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We conducted a phase 1/2 study of carfilzomib, pomalidomide, and dexamethasone (KPd) followed by another cohort of KPd with daratumumab (Dara-KPd) in relapsed/refractory multiple myeloma. The primary endpoints were identification of a maximum tolerated dose (MTD) of KPd for phase 1, and rates of overall response (ORR) and near complete response (nCR) after 4 cycles of KPd and Dara-KPd, respectively, for phase 2. The MTD for KPd was carfilzomib 20/27 mg/m2 on days 1, 2, 8, 9, 15, 16 (cycles 1-8) and days 1, 2, 15, 16 for cycles 9+; oral pomalidomide 4 mg on days 1-21; and oral dexamethasone 40 mg weekly in 28-day cycles. Sixty-six patients received KPd, including 34 at the MTD. The ORR after 4 cycles of KPd at the MTD was 27/34 (79%, 95% CI 62%-91%), meeting the statistical threshold for efficacy. At a median follow-up of 44 months, the median PFS and OS were 13 and 44 months, respectively. Twenty-eight patients received Dara-KPd. The rate of nCR or better after 4 cycles was 11/28 (39%, 95% CI 22%-59%), meeting the statistical threshold for efficacy. As best response to Dara-KPd, the ORR was 25/28 (89%) and the rate of measurable residual disease negativity by flow cytometry (10-5) was 17/26 (65%). At a median 26 months follow-up, the median PFS and OS for Dara-KPd were not reached. Dara-KPd induced deeper and more durable responses than KPd without compromising safety in a predominantly high risk, lenalidomide-refractory population, warranting further evaluation of this quadruplet for this patient population. This trial is registered at www.clinicaltrials.gov as NCT01665794.

Introduction: Proteasome inhibitors (PI) and immunomodulatory drugs have become the backbone of therapy for multiple myeloma (MM). The oral boron-containing selective and reversible proteasome inhibitor ixazomib has shown to induce deep and durable responses (Kumar RK et la, Blood 2016. 128(20):2415-2422). Triplets containing ixazomib, has shown to be more efficacious than doublet regimens in the relapse setting (Moreau P, et al. N Engl J Med 2016. 374:1621-1634).However, to date, there is not companion diagnostics capable of predicting PI response. We have recently discovered that MM patients resistant to PI lack of the ankyrin (ANK) and death domain (DD) present in the 3'-end of NFKB2. Loss of NFKB2 3'end frequently resulted from a structural rearrangements. We found that NFKB2-ANK and -DD are crucial at initiating bortezomib's apoptotic signal by facilitating caspase-8 activation (unpublished data). Based on this findings, we designed this study to examine the efficacy of NFKB2 break apart FISH to predict the response to ixazomib and dexamethasone (Id) vs. ixazomib, lenalidomide and dexamethasone (IRd) in early relapse MM patients. Methods: In this phase 2 biomarker-driven open-label trial, relapsed patients with Results: At the moment of the interim analysis, 60 patients have achieved 4 cycles of treatment. All treatment groups (NFKB2 FISH [-] Id, n=27, NFKB2 FISH [+] Id, n=20 and IRd, n=19) received a median of 2 prior lines of therapy. A trend to higher ORR was observed in NFKB2 FISH negative treated with Id compared with NFKB2 FISH positive (41% CI:58%-97% vs. 30% CI:8%-60%, P=0.4, target p-value goal 0.15), including significantly higher rates of ≥ very good partial response, ≥ partial response, ≥ minimal response (15%, 25%, 15% vs. 4%, 25%, 10%, respectively). ORR for IRd arm is for now 57% CI:27%-80%. Interestingly, >G3 treatment related adverse events were higher in Arm A (15%) and Arm C (13%) vs Arm B (0%). The most common (≥10%) ≥ grade 3 include URI/pneumonia 16% and diarrhea 12% in Id NFKB2 FISH negative vs. neutropenia 18% and diarrhea (10%) in the IRd NFKB2 FISH positive arm. Treatment discontinuations only occurred in 3 NFKB2 FISH positive Id treated patient (13%). Conclusion: Interim analysis demonstrates a trend higher efficacy and ≥G3 toxicity of ixazomib with dexamethasone in MM patients with negative NFKB2 break-apart FISH compared to those with a positive test. Efficacy and toxicity of the triplet regimen are comparable to what is seen in the Tourmaline 1 trial. This study is registered clinicaltrials.gov# NCT02765854 Disclosures Bernal-Mizrachi: Kodikaz Therapeutic Solutions: Consultancy, Current holder of individual stocks in a privately-held company, Patents & Royalties; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Winship Cancer Institute of Emory University: Current Employment; Bigene: Membership on an entity's Board of Directors or advisory committees. Nooka: Takeda: Consultancy, Research Funding; Janssen Oncology: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Other: Travel expenses; Sanofi: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding; Oncopeptides: Consultancy; Adaptive technologies: Consultancy; Karyopharm Therapeutics: Consultancy. Ye: Alexion, AstraZeneca Rare Disease: Other: Study investigator. Vij: BMS: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; BMS: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria; Karyopharm: Honoraria; CareDx: Honoraria; Legend: Honoraria; Biegene: Honoraria; Adaptive: Honoraria; Harpoon: Honoraria. Hofmeister: Ohio State University: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: IP rights, Patents & Royalties; Medscape: Other: Non-pharma speaker for education, research, marketing; DAVA Oncology: Other: Non-pharma speaker for education, research, marketing; TRM Oncology: Other: Non-pharma speaker for education, research, marketing; Verascity: Other: Non-pharma speaker for education, research, marketing; Aptitude Health: Other: Non-pharma speaker for education, research, marketing; BlueBird Bio: Other: Non-CME speaker; Amgen: Other: Non-CME speaker; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Philips Gilmore: Other: CME speaker; Non-pharma speaker for education, research, marketing; BioAscend: Other: CME speaker; Imbrium: Membership on an entity's Board of Directors or advisory committees; Myeloma360: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Local PI of CST; Oncolytics: Other: National PI for CST; PI or co-PI IST; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; BMS/Celgene: Other: National PI for CST; PI or co-PI IST; Local PI of CST; Sanofi: Other: National PI for CST; PI or co-PI IST. Rushton: KSL: Current Employment. Lonial: Merck: Honoraria; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Kaufman: Incyte, celgene: Consultancy; Genentech, AbbVie, Janssen: Consultancy, Research Funding; Tecnofarma SAS, AbbVie: Honoraria; Heidelberg Pharma: Research Funding; Janssen: Honoraria; Novartis: Research Funding; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Fortis Therapeutics: Research Funding; BMS: Consultancy, Research Funding; Amgen: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Sutro, Takeda: Research Funding.

BACKGROUND Aneuploidy, defined by abnormal copy number changes of chromosomes, contributes to genome instability in multiple myeloma and has potential prognostic impact. Previous research has explored transcriptional pathways affected by aneuploidy. We aim to evaluate aneuploidy, clinical prognosis, and gene expression in RRMM patients (pts) who participated in MMRF (Multiple Myeloma Research Foundation) sequencing study at University of Michigan. We further used gene set analysis to identify enrichment and variation of genetic pathways associated with aneuploidy and overall survival (OS). This was a pilot study in view of applying similar methods to larger populations. METHODS DNA and RNA materials were obtained from 51 RRMM pts at the time of disease relapse. Targeted sequencing was performed with the Onco1700 panel and RNA sequencing was performed with a capture protocol using Agilent SureSelect All Exon V4, followed by paired end sequencing. Copy number variation (CNV) was estimated using an in-house pipeline using matched normal samples. Arm-level aneuploidy was defined as copy number status (gain, loss or neutral) with maximal proportion for each chromosomal arm. Aneuploidy score was determined by total number of arm-level CNV aberrations, with the median score defining high and low aneuploidy groups. Survival analysis was performed using Kaplan-Meier (KM) and Cox regression. RNA-seq libraries were aligned with STAR aligner to the hg38 reference and read quantification were performed with featureCounts. We used gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) to obtain genetic pathway-level summaries for 50 hallmark pathways representative of cancer from the GSEA Molecular Signatures Database (https://www.gsea-msigdb.org/). Supervised GSEA was performed, based on differential analyses comparing gene expression profiles between high versus low aneuploidy groups to identify the differences in genetic pathways in RRMM pts. Unsupervised GSVA was applied to RNAseq count data of RRMM and newly-diagnosed multiple myeloma (NDMM) pts from the MMRF CoMMpass study (797 pts). Univariate Cox proportional hazard model was used to identify pathways having significant association with OS. RESULTS Arm scale aneuploidy analysis revealed high frequency of gains and losses in multiple chromosomes (Figure 1). RRMM pts with high aneuploidy scores had worse OS (median 15.9 months since study enrollment) compared to those with low scores (median not reached, p=0.027). Multivariate analysis demonstrated that high aneuploidy score is persistently associated with poor OS (hazard ratio (HR): 3.9, p=0.006), adjusting for t(4;14) and t(11;14). Hyperdiploidy (any whole chromosome carrying >2 copies) was identified in chromosomes 3, 5, 7, 9, 11, 19, 21, with frequency >20%. Pts with hyperdiploidy had better OS via KM (p=0.04). Using RNAseq gene expression data and GSEA analysis, we found enrichment of gene markers involving the pathways for targets of E2F transcription factors (Normalized Enrichment Score (NES) = 2.07), G2-M checkpoint in the cell division cycle (NES = 1.87), MYC proto-oncogene (NES = 1.93 and 1.85), and DNA repair (NES = 1.68) in RRMM pts with high aneuploidy compared against those with low scores (Benjamini-Hochberg adjusted p-value GSVA analysis revealed 21 genetic pathways associated with survival in NDMM and RRMM pts, with 8, 2, and 11 pathways associated with OS in NDMM only, RRMM only, and both, respectively (Figure 3). Enrichment of several biological pathways involved with cellular growth, cell cycle regulation, and stress response (E2F, G2-M, MYC, DNA repair, mTORC1 signaling, UV radiation, mitotic spindle assembly, unfolded protein response, and peroxisome) are associated with poor survival (HR>1) in both NDMM and RRMM pts. Downregulation of KRAS signaling pathway is associated with better survival (HR CONCLUSION Aneuploidy, adjusted for chromosomal translocations, is an independent adverse prognostic factor for RRMM. Aneuploidy is correlated with dysregulation of major biological pathways involving cell cycle regulation, cellular division, oncogenes, and DNA damage repair. The majority of common pathways shared between RRMM and NDMM are linked to or reflective of genomic instability, and may explain association with poor survival. Disclosures Talpaz: IMAGO: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Ye:Janssen: Research Funding; Portola: Research Funding; Millennium: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding; Nektar: Research Funding; AbbVie: Research Funding.

Background: Aspagarinase is a fundamental component for the treatment of patients with acute lymphoblastic leukemia (ALL). Venous thromboembolism (VTE) is a known complication of asparaginase therapy during treatment for ALL. This is attributed to the depletion of anticoagulants, particularly acquired antithrombin deficiency following asparaginase administration. The incidence of thrombosis following asparaginase is more prevalent in adults versus children and is estimated to be around 5-35 % and 2.4-8% respectively. Multiple studies have investigated the efficacy and safety of antithrombin supplementation. The recent THROMBOTECT study showed that prophylactic use of antithrombin (AT) or low molecular weight heparin (LMWH) is associated with significant risk reduction of thromboembolism in children and adolescents during induction chemotherapy of ALL. Our study sought to review the cohort studies comparing VTE in adults with and without AT supplementation in ALL receiving asparaginase and specifically evaluate the efficacy of this strategy. Methods: We performed a systematic search using PubMed, Google Scholar, EMBASE, SCOPUS and ClinicalTrials.gov without language restriction up until July 20th 2020. A random effects model was utilized to calculate risk ratio (RR) and mean difference (MD) with 95% confidence interval (CI). Results: Eight studies fulfilled our inclusion criteria (table 1) and were retrospective cohort studies. In adult patients, with ALL treated with asparaginase, the incidence of VTE was significantly lower in those who received AT [RR=0.46 (95 % CI= 0.31-0.70; p= 0.0002) (figure 1.1). The threshold for AT supplementation was 60-70% in most of the studies, with the exception of two studies where the threshold was 50%. Conclusion: In our meta-analysis of the current available data,Antithrombin supplementation in adults with ALL receiving asparaginase was associated with a significant decrease in the risk of venous thromboembolism compared to those who didn't receive thromboprophylaxis. Our data suggest the benefit of antithrombin supplementation in adults with ALL treated with asparaginase. We suggest that this strategy be implemented in a large prospective clinical trial to further confirm the benefit of this intervention. Disclosures No relevant conflicts of interest to declare.

