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This version of the article has been accepted for publication, after peer review and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at https://doi.org/10.1007/s13225-021-00493-7. Fungi are highly important biotic components of terrestrial ecosystems, but we still have a very limited understanding about their diversity and distribution. This data article releases a global soil fungal dataset of the Global Soil Mycobiome consortium (GSMc) to boost further research in fungal diversity, biogeography and macroecology. The dataset comprises 722,682 fungal operational taxonomic units (OTUs) derived from PacBio sequencing of full-length ITS and 18S-V9 variable regions from 3200 plots in 108 countries on all continents. The plots are supplied with geographical and edaphic metadata. The OTUs are taxonomically and functionally assigned to guilds and other functional groups. The entire dataset has been corrected by excluding chimeras, index-switch artefacts and potential contamination. The dataset is more inclusive in terms of geographical breadth and phylogenetic diversity of fungi than previously published data. The GSMc dataset is available over the PlutoF repository.

SummaryFungi play pivotal roles in ecosystem functioning, but little is known about their global patterns of diversity, endemicity, vulnerability to global change drivers and conservation priority areas. We applied the high-resolution PacBio sequencing technique to identify fungi based on a long DNA marker that revealed a high proportion of hitherto unknown fungal taxa. We used a Global Soil Mycobiome consortium dataset to test relative performance of various sequencing depth standardization methods (calculation of residuals, exclusion of singletons, traditional and SRS rarefaction, use of Shannon index of diversity) to find optimal protocols for statistical analyses. Altogether, we used six global surveys to infer these patterns for soil-inhabiting fungi and their functional groups. We found that residuals of log-transformed richness (including singletons) against log-transformed sequencing depth yields significantly better model estimates compared with most other standardization methods. With respect to global patterns, fungal functional groups differed in the patterns of diversity, endemicity and vulnerability to main global change predictors. Unlike α-diversity, endemicity and global-change vulnerability of fungi and most functional groups were greatest in the tropics. Fungi are vulnerable mostly to drought, heat, and land cover change. Fungal conservation areas of highest priority include wetlands and moist tropical ecosystems.

This paper explores the thinking and practice of ‘action inquiry’ an embedded learning practice that can help navigate complexity when practising change together. The paper uses examples from socia...

15 páginas.- 6 figuras.- 93 referencias, Fungi are highly diverse organisms, which provide multiple ecosystem services. However, compared with charismatic animals and plants, the distribution patterns and conservation needs of fungi have been little explored. Here, we examined endemicity patterns, global change vulnerability and conservation priority areas for functional groups of soil fungi based on six global surveys using a high-resolution, long-read metabarcoding approach. We found that the endemicity of all fungi and most functional groups peaks in tropical habitats, including Amazonia, Yucatan, West-Central Africa, Sri Lanka, and New Caledonia, with a negligible island effect compared with plants and animals. We also found that fungi are predominantly vulnerable to drought, heat and land-cover change, particularly in dry tropical regions with high human population density. Fungal conservation areas of highest priority include herbaceous wetlands, tropical forests, and woodlands. We stress that more attention should be focused on the conservation of fungi, especially root symbiotic arbuscular mycorrhizal and ectomycorrhizal fungi in tropical regions as well as unicellular early-diverging groups and macrofungi in general. Given the low overlap between the endemicity of fungi and macroorganisms, but high conservation needs in both groups, detailed analyses on distribution and conservation requirements are warranted for other microorganisms and soil organisms., The bulk of the funding is derived from the Estonian Science Foundation (grants PRG632, PRG1170, PRG1615, MOBTP198), EEA Financial Mechanism Baltic Research Programme (EMP442), and Novo Nordisk Fonden (NNF20OC0059948).

Emil Holub was a nineteenth century, Austro-Hungarian Czech, medical doctor with wide-ranging interests in ethnography and the natural sciences. During visits to southern Africa in the 1870s, he meticulously recorded everything that he encountered. Amongst his vast collection of artifacts, natural history specimens and notes were several sketches of fungi. These illustrations are reproduced here to document this valuable historical knowledge, tentatively identifying them in the context of the habitats through which Holub travelled.

