myeloma XI recruited newly diagnosed patients of all ages, with pathways for transplant eligible (TE) and ineligible (TNE) patients. An induction randomisation compared the triplet combination of cyclophosphamide, lenalidomide and dexamethasone to a similar combination with thalidomide (CRD vs CTD). Eligible patients underwent autologous stem cell transplant (ASCT) and in both pathways a maintenance randomisation compared lenalidomide (+/-vorinostat) until disease progression versus observation. We compared baseline characteristics of males and females using Fisher's Exact test for categorical characteristics and the Wilcoxon-Mann-Whitney test for continuous characteristics with p1 lesion present. Results: Of 3894 patients enrolled in the trial 2268 (58%) were male and 1626 (42%) were female, in keeping with the known sex disparity in MM. There was no difference in the median age, WHO performance status, ethnicity and most laboratory values of the two groups. Females were more likely to have the molecular risk lesions t(14;16) and del(17p) and had proportionately more HiR and UHiR disease, Table 1. Despite these differences, PFS and OS from induction randomisation did not significantly differ (PFS: Males 25 months, [95% CI 24, 26], Females 24 months, [95% CI 22, 25] and OS: Males 67 months, [95% CI 62, 70], Females 70 months, [95% CI 64, 74]). Molecular lesions that have been associated with outcome remained prognostic in both sexes, with a stepwise reduction in PFS and OS with cumulative risk lesions. PFS: Males SR 29 months, HiR 23 months, UHiR 16 months (p < 0.0001), Females SR 27 months, HiR 18 months, UHiR 17 months (p = 0.0007); OS: Males SR 77 months, HiR 59 months, UHiR 34 months (p < 0.0001), Females SR 82 months, HiR 54 months, UHiR 41 months (p < 0.0001). There was, however, no significant difference in PFS or OS when we compared males and females with a given cytogenetic lesion or cytogenetic risk. There was a significant difference in the proportion of patients of either sex who continued through the trial and underwent ASCT in the TE pathway (Males 72%, Females 67%; p = 0.031), but no significant difference in those that entered the maintenance randomisation (TE: Males 56%, Females 50%, p = 0.107; TNE Males 45%, Females 42%, p = 0.249). There was no significant PFS or OS difference by sex when analysed within each treatment pathway (TE, TNE), induction regimen (CTD, CRD) and maintenance approach (lenalidomide maintenance, observation). Conclusions: Females had a higher proportion of the adverse molecular risk lesions del(17p) and t(14;16) and were more likely to have HiR and UHiR disease. In the context of Myeloma XI trial treatment this did not correspond to a difference in PFS or OS, either overall or within the induction or maintenance randomisation treatment options (even though males were more likely to undergo ASCT). This suggests that in women the treatment delivered may have been able to overcome some of the adverse effect of the risk lesions present or that other factors affecting outcome were more important. on behalf of the NCRI Haematological Oncology Clinical Studies Group. Disclosures Cairns: Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Davies:Janssen, Celgene: Other: Research Grant, Research Funding; Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor. Boyd:Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Honoraria, Speakers Bureau. Drayson:Abingdon Health: Consultancy, Equity Ownership. Gregory:Abbvie, Janssen: Honoraria; Amgen, Merck: Research Funding; Celgene: Consultancy, Research Funding. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jones:Celgene: Honoraria, Research Funding. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Owen:Celgene, Janssen: Honoraria; Celgene, Janssen: Consultancy; Celgene: Research Funding; Janssen: Other: Travel expenses. Russell:DSI: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau. Morgan:Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses; Celgene Corporation, Janssen: Research Funding. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Pawlyn:Amgen, Celgene, Takeda: Consultancy; Amgen, Janssen, Celgene, Takeda: Other: Travel expenses; Amgen, Celgene, Janssen, Oncopeptides: Honoraria. OffLabel Disclosure: CTD/CRD induction therapy for myeloma, Lenalidomide maintenance 10mg 21/28 days

