Purpose Histone deacetylase inhibitors (HDACi) have recently emerged as efficacious therapies that target epigenetic mechanisms in hematologic malignancies. One such hematologic malignancy, B-cell acute lymphoblastic leukemia (B-ALL), may be highly dependent on epigenetic regulation for leukemia development and maintenance, and thus sensitive to small molecule inhibitors that target epigenetic mechanisms. Experimental Design A panel of B-ALL cell lines was tested for sensitivity to HDACi with varying isoform sensitivity. Isoform specific shRNAs were used as further validation of HDACs as relevant therapeutic targets in B-ALL. Mouse xenografts of B cell malignancy derived cell lines and a pediatric B-ALL were used to demonstrate pharmacological efficacy. Results Non-selective HDAC inhibitors were cytotoxic to a panel of B-ALL cell lines as well as to xenografted human leukemia patient samples. Assessment of isoform specific HDACi indicated that targeting HDAC1-3 with class I HDAC specific inhibitors was sufficient to inhibit growth of B-ALL cell lines. Furthermore, shRNA mediated knockdown of HDAC1 or HDAC2 resulted in growth inhibition in these cells. We then assessed a compound that specifically inhibits only HDAC1 and HDAC2. This compound suppressed growth and induced apoptosis in B-ALL cell lines in vitro and in vivo while it was far less effective against other B-cell derived malignancies. Conclusions Here we show that HDAC inhibitors are a potential therapeutic option for B-ALL, and that a more specific inhibitor of HDAC1 and HDAC2 could be therapeutically useful for patients with B-ALL.

Highlights d PROTAC resistance via disruption of rather than adaptation to oncoprotein degradation d PROTACs using different E3s/CRLs: resistance via similar pathways but different genes d Result of using two PROTACs depends on E3, target, and sequential versus concurrent use d E3s essential for and highly expressed in tumor cells are useful for future PROTACs

Multiple Myeloma (MM) is a prototypical neoplasm for the study of tumor-microenvironment interactions and influences on drug response. These interactions within the bone marrow (BM) alter the signaling state of MM cells and their relative dependence on pharmacological targets. Conversely, many efforts to identify and validate drug targets in MM are conducted outside of this context. This raises the possibility that systematic re-evaluation of the current pharmacopeia may identify drugs with previously unappreciated capacity for targeting MM cells within the marrow environment. To this end, we utilized the compartment-specific bioluminescence platform (CS-BLI) to characterize the activity of 2,684 FDA-approved drugs from The Johns Hopkins Drug Library (JHDL) in three distinct MM subtypes, in the presence or absence of patient-derived CD138-negative bone marrow stromal cells (BMSCs). Anti-MM activity was evaluated at 100 nM concentrations over 72 h in MM1S (t(14;16), KRASG12A, TRAF3LOF), L363 (t(20;22), NRASQ61H, p53S261T), and OPM2 (t(4;14), FGFRK560E, p53R175H) lines. These lines demonstrate phenotypes of strong, medium, and low BMSC-induced growth enhancement, respectively. Active drugs were placed into 4 categories: type 1 - having potent anti-MM activity independent of BMSC interactions (no stromal effect), type 2 - having anti-MM activity only in the presence of BMSCs (stroma-dependent "synthetic lethality"), type 3 - having anti-MM activity that is decreased in the context of BMSCs (stroma-dependent resistance), and type 4 - otherwise inactive agents that demonstrate pro-MM activity in context of BMSCs (stroma-dependent stimulants). In this study, for MM1S, L363, and OPM2, respectively, we identified 103, 118, and 108 type 1 drugs, 217, 105, and 76 type 2 drugs, 128, 75, and 16 type 3 drugs, and 124, 33, and 38 type 4 drugs. For each category of drug phenotype, we assessed overlap across the three MM cell lines. We observed high degree of overlap for type 1 drugs (67 drugs active in all three models), while more diversity between lines was evident across the 3 lines for type 2-4 drugs, whose activity is altered by interaction with BMSCs (Figure 1). Specifically, focusing on agents demonstrating BMSC-associated stimulation, adrenergic drugs consistently stimulated MM growth in context of BMSCs, while glucocorticoids consistently grouped as type 3 agents (demonstrating BMSC-associated resistance). Interestingly, carfilzomib was also subject to BMSC-associated resistance. Despite