This book has an important ambition. It seeks to discuss the pitfalls and challenges of action learning and action research, to demystify them and better understand why they have been misunderstood...

Introduction Bortezomib plus lenalidomide and dexamethasone (VRD) is a standard induction therapy for newly diagnosed multiple myeloma (NDMM) patients. Given preclinical and clinical data suggesting the synergistic activity of the histone deacetylase inhibitor vorinostat with both bortezomib and lenalidomide for the treatment of multiple myeloma, we hypothesized that adding vorinostat to VRD (R2V2) would increase the rate and the quality of responses to induction treatment. Here we report the results of a phase 1 trial (NCT01038388) evaluating R2V2 as up-front treatment for NDMM patients. Patients and Methods R2V2 was tested as induction therapy in a dose-escalation phase 1 study in 30 NDMM patients deemed eligible for autologous stem-cell transplantation. Treatment consisted of 4 induction cycles with R2V2, followed by either autologous stem-cell transplantation or 4 additional R2V2 cycles and lenalidomide maintenance therapy. Results The maximum tolerated dose of vorinostat was 200 mg daily. The most common adverse events were gastrointestinal (87%), fatigue and peripheral neuropathy (60%), and thrombocytopenia (33%). R2V2 induced an objective response in 96% of patients, with 48% obtaining at least a complete remission. Median progression-free survival was 52 months, with 77% of patients alive at 5 years. Conclusion R2V2 as induction treatment for NDMM patients resulted in remarkable response rates at the cost of increased toxicity.

This paper develops understanding of appreciative action research that generates curiosity and motivation as a better platform for collaborative change. Blending theory and practice it draws on the example of the My Home Life leadership programme in Scotland that explores the concepts and approaches of ‘Caring Conversations’ and ‘playful provocation’ in care homes for older people. The paper shows how they expand notions of appreciation and help people to deepen inquiry, explore values, acknowledge and express emotion without dispute or judgement, articulate tacit knowledge and give voice to things previously thought to be ‘unsayable’. We explore how these generative approaches act as a powerful positive ‘disruption’ that brings existing relationships to life, supports a positive attitude to risk-taking and helps to devise new approaches to the local design and testing of approaches to problems. Ultimately these approaches play an important part in developing understanding of how to do appreciative action research to enhance relationships and more strengths or assets-based and collaborative ways of working and so, to develop new possibilities for changing social systems and a more future-making orientation to action research.

Leadership is key to quality improvement in nursing homes. This article reports on the initial analysis of the transformational My Home Life Leadership Support program for nursing home managers being implemented in Scotland. It analyses learning from a multimethod participatory descriptive study. Contribution analysis theory informed the evaluation. Evidence-Based Practice, Relationship-Centered Care, Appreciative Inquiry, and Caring Conversations informed the intervention to develop transformational leadership. Data generation methods included baseline and postintervention questionnaires to describe culture change within the study population, together with more in-depth qualitative data generated from group discussions throughout the leadership support program. Qualitative data analysis was an iterative collaborative process with participants to generate themes about the impact of the program on themselves and their practice. Data showed positive changes in managers' perceptions of their self-awareness, leadership communication and relationship skills, and development of positive cultures. This model offers lessons for those interested in ways to approach the emotional, educational, and cultural dynamics of change in other human service contexts.