Background: Numerous factors contribute to the financial burden experienced by the cancer population, including medical expenses and possible job disruption or loss. The financial burdens that accompany a cancer diagnosis can influence cancer-care decisions, including the delay of essential treatment or appointments, with deleterious effects on physical and mental quality of life (QOL). Further, certain sociodemographic groups face increased risk of financial burden. The aim of this study was to examine the relationships between financial burden, postponing care, and physical and emotional quality of life among patients with multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). Methods: 435 patients (72% MM; 28% CLL) enrolled in the Cancer Support Community's online survey, the Cancer Experience Registry, answered questions related to financial burden (8 items; yes/no response), postponing care (6 items; 5-point Likert scale), and QOL assessed using Patient-Reported Outcomes Measurement Information System (PROMIS-29v2.0) subscales (Anxiety, Depression, Physical Function, and Fatigue) with transformed T scores. We applied Structural Equation Modeling (SEM) to understand the direct and indirect relationship of financial burden (tally of "yes" responses to the 8 financial cost variables) with latent constructs comprising postponing care, physical QOL, and emotional QOL, and sociodemographic and clinical predictor variables. Results: Sample characteristics: mean age=62 yrs (9.2); 88% non-Hispanic White; 6% non-Hispanic Black; mean time since diagnosis=5.2 yrs (4.3); 28% ISS Stage 3 for MM or Rai Stage 3-4 for CLL. Regarding financial status, 21% have an annual income $500 in monthly out-of-pocket (OOP) costs to cover cancer care and an additional 23% spent over $250. Due to the financial costs of cancer care, 29% of participants depleted their savings, 19% borrowed against or used money from a retirement plan, 13% liquidated assets, 7% collected unemployment insurance, 4% took an extra job, 4% chose a less effective treatment, 4% cashed in a life insurance policy early, and 2% had their house foreclosed. While 41% were moderately to very seriously concerned about health insurance or money, 66% reported that no one from their health care team talked to them about costs. Based on the percent reporting sometimes, often, or always engaging in behaviors related to postponing care: 12% postponed doctor's appointments, 5% postponed follow-up screening or bloodwork, 6% postponed filling prescriptions, 5% skipped dosages of prescribed drugs, 12% delayed complementary treatment including therapy, and 16% postponed psychological counseling or support. SEM analyses demonstrate that age (standardized path coefficient β=-0.17), low income (β=0.24), OOP costs (β=0.18), time since diagnosis (β=0.11), and advanced stage (β=0.17) had a significant (p Conclusions: Findings highlight the significant effect of financial burden on postponing care and poorer QOL among MM and CLL patients. Financial burden was associated with patients' treatment decisions for both cancer and psychological care, and while many patients reported distress about money and health insurance, the majority did not discuss cost of care with their health care team. Thus, MM and CLL patients may benefit from access to no- or low-cost preventative and supportive psychosocial care, as well as financial counseling and assistance with health care team communication. Patient-focused organizations help address this need through no-cost resources, including distress screening tools, access to a financial counselor on a toll-free helpline, and information about treatment decision-making. Future research that incorporates cost of care into physician-patient communication is warranted. Disclosures Fortune: Boston Scientific Foundation: Research Funding; Genentech: Research Funding. Kranzler:Astellas Pharma US, Inc.: Research Funding; Pharmacyclics, Inc.: Research Funding; Jazz Pharmaceuticals: Research Funding; Takeda Oncology: Research Funding; Janssen Oncology: Research Funding. Leblanc:Agios, AbbVie, and Bristol Myers Squibb/Celgene: Speakers Bureau; AstraZeneca: Research Funding; AbbVie, Agios, Amgen, AstraZeneca, CareVive, BMS/Celgene, Daiichi-Sankyo, Flatiron, Helsinn, Heron, Otsuka, Medtronic, Pfizer, Seattle Genetics, Welvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; American Cancer Society, BMS, Duke University, NINR/NIH, Jazz Pharmaceuticals, Seattle Genetics: Research Funding; UpToDate: Patents & Royalties: Royalties. Zaleta:Athenex Oncology: Research Funding; Gilead Sciences, Inc: Research Funding; Pfizer, Inc.: Research Funding.

Introduction: Lenalidomide (LEN) is a cornerstone in the treatment of newly diagnosed MM both as part of induction and maintenance therapy. As a result, most patients at first or second relapse are LEN exposed/refractory creating a need for effective 2nd line and salvage therapies. While no standard of care regimen has been established in early relapse, several therapies have been evaluated combining second generation immunomodulatory agents, proteasome inhibitors, and daratumumab. We have previously reported the results from the phase I/II trial of KPd demonstrating excellent efficacy in a LEN-refractory patient population. Here, we present the first efficacy and safety results from the cohort in which DARA was added to KPd (D-KPd). Methods: This is a multi-center, open-label, Phase 1b/2 study in subjects with relapsed MM with two sequential treatment cohorts: KPd and D-KPd. Eligibility criteria and KPd doses and schedules were identical for both cohorts. Subjects with measurable disease that progressed after at least 1 prior therapy (LEN refractory disease was required for 2nd-line therapy and LEN refractory/exposed for ≥ 3rd line) were eligible. The KPd cohort has completed enrollment (n=67) and results have been previously reported. The D-KPd cohort received treatment on the following 28-day schedule: Pomalidomide 4 mg daily on days 1-21 for cycles 1-8+, Carfilzomib 20/27 mg/m2 on days 1,2,8,9,15,16 for C1-8, then 1,2,15,16 for C9+ (maintenance), dexamethasone 20 mg days 1,2,8,9,15,16,22,23 for C1-2, then 40 mg days 1,8,15,22 for C3+. DARA was administered as per standard schedule, weekly for the first 2 cycles, then every 2 weeks for cycles 3-6, and monthly thereafter. A Minimax two-stage design was employed for enrollment of subjects on this cohort. Twenty-one patients were required to accrue to the first stage, with at least 4 responders of ≥nCR at 4 cycles necessary to accrue to second stage for a total of 34 pts. Primary endpoint was rate of nCR/CR as per IMWG criteria. Minimal residual disease (MRD) was evaluated by 10-color flow cytometry with limit of detection (LOD) 10-4-10-5 and will also be assessed by next-generation sequencing (LOD 10-5-10-6). Secondary endpoints include overall response rate, depth of response, progression-free survival (PFS), and overall survival. Per study design, a nCR/CR rate of >35% (over the historical 20% rate) would support further study of the D-KPd regimen. Results: As of July 29, 2020, all 22 subjects who were enrolled into the D-KPd cohort were evaluable for safety and the primary endpoint. Median age was 62 (range 37-74) with a median of 1 (range 1-3) prior lines of therapy. 81% of patients were LEN refractory, and high-risk cytogenetics per IMWG criteria were present in 12/19 (68%) evaluable patients. Subjects completed a median of 12.5 cycles (range 2-33) of therapy and 21 (95%) subjects completed at least 4 cycles; 1 subject progressed after cycle 2. In the ITT population (n=22), after 4 cycles, 86% achieved ≥PR and 46% ≥nCR, warranting further enrollment to a second stage. At best response, the ≥PR was 86% with 55% ≥nCR/CR, 45% ≥sCR, and 55% MRD negativity by flow cytometry (n=22). The most common grade 3-4 hematologic adverse events included neutropenia (64%), lymphopenia (36%), and febrile neutropenia (18%). The most common grade 3-4 non-hematologic adverse events included fatigue (27%), respiratory infections (23%), diarrhea (14%), and insomnia (14%). There was one thrombotic event (4.5%) which was grade 2. In comparison to the KPd cohort (67 patients with similar baseline characteristics), there was an improvement in efficacy as demonstrated by an increase in rate of ≥nCR at the end of 4 cycles (from 7% to 46%), as well as the best response (from 20% to 55%). High risk cytogenetics did not significantly affect response (≥nCR 46% at best response [all sCR]). With 20 months of follow-up, median PFS was not reached in the D-KPd cohort and 12-month PFS is 84% vs 63% for KPd. Rates of grade 3/4 cytopenias were higher in the D-KPd cohort. There was no treatment related mortality and 19 of 22 pts are alive. Conclusion: D-KPd demonstrates high efficacy in a population of patients with relapsed/refractory multiple myeloma enriched for high risk cytogenetics. MRD negativity by flow cytometry was achieved in 55% of subjects. The ≥nCR rate of 55% with D-KPd compares favorably to the 20% rate with KPd alone; based on the study design, this warrants further evaluation of D-KPd. Disclosures Zonder: BMS, Celgene: Research Funding; Intellia, Amgen, Takeda, Janssen, Regeneron, Alnylam, Caelum, Oncopeptides: Consultancy. Reece:Janssen, Bristol-Myers Squibb, Amgen, Takeda: Consultancy, Honoraria; Janssen, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Research Funding; Otsuka: Research Funding. Berdeja:Kesios: Research Funding; Karyopharm: Consultancy; Acetylon: Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; Amgen: Consultancy, Research Funding; Bioclinica: Consultancy; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Cellularity: Research Funding; Constellation: Research Funding; CURIS: Research Funding; EMD Sorono: Research Funding; Genentech, Inc.: Research Funding; Glenmark: Research Funding; Janssen: Consultancy, Research Funding; Kite Pharma: Consultancy; Legend: Consultancy; Lilly: Research Funding; Novartis: Research Funding; Poseida: Research Funding; Takeda: Consultancy, Research Funding; Teva: Research Funding; Prothena: Consultancy; Servier: Consultancy; Bluebird: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding. Jakubowiak:Adaptive, Juno: Consultancy, Honoraria; AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction: Despite recent advances in the treatment of multiple myeloma, responses may be short-lived and therapeutic resistance develops almost invariably. Non-genetic cellular plasticity and dedifferentiation have recently emerged as a basis for therapeutic resistance in cancer as cells acquire transcriptional states which no longer depend on the drug target. Therefore, a better understanding of plasticity and adaptive state changes in myeloma cells is critical to develop effective therapeutic approaches that can overcome drug resistance. Here we show that cellular plasticity, though frequently invoked as a basis for therapeutic resistance in cancer, can also lead to new therapeutic opportunities. Methods: To define transcriptional states in myeloma at a single cell level, we performed fluorescence activated cell sorting and full-length single-cell RNA sequencing. We assayed a total 6000 CD38+CD138+ plasma cells and CD45+ immune cells from the bone marrow of 8 patients with relapsed and refractory multiple myeloma (RRMM) before and after immuno-modulatory treatment on a clinical trial with elotuzumab, pomalidomide, bortezomib and dexamethasone (Elo-PVD; NCT02718833) and 2 healthy donors. Surface expression of selected markers was validated by flow cytometry. Results: Assessing pre-treatment samples, we discovered that the transcriptional states of single myeloma cells are highly distinct between individual patients, despite the presence of the same established genomic classifiers, such as t(11;14). Furthermore, distinct transcriptional states co-exist within individual patients, indicating there is substantial inter- and intra-individual heterogeneity. Transcriptional states diverge from normal plasma cells towards more immature cells, of the B lymphoid lineage, suggesting a substantial cellular plasticity. Notably, we detected co-expression of myeloid and lymphoid developmental programs in the same single cells. Interestingly, these altered differentiation states were associated with up-regulation of potential immunotherapeutic targets, such as CD20, CD19, and CD33, indicating that this plasticity may result in novel therapeutic vulnerabilities. To define gene-regulatory relationships, we identified a shared core regulatory network present in malignant and normal plasma cells with the active transcription factors XBP1, ATF4, and CREB3, suggesting that myeloma cells retain lineage-specific regulons. However, we further identified patient-specific regulons not detected in any of the mature immune cell populations assayed, such as TEAD4, ELF3 and SNAI1, illustrating an aberrant and promiscuous activation of transcriptional regulators in myeloma cells. Consistent with this finding, we observed an increased number of expressed genes in myeloma cells compared to normal plasma cells as well as an increase in single cell transcriptional entropy, measures that have been linked to cell potency in normal development and cancer. Comparison of pre- and post-treatment samples interestingly revealed a further increase in transcriptional diversity and signatures associated with stemness and developmental potential following treatment. Conclusions: In conclusion, we find that higher transcriptional diversity and activation of alternate gene regulatory programs facilitate the emergence of altered transcriptional states. Interestingly, these altered states are associated with up-regulation of putative immune-therapeutic targets in myeloma cells, thus providing novel therapeutic vulnerabilities. Disclosures Lipe: amgen: Research Funding; Celgene: Consultancy; amgen: Consultancy. O'Donnell:Celgene: Consultancy; Takeda: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Amgen: Consultancy. Munshi:Celgene: Consultancy; Amgen: Consultancy; Oncopep: Consultancy; Janssen: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Adaptive: Consultancy; Oncopep: Consultancy; Takeda: Consultancy. Richardson:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Anderson:Gilead Sciences: Other: Advisory Board; Janssen: Other: Advisory Board; Sanofi-Aventis: Other: Advisory Board; OncoPep: Other: Scientific founder ; C4 Therapeutics: Other: Scientific founder . Lohr:T2 Biosystems: Honoraria; Celgene: Research Funding. OffLabel Disclosure: Samples for ancillary research were obtained in the context of a phase II clinical trial evaluating Elotuzumab, pomalidomide, bortezomib, dexamethasone The combination of elo-PVD is off label.

Objective To identify the association between aneuploidy and clinical outcome in patients with relapsed and/or refractory multiple myeloma (RRMM) who participated in MMRF (Multiple Myeloma Research Foundation) sequencing study at University of Michigan. Background: Aneuploidy, defined by abnormal copy number changes of chromosomes, is one of the hallmarks in cancer, reflecting and also contributing to genome instability (Ye, Regan et al. 2018). Approximately 90% of cancers have gained or lost one or both arms of at least one chromosome (Taylor, Shih et al. 2018). In recent years, large scale sequencing efforts have extended aneuploidy study, identifying DNA somatic copy number alterations (SCNAs). Published data suggest aneuploidy has a stronger impact on prognosis than gene mutations in multiple myeloma (Walker, Boyle et al. 2015; Bolli, Biancon et al. 2018; Jamal-Haniani, Wilson et al. 2017). Methods: Fifty one RRMM patients from our institute participated in Clinical-Grade Molecular Profiling of Patients with Multiple Myeloma and Related Plasma Cell Malignancies (MMRF-002) from Multiple Myeloma Research Foundation (MMRF) between March 2016 and November 2018. Genomic DNA was obtained from CD138+ sorted myeloma cells and a peripheral blood sample from each patient. Capture exome sequencing on a targeted panel of 1500 genes was performed by the Illumina HiSeq 2500 (2x115bp paired-end reads, average 520X coverage). Copy number changes, loss of heterozygosity (LOH) and tumor purity were jointly estimated using an in-house pipeline for matched tumor/normal libraries. We assessed aneuploidy using chromosomal and arm level SCNAs which are determined by the median of SCNAs and summation of gain and loss of SCNAs for a given chromosomal arm, which are then used for a time-to-event analysis of overall survival (OS) of the patients. The differences between Kaplan-Meier overall survival curves were tested using the log-rank test. Hazard ratios (HR) were estimated from Cox proportional hazard regression. A threshold of significance was taken as p Results Patient demographic data is summarized in Table 1. All the patients in this study harbor DNA somatic copy-number abnormalities (SCNAs) on the arm level for at least one chromosome (Figure 1). Gain of a chromosome or a whole arm mostly occurs on 1q, 3, 5, 7, 9, 11, 15, 19, 21 while loss was noted in 1p, 8p, 13, 16q, and 17p. At a global-level, we find that whole genomic aneuploidies (genomic-level across all chromosomes) have a significant association with inferior OS. Specifically, patients with a high frequency of genomic aneuploidies (defined as number of SCNA >8, the first quartile) had a significantly worse prognosis than those with low number of SCNA events ( Using univariate analysis, we identified five arm-level aneuploidies which are significantly associated with worse OS: 10p, 10q, 11p, 18q and 20q. It is noteworthy that aneuploidies in either arm of chromosome 10 (10p and 10q) had significant negative OS prognostic effect: 10p (median survival for diploid 28.9 vs. aneuploid 4.1 mo; p Given the small sample size we did not conduct a multivariable analyses and multiplicity adjustment in this preliminary analyses. Conclusion Aneuploidy measured by SCNAs is correlated with unfavorable survival in relapsed/refractory myeloma. The higher the occurrence of aneuploidies, the worse the overall survival, illustrating of the impact of cancer genome instability. Disclosures Ye: Janssen: Research Funding; Karyopharm: Research Funding; Portola: Research Funding; MingSight: Research Funding; Sanofi: Research Funding. Talpaz:Imago BioSciences: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding; Constellation: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Samus Therapeutics: Research Funding. Bergsagel:Celgene: Consultancy; Ionis Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy.