differences in drugs demonstrating stroma-induced lethality across the MM cell lines, salicylates were commonly represented in this category. In addition to the salicylates, tofacitinib, a Janus kinase (JAK) inhibitor, demonstrated a strong capacity to elicit a stroma-dependent synthetic lethal phenotype and ruxolitinib, another inhibitor in the same class, showed a similar, yet distinct pattern of stroma-mediated sensitization. In conjunction with our screen, we performed an RNA-seq analysis to assess differential gene expression between MM in monoculture vs. in co-culture with BMSCs. Expression analysis revealed 4.0 fold increase in JAK3 expression induced by co-culture with primary BMSCs, as well as induction of a STAT3 transcription factor fingerprint by ChIP-seq enrichment analysis. A detailed dose-response analysis of tofacitinib revealed no anti-MM activity against MM cells in isolation at physiological concentrations, but showed typical sigmoidal log-dose response dynamics in the presence of stroma and a dynamic range that completely abrogated the growth advantage attributable to stromal stimulation. This phenomenon of BMSC-dependent pharmacology identifies tofacitinib as an intriguing candidate for repurposing as an agent demonstrating stroma-induced synthetic lethality against MM. Further evaluation of this agent in combination with other anti-MM agents, like bortezomib, is also warranted. Taken together, this study demonstrates specific anti-MM activity for a wide array of clinically relevant drugs and drug classes in the context of BM microenvironment interactions and provides context for further validation and potential suitability for repurposing to treat MM within the medullary compartment. Figure 1. Figure 1. Disclosures Aftab: Cleave Biosciences, Inc.: Research Funding; Omniox, Inc.: Research Funding; Atara Biotherapeutics, Inc.: Employment, Equity Ownership; Onyx Pharmaceuticals, Inc.: Research Funding. Off Label Use: The use of tofacitinib citrate and ruxolitinib will be discussed in preclinical contexts for treatment of multiple myeloma. Other approved drugs and drug classes will be generally presented in similar off-label context..

Background: Functional genomics studies based on CRISPR and shRNA have documented that multiple myeloma (MM) cells are preferentially dependent (compared to other neoplasias) on a series of TFs, including IKZF1 and IKZF3 (which are targeted by thalidomide derivatives) and others that are not amenable to degradation or small molecule inhibition. Transcriptional co-factors have been therapeutically targeted, for example, inhibitors of BRD4, a co-factor for pTEFB, can be used to down-regulate c-myc. Aim: To identify new transcriptional vulnerabilities in MM with an emphasis on transcriptional co-factors Methods: We integrated results from genome-scale studies using the AVANA library for loss-of-function by gene editing (in 19 MM lines) and the Calabrese library for CRISPR-mediated gene activation (in 5 MM lines) to identify critical transcriptional co-factors (co-TFs). RNA-Seq analysis was used to identify critical pathways affected by POU2AF1 activation and existing ChIP-Seq tracks in MM cells were reanalyzed. Results: POU2AF1 (OCA-B) was the most preferentially essential TF co-factor in MM cell lines vs. non-MM and one of top genes which, upon CRISPR activation in genome-scale studies, increased MM cell fitness in vitro. We further confirmed the role of this gene using focused libraries of sgRNAs against POU2AF1 in vitro and in an in vivo model of MM cell growth in bone marrow-like scaffolds "functionalized" with humanized mesenchymal bone marrow stromal cells to simulate the human BM. CRISPR activation of POU2AF1 is associated with increased MM cell growth. RNA-Seq of POU2AF1 activation in LP1 cells a transcriptional program characterized by upregulation of other genes that are preferentially essential for MM including PRDM1, SUPT7L, UBE2G2 and TSC1; broad-spectrum oncogenic dependencies (e.g KRAS) and genes known or proposed to be involved in the pathophysiology of MM or other neoplasias (e.g. RUNX2, FGFR3, SMO, CREB5, TNFRSF13B, MEF2D, PCGF2). POU2AF1 overexpression was also associated with down-regulation of CDKN1C; of MHC class II molecules and their transcriptional activator CIITA, suggesting that POU2AF1 activation could also contribute to increased MM growth in vivo by allowing escape from immune surveillance. ATAC-Seq data and genome-wide ChIPseq for