Proteasome (PIs) and hystone deacetylase inhibitors (HDACis) have previously shown synergistic activity in the treatment of relapesed/refractory multiple myeloma (RRMM) patients. In this phase 1 study, we combined carfilzomib, a second generation PI, with panobinostat, a HDACi, to determine the maximum tolerated dose (MTD) of the combination (CarPan) and assess safety and efficacy among RRMM patients. Thirty-two patients (median of 4 prior lines of therapy) were enrolled. The MTD was carfilzomib 36 mg/m2 (on days 1, 2, 8, 9, 15, and 16) and panobinostat 20 mg (TIW, 3 weeks on/1 week off, every 28 days), administered until progression. At the MTD, the most common grade 3/4, treatment-related adverse events were thrombocytopenia (41%), fatigue (17%), and nausea/vomiting (12%). The objective response rate (ORR) and clinical benefit rate were 63% and 68%, respectively. Median progression-free survival (PFS) and overall survival (OS) for the entire population were 8 and 23 months, respectively. No differences in terms of ORR (55% vs. 57%), median PFS (months 8 vs. 7 months) and OS (24 vs. 22 months) were observed between bortezomib-sensitive and -refractory patients. CarPan proved to be a safe and effective steroid-sparing regimen in a heavily pre-treated population of MM patients. (Trial registered at ClinicalTrial.gov: NCT01549431), Key points CarPan is a highly active, steroid-sparing regimen, effective in both bortezomib-sensitive and refractory patients.The safety profile of CarPan, particularly thrombocytopenia and gastrointestinal adverse events, compares favorably with that of panobinostat and bortezomib.

Carfilzomib (Kyprolis®), a second generation proteasome inhibitor, is FDA approved for single-agent use among relapsed/refractory multiple myeloma (MM). To enhance the therapeutic efficacy of carfilzomib, we sought to combine carfilzomib with other novel agents. TG02, a multi-kinase inhibitor, targets JAK2 and CDK9. The rationale for co-treatment with carfilzomib and TG02 is that both independently target Mcl-1 and most myeloma cells are dependent on this anti-apoptotic protein for survival. We observed at least additive effects using the combination treatment in MM cell lines and patient samples. To determine how the bone marrow environment affects the efficacy of the combination we conducted co-culture experiments with Hs-5 stromal cells. We also examined the mechanism of increased apoptosis by determining the affect on expression of the Bcl-2 family of proteins. We found that carfilzomib increases NOXA mRNA expression, as expected, and TG02 treatment caused a decrease in Mcl-1 protein but not mRNA levels. Consistent with this possibility, we find silencing CDK9 does not change carfilzomib sensitivity in the same manner as addition of TG02. Since changes in Mcl-1 protein occur in the presence of a proteasome inhibitor we hypothesize that regulation of Mcl-1 translation is the most likely mechanism. Taken together our data suggest that dual inhibition of Mcl-1 via decreased expression and the induction of its antagonist NOXA by the combination of carfilzomib and TG02 is active in myeloma and warrants further testing preclinically and in clinical trials. Moreover, regulation of Mcl-1 by TG02 is more complex than initially appreciated.

Does the world need yet another book on organisational change? Our bookshelves are crowded, our time is short. By starting with this question the authors set the bar high. From the perspective of a...

Domestic violence has been recognized as a major contributory factor to homelessness in the UK and elsewhere, with women more likely to be affected. In the UK and other countries undergoing welfare reform, moves toward 'active citizenship' increase the complexity of the relationship between states and citizens and open up new strategies for both. However, analysts have noted some strategies can create new forms of inequality, including gender-based ones. This article considers the impact of prevention-centred homelessness policy responses to domestic violence, with specific reference to the 'Sanctuary' model. Sanctuary schemes support women facing homelessness due to domestic violence to remain in their current residence, protected against attack from outside the home. Drawing on analysis of the literature and empirical work, we compare the experiences of women who have used traditional forms of support and Sanctuary services. We argue that while the model has the potential to provide greater autonomy to some women in these circumstances, it is not appropriate for all. Increased emphasis on Sanctuary schemes could make it more difficult for women who might prefer to move. We conclude that more attention needs to be paid to addressing the origin of women's homelessness due to domestic violence.

This article discusses the use of action learning as a structured and deliberate learning process to support practitioners to implement change in an action research project. It discusses both action learning and action research before describing the context of the study. The article then goes on to discuss how the process of action learning contributed significantly to dimensions of the research process. This included enhancing the quality of the data collected about both the process of change and the issue of end of life care, making learning a deliberate process and enhancing the skills of participants as co‐researchers. It concludes by stressing the potential of action learning to generate and transfer knowledge into practice through the development of a community of inquiry within a community of practice.