Introduction: Proteasome inhibitors (PI) and immunomodulatory drugs have become the backbone of therapy for multiple myeloma (MM). The oral boron-containing selective and reversible proteasome inhibitor ixazomib has shown to induce deep and durable responses (Kumar RK et la, Blood 2016. 128(20):2415-2422). Triplets containing ixazomib, has shown to be more efficacious than doublet regimens in the relapse setting (Moreau P, et al. N Engl J Med 2016. 374:1621-1634).However, to date, there is not companion diagnostics capable of predicting PI response. We have recently discovered that MM patients resistant to PI lack of the ankyrin (ANK) and death domain (DD) present in the 3'-end of NFKB2. Loss of NFKB2 3'end frequently resulted from a structural rearrangements. We found that NFKB2-ANK and -DD are crucial at initiating bortezomib's apoptotic signal by facilitating caspase-8 activation (unpublished data). Based on this findings, we designed this study to examine the efficacy of NFKB2 break apart FISH to predict the response to ixazomib and dexamethasone (Id) vs. ixazomib, lenalidomide and dexamethasone (IRd) in early relapse MM patients. Methods: In this phase 2 biomarker-driven open-label trial, relapsed patients with Results: At the moment of the interim analysis, 50 patients have achieved 4 cycles of treatment. All treatment groups (NFKB2 FISH [-] Id, n=24, NFKB2 FISH [+] Id, n=13 and IRd, n=12) received a median of 2 prior lines of therapy. A trend to higher ORR was observed in NFKB2 FISH negative treated with Id compared with NFKB2 FISH positive (48% CI:58%-97% vs. 23% CI:8%-60%, P=0.1), including significantly higher rates of ≥ very good partial response, ≥ partial response, ≥ minimal response (16%, 29%, 12.5% vs. 0.7%, 18%, 18%, respectively). ORR for IRd arm is for now 54% CI:27%-80%. Interestingly, >G3 treatment related adverse events were higher in Arm A (45%) and Arm C (60%) vs Arm B (15%). The most common (≥10%) ≥ grade 3 include URI/pneumonia 16% and diarrhea 12% in Id NFKB2 FISH negative vs. neutropenia 18% and diarrhea (10%) in the IRd NFKB2 FISH positive arm. Treatment discontinuations only occurred in 3 NFKB2 FISH positive Id treated patient (13%). Conclusion: Interim analysis demonstrates a trend higher efficacy and ≥G3 toxicity of ixazomib with dexamethasone in MM patients with negative NFKB2 break-apart FISH compared to those with a positive test. Efficacy and toxicity of the triplet regimen are comparable to what is seen in the Tourmaline 1 trial. This study is registered clinicaltrials.gov# NCT02765854 Disclosures Bernal-Mizrachi: TAKEDA: Research Funding; Winship Cancer Institute: Employment, Patents & Royalties; Kodikas Therapeutic Solutions, Inc: Equity Ownership. Nooka:GSK: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation; GSK: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation; Janssen: Honoraria, Other: advisory board participation; Celgene: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation; Takeda: Honoraria, Other: advisory board participation; Amgen: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation. Ye:Portola Pharmaceuticals: Research Funding; MingSight: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Vij:Takeda: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria. Hofmeister:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees. Rushton:KSLBiomedical: Employment. Lonial:Genentech: Consultancy; Karyopharm: Consultancy; Celgene Corporation: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy; BMS: Consultancy; Janssen: Consultancy, Research Funding; GSK: Consultancy. Kaufman:Amgen: Consultancy; Winship Cancer Institute of Emory University: Employment; AbbVie: Consultancy; Takeda: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria.

Introduction: Selinexor is a novel, oral selective inhibitor of nuclear export (SINE) which forces nuclear retention and activation of tumor suppressor proteins. Selinexor plus low dose dexamethasone (Sel-dex) was recently approved in the United States based on data from the STORM study wherein, Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. The presence of high-risk cytogenetic abnormalities is known to have a poor prognosis in multiple myeloma, with transient responses. We performed post-hoc analyses to determine the outcomes in patients with relapsed/refractory myeloma treated with Sel-dex based on the baseline cytogenetic abnormalities. Methods: STORM was a phase 2b, open-label study which enrolled patients with relapsed and refractory myeloma. Selinexor 80 mg in combination with dexamethasone 20 mg was administered orally, twice weekly. The primary endpoint was ORR. For this analysis, we pooled 78 patients (48 quad-refractory and 30 penta-refractory) from STORM, part 1 and 122 patients (penta-exposed and triple class refractory) from STORM, part 2 to compare outcomes between high-risk and standard risk cytogenetics groups. High-risk cytogenetics was defined as having at least 1 of the following abnormalities by fluorescence in-situ hybridization (FISH) at baseline: del(17p), t(4;14), t(14;16), and gain(1q) in >5% of screened plasma cells. The FISH analyses were performed at a central laboratory and used to assess cytogenetic risk status. Results: Of the 200 patients, 122 (61%) had high-risk disease (del(17p): 36%, t(4;14): 18%, t(14;16): 5%, and gain(1q): 36%). The ORR in high-risk patients was 20.5% (very good partial response [VGPR)]: 5.7% and partial response [PR]: 14.8%) and the ORR was 29.5 % (complete response [CR]: 2.6%, VGPR: 3.8%, and PR: 23.1%) in standard-risk patients. The clinical benefit rate (CBR) was 35.2% in high-risk patients compared with 38.5% in standard-risk patients. Median duration of clinical benefit (DOCB) was 4.4 and 6.2 months in the high-risk and standard-risk patients respectively. Median progression-free survival (PFS) was 3.8 and 4.2 months and overall survival (OS) was 8.6 and 9.4 months in the high-risk and standard-risk patients, respectively. Efficacy by specific cytogenetic abnormality is presented in Table 1 below (Due to the small sample size (n=11), data for the t(14;16) subgroup are not presented separately). Conclusions: Sel-dex demonstrated a similar CBR in patients with high risk and standard risk disease and preserved clinical benefit in heavily pre-treated patients who had rapidly proliferative disease and high-risk cytogenetics at baseline. The benefit was maintained across cytogenetic risk subgroups with a higher ORR in the t(4;14) and gain(1q) subgroups. The DOR and OS was similar across all the subgroups. These analyses support the use of Sel-dex in patients with high-risk cytogenetics and warrant further evaluation of selinexor in combination with other anti-myeloma therapies in high-risk disease. Disclosures Nooka: GSK: Honoraria, Other: advisory board participation; Amgen: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation; Janssen: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation; Celgene: Honoraria, Other: advisory board participation; Takeda: Honoraria, Other: advisory board participation. Yee:Adaptive: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Huff:Karyopharm, Sanofi, MiDiagnostics: Consultancy; Member of Safety Monitoring Board for Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees. Vogl:Karyopharm Therapeutics: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Active Biotech: Consultancy. Chari:Novartis Pharmaceuticals: Research Funding; GlaxoSmithKline: Research Funding; Array Biopharma: Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Oncoceutics: Research Funding. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; alexion: Consultancy; Janssen: Consultancy. Lonial:Genentech: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy; BMS: Consultancy; Janssen: Consultancy, Research Funding; GSK: Consultancy; Celgene Corporation: Consultancy, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding. Vij:Takeda: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Genentech: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Tuchman:Karyopharm: Honoraria; Celgene: Honoraria, Research Funding, Speakers Bureau; Amgen: Research Funding; Merck: Research Funding; Prothena: Research Funding; Roche: Research Funding; Sanofi: Research Funding; Alnylam: Honoraria, Research Funding. Biran:Bristol Meyers Squibb: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Siegel:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Richardson:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liu:Karyopharm Therapeutics: Employment, Equity Ownership. Joshi:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jagannath:Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Merck: Consultancy.

Introduction: Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that selectively binds and inactivates XPO1, therefore forcing the nuclear retention and re-activation of cell cycle regulators such as p53, FOXO, IkB, and Rb. Selinexor in combination with low dose dexamethasone (Sel-dex) was recently approved based on data from the STORM study, which induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma (TCR-MM). Patients with TCR-MM often present with plasmacytomas along with serological markers of MM. Methods: Here we analyzed the effects of Sel-dex in patients from the STORM study who had baseline plasmacytomas. Results: 122 patients were in enrolled in the STORM study including 27 with a baseline plasmacytoma. The majority of plasmacytomas were soft tissue (22 patients) and 5 patients had soft tissue disease extension from a bone (rib (2), iliac (2), sacral vertebral). The median age of patients with plasmacytomas was 64 years, the median prior therapies were 7 (range 4 - 15), and 8/27 patients with a plasmacytoma had high risk cytogenetics. Of the 27 patients, 11 patients did not have a follow up plasmacytoma assessment: 6 were not evaluable for response as they came off therapy due to clinical progression and/or adverse events, 4 had stable disease (SD) with no evidence of plasmacytoma change, and 1 had progressive disease (PD) on serum M-protein with no evidence of plasmacytoma change. Sixteen of the 27 patients did have follow-up plasmacytoma assessments (methods of measurements included PET, CT, MRI or Clinical). The median days from baseline plasmacytoma evaluation to follow up was 41 days (range 22 - 119). Five patients had objective responses, based upon para-protein and plasmacytoma reductions according to IMWG criteria (1 very good partial response [VGPR], 4 partial responses [PR]) for an ORR of 18.5%. In addition, 2 patients had a minimal response (MR), 4 had SD and 5 had objective PD. Among the 5 patients with ≥PR, 3 plasmacytomas completely resolved, 1 showed near complete resolution, and another showed size reduction with no metabolic activity on PET. Of the 2 patients with a MR, 1 plasmacytoma completely resolved and 1 showed reduced PET uptake. Among the 4 patients with SD, 1 plasmacytomas completely resolved, 1 increased in size and 2 had unknown outcomes as they were assessed clinically. Among the 5 patients with PD, 1 plasmacytomas decreased in size, 1 increased in size, and 3 had unknown outcomes as they were assessed clinically. Conclusions: Of the 16 patients with TCR-MM and a follow up plasmacytoma assessment enrolled on STORM, 9/16 of the plasmacytomas either completely resolved or decreased in size and/or metabolic activity. Effects on plasmacytomas occurred in patients with objective responses (≥PR), as well as in patients with MR, SD and PD. These observations support the finding that Sel-dex is active in patients with plasmacytomas and heavily pretreated TCR-MM. Disclosures Yee: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Karyopharm: Consultancy; Adaptive: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding. Huff:Member of Safety Monitoring Board for Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees; Karyopharm, Sanofi, MiDiagnostics: Consultancy. Chari:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Oncoceutics: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; GlaxoSmithKline: Research Funding; Novartis Pharmaceuticals: Research Funding. Vogl:Active Biotech: Consultancy; Janssen: Consultancy; Karyopharm Therapeutics: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy. Gavriatopoulou:Genesis: Honoraria, Other: Travel expenses; Amgen: Honoraria; Janssen: Honoraria, Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses. Nooka:Adaptive technologies: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; GSK: Honoraria, Other: advisory board participation; Janssen: Honoraria, Other: advisory board participation; Amgen: Honoraria, Other: advisory board participation; Takeda: Honoraria, Other: advisory board participation; Celgene: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation. Moreau:AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Lonial:Janssen: Consultancy, Research Funding; GSK: Consultancy; Karyopharm: Consultancy; BMS: Consultancy; Celgene Corporation: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Genentech: Consultancy. Dimopoulos:Sanofi Oncology: Research Funding. Vij:Takeda: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Genentech: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Tuchman:Prothena: Research Funding; Amgen: Research Funding; Karyopharm: Honoraria; Alnylam: Honoraria, Research Funding; Sanofi: Research Funding; Merck: Research Funding; Roche: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Hoffman:Celgene: Speakers Bureau. Costa:Abbvie: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor. Biran:Janssen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding; Takeda: Consultancy, Honoraria. Siegel:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Picklesimer:Karyopharm Therapeutics: Employment, Equity Ownership. Saint-Martin:Karyopharm Therapeutics: Employment, Equity Ownership. Li:Karyopharm Therapeutics: Employment, Equity Ownership. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Richardson:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Jagannath:Multiple Myeloma Research Foundation: Speakers Bureau; Medicom: Speakers Bureau; Merck: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy.