Background Early trials of long-term lenalidomide (len) use reported an increased incidence of second primary malignancy (SPM), particularly AML and MDS. Later, meta-analysis suggested the link to be secondary to len in combination with melphalan. Myeloma XI is a large phase III randomised trial in-which len is used as an induction and maintenance therapy. We have previously reported on early SPM incidence in the context of this trial and shown that haematological SPM (hSPM) incidence was not increased in association with len (Cumulative incidence 0.7% at 3 years). We have also published data showing that maintenance len is associated with improved survival in post-transplant patients. Here we present for the first time, a long-term analysis of SPM incidence in 4358 patients who have received maintenance therapy versus observation in the context of the Myeloma XI trial. Methods Myeloma XI is a phase III, randomised, multi-centre, parallel group design, open-label trial comparing thalidomide, len, carfilzomib and bortezomib combinations and len as maintenance treatment in NDMM patients. The trial includes transplant eligible (TE) and transplant non-eligible (TNE) pathways. TE patients received high dose melphalan supported by autologous stem cell transplantation if they achieve a very good partial response or better. Patients in both pathways were randomised to maintenance with len (+/- vorinostat) or active observation. Since May 2010, 4358 patients have been treated and assigned to induction. Median follow up is now 68 months (IQ range 49-83), with over 1100 patients enrolled for more than 5 years. A total of 1971 patients have entered maintenance with 1137 randomised to len and 834 observation (median 24 cycles (range 1-97)). Results The median time to SPM development from induction is 41.6 months (range 1.4 - 97.1). Cumulative incidence of all SPMs is 4.1% (95% CI 3.5, 4.7), 7.4% (6.6, 8.3) and 10.8% (9.5, 12.1) at three, five and seven years respectively (figure 1). 378 SPMs have been reported in 318 patients, 180 (57%) treated in the TNE pathway (IR 9.9%) and 138 (43%) in the TE pathway (IR 5.5%). The average age at the time of SPM is 78 and 68 for the TNE and TE pathways, respectively. Of the patients who developed an SPM 195 (61%) did so following maintenance randomisation. The incidence was highest in those receiving len based maintenance (n=145, IR 10.8%). In the observation arm 50 patients developed an SPM (IR 5.6%). The median time to SPM development from maintenance randomisation was 43 months in those receiving len and 40 months in the observation only group. One hundred and ten of the patients who developed an SPM following maintenance randomisation were in the TNE pathway with 77 patients receiving len. The overall incidence of SPM development in TNE patients receiving len maintenance is 15.4% and 9.9% for observation. Within the TE arm 85 SPM cases developed following maintenance randomisation with 68 patients receiving len. The overall incidence of SPM development in the TE patients treated with len maintenance is 7.7% and 3.1% for observation. Of the remaining patients 98, (31%) developed an SPM during induction and twenty five (8%) following induction but prior to maintenance. Forty eight patients developed a hSPM (IR 1.1%), MDS (n=20), AML (n=13), BLCBL (n=6), B-ALL (n=4), CML (n=1), mixed phenotype leukaemia (n=1), T-ALL (n=1), Burkitt lymphoma (n=1) and Hodgkin's Lymphoma (n=1). Of these cases, 35 patients were TE pathway treated, with 25 receiving lenlidomide maintenance (IR 2.8%). The median time to hSPM development in the TE patients was 51.8 months. The remaining 13 cases occurred in the TNE treated patients with 7 receiving lenalidomide maintenance (IR 1.4%). The median time to hSPM development in the TNE patients was 42.3 months. Of the remaining cases, 107 patients developed non-melanoma skin cancers (NMSC) (TE n34, IR 1.3% / TNE n73, IR 4.0%) and 181 patients developed solid tumours (TE n78, IR 3.1% / TNE n103, IR 5.6%). Forty one patients developed >1 SPM. Outcome analysis is underway and will be presented at the meeting. Conclusions The overall incidence of SPM is highest in TNE patients receiving lenalidomide maintenance but hSPM rates remain low. This suggests that advanced age is a considerable risk factor for the development of second cancers, particularly NMSC. Second haematological cancers were low in all groups, irrespective of maintenance allocation. Disclosures Jones: Celgene: Honoraria, Research Funding. Cairns:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Pawlyn:Amgen, Celgene, Takeda: Consultancy; Amgen, Celgene, Janssen, Oncopeptides: Honoraria; Amgen, Janssen, Celgene, Takeda: Other: Travel expenses. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Mottram:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Drayson:Abingdon Health: Consultancy, Equity Ownership. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau. Gregory:Amgen, Merck: Research Funding; Abbvie, Janssen: Honoraria; Celgene: Consultancy, Research Funding. Owen:Celgene, Janssen: Honoraria; Celgene, Janssen: Consultancy; Celgene: Research Funding; Janssen: Other: Travel expenses. Boyd:Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Morgan:Celgene Corporation, Janssen: Research Funding; Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses.