Fungi play major roles in ecosystem processes, but the determinants of fungal diversity and biogeographic patterns remain poorly understood. Using DNA metabarcoding data from hundreds of globally distributed soil samples, we demonstrate that fungal richness is decoupled from plant diversity. The plant-to-fungus richness ratio declines exponentially toward the poles. Climatic factors, followed by edaphic and spatial variables, constitute the best predictors of fungal richness and community composition at the global scale. Fungi show similar latitudinal diversity gradients to other organisms, with several notable exceptions. These findings advance our understanding of global fungal diversity patterns and permit integration of fungi into a general macroecological framework.

Cedar (Children Experiencing Domestic Abuse Recovery) provides a therapeutic 12-week group work programme for children and young people in recovery from domestic abuse, alongside a concurrent group work programme for their mothers. The programme is an evidence-based approach originally developed in Canada (Marshall et al., 1995).

Introduction: Patients with myeloma ultimately become refractory to current therapies, requiring new approaches to treatment. Carfilzomib is a second generation proteasome inhibitor that has demonstrated significant activity in patients with relapsed and refractory disease. Panobinostat is a pan-deacetylase inhibitor that has been shown to be effective and overcome resistance in combination with bortezomib in refractory patients. In addition, patients treated with a combination of bortezomib/dexamethasone/panobinostat had a significant improvement in progression free survival (PFS) compared to bortezomib/dexamethasone alone. Based on preclinical data supporting combined HDAC and proteasome inhibition, we hypothesized that carfilzomib and panobinostat would be safe and effective in relapsed/refractory myeloma patients. Herein we report the initial findings of the MMRC multicenter phase I study of the combination. Methods: The primary objective is to determine the maximum tolerated dose (MTD) of the combination of panobinostat and carfilzomib using a standard 3+3 alternate dose escalation design with 4 cohorts. An additional 12 patient expansion group will be treated at the MTD to further assess the activity and safety of the combination. Secondary objectives are to evaluate the extended safety of this combination and to assess response, response duration and progression free survival (PFS). Panobinostat is administered orally three times weekly for three of four weeks, ranging from 15 to 20 mg. Carfilzomib is administered IV days 1, 2, 8, 9, 15, and 16, ranging from 20/27 mg/m2 to 20/45mg/m2. Cycles are repeated every 4 weeks. Dose limiting toxicities (DLT) are determined in the first cycle, and all adverse events are assessed according to CTCAE V4. Responses are assessed using IMWG criteria (plus MRs as per the EBMT criteria). Results: To date, 20 patients in four cohorts have been enrolled and all have completed the first cycle. Median age is 64.5 years (48-75). All patients had refractory and progressive disease; with a median number of 4) prior treatment lines. Three DLTs occurred. One patient had grade 4 thrombocytopenia with grade 3 acute kidney injury, one patient developed persistent grade 4 thrombocytopenia without bleeding and one patient had grade 3 diarrhea uncontrolled by maximal medical therapy. The MTD is panobinostat 20 mg and carfilzomib 20/36 mg/m2. The most common grade 3 toxicities were hematologic. Regardless of causality, grade 3 or higher anemia, thrombocytopenia and neutropenia occurred in 35%, 35%, and 20% of patients, respectively. The most common grade 3/4 or higher nonhematologic toxicities were fatigue (15%), anorexia (10%), hyponatremia (10%) and nausea (10%). The overall response rate is 50% with 30% PRs and 20% VGPR or better. The median PFS is 14.3 months. Conclusion: The combination of carfilzomib and panobinostat is well tolerated with no unexpected toxicities. Response, durability of response, and PFS are encouraging and warrant further study. Disclosures Kaufman: Millennium: The Takeda Oncology Co.: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; Merck: Research Funding. Off Label Use: Carfilzomib treatment in amyloidosis . Zimmerman:Onyx: Honoraria. Heffner:Amgen: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Dana Farber CI: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Idera: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Spectrum: Honoraria, Research Funding; Talon Therapeutics: Honoraria, Research Funding. Harvey:Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Research Funding; Celgene: Research Funding; Acetylon: Research Funding; Amgen: Research Funding. Gleason:Celgene: Consultancy; Novartis: Consultancy. Lewis:Array BioPharma: Consultancy. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