Background Elotuzumab is an approved monoclonal antibody targeting SLAMF7 on plasma and NK cells that enhances the activity of lenalidomide, pomalidomide, and bortezomib in multiple myeloma (MM). A recent study showed improved outcomes with the combination of pomalidomide, bortezomib, and dexamethasone vs. bortezomib and dexamethasone in relapsed or refractory MM (Richardson PG et al., Lancet Oncol 2019). We therefore studied elotuzumab with pomalidomide, bortezomib, and dexamethasone (elo-PVD) in relapsed and refractory MM. Methods The primary objective was to determine the overall response rate (ORR). Patients with relapsed and refractory disease and ≥1 prior lines of treatment (including lenalidomide and a proteasome inhibitor) were eligible to participate. Prior treatment with pomalidomide was permitted. Elotuzumab was weekly for the first 2 cycles and then every other week. Pomalidomide was given on days 1-21; bortezomib was on days 1, 8, 15; and dexamethasone was weekly. Each cycle was 28 days. Results The trial has completed accrual in September 2018 with 48 patients receiving treatment. The median age was 64 (range 40-80), and median number of prior regimens was 3 (range 1-9); 25% had high risk FISH. All patients had prior lenalidomide and proteasome inhibitor (bortezomib 96%, 29% carfilzomib) and were refractory to their last line of therapy. Other prior therapies included: autologous stem cell transplant (48%), pomalidomide (33%), daratumumab (25%), and isatuximab (4%). 46 patients were assessable for response (2 patients did not complete cycle 1 and were not evaluable for response: 1 due to rapid disease progression; 1 stroke. The median length of follow up was 18.8 months (range 0.5-23.4): 16 patients continue on study; 27 patients discontinued for progressive disease; 3 patients discontinued for adverse events (AEs) (sepsis, pneumonia, stroke); 1 patient underwent auto SCT; and 1 patient was lost to follow up. Best ORR was 61% (PR = 16, VGPR = 10, CR = 2). ORR for patients with prior anti-CD38 antibody, 46%; carfilzomib, 46%; pomalidomide, 43%. Median PFS was 9.8 months (95% CI 6.8-Inf). In patients with 1 prior line of therapy, ORR was 74% and median PFS was not reached (95% CI 12-Inf); 18 month PFS was 68%. Grade ≥ 3 hematologic AEs included anemia (10%), neutropenia (29%), and thrombocytopenia (15%). Additional common grade ≥ 3 AEs included lung infection (27%) and hypophosphatemia (15%). Common non-hematologic AEs all grades included fatigue (grade 1-2 only, 70%), upper respiratory infection (grade 1-2, 56%; grade 3, 2%), diarrhea (grade 1-2 only, 42%), constipation (grade 1-2 only, 35%), hyperglycemia (grade 1-2, 46%; grade 3, 4%), and sensory neuropathy (grade 1-2 only, 31%), with 2 possibly related deaths (sepsis, pneumonia). Conclusions Elo-PVD is one of the first trials of a quadruplet regimen in relapsed and refractory MM incorporating a monoclonal antibody. In patients with refractory disease, elo-PVD shows encouraging responses. With the limitations of cross trial comparisons and small patient numbers, for patients with 1 prior line of treatment and refractory disease, a PFS at 18 months of 68% with elo-PVD compares favorably with a median PFS of 17.8 months in a similar subgroup of PVD in the OPTIMISMM trial (Dimopoulos MA et al., ASH 2018). Patients who received prior pomalidomide, carfilzomib, and/or anti-CD38 monoclonal antibody also benefited. Treatment was well-tolerated with manageable toxicity and with attention to infectious AEs. Disclosures Yee: Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Karyopharm: Consultancy; Adaptive: Consultancy; Amgen: Consultancy, Honoraria. Lipe:Celgene: Consultancy; amgen: Research Funding; amgen: Consultancy. Nadeem:Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy. O'Donnell:Celgene: Consultancy; Amgen: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Branagan:Pharmacyclics: Consultancy; Janssen: Consultancy; Surface Oncology: Consultancy. Lohr:Celgene: Research Funding; T2 Biosystems: Honoraria. Anderson:Sanofi-Aventis: Other: Advisory Board; Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Richardson:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. OffLabel Disclosure: The combination of elotuzumab, pomalidomide, bortezomib, and dexamethasone is an off-label use in relapsed and refractory multiple myeloma.

Background: Isatuximab (ISA) targets CD38-expressing tumor cells through a combination of activities, including antibody-dependent cellular cytotoxicity, direct pro-apoptotic activity, and complement-dependent cytotoxicity. A phase I study evaluating ISA monotherapy demonstrated promising clinical activity in 35 patients with relapsed/refractory multiple myeloma (RRMM) (Martin T et al, J Clin Oncol 2014; 32:8532). This is an ongoing phase II study (NCT01084252) with 2 stages: stage 1 to select the dose for stage 2 of the study, and stage 2 to assess efficacy and safety of ISA monotherapy or in combination with dexamethasone in RRMM. In stage 1, patients were randomized to 1 of 3 dose groups: ISA 3 mg/kg Q2W, 10 mg/kg Q2W × 2 cycles then Q4W, or 10 mg/kg Q2W. Based on pharmacokinetic data, a fourth dose of 20 mg/kg QW × 4 doses then Q2W was added. The overall response rates (ORRs) for the 4 dosing schemes were 4% (1/23), 20% (5/25), 29% (7/24), and 24% (6/25), respectively. Based on these results, a dose of 20 mg/kg QW for cycle 1 followed by 20 mg/kg Q2W in subsequent cycles was chosen for stage 2 of the study (Richter J et al, J Clin Oncol 2016;34:8005). Here, we report the baseline characteristics and demographic data from stage 2 at the selected dosing scheme from stage 1. Full safety and efficacy data will be presented at the meeting. Methods: This study enrolled patients with MM who had previously received an immunomodulatory drug and a proteasome inhibitor. Patients received ISA monotherapy (20 mg/kg on Day 1, 8, 15, and 22 [QW] of cycle 1 followed by 20 mg/kg on Day 1 and 15 [Q2W] of subsequent cycles) or ISA in combination with dexamethasone (40 mg/day [20 mg/day in patients ≥75 years old]). The primary objective was to evaluate the activity of ISA as monotherapy and in combination with dexamethasone in patients with RRMM in terms of ORR. Results: A total of 165 patients received at least 1 cycle of treatment. Median age was 67 (37-85) years. Median time from diagnosis to first dose was 5.35 (0.7-23.0) years. Median number of prior lines was 4 (2-11) and median number of prior regimens was 6 (2-17). Patients received a median of 5 (1-17) cycles of treatment, with a median duration of exposure of 22 (1-69) weeks. Discontinuation occurred in 106 (64.2%) patients due to adverse events (15 patients, 9.1%), disease progression (85 patients, 51.5%), or patient decision (6 patients, 3.6%). Conclusion: The full efficacy and safety data for this heavily pre-treated RRMM population will be available for presentation at the meeting. Funding: Sanofi Disclosures Dimopoulos: Janssen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Bringhen:Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria. Anttila:Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Capra:Janssen: Research Funding, Speakers Bureau; Roche: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Research Funding; Sanofi: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Cavo:AbbVie: 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, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cole:University of Michigan: Employment; Cancer Support Community myeloma advisory board: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel; Takeda: Honoraria. Hungria:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Jenner:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vorobyev:Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Biocad: Consultancy; Takeda: Speakers Bureau; BMS: Speakers Bureau; Astellas: Speakers Bureau. Yanez Ruiz:Universidad de la Frontera: Employment. Yin:Sanofi: Employment. Hamlett:BDM Consulting Inc.: Employment; Sanofi: Consultancy. Vij:Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Introduction: Selinexor is a novel, oral Selective Inhibitor of Nuclear Export (SINE) compound that blocks exportin 1 (XPO1). Selinexor treatment results in nuclear accumulation and activation of tumor suppressor proteins, inhibition of NF-kB, and translational suppression of several oncoprotein mRNAs (e.g., c-myc, cyclin D).Multiple myeloma (MM) remains incurable, and most patients (pts) eventually progress through standard drug classes of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), anti-CD38 mAbs and others. The increased use of combinations in MM treatment, (PIs/IMiDs/mAbs), has led to a growing number of pts with penta-refractory MM (pts that have been treated with bortezomib (bort), carfilzomib (carfil), lenalidomide (len), pomalidomide (pom) and daratumumab (dara)). Active novel therapies with different mechanisms of actions are needed to address this unmet medical need. Part 1 of STORM enrolled pts with both quad- (bort, carfil, len, pom, treated MM) or penta-refractory MM and demonstrated an overall response rate (ORR) of 21% (Vogl et al, JCO 2018). Based on these findings, the Pivotal Part 2 of STORM was initiated, enrolling an additional cohort of 122 patients with penta-refractory MM. Methods: Pts with penta-refractory MM were treated with 80 mg selinexor plus 20 mg dexamethasone (Sd) twice weekly. Pts must have received an alkylator, bort, carfil, len, pom and dara, and had MM refractory to ≥1 PI, ≥1 IMiD, dara, a glucocorticoid, and their last therapy. Pts must have a total ANC ≥1000 mm3,platelets ≥50k/mm3 (or ≥75k if marrow plasma cells Results: As of 1-Jun-2018, 122 pts (71 M/ 51 F) were enrolled in 38 sites (US and EU). Pt characteristics were [medians (range)]: age 65 yrs (40-85); 7 (3 - 18) prior treatment regimens, 6.6 yrs ( Conclusions: Results of the pivotal STORM Part 2 in penta (PI, IMiD, dara)-refractory MM demonstrated that oral selinexor plus low-dose dexamethasone (Sd) was highly active with an ORR of 26.2%. Importantly, responses were rapid and deep with 2 patients achieving sCRs (both MRD negative) in these heavily pre-treated penta-refractory MM pts (median 7 prior regimens, 53% high risk). AEs are a function of dose/schedule/disease severity and can be managed with dose modifications and supportive care. No major organ toxicity was observed and AEs were typically transient and reversible. Sd is an all-oral, first in class mechanism with novel MOA and represents a potential therapeutic option to the growing number of pts with penta-refractory MM who have exhausted approved therapies. Disclosures Chari: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy. Vogl:Karyopharm Therapeutics: Consultancy. Dimopoulos:Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moreau:Amgen: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cole:University of Michigan: Employment; Cancer Support Community myeloma advisory board: Membership on an entity's Board of Directors or advisory committees. Dingli:Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Vij:Jazz Pharmaceuticals: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria, Research Funding; Bristol Myer Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Raab:BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Weisel:Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Delforge:Celgene and Janssen: Research Funding; Amgen, Celgene, Janssen and Takeda: Consultancy. Stewart:Amgen Inc., BMS, Celgene, Takeda, Roche, Seattle Genetics, Janssen, Ono: Consultancy; Amgen Inc., Celgene, Roche, Seattle Genetics: Research Funding. Mohty:Amgen: Consultancy, Honoraria; Molmed: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Servier: Consultancy; Jazz Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Bristol Myers: Consultancy, Research Funding. Sylvain:Gilead: Other: scientific advisor board. Costa:Celgene: Honoraria, Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding; Janssen: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; BMS: Research Funding. Shah:Karyopharm Therapeutics: Employment. Picklesimer:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therapeutics: Employment. Li:Karyopharm Therapeutics: Employment. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Jagannath:Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Multiple Myeloma Research Foundation: Speakers Bureau; Medicom: Speakers Bureau; Novartis: Consultancy; Merck: Consultancy.

OBJECTIVES: Several agents have recently been approved for relapsed/refractory multiple myeloma (RRMM), providing patients and providers with more treatment options. The existing literature on patient preferences for MM treatments is limited. This study aims to quantify these preferences using a discrete-choice experiment (DCE) survey coupled with a best-worst scaling (BWS) exercise to elicit treatment priorities and unmet needs. METHODS: The survey design utilized both a DCE and a BWS exercise that included attributes and levels that overlapped between the two types of patient preference questions (DCE and BWS) to provide multiple sources of information on treatment preferences. The attributes for the DCE and BWS exercise were informed by patient focus groups. The final DCE included six attributes with varying levels: progression-free survival (PFS, 6-24 months); risk of heart failure (0%-5%); peripheral neuropathy (none, mild-to-moderate, severe); risk of low blood counts, combining thrombocytopenia and neutropenia (0%-70%); gastrointestinal (GI) problems (none, nausea and vomiting, diarrhea, constipation); and mode and frequency of administration (daily and weekly pill, weekly injection, intravenous [IV] infusion 4 hours per week, IV 1 hour twice a week). The BWS exercise included 18 items (the modes and frequency of administration included in the DCE, additional treatment convenience items, mild and serious adverse events, and treatment side-effects). The final survey was administered online to patients recruited from the Multiple Myeloma Research Foundation CoMMpass study (NCT01454297). For the DCE data, latent-class analysis was used to identify patient subgroups with systematically different preferences. The relative strength of preference for each attribute level (i.e., relative preference weights) was estimated for all subgroups and was used to calculate the relative importance of attributes. For each item in the BWS exercise, a relative score was calculated by subtracting the number of times a feature was chosen as least bothersome from the number of times it was chosen as most bothersome, then dividing by the total number of times appeared in the design. RESULTS: The final sample consisted of 94 patient respondents with RRMM. Patients had an average age of 65 years, and 59% were male. The latent-class analysis identified two subgroups of respondents with systematically different preferences (Figure 1). Both subgroups expressed a willingness to trade PFS for less treatment toxicity. Members of subgroup 1 placed the greatest relative importance on toxicities (nerve damage, risk of low blood counts, GI problems). A change in nerve damage from none to severe was the most important attribute to subgroup 1, approximately 1.8 times more important than the relative importance of a change in the risk of low blood counts from 0% to 70%, and 2.7 times more than the relative importance of a change in PFS from 6 months to 1 year. Members of the second subgroup considered PFS the most important attribute, followed by nerve damage and mode of administration. Subgroup 2 considered the relative importance of a change in PFS from 6 months to 2 years to be more than two times as important as the relative importance of changes in all other attributes. In the BWS exercise, respondents evaluated kidney complications and low white blood cell count as the most bothersome medicine characteristics, while taking pills once a week for 3 weeks per month or pill taken daily were the least bothersome (most favorable) characteristics. CONCLUSIONS: Patients with RRMM place importance on PFS and nerve toxicity when considering treatment features and modes of administration. Results from the preference study indicate that there are subgroups of patients with systematically different treatment preferences. Understanding how different patients value treatment attributes may help decision makers improve the quality of patient-centered care. Figure 1. Figure 1. Disclosures Mansfield: Takeda Pharmaceuticals International Co: Consultancy; Genentech: Consultancy. Chari:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array Biopharma: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Consultancy. Cole:Cancer Support Community myeloma advisory board: Membership on an entity's Board of Directors or advisory committees; University of Michigan: Employment. Kaufman:Karyopharm: Other: data monitoring committee; Roche: Consultancy; BMS: Consultancy; Janssen: Consultancy; Abbvie: Consultancy. Siegel:BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Zonder:Takeda: Honoraria; Alnylam: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Coelum: Honoraria; BMS: Research Funding; Pharmacyclics: Other: DSMC. Mange:Takeda Pharmaceutical Company: Consultancy. Dalal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA: Employment, Equity Ownership. Mikhael:Onyx, Celgene, Sanofi, AbbVie: Research Funding.

