Citations

Abstract Introduction: For decades conventional skeletal survey (CSS) has been the standard imaging technique for the detection of bone impairment caused by Multiple Myeloma (MM). The development of cross-sectional imaging techniques like Whole Body Computed Tomography (WBCT) with or without Positron Emission Tomography (PET/PET-CT) and magnetic resonance imaging (MRI) led to the use of these techniques in several centers worldwide and to the implementation of their findings into the revised diagnostic criteria of MM. The aim of the current multicenter study was to compare sensitivity and prognostic significance of WBCT and CSS in patients with monoclonal plasma disorders. Methods: For the current retrospective analysis 308 patients with different stages of monoclonal plasma cell disorders from 8 centers were included. Compact discs with pseudonymized imaging data of WBCT and CSS were sent to the organizing center and uploaded to the picture archiving and communication system. In addition, questionnaires were completed by each center to collect clinical data of the patients. Image analysis was performed in consensus reading by three experienced radiologists (LAM, SD, VK) blinded to the clinical data of the patients. Osteolytic lesions in 19 pre-specified anatomic regions were characterized as "definitely present", "probably present", "probably absent" and "definitely absent". For the analysis only "definitely present" and "probably present" entries were counted as myeloma lesions. To define symptomatic or active versus smoldering myeloma based on the presence of bone lesions, findings of CSS were used to simulate the situation before the introduction of WBCT. For comparison of WBCT and CSS only those anatomic regions having valid measurements from both methods performed within 30 days without treatment in the meantime were considered. WBCT and CSS were tested for differences in detection sensitivity with the exact McNemar test. Results: Of 308 submitted datasets; 160 patients were without prior treatment and 56 of them had smoldering myeloma. Of 160 patients 80 (50%) had no osteolytic lesions on either CSS or WBCT and 33 (20.6%) showed osteolyses on both techniques. In 9 patients (5.6%) osteolyses were found on CSS but not in WBCT while 38 patients (23.8%) were positive on CT alone. Of note is that for some CT-scans, the upper extremities were not evaluable due to positioning during the examination. Odds ratio for osteolyses on WBCT compared to CSS was 4.22 (P < 0.0001). The regions where WBCT was most significantly superior in detecting osteolyses were the iliac bone, thoracic and lumbar spine as well as the ribs. CSS compared to WBCT revealed osteolyses in more patients only in the proximal extremities: for left humerus 10 (6.5%) versus 3 (1.9%), right humerus 12 (7.7%) versus 4 (2.6%), left femur 11 (7.1%) versus 7 (4.5%) and right femur 10 (6.5%) versus 8 (5.2%) respectively. Of 157 evaluable patients 63 (40.1%) showed osteoporosis (defined by radiological criteria) on both techniques while 29 (18.5%) had osteoporosis on WBCT only and 10 (6.4%) on CSS only (OR 2.90, P = 0.003). In the 56 patients with smoldering myeloma, with bone disease being defined according to the findings of CSS 12 (21.4%), were positive for osteolyses on WBCT (P = 0.0005). Conclusion: WBCT shows significantly more sites of bone destruction compared to conventional X-ray imaging particularly in skeletal regions composed primarily of trabecular bone while CSS shows more osteolyses in the appendicular skeleton - in part due to a limited field of view. More than 20% of patients with smoldering myeloma based on CSS have active disease that needs treatment based on WBCT. Therefore, WBCT is the current standard for the detection of osteolytic lesions in myeloma. The prognostic significance of WBCT and CSS findings for survival and correlation with clinical parameters will be reported at the meeting. Disclosures Hillengass: Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Research Funding; Amgen: Consultancy, Honoraria; Sanofi: Research Funding. Plesner:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: 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; Genesis: Consultancy, Honoraria. Goldschmidt:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Lentzsch:Celgene: Consultancy, Honoraria; BMS: Consultancy. Terpos:Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Genesis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria.