Carfilzomib (KyprolisTM) is a proteasome inhibitor that is FDA approved for single-agent use in relapsed and refractory multiple myeloma (MM). In order to enhance the therapeutic efficacy of carfilzomib, we sought to combine carfilzomib in a rational approach with other novel agents. TG02 is a multi-kinase inhibitor known to target JAK2 and CDK9. The rationale for co-treatment with carfilzomib and TG02 is that both independently target Mcl-1 and multiple myeloma cells are dependent on this anti-apoptotic protein for survival. Four different human myeloma cell lines (HMCL), MM1.s, RPMI 8226, H929 and U266, were initially treated for 24 hours with carfilzomib, TG02 or the combination. MM1.s were the most sensitive to carfilzomib treatment (IC50 8.4 nM) and H929 were the most resistant (IC50 25.5 nM). MM1.s was also the most sensitive to TG02 treatment (IC50 197.6 nM). Co-treatment with carfilzomib and TG02 resulted in at least additive cell death in all four lines (additive in RPMI 8226 and U266, greater then additive in MM1.s and H929). Pulse dosing of carfilzomib was also preformed to better mimic the pharmacokinetics of carfilzomib in the clinic. When cells were pulsed for 1 hour with carfilzomib, then treated with TG02 for 23 hours, or pulsed with both carfilzomib and TG02, then treated with TG02 for 23 hours, similar patterns of activity were observed with continuous dosing. However, higher concentrations of carfilzomib were required to reach an IC50. Activity of the combination was also observed in freshly isolated samples from relapsed/refractory MM patients. Co-culture of HMCL with Hs-5 stromal cells or the conditioned medium from these cells had mixed results. The combination did not overcome protection by co-culture or addition of conditioned medium in RPMI 8226 or KMS18 cells, but did in MM1.s and H929 cells. Interestingly the latter two lines are where synergistic activity of the combination is observed. We next determined the molecular basis for the increased apoptosis. HMCL were treated with carfilzomib, TG02 or the combination for 24 hours. After 6 hours cells were isolated for western blot analysis and RT-qPCR to determine protein and mRNA levels of the Bcl-2 family of proteins, respectively. Consistent with our hypothesis, treatment with carfilzomib caused an increase in NOXA, an inhibitor of Mcl-1, at the mRNA level in all cell lines. TG02 treatment resulted in a decrease in Mcl-1 protein expression. However, unexpectedly we also observed an increase in NOXA mRNA with TG02 treatment alone. More surprisingly the decrease in Mcl-1 protein did not appear to be due to the predicted decrease in Mcl-1 transcription. Mcl-1 mRNA levels did not change following TG02 treatment. Since the loss of Mcl-1 at the protein level occurs in the presence of carfilzomib, the effect of TG02 is unlikely to be due to increased degradation. Therefore we reasoned that regulation of translation of Mcl-1 is the most likely mechanism and data will be presented on this. Consistent with this possibility over expression of Mcl-1 in RPMI 8226 cells confers significantly less protection than over expression of Bcl-2 or Bcl-xL. Taken together these data suggest that dual inhibition of Mcl-1 through decreased expression and induction of NOXA by the combination of carfilzomib and TG02 is active in myeloma and warrants further testing preclinically and in clinical trials. Moreover, regulation of Mcl-1 by TG02 is more complex than initially appreciated. Disclosures: Burrows: Tragara Pharmaceuticals: Employment, Equity Ownership. Kaufman:Onyx: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy; Jansenn: Consultancy; Merck: Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy. Boise:Onyx Pharmaceuticals: Consultancy.