H3K27Ac in MM cell lines indicate that chromatin surrounding the POU2AF1 locus was highly accessible, concordant with the consistent expression of this TF in MM cell lines and patient-derived cells. CoMMpass data showed that POU2AF1 expression was enhanced in a subset of MM patients at relapse compared to diagnosis. Motif analysis of ChIP-seq data for POU2AF1 identified significant overlap with motifs for TFs relevant to the POU family (e.g. Oct11, Oct2, Oct4); members of the ETS family (e.g. ELF1, Elf4, GABPA); and other TFs with roles in MM including c-myc; IRF4; NF-kappaB, PRDM1, RUNX2 and the POU2AF1 target CREB5. These data suggest a functional interaction between POU2AF1 and other MM-relevant TFs. The transcriptional signature of POU2AF1 activation is enriched for genes downregulated by suppression/inhibition of MM-preferential TFs or epigenetic regulators including IRF4, PRDM1, IKZF1/3 and DOT1L. POU2AF1 binding motifs are also enriched in the promoter regions of MM-preferential dependencies including several MM-preferential TFs. Conclusions: POU2AF1 is essential for MM cells in vitro and in vivo; has a significantly more pronounced and recurrent role as a dependency in MM compared to most other neoplasias; and can further drive MM cell growth, through its ability to interact with several TFs critical for MM, forming multi-protein functional complexes. These results establish POU2AF1 as a central component in the regulatory network of oncogenic TFs in MM and highlight the value of further exploring POU2AF1 as a therapeutic target in MM. Disclosures Downey-Kopyscinski: Rancho BioSciences, LLC: Current Employment. Tsherniak:Cedilla Therapeutics: Consultancy; Tango Therapeutics: Consultancy. Boise:AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech: Membership on an entity's Board of Directors or advisory committees. Mitsiades:FIMECS: Consultancy, Honoraria; Ionis Pharmaceuticals, Inc.: Consultancy, Honoraria; Arch Oncology: Research Funding; Janssen/Johnson & Johnson: Research Funding; Karyopharm: Research Funding; TEVA: Research Funding; Takeda: Other: employment of a relative; Fate Therapeutics: Consultancy, Honoraria; Sanofi: Research Funding; Abbvie: Research Funding; EMD Serono: Research Funding.

Multiple Myeloma (MM) remains an incurable malignancy in part because of an incomplete understanding of which genes are critically responsible for MM cell survival and proliferation. To address this unmet need, and building on our recent functional genomics studies with the CRISPR/Cas9 gene editing platform (ASH 2015; Int. MM Workshop, Rome 2015), we reasoned that quantification of sgRNA depletion in the absence of any treatment could identify genes essential for the survival or proliferation of MM cells and better define their role as candidate therapeutic targets. To this end, we transduced Cas9-expressing RPMI-8226 and MM.1S cells with the lentiviral genome-scale GeCKO pooled library of sgRNAs. After culture of these cell lines for 2, 6, 8 or 12 weeks without any treatment, we identified, based on next generation sequencing for the sgRNA sequences, genes with significantly depleted sgRNAs (4-6 sgRNAs/gene, >2-fold average depletion, FDR=0.05, based on MAGECK algorithm) in Cas9+ cells compared to their initial sgRNA plasmid pools, baseline cultures, or isogenic parental Cas9-negative cells. These results were confirmed for each cell line with a 2nd independent genome-wide analysis and with a focused sgRNA library containing a subset of candidates defined by the genome-wide analyses. We compared these results with data from our in-house or publicly available CRISPR/Cas9 gene editing studies, involving a total of 50 cell lines from other hematologic malignancies (leukemia, lymphoma) and from 8 different types of solid tumors. We identified 3 broad categories of essential genes in MM cells: a) core essential genes, with sgRNA depletion across the majority of MM and non-MM lines of our study, representing cellular processes critical for practically all lineages (e.g. genes involved in regulation of basic transcription factor complexes, ribosomal function, proteasome, spliceosome, structural proteins for mitochondria and other key organelles, et.c.); b) genes selectively essential for MM cell lines, but not for the overwhelming majority of leukemia, lymphoma or solid tumor cell lines; c) genes with a role in small subset(s) of cell lines, across diseases, which harbor defined genetic features correlating with this