Background: Immunomodulatory (IMiD) compounds are effective therapies for multiple myeloma (MM) acting via modulation of the CUL4 E3-ubiquitin ligase cereblon. Based on their structure individual IMiD compounds have different substrate specificities altering both their efficacy and side effect profile. These mechanistic differences impact the optimum sequencing of these agents as induction and maintenance. Within the UK NCRI Myeloma XI trial we compared triplet induction regimens containing Lenalidomide (Len) or Thalidomide (Thal) and maintenance treatment with Len or observation. With extensive long term follow up data we have explored the interaction of the induction and maintenance use of Thal and Len before and after ASCT. Methods: Myeloma XI is a multicenter, randomized controlled trial for newly diagnosed MM, with pathways for transplant eligible (TE) and non-eligible patients. TE patients were randomized between Len or Thal plus cyclophosphamide and dexamethasone (CRD vs CTD) continued for a minimum of 4 cycles and to max. response. For patients with a suboptimal response there was a subsequent randomization to intensification with a proteasome inhibitor containing triplet or no further therapy prior to ASCT. A maintenance randomization at 3 months post ASCT compared Len till disease progression vs observation (Obs). Analyses by molecular risk strata were pre-specified in the protocol. Adverse cytogenetic abnormalities were defined as gain(1q), t(4;14), t(14;16), t(14;20), or del(17p): standard risk (SR, no adverse cytogenetic abnormalities), high risk (HiR, one adverse cytogenetic abnormality), or ultra-high risk (UHiR, two or more adverse cytogenetic abnormalities). Results: 2042 TE patients were randomized to CRD n=1021 and CTD n=1021. After a median follow up of 68 months (interquartile range 49-83) for the induction randomization, 1378 PFS and 728 OS primary endpoint events had occurred. Patients received a median (range) of 5 (1-18) cycles of CRD and 5 (1-13) cycles of CTD induction therapy. There were higher rates of haematological toxicity with CRD and peripheral neuropathy with CTD. CRD induction was associated with a significantly improved median PFS (hazard ratio (HR) 0.86, 95%CI 0.77, 0.96, CRD 36 months vs CTD 33 months, P=0.005, Figure 1A) and median OS (HR 0.81, 95%CI 0.70, 0.93, CRD 96 months vs CTD 85 months, P=0.004, Figure 1B). Responses were deeper with CRD (>=VGPR 65.3%, PR 24.5%) than CTD (>=VGPR 52.8%, PR 33.2%) and depth of response was associated with outcome. Significant heterogeneity in PFS outcome was identified between molecular risk groups with HiR and UHiR benefiting most from induction with CRD rather than CTD (SR HR 0.99 [95%CI 0.79, 1.24], HiR HR 0.58 [0.44, 0.78], UHiR HR 0.60 [0.38, 0.94], P.het 0.01). 897 TE patients were randomized to Len (n=496) and Obs (n=401). After a median follow up of 68 months (interquartile range 51-84) for the maintenance randomization, 527 PFS primary endpoint events had occurred. Lenalidomide was associated with a significant improvement in PFS compared to observation (median PFS Len 64 [54,76] vs Obs 32 [28,36], HR 0.52 [0.45,0.61], P Optimum outcomes were seen in those receiving Len as both induction and maintenance therapy (Figure 1C). Patients receiving CRD induction followed by Len maintenance (CRD-R) had a median PFS of 77 months [56, 86] compared to CTD-R 64 [49, 74], CRD-Obs 37 [33, 42] and CTD-Obs 44 [38, 51]. Conclusions: In this study the use of Len as both induction and maintenance was associated with the best outcomes irrespective of cytogenetic risk group. With long term follow up CRD induction for newly diagnosed transplant eligible myeloma patients was associated with both a PFS and OS benefit compared to CTD and was better tolerated. The PFS impact of CRD was particularly notable in patients with high and ultra-high risk disease. Lenalidomide maintenance was associated with significantly longer PFS than observation across all risk groups. on behalf of the NCRI Haematological Oncology Clinical Studies Group Disclosures Jackson: Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Pawlyn:Amgen, Celgene, Janssen, Oncopeptides: Honoraria; Amgen, Celgene, Takeda: Consultancy; Amgen, Janssen, Celgene, Takeda: Other: Travel expenses. Cairns:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Jones:Celgene: Honoraria, Research Funding. Kishore:Celgene, Takeda, Janssen: Honoraria, Speakers Bureau; Celgene, Jazz, Takeda: Other: Travel expenses. Garg:Janssen, Takeda, Novartis: Other: Travel expenses; Janssen: Honoraria; Novartis, Janssen: Research Funding. Lindsay:Celgene: Other: personal fees and non-financial support ; Takeda: Other: personal fees and non-financial support ; Amgen: Other: non-financial support. Russell:Jazz: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Drayson:Abingdon Health: Consultancy, Equity Ownership. Owen:Janssen: Other: Travel expenses; Celgene, Janssen: Honoraria; Celgene, Janssen: Consultancy; Celgene: Research Funding. Gregory:Abbvie, Janssen: Honoraria; Celgene: Consultancy, Research Funding; Amgen, Merck: Research Funding. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding. Morgan:Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses; Celgene Corporation, Janssen: Research Funding. OffLabel Disclosure: CTD/CRD induction therapy and Lenalidomide maintenance 10mg 21/28 days