Great strides have been made in the last 15 years in the treatment of multiple myeloma, with FDA approval of both IMIDs and proteasome inhibitors, 10-year survival rates are now achievable in around 25% of patients. However, for the remaining 75%, disease relapse due to drug resistance remains a significant clinical concern. Therefore novel therapeutic approaches to be used in combination with the current active agents are required. The Bcl-2 family of proteins regulates apoptosis and presents an exciting target for therapy. We have demonstrated that myeloma cell lines can be dependent on the anti-apoptotic protein Mcl-1 or can be co-dependent on Mcl-1 and Bcl-2/xL for survival. The distinction between Mcl-1 dependence and co-dependence is the distribution of the pro-apoptotic BH3-only protein Bim. In Mcl-1-dependent lines, Bim is primarily associated with Mcl-1. In contrast in the co-dependent lines, Bim is either predominately associated with Bcl-2/xL or when it is released from Bcl-2/xL it cannot bind to Mcl-1 because of the presence of the Mcl-1 inhibitor, Noxa. This renders these cells sensitive to the Bcl-2/xL inhibitor ABT-737. We have confirmed these findings in freshly isolated patient samples and demonstrated that among the 5 patient samples tested, Bim was associated with both Mcl-1 and Bcl-xL and the cells were sensitive to ABT-737. This suggests that co-dependence on Mcl-1 and Bcl-2/xL may be a common phenomena in myeloma. However, given the adverse effects seen with Bcl-xL inhibition, ABT-737 or the related compound Navitoclax may be difficult to use for the treatment of multiple myeloma. However, ABT-199, a Bcl-2-specific inhibitor, has been developed and we report on preclinical testing in multiple myeloma. Freshly isolated plasma cells from 3 myeloma patients were treated with either ABT-737 or ABT-199 for 24 h and IC50s for each drug were compared. In each patient sample, the plasma cells were less sensitive to ABT-199 than to ABT-737 (MM49: 199 IC50 1.4 μM vs. 737 IC50 0.9 μM; MM51: 199 IC50 0.34 μM vs. 737 IC50 0.07 μM; MM52: 199 IC50 1.3 μM vs. 737 IC50 0.25 μM), and only MM51 was truly sensitive to ABT-199. CoIP studies in MM51 revealed very little Bim bound to Mcl-1 and none bound to Bcl-xL, suggesting the majority of the Bim present in the cell must be bound to Bcl-2. These data suggest that myeloma cells are more likely to be co-dependent on Mcl-1 and Bcl-xL for survival than Mcl-1 and Bcl-2. However Bcl-2 dependence can exist in myeloma. We also performed dose curves in 4 multiple myeloma cells lines, representing 4 different Bim binding patterns and sensitivity to ABT-737. 8226, MM.1s, and KMS18 are all co-dependent cell lines (sensitive to ABT-737), while KMS11 is Mcl-1 dependent. Of these cell lines, KMS18 is the only one with the majority of Bim bound to Bcl-2, therefore should be sensitive to ABT-199. Surprisingly this was not the case. 8226 was the only cell line that was sensitive to ABT-199 (IC50 2.2 μM), while MM1.s, KMS18, and KMS11 were insensitive with IC50s of 6.2 μM, 6.8 μM, and 24.7 μM respectively. In order to gain a mechanistic understanding of these data, we performed CoIP studies to determine the pattern of Bim binding to Mcl-1, Bcl-xL, and Bcl-2 following treatment with ABT-199. We found in KMS18 cells, upon treatment, Bim is released from Bcl-2 and bound by Mcl-1 thereby preventing apoptosis. We have already demonstrated that very little Bim is bound to Bcl-2 in KMS11 and MM.1s, which is consistent with the lack of sensitivity in these cell lines. However in 8226 cells, the high expression of Noxa prevents the Bim released from Bcl-2 from binding to Mcl-1, thereby promoting apoptosis. Silencing of Noxa in this cell line raises the IC50 of ABT-199 2-fold. Next we investigated the effectiveness of combining ABT-199 with the proteasome inhibitor carfilzomib, which has been shown to be a potent inducer of Noxa. A synergistic response to this drug combination was seen in KMS18 cells. CoIP studies revealed that in the presence of Cz, the Bim released from Bcl-2 by ABT-199 could no longer bound to Mcl-1, and was free to activate Bak and Bax. Only additive responses were seen in 8226, MM.1s and KMS11 cell lines. Taken together these data suggest ABT-199 alone may only be an effective treatment for multiple myeloma in a small subset of patients. However, combining it with either Noxa inducers or Mcl-1 inhibitors could be a promising approach for the treatment of this disease. Disclosures: Kaufman: Jansenn: Consultancy; Millennium Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy; Merck: Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy. Boise:Onyx Pharmaceuticals: Consultancy.