Introduction: Proteasome inhibitors (PI) and immunomodulatory drugs have become the backbone of therapy for multiple myeloma (MM). The oral boron-containing selective and reversible proteasome inhibitor ixazomib has shown to induce deep and durable responses (Kumar RK et la, Blood 2016. 128(20):2415-2422). Triplets containing ixazomib, has shown to be more efficacious than doublet regimens in the relapse setting (Moreau P, et al. N Engl J Med 2016. 374:1621-1634).However, to date there is not companion diagnostics capable of predicting PI response. We have recently discovered that MM patients resistant to PI lack of the ankyrin (ANK) and death domain (DD) present in the 3'-end of NFKB2. Loss of NFKB2 3'end frequently resulted from a structural rearrangements. We found that NFKB2-ANK and -DD are crucial at initiating bortezomib's apoptotic signal by facilitating caspase-8 activation. Activation of this caspase resulted from NFKB2 interaction with FADD/caspase-8/p62 (unpublished data). Based on this findings, we design this study to examine the efficacy of NFKB2 break apart FISH to predict the response to the duplet ixazomib and dexamethasone (Id) vs ixazomib, lenalidomide and dexamethasone (IRd) in early relapse MM patients (1-3 lines of therapy). Methods: In this phase 2 biomarker driven open label trial, relapse patients with Results: At the moment of interim analysis, 26 patients have achieved 4 cycles of treatment. All treatment groups (NFKB2 FISH [-] Id, n=16, NFKB2 FISH [+] Id, n=6 and IRd, n=4) received a median of 2 prior lines of therapy. A higher ORR was observed in NFKB2 FISH negative treated with Id compared with NFKB2 FISH positive (56.3% CI:29.9%-80.3% vs. 16.7% CI:0.4%-64.1%, P=0.16), including significantly higher rates of ≥very good partial response, ≥ partial response, ≥ minimal response (12%, 37.5%, 6% vs. 0%, 0%, 16%, respectively). ORR for IRd arm is for now 25% CI:0.6%-80.6%. Patients that continue treatment after cycle 4 that achieve minimal response or better improved their depth of response in 6% in Id treated NFKB2 FISH negative patients and 25% of IRd treated NFKB2 FISH negative patients. The most common (≥10%) grade 2/4 include pneumonia 20% (Id treated NFKB2 FISH negative), thrombocytopenia 16% (Id NFKB2 FISH positive), neutropenia 60% (IRd NFKB2 FISH positive. Treatment discontinuations only occurred in 1 Id treated patient (5%). Conclusion: Interim analysis demonstrate a trend higher efficacy of ixazomib with dexamethasone in MM patients with negative NFKB2 break-apart FISH compared to those with a positive test. Efficacy and toxicity of the triplet regimen are comparable to what is seen in Tourmaline 1 trial. This study was registered at www.clinicaltrials.gov as # NCT02765854. Disclosures Bernal-Mizrachi: Takeda Pharmaceutical Company: Research Funding; Kodikaz Therapeutic Solutions: Consultancy, Equity Ownership. Cole:Cancer Support Community myeloma advisory board: Membership on an entity's Board of Directors or advisory committees; University of Michigan: Employment. Heffner:ADC Therapeutics: Research Funding; Kite Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vij:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kelkar:Empire Genomics: Employment. Lonial:Amgen: Research Funding. Kaufman:Karyopharm: Other: data monitoring committee; Abbvie: Consultancy; Roche: Consultancy; BMS: Consultancy; Janssen: Consultancy.

Introduction: Despite therapeutic advances, most patients (pts) with multiple myeloma (MM) eventually develop relapsed/refractory (RR) disease, and observational studies of pts refractory to immunomodulatory drugs and proteasome inhibitors have demonstrated a median overall survival (OS) of 13 mo (Kumar et al, Leukemia 2017;31:2443-8). Elotuzumab, an immunostimulatory monoclonal antibody targeted to SLAMF7, directly activates natural killer cells and mediates the killing of MM cells through antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. Elotuzumab, combined with lenalidomide (len) and dexamethasone (dex), is indicated in the USA and EU for RRMM in pts who have received ≥1 prior therapy. Pomalidomide (pom), a 2nd-generation immunomodulatory drug, appears to synergize with elotuzumab. The phase 2, randomized, international, exploratory ELOQUENT-3 study (NCT02654132) assessed elotuzumab combined with pom and dex (EPd) vs pom and dex (Pd); after a minimum follow-up of 9 mo, median progression-free survival (PFS) with EPd was 10.3 vs 4.7 mo with Pd (hazard ratio=0.54) and the overall response rate (ORR) was 53% vs 26% (Dimopoulos et al, EHA 2018 [LB2606]). In this supportive study, with a minimum follow-up of 16 mo, we present initial efficacy and safety data for EPd in pts with relapsed and/or refractory MM. Methods: This phase 2, multicenter, non-comparative study (NCT02612779) enrolled pts ≥18 y of age with MM who were relapsed, refractory, or intolerant to len (received for ≥2 consecutive cycles), 1-2 prior therapies, disease progression during or after their last therapy, and with an Eastern Cooperative Oncology Group performance status of ≤2. Prior pom was not permitted. Pts received elotuzumab 10 mg/kg IV weekly for the first two 28-d cycles and 20 mg/kg IV every 4 wk thereafter. Pom 4 mg orally was given on Days 1-21 of each cycle and dex 40 or 20 mg oral equivalent was given weekly for pts ≤75 or >75 y of age, respectively. Primary endpoint was PFS; additional endpoints included OS, ORR, and safety. Results: At database lock (Apr 4, 2018), 68 pts had received EPd. At baseline, median age was 67 y, 35 pts (51%) were male, and 21 (31%) had International Staging System stage II-III disease. Median (range) prior number of therapies was 2 (1-5) and 34 pts (50%) were relapsed and refractory to their most recent therapy; 6 pts had received ≥3 prior therapies. Prior therapies included len (n=68, 100%), bortezomib (n=59, 87%), cyclophosphamide (n=20, 29%), carfilzomib (n=14, 21%), and autologous stem cell transplantation (n=38, 56%). At analysis, pts had received a median of 9 cycles of EPd and 13 (19%) were still on treatment. The most common reasons for discontinuation were disease progression (n=26, 38%) and maximum clinical benefit (n=10, 15%). Median PFS was 11.1 mo (Figure) and ORR was 51%. Overall, 9 pts (13%) achieved very good partial response or better, 26 (38%) achieved partial response, and 12 (18%) achieved minimal response. Median (95% CI) duration of response was 16.7 (11.3, not estimable [NE]) mo. Median time to first response was 1 mo, and to best response was 2.8 mo. Median (95% CI) OS was 22.4 (21.8, NE) mo. Pts with ≥2 prior therapies had a median (95% CI) PFS of 11.1 (5.6, 15.0) mo and an ORR of 46%. The most frequent all-cause non-hematologic adverse events (AEs) were fatigue (n=37, 54%), diarrhea (n=23, 34%), and upper respiratory tract infection (n=23, 34%); all-cause infections were reported in 47 pts (69%). No second primary malignancies were reported. The most common all-cause hematologic AE was neutropenia, reported in 24 pts (35%) and grade 3-4 in 11 (16%). Anemia was reported in 15 pts (22%) and was grade 3-4 in 4 (6%). Infusion reactions were reported in 5 pts (7%), all grade 1-2. In total, 7 pts (10%) experienced grade 5 AEs, 1 of which (pulmonary sepsis) was considered related to treatment. Overall, 11 pts (16%) experienced AEs leading to discontinuation. Conclusions: EPd was associated with a median PFS of 11.1 mo and ORR of 51% in pts with RRMM. Safety was consistent with prior reports of elotuzumab and pom, with no new safety signals. These data, coupled with findings from the randomized ELOQUENT-3 study, support EPd as a new, effective treatment option for pts with RRMM. Study support: BMS. Medical writing: Adam Gill, Caudex, funded by BMS Disclosures Jagannath: Merck: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Multiple Myeloma Research Foundation: Speakers Bureau; Medicom: Speakers Bureau. Berdeja:Teva: Research Funding; Glenmark: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Bluebird: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Sanofi: Research Funding. Rifkin:Celgene: Consultancy; EMD Serono: Consultancy; Takeda: Consultancy; Sandoz: Consultancy; McKesson: Equity Ownership; Boehringer Ingelheim: Consultancy; Amgen: Consultancy. Cole:University of Michigan: Employment; Cancer Support Community myeloma advisory board: Membership on an entity's Board of Directors or advisory committees. Thompson:Syapse Precision Medicine Council: Other: Member; Strata Oncology: Membership on an entity's Board of Directors or advisory committees; VIA Oncology: Other: Co-Chair Medical Hematology ITP Committee, Co-Chair Medical Oncology Indolent Lymphoma Committee; Plasma Cell Dyscrasias: Patents & Royalties: Peer Review for Plasma Cell Dyscrasias (Editor: Robert Kyle); Glaxosmith Kline: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Multiple Myeloma Registry; AIM Specialty Health: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Connect MDS/AML Registry - Scientific Steering Committee Member. Vij:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Popa-McKiver:Bristol-Myers Squibb: Employment. Saleem:Bristol-Myers Squibb: Employment. Sy:Bristol-Myers Squibb: Employment. Bensinger:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

BACKGROUND:In recent years,we saw four patients with iron deficiency anemia (IDA) in our clinical practices who developed a compulsive craving for certain odors including rubber tires, gasoline, Pine-Sol® (a popular household alcohol ethoxylate-based cleaning agent), and "musty odor of the basement." Such behavior resolved after treatment of IDA, and recurred in a patient whose IDA relapsed. This resembled pica, a craving to eat non-nutritive items, which is commonly associated with IDA. Because we had never heard of or read about this phenomenon, we reviewed the English medical literature and World Wide Web to determine if such experience had been previously reported. METHODS: We searched the PubMed, Google, and Google Scholar to find publications, reports, presentations, or testimonies of individual in online blogs using a combination of search terms including "nasal, olfactory, smell, craving, iron deficiency, and anemia." RESULTS: We found no scientific publication, report, or presentation similar to our experience in PubMed and Google Scholar. However, using Google search engine, we found several testimonies of individuals in online blog posts (mostly at babycenter.com and medhelp.org), several of which were pregnancy blogs that reported these peculiar symptoms. Individuals were reporting powerful cravings of olfaction, frequently being overtaken by a desire to smell certain odors. The types of substances for which they craved and their associated medical conditions (when reported) are summarized in the Table. CONCLUSIONS:These preliminary findings and testimonies give suggestive evidence that a condition, entirely separate from pica, exists in certain patients suffering from IDA or during pregnancy. For this, we propose the name, desiderosmia, derived from the Latin word "desiderare" for desire and the Greek word "osme" for smell. In naming this condition, we hope to inspire further investigation, and hopefully shed some light for patients who suffer from this newly described olfactory symptom. Table Reports of smell cravings and associated medical conditions found in online blogs Table. Reports of smell cravings and associated medical conditions found in online blogs Disclosures No relevant conflicts of interest to declare.

Introduction - With over 12,000 deaths from MM anticipated in 2016, nearly all patients (pts) with multiple myeloma (MM) will become "quad refractory" to IMIDs (lenalidomide and pomalidomide) and proteasome inhibitors (bortezomib and carfilzomib), and eventually "penta refractory" to anti-CD38 Abs (daratumumab and isatuximab), defining high unmet need populations. Selinexor, an oral selective XPO1 inhibitor, induces nuclear accumulation and activation of tumor suppressor proteins, inhibition of NF-kB, and inhibition of translation of several oncoprotein mRNAs such as c-myc and cyclin D. Selinexor showed potent induction of apoptosis of MM cells independent of p53 signaling. In phase 1 clinical studies, selinexor with low dose dexamethasone (Sd) demonstrated potent anti MM activity in pts with MM. Methods - This phase II clinical trial evaluated Sd in pts with MM refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide ("quad"), with a subset also refractory to an anti-CD38 Ab ("penta"). Inclusion required CrCL≥20 mL/min, ANC≥1000/µL, platelets ≥50K/µL (≥30K if plasma cells were ≥50% of marrow cellularity). Pts were treated twice weekly (BIW) with oral selinexor 80 mg for 6 or 8 doses per 28 day cycle and dexamethasone (dex) 20 mg BIW. All pts received 5-HT3 antagonists. The primary objective was to determine the overall response rate (ORR) per IMWG criteria and duration of response (DOR), both adjudicated by an independent review committee (IRC). Secondary endpoints include progression free survival (PFS) and overall survival (OS). FISH analyses and gene expression profiling were performed on bone marrow aspirates. Results - 79 pts were enrolled: 48 quad (24 M/24 F, median age 62 yrs) and 31 penta (13 M / 18 F, median age 68 yrs). Both groups had a median of 7 prior treatment regimens including multiple dex-containing regimens. Baseline laboratory abnormalities included grade (Gr)≥3 anemia in 13% and Gr≥3 thrombocytopenia in 8%. Most penta pts received 8 doses / cycle (65%); most quad pts received 6 doses / cycle (83%). Common treatment-related adverse events (TRAEs) hematological: thrombocytopenia (72%, Gr 3/4 58%), anemia (48%, Gr 3 25%) and neutropenia (29%, Gr≥3 21%). TRAEs non-hematological: nausea (72%, Gr 3 6%), fatigue (62%, Gr 3 14%) anorexia (49%, Gr 3 3%), vomiting (43%, Gr3 4%), asymptomatic hyponatremia (42%. Gr 3 20%), diarrhea (42%, Gr 3 5%) and weight loss (33%, Gr 3 1%). There was one case of febrile neutropenia (1%) and one case of clinically significant bleeding related to thrombocytopenia (1%). Seventy pts have discontinued therapy: PD (73%), AEs (17%), physician/pt preference (1%) and 6 deaths (one case related to selinexor, intracranial bleed in pt with Gr4 thrombocytopenia). Nine pts remain on study. Efficacy was evaluated in 78 pts (1 pt did not have measurable disease). The IRC-determined ORR (≥PR) for all pts was 21%, including 5% VGPR. ORR was 21% for quad pts and 20% for penta pts. Clinical benefit rates (≥MR) were 32% (all), 29% (quad), and 37% (penta). Median OS was 9.3 months (mo) for all pts, >11 mo (median not reached) for responders (≥PR), and 5.7 mo for non-responders. Median DOR in responding pts was 5 mo, and median PFS in all pts was 2.1 mo. Baseline cytogenetics were assessed in 41 pts. The ORR in 18 pts with high-risk FISH abnormalities was 33% (Table 1). Notably, 3 of the 13 pts with a 17p abnormality responded (ORR 23%). Transcriptomic profiling revealed differentially expressed genes (DEGs) between responders and non-responders in both whole blood RNA and CD138+ bone marrow cells. Pathways enriched in responders included IL-6, IL-8 and IGF-1 pathways. Conclusions - Oral Sd is active in heavily pretreated pts with refractory MM, including those with MM refractory to anti-CD38 Ab and those with high-risk cytogenetic abnormalities. Response was associated with longer survival. The main toxicities of Sd are thrombocytopenia, nausea, anorexia, and fatigue. AEs were manageable with supportive care and dose interruptions/reductions. To our knowledge, this is the first report of anti-tumor activity in the penta-refractory MM population. This population of MM pts has exhausted all currently available treatment options and has an extremely poor prognosis and therefore requires new therapies. Expansion of this trial in this high unmet medical need, penta refractory population is planned. Table 1 Activity of Sd in Patients with High Risk MM Cytogenetics Table 1. Activity of Sd in Patients with High Risk MM Cytogenetics Disclosures Vogl: Constellation: Research Funding; Karyopharm: Consultancy; Acetylon: Research Funding; GSK: Research Funding; Calithera: Research Funding; Teva: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Research Funding. Jagannath:Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Merck: Consultancy; Celgene: Consultancy. Baz:Bristol-Myers Squibb: Research Funding; Takeda/Millennium: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Signal Genetics: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Merck: Research Funding. Nooka:Spectrum, Novartis, Onyx pharmaceuticals: Consultancy. Richter:Takeda: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Janssen: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Vij:Karyopharm: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Consultancy; Takeda: Honoraria, Research Funding; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria. Schiller:Incyte Corporation: Research Funding. Costa:Sanofi: Honoraria, Research Funding. Chari:Array Biopharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Novartis: Consultancy, Research Funding. Siegel:Takeda: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Merck: Honoraria. Fonseca:Janssen: Consultancy; AMGEN: Consultancy; Millennium, a Takeda Company: Consultancy; Bayer: Consultancy; Sanofi: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; AMGEN: Consultancy; Novartis: Consultancy; Millennium, a Takeda Company: Consultancy; Sanofi: Consultancy; AMGEN: Consultancy; Janssen: Consultancy; BMS: Consultancy; Celgene: Consultancy; BMS: Consultancy; Millennium, a Takeda Company: Consultancy; Millennium, a Takeda Company: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Bayer: Consultancy; Novartis: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Celgene: Consultancy. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Saint-Martin:Karyopharm: Employment. Picklesimer:Karyopharm: Employment. Friedlander:Karyopharm Therapeutics: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment.