dependency. We integrated our CRISPR/Cas9-based data on MM-selective essential genes with a reanalysis of the Achilles Heel shRNA screen in MM and non-MM cell lines (10 and 493, respectively) of the Cell Line Encyclopedia Program (CCLE) program. We applied a series of statistical tests (e.g. Wilcoxon rank test or marker selection feature of GENE-E algorithm with 1000 permutation tests) to identify genes with a significantly lower rank in sgRNA or shRNA depletion in MM vs. non-MM cell lines, across different specific thresholds for fold change and statistical significance. We identified more than 50 high-value candidate target genes with preferential essentiality in MM, compared to non-MM cell lines of diverse lineages. Prominent examples of such MM-selective, essential genes included: transcription factors (e.g. IRF4, CCND2, MAF, NFKB1, NFKB2, RELA, RELB); otherNF-kB-related genes (e.g. IKBKB); PIM2 (but not PIM1 or PIM3 in this cell line panel); regulators of protein homeostasis, including diverse E2 and E3 ubiquitin ligases; and several other known or biologically-plausible dependencies which are under further evaluation. Many of these MM-selective dependencies exhibited significantly higher expression in MM, compared to non-MM cells, both in cell lines (based on the CCLE dataset) and patient-derived samples (comparison of Broad/MMRF vs. TCGA datasets, respectively). Notable observations of context-dependent essential genes include ARID1A in MM.1S cells (plausibly due to deficiency in its paralog ARID1B); and cases of both MM and non-MM cells with RAS mutations but lack of dependency on that gene. Targeting of lineage-specific dependencies (e.g. ER or AR in breast or prostate Ca, respectively) has provided major clinical benefit in some tumors; while context-specific dependencies are a cornerstone of molecularly-guided individualized treatments. Therefore, by identifying lineage- and context-dependent essential genes for MM, our integrated genome-wide CRISPR/Cas9 and shRNA analyses in molecularly annotated panels of MM vs. non-MM cell lines provide an attractive framework towards designing novel therapies for MM. Disclosures No relevant conflicts of interest to declare.

Multiple Myeloma (MM) remains incurable in part due to an incomplete understanding of the genes critically responsible for MM cell survival and proliferation. We reasoned that CRISPR/Cas9-based functional genomics could identify genes essential for survival or proliferation of MM cells and define candidate therapeutic targets. We transduced Cas9-expressing RPMI-8226 and MM.1S cells with lentiviral genome-scale GeCKO pooled libraries of sgRNAs. After culture of these cell lines for 2-12 weeks without treatment we identified, based on next generation sequencing, genes with significantly depleted sgRNAs (4-6 sgRNAs/gene, >2-fold average depletion, FDR<0.05, using MAGECK algorithm) in Cas9+ cells compared to initial sgRNA plasmid pools, baseline cultures, or isogenic parental Cas9-negative cells. These results were confirmed for each cell line with a 2nd independent genome-wide analysis and with a focused sgRNA library containing a subset of candidates defined by the genome-wide analyses. We compared these results with data from our in-house or publicly available CRISPR/Cas9 gene editing studies, involving a total of 175 cell lines from other hematologic malignancies and solid tumors. We next integrated our functional data for these genes with their: a) Achilles Heel shRNA data; b) gene expression (RNASeq); c) gene copy number status; d) mutation status; e) proximity to superenhancers; and f) altered expression in MM cells co-cultured with bone marrow stromal cells. We applied a series of statistical tests (e.g. Wilcoxon rank) to identify genes with significantly higher rank in sgRNA or shRNA depletion in MM vs. non-MM lines and stringently identified 50+ candidate genes with preferential dependency in MM. Prominent examples included: transcription factors (e.g. IRF4, CCND2, MAF, NFKB1, NFKB2, RELA, RELB); other NF-κB-related genes (e.g. IKBKB); PIM2; regulators of protein homeostasis; and several other known or biologically plausible dependencies which are under further evaluation. In >90% of MM patients, the candidate MM-preferential essential genes are not mutated. Some of these genes are overexpressed in MM vs. non-MM cell lines (CCLE dataset) or patient-derived samples (Broad/MMRF vs. TCGA datasets); induced by BMSC co-culture; proximal to superenhancers; or