Abstract 336 Background: The combination of lenalidomide (R), bortezomib (V), and dexamethasone (D) (RVD) in newly diagnosed MM patients is well tolerated and associated with a very high overall response rate (Richardson et al, Blood 2010; Kumar et al, Blood 2012). The addition of a novel targeted agent to RVD may improve depth of response as reflected by an increase in complete remission (CR) rate. Preclinical studies have demonstrated that vorinostat (Vor), a histone deacetylase inhibitor, is synergistic with bortezomib, immunomodulatory compounds and dexamethasone. Clinical studies in the relapsed setting using either bortezomib or lenalidomide with vorinostat have yielded promising results with manageable toxicity. The aim of this study was to determine the tolerability and activity of the combination of RVD with vorinostat in newly diagnosed patients with symptomatic MM. Methods: Patients (pts) received the classical RVD regimen (lenalidomide 25 mg days 1–14, bortezomib 1.3 mg/m2 days 1, 4, 8, 11 and dexamethasone 20/10 mg PO [cycles 1–4/5–8] days 1, 2, 4, 5, 8, 9, 11, 12 for up to 8 21 day cycles) combined with oral vorinostat (Vor), provided by Merck and Co. Inc., at 100, 200, 300 or 400 mg daily days 1 – 14 of each cycle. Pts were assigned to one of the four dosing cohorts according to the Bayesian Escalation with Overdose Control (EWOC) algorithm. Dose limiting toxicity (DLT) (Grade (G) 3 non hematologic toxicity, G4 hematologic toxicities defined as G4 thrombocytopenia of any duration; failure of recovery of neutrophils to 1,000/μL or platelets to 50,000/μL within 14 days of the last treatment; or inability to receive Day 1 dose for Cycle 2 due to continued drug-related toxicity from cycle 1) was determined in the first cycle of therapy. Toxicities were assessed and graded for all cycles using the NCI CTCAE v 3.0. Responses were assessed by modified European Group for Blood and Marrow Transplantation and Uniform Criteria. Pts with partial remission (PR) or better could proceed to autologous transplant after 4 cycles. After completion of 8 cycles, patients could continue maintenance with lenalidomide +/− bortezomib, with Vor not administered during maintenance therapy. Results: Thirty pts (median age 56 years [range 40–76], 63% men) were enrolled with 4 pts in cohort 1 (Vor 100mg), 15 pts in cohort 2 (Vor 200mg), 8 pts in cohort 3 (Vor 300 mg) and 3 pts in cohort 4 (Vor 400mg). The maximum tolerated dose was determined to be 200 mg Vor with RVD. Including maintenance, the median number of cycles completed was 4 (range Conclusion: The combination of RVD with vorinostat using the classical dose and schedule proved most tolerable at 200mg Vor dosing D1-14 every 21 days. The remarkably high VGPR/CR rate after 4 cycles and favorable progression free survival suggest that this combination is very effective. Alternative dosing and schedule of Vor may improve tolerability and so enhance clinical benefit, thus warranting further study. Disclosures: Kaufman: Onyx: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Merck: Research Funding. Off Label Use: use of vorinostat in myeloma; use of lenalidomide as induction. Shah:Novartis: Honoraria, Research Funding, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harvey:Celgene: Research Funding. Heffner:Millenium: Research Funding. Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Orlowski:Celgene: Honoraria, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lonial:Millennium, Celgene, Novartis, BMS, Onyx, Merck; all < $10,000 per year and disclosed to my institution: Consultancy.