Background There are an increasing number of multiple myeloma (MM) patients (pts) refractory to currently available drugs, including the proteasome inhibitors bortezomib and carfilzomib (CFZ), necessitating development of novel therapeutics. Pre-clinical evaluation of selinexor (SEL), an orally available Selective Inhibitor of Nuclear Export (SINE) compound, demonstrated synergistic myeloma cell death with CFZ and mechanistic rationale for overcoming resistance to CFZ (Rosebeck et al., 2016), providing support for this phase 1 trial. Aims The primary objectives were to assess the maximum tolerated dose (MTD) of a SEL, CFZ and dexamethasone (DEX) combination and to obtain preliminary efficacy data for this novel regimen in RRMM pts. Methods Pts with RRMM who progressed after at least two prior treatment regimens of myeloma therapy were eligible for enrollment. Dose escalation followed the 3+3 design with pts receiving 30 mg/m2 - 40 mg/m2 SEL PO on days (D) 1, 3, 8, 10, 15, 17; 20 mg/m2 - 56 mg/m2 CFZ IV on D 1, 2, 8, 9, 15, 16, and DEX PO (20mg cycles 1-4/ 10mg cycles 5+) in 28-day cycles (C) in up to 5 dose levels. An expansion cohort has enrolled additional pts to a total of 12 CFZ-refractory pts treated at the recommended Phase 2 dose (RP2D). Dose Limiting Toxicities (DLTs) were evaluated through C2D1. Responses were assessed by IMWG criteria plus near complete response (nCR). Results As of July 1st, 2016, the study has completed dose escalation and enrolled a total of 18 pts; 5 at dose level 1 (30 mg/m2 SEL, 20/27 mg/m2 CFZ, 20/10 mg DEX), 3 at dose level 2a (30 mg/m2 SEL, 20/36 mg/m2 CFZ, 20/10 mg DEX), and a total of 10 (7 in dose escalation, 3 in cohort expansion) at dose level 2b (60mg flat dose SEL, 20/27 mg/m2 CFZ and 20/10 DEX). Pts age ranged between 55 to 74 years with a median of 63.5 years; and had a median of 4 prior treatment regimens (range 2-10). Sixteen pts were evaluable for response, all refractory to their last line of therapy. All 16 response evaluable pts were refractory to CFZ, of which 11 were refractory to CFZ combinations as their last line of therapy, including 8 to a KPd combination of CFZ, pomalidomide, and DEX. Fifteen pts were evaluable for DLT and 3 of 18 pts required replacement for DLT evaluation (1 had DEX reduced not due to DLT; 2 did not receive all scheduled C1 doses). In the dose escalation phase, there was one DLT of cardiac amyloidosis (CA) in a pt with history of prior congestive heart failure and CA at baseline. While the maximum tolerated dose (MTD) has not been reached, the RP2D was identified at dose level 2b based on tolerability. Grade 3/4 adverse events (AEs) included: thrombocytopenia (67%), neutropenia (33%), anemia (17%), fatigue (17%), and infections (11%). The most common all grade AEs included: gastrointestinal disorders (78%), thrombocytopenia (73%), fatigue (72%), anemia (47%), dyspnea (33%), and elevated liver and pancreatic enzymes (28%). There were 2 (11%) serious AEs, 1 upper respiratory infection and 1 lower gastrointestinal bleeding. All adverse events were manageable with concomitant medications. Response rates for all evaluable pts were 75% ≥MR (12 of 16), 63% ≥PR, and 25% ≥VGPR. Response rates in CFZ-refractory pts at last line of treatment were 73%, 64%, and 18% respectively. Responses occurred rapidly; after C1 with 75% ≥MR. As of the data cutoff date, 15 pts progressed (between 1 and 14 months on study) and 3 pts remained on treatment (1 - 4 months). Conclusions The combination of SEL, CFZ, and DEX demonstrates encouraging activity and safety in heavily pretreated, mostly CFZ-refractory myeloma. In addition, with 64% PR or better for pts progressing on CFZ, these results provide early clinical evidence that selinexor has the ability to overcome CFZ resistance, warranting further investigation of this regimen in RRMM. Disclosures Jakubowiak: Sanofi: 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; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenbaum:Celgene: Speakers Bureau. Chari:Novartis: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Pharmacyclics: Research Funding; Array Biopharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Zonder:Pharmacyclics: Other: DSMC membership; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Prothena: Consultancy, Honoraria.

Background There is an increasing number of multiple myeloma patients (pts) refractory to currently available drugs, including the proteasome inhibitors bortezomib and Carfilzomib (CFZ), necessitating development of novel effective therapeutics. Pre-clinical evaluation of selinexor, a novel orally available selective inhibitor of nuclear export (SINE), in human myeloma cell lines (HMCL), primary plasma cells derived from myeloma patients, and HMCL tumor-bearing mice demonstrated synergistic myeloma cell death with CFZ (Rosebeck et al. ASH 2013) and the ability to overcome resistance to CFZ (Rosebeck et al. ASH 2014). Aims The primary objective is to assess the maximum tolerated dose (MTD) of selinexor and CFZ in combination with DEX in RRMM pts and to provide preliminary evaluation of efficacy of this novel triplet regimen. Methods Pts with RRMM, including CFZ-refractory pts, who have failed at least two prior treatment regimens of myeloma therapy, were eligible for enrollment. Dose escalation follows the 3+3 design with pts receiving 30 mg/m2 - 40 mg/m2 selinexor PO on days 1, 3, 8, 10, 15, 17; 20 mg/m2 - 56 mg/m2 CFZ given IV on days 1, 2, 8, 9, 15, 16, and DEX PO 20/10mg (cycles 1-4/cycles 5+) in 28-day cycles. At least 12 and up to 48 pts are planned for evaluation. Dose Limiting Toxicities (DLT) are measured for the Cycle 1 as well as Day 1 of Cycle 2. Dose modifications are allowed to manage toxicities. Response was assessed by IMWG criteria plus near complete response (nCR). Results As of July 1st, 2015 the study has enrolled 8 pts, 5 pts were treated at dose level 1 (30 mg/m2 selinexor, 20/27 mg/m2 CFZ, 20/10 mg DEX) and 3 patients were treated at dose level 2a (30 mg/m2 selinexor, 20/36 mg/m2 CFZ, 20/10 mg DEX). Pts had median age of 65.5 (range 55-73) and a median of 5 prior treatment regimens (range 2-5). Six pts were refractory to CFZ combinations at their last line of therapy, including 4 to CFZ, pomalidomide (POM), and DEX. Of the 2 remaining pts, 1 was refractory to high dose CFZ with DEX in prior line of therapy and both were refractory to last line of therapy. Six pts were DLT-evaluable and two pts required replacement for DLT evaluation (1 pt had DEX reduced in cycle 1 not due to DLT; 1 pt did not receive all scheduled cycle 1 doses due to progressive disease). There have been no DLTs and MTD is not yet established. Adverse events (AEs) were reversible and managed with concomitant therapy. G3/4 hematologic AEs include thrombocytopenia (75%), neutropenia (50%), leukopenia (37.5%), lymphopenia (25%), and anemia (25%). The most common G3/4 non-hematologic AEs included fatigue (25%) and upper respiratory tract infection (25%). The most common G1/2 AEs are fatigue (75%), dyspnea (62.5%), nausea (62.5%), anemia (50%), leukopenia (50%), and thrombocytopenia (50%). Response rates for all enrolled pts are 87.5% ≥MR, 75% ≥PR, 12.5% ≥VGPR. Responses occurred rapidly; after 1 cycle: 75% ≥MR, 63% ≥PR, 12.5% VGPR. As of the cut off date, 4 pts have progressed (after 1, 2, 4, and 4 months) and 4 pts remain on treatment (10+, 1+, 1+, and 1+ months); 1 pt did not respond and died due to progression of disease. Conclusions Although still very early, the combination of selinexor, CFZ, and DEX demonstrates encouraging activity with 75% PR or better and no unexpected toxicities in highly refractory MM pts, including those previously refractory to CFZ. Responses in pts refractory to very active CFZ combinations in the last line of therapy suggest that this regimen has the ability to overcome CFZ resistance. Disclosures Jakubowiak: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SkylineDx: Membership on an entity's Board of Directors or advisory committees; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: institutional funding for support of clinical trial conduct, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: The combination of Carfilzomib and Selinexor is being used for the treatment of Multiple Myeloma. Rosenbaum:Celgene: Speakers Bureau. Zonder:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: research support; Prothena: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Chari:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Rashal:Karyopharm Therapeutics Inc: Employment. Youssoufian:Karyopharm Therapeutics Inc: Employment. Henry:Karyopharm: Employment, Equity Ownership. Shacham:Karyopharm: Employment, Equity Ownership. Kauffman:Karyopharm: Employment, Equity Ownership.

Background: Ricolinostat, an oral selective HDAC6 inhibitor, is well tolerated as monotherapy (Raje Blood 2012;120:4061) and demonstrates potent synergistic activity with lenalidomide (Len) and pomalidomide (Pom) in preclinical models (Quayle Blood 2013;122:1952). In an ongoing trial of ricolinostat in combination with Len and dexamethasone (Dex) in patients with relapsed or refractory multiple myeloma (MM), no dose limiting toxicities (DLTs) were observed at up to doses of 160 mg BID, with excellent activity and tolerability (Yee Blood 2014;124:4772). Pan-HDAC inhibitors vorinostat and panobinostat are active in MM in combination with bortezomib (Btz) and Len, but toxicities (thrombocytopenia, fatigue, and GI events) limit dosing exposure. This trial explores activity of ricolinostat in combination with Pom and Dex in a patient population comparable to that in MM-003 (San Miguel Lancet Oncol 2013;14:1055-66). At the time of achieving the primary endpoint of PFS in MM-003, the ORR was 16.6% at 18.1 weeks median follow-up (EMA Pom Celgene Assessment Report EMA/CHMP/427059/2013), and was 31% at 10 months in the same clinical trial (San Miguel Lancet Oncol 2013;14:1055-66). Methods: Phase 1b was a 3+3 design which explored ricolinostat 160 mg QD or BID combined with Pom (4 mg) for 21 days of a 28 day cycle with Dex (40 mg) on days 1, 8, 15 and 22. Patients had measurable disease, adequate BM reserve and hepatic function with CrCl ≥45 mL/min. Refractory was defined as PD on or within 60 days of last therapy. Patients with non-secretory MM, prior Pom or HDAC inhibitor therapy were excluded. Peripheral blood samples were obtained for PK/PD assessment of acetylated tubulin and histones. Patients with serum FLC only disease were excluded from Phase 2. The dose level of 160 mg dose was chosen based on prior experience in which PK plateau was reached at 160 mg of ricolinostat. A sample size of 66 was determined to be adequate to detect an ORR of 44% against a historical rate of 29%. Results: 7 patients were treated in phase 1b: 3 at 160 mg QD and 4 at 160 mg BID. No DLTs were observed; however, all 4 patients had grade 2 diarrhea in the 160 mg BID cohort and grade 3 fatigue and grade 3 or 4 neutropenia attributed to Pom were reported in patients in phase 1b. 1 patient remained on study for 12 cycles before PD; the other 6 Phase 1b patients were withdrawn for PD at 2-4 cycles. Following safety review committee (SRC) review, phase 2 opened at a dose of 160 mg BID, with a predetermined SRC review to occur after 6 patients had completed 1 cycle of therapy. 3 of the 6 patients had clinically relevant diarrhea requiring ricolinostat dose reduction to 160 mg QD in cycle 2 leading to SRC recommendation of QD dosing of ricolinostat. As of April 28, 2015 39 phase 2 patients were evaluable for safety and 28 evaluable for response. Median age was 68 and median number of prior regimens was 4 (2-9) in 3 (2-6) line of therapy. 37 patients were refractory to Len as defined in the entry criteria. Common toxicities were predominantly low grade and included fatigue (40%), diarrhea (38%), neutropenia (36%), anemia (31%), thrombocytopenia (26%), and constipation (21%). Important grade 3/4 related toxicities included neutropenia (5 patients, 13%) and diarrhea (3 patients, 8%). PK of ricolinostat was similar to that observed in combination with Btz and Len. There was no evidence of ricolinostat accumulation or drug-drug interaction with Pom. Median follow-up of 12 (4-32) weeks; ORR (≥PR) was 29% with 3 VGPR and clinical benefit rate (≥MR) was 50% with 68% SD or better for the 28 response evaluable patients. Updated safety and efficacy data will be presented as enrollment continues and data matures including for the 49 patients enrolled in phase 2 to date. Conclusion: These early data with a median follow-up of 12 weeks (compared to historical control of 16.6% ORR at 18.1 weeks for Pom/Dex alone in MM-003) in a rigorously defined patient population suggest that selective HDAC6 inhibition is associated with encouraging tolerability and promising clinical activity. Accrual is continuing in US, Canada, and Europe. Overall, ricolinostat is an active and safe oral agent which combines favorably with Pom and Dex in relapsed-and-refractory MM. Disclosures Raje: Novartis: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Eli Lilly: Research Funding; AstraZeneca: Research Funding; Millenium: Consultancy; Onyx: Consultancy; Acetylon: Research Funding; Celgene Corporation: Consultancy; BMS: Consultancy. Bensinger:Sanofi: Research Funding; Acetylon Pharmaceuticals, Inc: Research Funding; BMS: Research Funding; Novartis: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Research Funding; Onyx: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Lonial:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Jagannath:BMS: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria; Janssen: Honoraria; MERCK: Honoraria; Celgene: Honoraria. Valent:Takeda/Millennium: Speakers Bureau; Celgene: Speakers Bureau. Harb:Idera Pharmaceuticals: Research Funding; Astex Pharmaceuticals, Inc.: Research Funding. Sandhu:Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Bahlis:Johnson & Johnson: Research Funding; Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Reece:Merck: Research Funding; Lundbeck: Honoraria; Amgen: Honoraria; Onyx: Consultancy; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Millennium Takeda: Research Funding; Otsuka: Research Funding. Terpos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Takeda: Honoraria; Celgene: Honoraria, Other: Travel expenses; Novartis: Honoraria; Amgen: Honoraria, Other: Travel expenses, Research Funding. Tamang:Acetylon Pharmaceuticals, Inc.: Employment. Jones:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Wheeler:Acetylon Pharmaceuticals, INC: Employment. Markelewicz:Acetylon Pharmaceuticals, Inc: Employment. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.