correlating with clinical outcome. However, these molecular results were not sufficient, collectively or individually, to identify this cohort of MM-preferential essential genes independently of the CRISPR functional data. Targeting lineage-specific dependencies (e.g. ER or AR in breast or prostate Ca, respectively) has provided major clinical benefit in some tumors; while context-specific dependencies are a cornerstone of molecularly-guided individualized treatments. Therefore, by identifying lineage- and context-dependent essential genes for MM, our functional genomic studies in molecularly annotated MM vs. non-MM cell lines provide an attractive framework towards designing novel therapies for MM. Citation Format: Geoffrey M. Matthews, Ricardo de Matos Simoes, Yiguo Hu, Michal Sheffer, Olga Dashevsky, Eugen Dhimolea, Paul J. Hengeveld, Brian J. Glassner, Sara Gandolfi, Megan A. Bariteau, Quinlan Sievers, Benjamin L. Ebert, Franciska Vazquez, Aedin Culhane, Constantine S. Mitsiades. Characterization of lineage vs. context-dependent essential genes in multiple myeloma using CRISPR-Cas9 genome editing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-118. doi:10.1158/1538-7445.AM2017-LB-118

Multiple myeloma (MM) is an incurable malignancy with an unmet need for novel therapeutic modalities. Moreover, acquired or de novo resistance to established or novel therapeutics remains a major challenge in this, and other, neoplasias. BET Bromodomain inhibitors (BBIs), including JQ1, have potent anti-MM activity in vitro and in in vivo, but do not provide curative outcome and do not induce apoptosis in most cell types. We sought to investigate dBET, a class of BBIs that induce degradation of BET Bromodomains (BRDs) through CRBN-mediated ubiquitination and proteasomal degradation, in drug-resistant MM. Additionally, we posited that resistance to dBET treatment would emerge through genetic perturbations and wished to uncover potential mechanisms prior to its clinical utilization. To address this, we compared effects of optimized lead compound, dBET6, with JQ1 on a panel of MM cell lines, including clones resistant to JQ1 or bortezomib and assessed viability using CS-BLI/CTG assay and BRD/c-MYC expression by western blot. Using an open-ended unbiased genome-wide CRISPR (clustered regularly interspaced short palindromic repeats)-associated Cas9 approach, we examined whether we could uncover genes associated with resistance to dBET6. MM1.S cells were transduced with Cas9 and pooled lentiviral particles of the GeCKO library, consisting of 2 pooled sgRNA sub-libraries (∼120,000 sgRNAs; targeting ∼19,000 genes and ∼1800 miRNAs). Using this CRISPR/Cas9-based approach we sought to expedite the isolation of MM cells resistant to dBET6. We treated the pool of cells thrice with dBET (≥IC80), allowing regrowth between treatments and maintaining a coverage of 1000 cells/sgRNA. dBET6-resistant cells were processed to quantify sgRNA enrichment or depletion, using deep sequencing. We observed dBET6 to have significantly greater potency against MM cells than JQ1, or its combination with lenalidomide, and that MM1S.CRBN-/- cells were resistant to dBET6. Resistance to neither JQ1 nor Bortezomib conferred resistance to dBET6. We observed dBET6 to induce rapid (<4hrs) degradation of BRD2, BRD3 and BRD4 and complete absence of c-MYC protein, in contrast to JQ1 which caused dose-dependent down-regulation of c-MYC, and apparent upregulation of BRD4. As predicted, our CRISPR/Cas9 screen identified significant enrichment of sgRNAs targeting CRBN, as well as the Cullin-RING ligase (CRL) complex, known to play a critical role in E3 ubiquitin ligase activity. In summary, our data support the development of dBET for the treatment of drug-resistant MM. Additionally, our results demonstrate that loss of function of CRBN or the CRL complex induces dBET resistance by perturbing dBET-mediated BRD4 degradation. However, it is plausible that additional CRBN/CRL-independent mechanisms of dBET resistance exist that allow cells to survive despite complete degradation of BRDs and this will be a key question to be answered in future studies. Citation Format: Geoffrey M. Matthews, Yiguo Hu, Michal Sheffer, Paul J. Hengeveld, Dennis L. Buckley, Megan A. Bariteau, Haley Poarch, James E. Bradner, Constantine S. Mitsiades. BET bromodomain degradation as a therapeutic strategy in drug-resistant multiple myeloma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4713.

Pharmacological inhibition of the canonical proteasome by inhibitors targeting its beta5 (PSMB5) subunit represent a cornerstone of the therapeutic management of plasma cell neoplasias. However, proteasome inhibitors have limited clinical applications in other hematologic malignancies. Notably, a broad spectrum of cell lines and patient-derived samples from lymphoma, leukemia and myeloma tend to express high levels of transcripts for and exhibit substantial activity of the immunoproteasome, an alternative proteasome particle which is enriched in hematopoietic/immune tissues. Established proteasome inhibitors used in clinical practice (e.g. bortezomib, carfilzomib, ixazomib) target both the canonical 20S proteasome and the immunoproteasome. We reasoned though that targeting of the immunoproteasome with more selective small molecule inhibitors that largely spare the canonical proteasome may provide insights into the specific functional role of the immunoproteasome in hematologic neoplasias, and importantly may also uncover underappreciated therapeutic opportunities related to targeting of hematologic neoplasias beyond myeloma, that might be more dependent on the immunoproteasome vs. the canonical proteasome; as well as potential benefits related to the therapeutic index of these agents. To address these questions, we characterized the activity of the previously disclosed selective immunoproteasome inhibitor M3258, which targets the LMP7 (beta5i subunit). The bortezomib-resistant cell line MM1VDR, which has a "gatekeeper" PSMB5 mutation preventing bortezomib binding to the canonical proteasome, remained sensitive to in vitro treatment with M3258, in further support of the functional specificity of this inhibitor. To obtain a comprehensive assessment of the activity of M3258 across hematologic malignancies, we studied a pool of 74 "DNA-barcoded" cell lines (PRISM system) from hematologic malignancies, including multiple myeloma (MM), leukemias and lymphomas, which were treated for 48hr with M3258. MM cell lines (9/16) were strongly represented among the sensitive lines which displayed <50% relative cell viability (compared to DMSO control) after M3258 treatment. Notably, 15 of 58 non-MM lines also exhibited >50% reduction in their cell viability in this analysis; and their responsiveness did not differ significantly from the M3258-responsive MM lines. Importantly, we observed no correlation between the responses of leukemia, lymphoma or MM lines to in vitro treatment with M3258 vs. clinically-relevant pulse of bortezomib. Furthermore, 7 of the 15 lymphoma/leukemia lines that were M3258-responsive had limited, if any, response to a clinically-relevant pulse of bortezomib. Taken together, these observations suggest that immunoproteasome inhibition with M3258 can be active against subsets of hematologic neoplasias with resistance/limited responsiveness to canonical proteasome inhibitors. To further examine the in vivo relevance of these observations, we studied the in vivo activity of M3258 against the MM.1S myeloma cell line, which has only moderate in vitro response to M3258 compared to other blood cancer cell lines tested in our "DNA-barcoded" pooled analysis. M3258 significantly increased the overall survival of mice with diffuse MM-bone lesions established after tail vein injection of MM.1S cells; and of mice harboring MM.1S lesions within a subcutaneously implanted ceramic scaffold-based system engineered to establish a bone marrow-like histological and functional unit with a "humanized" stromal compartment. The anti-tumor activity of M3258 in this scaffold model exhibited a trend for increased efficacy compared to twice weekly subcutaneous treatments with bortezomib. These results highlight that in vivo administration of M3258 exhibits anti-tumor activity against clinically-relevant models of MM lesions, even from cell lines that have modest in vitro responsiveness to this immunoproteasome inhibitor. Furthermore, our studies with a large panel of "DNA-barcoded" cell lines indicates that the anti-tumor effects of M3258 may extend beyond MM and into other classes of hematologic malignancies, including subsets of leukemias and lymphomas, identifying previously underappreciated therapeutic implications for the class of selective immunoproteasome inhibitors. Disclosures Walter: Merck Healthcare KGaA: Employment. Friese-Hamim:Merck Healthcare KGaA: Employment. Goodstal:EMD Serono Research and Development Institute: Employment. Sanderson:Merck Healthcare KGaA: Employment. Mitsiades:Takeda: Other: employment of a relative ; Ionis Pharmaceuticals: Honoraria; Fate Therapeutics: Honoraria; Arch Oncology: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding; Abbvie: Research Funding; TEVA: Research Funding; EMD Serono: Research Funding; Janssen/Johnson & Johnson: Research Funding.