Background: Isatuximab (SAR650984) is a humanized IgG1 monoclonal antibody that binds selectively to a unique epitope on the human CD38 receptor. In the dose escalation part of the Phase I portion of the trial (NCT01749969), isatuximab ≥10 mg/kg IV given every other week (q2w) or 10 mg/kg weekly (qw) induced responses in 6/19 recipients (ORR 32%). Responses were noted at doses as low as 1 mg/kg q2w. The maximum tolerated dose (up to 20 mg/kg IV qw) was not reached. The most common treatment-emergent adverse events (TEAEs) were fatigue and nausea; few serious grade 3/4 TEAEs were reported (pneumonia 6%). The most common category of drug-related TEAE involved infusion-associated reactions (IARs) occurring in half of the patients, with grade 3/4 IARs in Methods: In Phase II, eligible patients were originally randomly assigned (1:1:1) to one of 3 treatment groups: 3 mg/kg q2w, 10 mg/kg q2w, and 10 mg/kg q2w x 4 doses then q4w. A 4th treatment group was enrolled at a higher isatuximab dose with an optimized schedule of 20 mg/kg qw x 4 doses then q2w. Patient assignment was stratified by prior anti-myeloma therapy (Stratum 1: prior treatment with pomalidomide (POM) and/or carfilzomib (CAR); Stratum 2: no prior POM or CAR). Patients continued therapy until disease progression, unacceptable AEs or physician/patient decision. Eligible patients had measurable disease (serum M-protein >1 g/dL or urine M-protein ≥200 mg/24 h, or serum free light chain ≥10 mg/dL), prior exposure to ≥3 lines of anti-myeloma therapy or were double-refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), prior treatment with an alkylating agent, and adequate baseline bone marrow reserve and organ function. Enrollment of 24 patients was planned for each treatment group. An interim efficacy analysis is planned when all patients have completed ≥2 disease assessments, with central review of these data currently ongoing. Enrollment has now been completed and all patients who completed at least 1 cycle of isatuximab at the cutoff date (5/29/15) are included in this preliminary analysis. Results: Patient characteristics (n=96): median age 62.5 yrs (range 38-85); median time from initial diagnosis to study treatment 5.85 yrs (1.2-24.1); 76% had IgA/G MM; 24% had light-chain only disease; and 22%, 22%, and 44% had Stage I, II, and III disease, respectively. The median number of prior lines of therapy was 5 (2-14) with 100%, 99%, and 98% having prior exposure to PIs, IMiDs, and alkylator-containing therapy, respectively. Overall, 78% of patients had previously received POM and/or CAR; 55% had been exposed to both of these agents. At data cut-off, 36.5% of patients remained on therapy and 53.1%, 6.3%, and 4.2% had discontinued therapy due to disease progression, AEs, or other reason, respectively. The median number of cycles received was 3 (1-9), with a median duration of treatment of 11.7 wks. Approximately 17% of patients required at least 1 dose delay and 7.3% of isatuximab infusions were interrupted. TEAEs occurred in 93% of patients, with 51% being grade ≥3. Drug-related TEAEs occurred in 61% of patients (grade ≥3, 10%). The most common drug-related TEAEs (>5% of patients) were nausea (14.6%), chills (14.6%), dyspnea (13.5%), chest discomfort (10.4%), flushing (7.3%), headache (7.3%), cough (6.3%), and vomiting (5.2%). The majority of the symptoms occurred within 24 h of isatuximab infusion and were attributed to an IAR. IARs occurred in 50% of patients, were predominantly grade 1/2 (grade ≥3, 3.1%), and were mostly limited to Cycle 1 (2 patients had IARs in Cycle 2). Pneumonia (6.3%) and sepsis (5.2%) were the most common serious TEAEs. Six deaths have occurred within 30 days of last dose, 4 due to disease progression, and 2 due to serious AEs unrelated to study therapy (cardiopulmonary arrest and cerebral hemorrhage). Conclusion: Isatuximab administered to heavily pre-treated patients with RRMM appears well tolerated. IARs are common in Cycle 1, but typically do not recur. Results by treatment arm, including interim analysis response data, will be presented. Disclosures Martin: Sanofi: Research Funding. Richter:Takeda: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau. Vij:Millennium: Honoraria, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy. Zonder:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS, Amgen, Prothena, Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Kaufman:Spectrum: Consultancy; Merck: Research Funding; Onyx: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Millenium: Consultancy. Bensinger:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acetylon: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Millenium: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimopoulos:Novartis: Honoraria; Amgen: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Honoraria. San Miguel:Millennium, Celgene, Novartis, Janssen, Onyx, BMS, MSD: Membership on an entity's Board of Directors or advisory committees. Zimmerman:Onyx: Honoraria; Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Hari:Celgene: Consultancy; Takeda: Consultancy; BMS: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Sanofi: Consultancy. Gasparetto:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kumar:Skyline, Noxxon: Honoraria; Celgene, Millennium, Onyx, Janssen, Noxxon, Sanofi, BMS, Skyline: Consultancy; Celgene, Millennium, Onyx, Novartis, Janssen, Sanofi: Research Funding. Hsu:Sanofi: Employment. Charpentier:Sanofi: Employment. Strickland:Alexion Pharmaceuticals: Other: Advisory Board Particpation; Amgen: Other: Advisory Board Particpation; Daiichi-Sankyo: Other: Advisory Board Particpation; Boehringer-Ingelheim: Other: Advisory Board Particpation; Sunesis Pharmaceuticals: Other: Steering Committee and Advisory Board Participation. Mikhael:Sanofi: Research Funding; Onyx: Research Funding; Celgene: Research Funding; AbbVie: Research Funding.

Background: The US prevalence of multiple myeloma (MM) is estimated at 83,118 as of January 1, 2011(SEER, 2014), and about 24,050 new MM cases will be diagnosed in 2014 (ACS, 2014). With advances in treatment, MM patients are living longer and are confronted with increasingly complex therapeutic decisions. Frequently patients are not fully prepared to discuss the possible treatment options effectively with their provider. Methods: From July 2013 to July 2014, the Cancer Support Community (CSC) registered 495 people living with MM to the Cancer Experience Registry: MM, an online initiative designed to investigate and raise awareness about the psychosocial impact of MM. Registrants were recruited through an outreach program that included the CSC and The Leukemia & Lymphoma Society (LLS) network of community-based affiliates/chapters, CSC and LLS online communities, CSC’s helpline and LLS’s information resource center, other advocacy organizations, social and other media channels. Those who registered completed a survey about their MM history, status and treatment. Results: General: 406 (82%) registrants responded to the questionnaire. The present analysis is limited to 280 US based registrants who answered on treatment decision making. The participant median age was 64 years; 54% female, 87% Caucasian, 9.5% African American. Total annual income: 35% Conclusion: Although nearly three-quarters of the sample were satisfied with various aspects of treatment decision-making, including communication about treatment decisions with physicians, more than one-third of MM patients thought they had no choice or felt rushed in making a decision. Those who prepared a list of questions prior to a consultation with the doctor felt significantly more prepared to make appropriate decisions. While most patients reported receiving information about their treatment options, less than half report being knowledgeable about treatment options, and a significant proportion reported not having enough knowledge or support to fully engage in treatment decisions. Further efforts are needed to address gaps in the delivery of treatment decision support to MM patients. Disclosures No relevant conflicts of interest to declare.

Abstract 3647 Introduction: BR chemoimmunotherapy was shown to have an overall response rate (ORR) of 59%, a median progression-free survival (PFS) of 14.7 months, and an acceptable toxicity profile in R/R CLL (Fischer K, et al. J Clin Oncol 2011). Given the single-agent activity of lenalidomide in R/R CLL/SLL, we hypothesized that maintenance lenalidomide after BR induction could improve PFS. Methods: Thirty-four patients requiring therapy for R/R CLL/SLL were treated with bendamustine 90 mg/m2 IV on days 1 & 2 and rituximab 375 mg/m2 IV on day 1 every 28 days for a maximum of 6 cycles. Growth factor support was permitted. Patients achieving at least a minor response (objective improvement even if not meeting criteria for partial response) were eligible to proceed with 12 cycles of maintenance therapy with lenalidomide 5–10 mg/day orally given continuously in each 28-day cycle. Patients were eligible if they had histologically proven CLL/SLL and had received >1 but ≤5 prior cytotoxic chemotherapy regimens (retreatment with an identical regimen was not counted as a separate treatment). The primary endpoint was PFS. Results: Baseline characteristics include median age 67 (range 38–86), 25 men/9 women, 26 CLL/8 SLL, and median of 2 prior therapies (range 1–4). Cytogenetic profiling by FISH analysis was available in 22 patients (65%), with 11/22 demonstrating presence of 17p and/or 11q deletions. Twenty-five patients (74%) completed 6 cycles of induction BR. Two patients died from toxicities of pneumonia and heart failure during cycle 1; 7 patients received Conclusions: In our multicenter trial for patients with R/R CLL/SLL, the BR induction produced an ORR that is comparable to historical observations (65% vs 59%). However, the median PFS is longer (24.3 vs 14.7 months), suggesting maintenance lenalidomide may be contributing to an improved response duration. Based upon these promising results, we have initiated a successor study in which patients will receive lenalidomide plus rituximab maintenance after a BR induction. Disclosures: Chang: Celgene: Research Funding; Genentech: Research Funding. Off Label Use: Lenalidomide as maintenance therapy for CLL after induction rituximab + bendamustine chemoimmunotherapy. Fenske:Spectrum Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Kahl:Millennium: Consultancy, Research Funding; Roche: Consultancy; Genentech: Consultancy, Research Funding.

Abstract 2086 Background: Studies incorporating measurement tools for emotional distress into clinical care for hematology patients are rare. We previously reported that distress levels of >5 on the National Comprehensive Cancer Network (NCCN) distress thermometer (DT) were significantly more likely to occur in patients who were seen within the first 30 day of presentation, women, younger patients, those with previous depression/anxiety, and those who are unmarried. However, the diagnosis of malignant or non-malignant hematologic disorder was not associated with DT levels >5. Since this report, the DT indicator of distress was adjusted to ≥4. AIM: To assess and measure psychosocial distress in adult patients with hematological malignancies pertaining to Hodgkin's Lymphoma (HL), Non-Hodgkin's Lymphoma (NHL), Multiple Myeloma (MM), and Chronic Lymphocytic Leukemia (CLL) at a multidisciplinary community-based hematology/oncology clinic, and identify the specific factors of these subjects associated with the most distress. Methods: Consecutive adult subjects with HL, NHL, MM, and CLL (n=302) seen at the Gundersen Lutheran Center for Cancer and Blood Disorders were approached over a period from September 2010 to March 2011. Study subjects consented to a one-time assessment of two prospective surveys that included the DT (scale of 0–10) and the Hospital Anxiety and Depression Scale (HADS), which indicates the specific factors that cause distress in daily life. Subjects were excluded for incomplete surveys. The Charlson Comorbidity Index (CCI) was utilized to assess comorbid conditions at the time of consent and is predictive of mortality within one year. Additional medical information including history of anxiety/depression, as well as disease related information and disease state (diagnosed, observation, remission, treatment) were collected by chart review. A score ≥4 was used an indicator of distress for the DT, and a score of ≥8 was used as a positive indicator of anxiety/depression for the HADS. All prospective surveys were completed prior to the subject's clinic appointment. Results: A total of 190 subjects (63%) consented and completed both the DT and HADS (mean age 65.8±13.4 yrs; 62% men). Subjects were grouped into hematological malignancy cohorts, with 31% having NHL, 25% CLL, 11% HL and MM 20%. The mean DT score was 2.8±2.5 and the mean CCI was 4.5±1.4, with 34% of subjects rating distress ≥4 and 31% of subjects having a positive HADS result. No differences between hematological malignancy cohorts were found for subjects with a history of anxiety/depression (p=0.079), DT ≥4 (p=0.468) or positive HADS results (p=0.079); however, the percentage of subjects with a positive HADS result trended higher in HL subjects (52%). When stratified by DT score (≥4 vs. 0–3), no differences were found for hematological malignancy cohorts, disease state, sex, age, marital status or CCI. However, a positive HADS result was associated with a DT score ≥4 (p=0.001), thereby validating DT as a screening tool for anxiety/depression. Women were more likely to have a history of depression (p=0.008), but a history of anxiety/depression or medication usage was strongly associated with a DT score ≥4 (p=0.001) for the entire population. Conclusion: In subjects with common hematologic malignancies, a history of anxiety/depression was a very strong indicator of distress. Degree of comorbid illness, disease status and type of hematologic malignancy were not associated with distress. Based on these results, patients with hematologic malignancies who have a DT score ≥4 and/or a positive HADS result should be considered for aggressive management of prior anxiety and depression to ensure treatment that encompasses patient-centered care. Disclosures: No relevant conflicts of interest to declare.

Background: Lenalidomide (Revlimid®) has been reported to show activity in non-Hodgkin’s Lymphoma (NHL). However, prognostic factors predicting an individual patient’s response were unavailable. Aim: To investigate prognostic factors for lenalidomide response in patients with relapsed/refractory aggressive NHL. Methods: Patients with relapsed/refractory aggressive NHL with measurable disease ≥2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1-21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Univariate analyses using Fisher’s exact test and multivariate analyses using logistic regression were conducted to investigate associations of prognostic variables with response. Results: Forty-nine patients received lenalidomide oral monotherapy. The median age was 65 (23-86) and 24 were female. Histology was diffuse large B-cell lymphoma (n=26), follicular center lymphoma grade 3 (n=5), mantle cell lymphoma (n=15) and transformed (n=3). Median time from diagnosis was 2.7 (0.4-32) years and median number of prior treatment regimens was 4 (1-8). Forty-five (92%) of the patients had received prior rituximab and 63% were rituximab-refractory. Seventeen patients (35%) exhibited an objective response (2 complete responses, 4 complete responses unconfirmed and 11 partial responses). Response to lenalidomide was the same for patients who were refractory to rituximab (30%) and those who were not (31%). Three of 4 patients who were rituximab naive responded. Multivariate analysis including IPI, ECOG PS, stage, LDH, # of extranodal sites, age, sex, # of prior regimens and time from diagnosis identified only time since last rituximab and tumor burden as correlated with response. Response to lenalidomide was associated with low tumor burden (52% for 0.6 × 109/L v 9% for ≤0.6 × 109/L, P=0.071). Conclusion: Tumor burden and host immune competence may determine the response of relapsed/refractory aggressive NHL to lenalidomide monotherapy.

Background: Patients with diffuse large B-cell lymphoma (DLBCL) not cured by first line R-CHOP chemotherapy or second line high-dose chemotherapy with autologous stem cell rescue have a poor prognosis and represent a clear unmet medical need. Lenalidomide (Revlimid®), an immunomodulatory drug, has activity in hematological malignancies including relapsed/refractory multiple myeloma, chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Aim: To determine the activity and safety of lenalidomide monotherapy in relapsed/refractory DLBCL. Methods: Patients with relapsed/refractory DLBCL with measurable disease after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Univariate analyses using Fisher’s exact test was conducted to investigate and characterize associations of prognostic variables with response. Results: Twenty-six patients with DLBCL lymphoma were enrolled. The median age was 66 (45–86) and 13 were female. Median time from diagnosis to lenalidomide was 2.4 (0.5–12) years and median number of prior treatment regimens was 3 (1–6). Three patients (12%) exhibited an objective complete response (1 complete response (CR) and 2 complete responses unconfirmed (CRu)). Two patients had a partial response (PR) for an overall response rate of 19% and 7 had stable disease (SD). Response to lenalidomide was associated with low disease burden (33% for < 50 cm2v 0% for ≥ 50 cm2, P=0.06) and longer time from rituximab to lenalidomide treatment (33% for ≥ 230 days v 0% for < 230 days, P=0.05). Patients with favorable values for both these prognostic factors (N = 10) had a 50% response rate [RR] (30% CR/CRu RR) compared with a 0% RR for patients with unfavorable values (N = 16; P < 0.004) and a progression free survival (ongoing) of 7.4 months v 1.9 months. Although there were no responses in the poor prognosis group, 4 patients exhibited stable disease with an ongoing median PFS of > 4.2 months (> 3.6 - > 6.2). Eight patients (31%) required at least one dose reduction with a median time to first dose reduction of 1.8 months (0.4–2.9). One patient each (4%) had Grade 4 anemia, cauda equinine syndrome, febrile neutropenia, intermittent rash, lymphopenia, neutropenia, pneumonitis and thrombocytopenia. Most common Grade 3 adverse events were neutropenia (19%), thrombocytopenia (15%) and leukopenia (12%). Conclusion: The prognostic factors of tumor burden and time from last dose of rituximab appear to identify relapsed/refractory DLBCL patients with a high likelihood of response to lenalidomide oral monotherapy.

Background: Distress is an unpleasant psychosocial response that may impede the capacity of patients to cope successfully with a disease, its physical symptoms, and its treatment. Measurements of distress have been extensively evaluated in patients with solid tumor malignancies. The National Comprehensive Cancer Network (NCCN) has recommend standards of care for distress management. However the degree of distress in patients with hematologic diseases (both malignant and non-malignant) is under-investigated. Aim: This study was designed to assess and compare distress in patients with malignant or non-malignant hematological disorders. Methods: Of 617 adult hematology patients enrolled between July 2006 and December 2006, 572 reported distress scores and were prospectively followed, while 45 patients who did not rate their distress were excluded. The NCCN Distress Thermometer (scale of 0–10) accompanied by a modified problem checklist was administered to hematology patients 18 years of age and older seen at the Gundersen Lutheran Center for Cancer and Blood Disorders. Additional demographics, diagnoses, and disease-related information were gathered by chart review. Patients reporting a high score were contacted by a social worker to assess the etiology of distress. Results: At initial visit during the study period, 572 patients reported a distress score (mean = 3.4 ± 2.7). Patients with malignant (3.2 ± 2.7) or non-malignant (3.6 ± 2.6) disease reported similar distress (p = 0.125). Females (4.0 ± 2.8) were more distressed than males (2.9 ± 2.4; p < 0.001). Other factors significantly associated with distress were history of anxiety (p < 0.001), depression (p < 0.001), younger age (p = 0.001), and time from diagnosis (visit day 3.6 ± 2.4; 1–90 days 4.2 ± 2.9; 3mo-1 year 2.9 ± 2.6; 1+ years 3.4 ± 2.7; p = 0.028). Distress based on disease status was (relapse 5.0 ± 3.1, remission/stable 3.3 ± 2.6, treatment 3.7 ± 2.7) also significantly different (p = 0.009). Conclusion: We found no significant difference in levels of reported distress between patients with malignant and non-malignant hematologic disorders. Significantly higher distress levels were reported in women, younger patients, those with previous psychiatric disease, date of visit, and those at relapse. Patients with either malignant or non-malignant hematologic disorders should be considered for distress screening and management.

Background: Indolent non-Hodgkin’s lymphoma (NHL) has a median survival as long as 10 years but is rarely cured. Lenalidomide (Revlimid®), an immunomodulatory drug, is approved in the US for treatment of myelodysplastic syndromes associated with a del[q5] cytogenetic abnormality and is approved both in the US and the EU for the treatment of relapsed/refractory multiple myeloma. Lenalidomide also has activity in chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Aim: This study was designed to assess the safety and efficacy of lenalidomide monotherapy in patients with relapsed/refractory indolent NHL. Methods: Patients with relapsed/refractory indolent NHL with measurable disease ≥ 2cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Results: Forty-three patients were enrolled in the study and included in this analysis. The median age was 63 (43–89) and 17 were female. Histology was small lymphocytic lymphoma [SLL] (n=18), follicular center lymphoma grades 1, 2 [FCL] (n=22), nodal marginal B-cell lymphoma (n=2) and extranodal marginal zone B-cell lymphoma of MALT type (n=1). Median time from diagnosis to lenalidomide treatment was 4.5 (0.4–24) years and median number of prior treatment regimens was 3 (1–15). Eleven of the 43 patients (26%) exhibited an objective response (2 complete responses (CR), 1 complete response unconfirmed (CRu), 8 partial responses (PR)), 15 had stable disease (SD), 13 had progressive disease (PD) and 4 were not evaluated. Responses included 4/18 SLL (22%) and 7/22 FCL (32%). Median time to response was 3.6 months (range 1.7–4.1). Progression free survival is 4.6 months for all patients, > 7.7 months (range 4.4 - > 13.5) for responding patients and ongoing. Sixteen patients (37%) required at least one dose reduction with a median time to first dose reduction of 2 months (0.5–9.6). The most common Grade 4 adverse event was neutropenia (14%) and the most common Grade 3 adverse events were neutropenia (21%) and thrombocytopenia (12%). Conclusion: Lenalidomide oral monotherapy is active with manageable side effects in relapsed/refractory indolent NHL.

Background: Angiogenesis and thrombosis, two conditions associated with perturbation of the vascular endothelium and increased CECs, are frequently observed in PV. We performed this study to quantify and characterize CECs in patients with PV and to determine whether CEC profile is associated with thrombotic complications. We also quantified CEPs in a subgroup of patients. Methods: We used flow cytometry to prospectively analyze CECs and CEPs in the whole blood of healthy patients (n=20) and patients with PV (n=30; 13 treated with hydroxyurea, 12 undergoing phlebotomy alone, and 5 never treated). CECs (CD45−/CD31+/CD146+) were quantified and characterized to determine their apoptotic (annexin stain) or activation (CD106+) states. Cells with CD45−/CD31+/CD133+/VEGF-R2+ immunophenotype were considered CEPs. Results: CEC levels in PV patients were higher compared to healthy controls (median 53 cells/mL [range, 11–392] vs 18.5 cells/mL [range, 4–66]; P< .0001). However, the proportions of apoptotic (17.3% [range, 0–87.5] vs 25.9% [range, 0–57.1]; P= .87) and activated (0.7% [range, 0–28.6] vs 0% [range, 0–57.1]; P= .14) CECs were similar between the two groups. In PV patients with high levels (≥2 SD above control mean or ≥53 cells/mL) of CECs (n=14), 5 (36%) developed thromboses. Four (25%) of 16 PV patients with CEC levels similar to healthy controls developed thromboses. The rates of thrombosis between the groups were not statistically different (P= .69). In addition, CEC count, activation, and apoptosis were similar between the hydroxyurea-treated group and the group not treated with hydroxyurea. We detected low numbers of CEPs in PV patients (n=25) that were similar to controls (4 cells/mL [range, 0–100] vs 8 cells/mL [range, 0–60]; P= .34). Conclusions: CECs, but not CEPs, are significantly increased in PV patients. However, there appears to be no association between CEC number, activation or apoptotic state and the development of thromboses. In addition, hydroxyurea therapy does not appear to effect endothelial cells.

Background: Data regarding long-term follow up of patients (pts) with cold agglutinin disease (CAD) are limited. Methods: We reviewed our institutional database of pts with CAD from 1981–2003. The diagnosis of CAD was confirmed by the following criteria: hemolysis and/or cold induced agglutination symptoms, cold agglutinin titre of ≥ 1:40, and typical direct anti-globulin test findings. We retrospectively collected pertinent clinical data including: demographics, dates of diagnosis and last follow up, associated hematologic diseases, baseline laboratory test results, treatment, clinical course, and subsequent development of lymphoproliferative diseases. Results: We identified 18 pts with CAD. Most (15) were females. The median age at diagnosis was 71.5 years (range, 22–92). While all pts presented with hemolysis, only 2 had cold-induced acral signs or symptoms. The median presenting hemoglobin level was 8.4 gm/dl (range, 4.5–13.5). The cause was considered idiopathic in 10 pts, while 8 pts had concomitant lymphoproliferative disorders at diagnosis: chronic lymphocytic leukemia, 1 pt; non-Hodgkin lymphoma (NHL), 3 pts; and monoclonal gammopathy of undetermined significance (MGUS), 5 pts. A serum protein electrophoresis was obtained in 16 pts. Five pts had monoclonal proteins, all IgM (3 κ, 2 λ). Thirteen (72%) pts required treatment for CAD or associated lymphoid malignancies at some point in the course of their disease. The most common treatments administered for CAD were prednisone (9 pts) and cyclophosphamide (3 pts). Prednisone produced an overall response rate of 78%. The responses were durable with a median of 95 months (range, 15–414). No one responded to cyclophosphamide. After a median follow up of 55.5 months (mean, 99.5; range, 12–449), 8 pts were alive, 5 in complete remission (2 maintained on prednisone), and 3 in partial remission (all off therapy). Of those who died (10 pts), only 1 died of CAD due to complications from severe anemia. Two pts subsequently developed lymphoproliferative diseases, MGUS (IgMk) and low grade NHL, 125 and 175 months after diagnosis, respectively. The clinical course of CAD did not seem to be any worse in pts with lymphoid malignancies. Conclusions: In our series, pts with CAD are frequently associated (44%) with lymphoproliferative disease at diagnosis. They have a relatively benign clinical course with a good likelihood of long-term disease remission. Unlike previous reports, prednisone is quite effective. Among those pts considered to have idiopathic CAD, a lymphoproliferative disease may develop later during the course of their disease.

Background: The profile of CEC can potentially be a biomarker of angiogenesis. As angiogenesis is increased in patients with MM, we studied the CEC and their relationships to angiogenesis-related factors in the blood and disease activity. Methods: We prospectively quantitated (CD45-/CD146+/CD31+) and characterized (apoptotic [annexin stain], activated [CD106]) the CEC in the whole blood of 20 patients with MM (7 untreated [4 newly diagnosed, 3 smoldering], 9 receiving therapy, and 4 treated previously) using four-color flow cytometry and compared the findings to those from 20 normal volunteers. In addition, we determined the associations between CEC and disease activity and the plasma levels of several angiogenesis-related factors (vascular endothelial growth factor [VEGF], fibroblast growth factor-2 [FGF-2], hepatocyte growth factor [HGF], and thrombospondin-1 [TSP-1]) pertinent to MM. Results: The median level of CEC was higher (P Conclusions: Increased levels of CEC can be detected in some patients with MM. In these patients, measurement of CEC may be useful as a biomarker of angiogenesis. As we did not find a significant association between CEC and disease activity, additional studies are necessary to determine the clinical significance of increased CEC in MM.