Abstract Background In 2015, the FDA approved 5 new agents and/or combination regimens for the treatment of patients with relapsed/refractory (R/R) MM. In addition, new clinical data support using new regimens in the first-line setting. This rapid expansion of available treatment options has greatly increased the complexity of treatment decisions for patients in this disease setting. Clinical practice guidelines list multiple preferred treatment options for MM and can be challenging to apply to specific patients with a mixture of presenting features. Since 2013, we have developed and updated an MM online decision support tool designed to provide clinicians with expert guidance on optimal treatment for defined patient scenarios. An analysis of the tool over the years has shown that experts rapidly integrate new data and available agents into practice whereas many tool users do not. Here we report data from the most recent version (2016) of this tool, capturing the impact of the rapid expansion of new therapies on expert treatment recommendations. Methods In June 2016, a panel of 5 experts provided treatment recommendations for 688 case scenarios across 3 settings: induction, maintenance, and R/R disease. These distinct scenarios were defined by key patient and disease characteristics that the experts considered important when making treatment choices, including: eligibility for autologous stem cell transplantation, results of chromosome analysis (cytogenetics/FISH), ECOG performance status, previous therapy and response, and preexisting comorbidities. To use the tool, these patient and disease factors and the intended treatment for that specific patient were entered through drop-down menus to display the expert choices for that case. Users were then asked to indicate the impact of the expert recommendations on planned treatment. Results We compared expert recommendations from the 2 most recent versions of our MM tool, compiled in March 2015 and June 2016, to assess the impact of the new data and FDA approvals on treatment patterns. The experts are generally not recommending these agents as induction or maintenance therapy. Three out of 5 experts recommended carfilzomib/lenalidomide/dexamethasone as induction therapy for preexisting peripheral neuropathy (PN) and 1 expert recommended ixazomib-based regimens as induction and maintenance therapy for patients with high-risk cytogenetics and both renal insufficiency and PN. The new agents did have a substantial impact on expert recommendation in the R/R setting. In the 2016 tool, the type of previous therapy was the primary factor affecting expert selections, whereas the number of previous lines of therapy (1-3 vs >3) had minimal impact in the R/R setting. For example, in patients refractory to previous proteasome inhibitor (PI) therapy, regimens containing either elotuzumab (30%) or daratumumab (25%) were selected frequently by experts with pomalidomide-containing regimens recommended in another 40% of these specific cases. In the 2016 tool, the use of lenalidomide/dexamethasone alone without a newly approved agent was not recommended by any expert in the R/R setting, although it had been recommended by experts in 25% of R/R case scenarios in the 2015 tool. For patient scenarios refractory to previous immunomodulatory drugs and PIs, the experts recommended daratumumab-based regimens in 67.5% of the cases in the 2016 tool whereas the use of carfilzomib/pomalidomide/dexamethasone fell from 45% in 2015 to 10% of the cases in 2016. None of the experts recommended regimens with panobinostat as their preferred choice in any patient scenario in either 2015 or 2016. Conclusions Expert opinions regarding optimal MM therapy continue to evolve with new evidence and FDA approvals. Our data show that newly approved therapies are having a large impact on expert recommendations for specific case scenarios in the relapsed/refractory MM setting. A detailed and updated analysis of expert and user data that captures practice trends in this rapidly evolving environment will be presented. Disclosures Kumar: Kesios: Consultancy; Array BioPharma: Consultancy, Research Funding; AbbVie: Research Funding; Onyx: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Research Funding; BMS: Consultancy; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding. Lentzsch:Celgene: Consultancy, Honoraria; BMS: Consultancy. Lonial:Merck: Consultancy; Novartis: Consultancy; Millenium: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Janssen: Consultancy; Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy; BMS: Consultancy. Roodman:Amgen: Consultancy. Anderson:Oncopep: Other: Scientific Founder; Acetylon: Other: Scientific Founder; Sonofi Aventis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: Daratumumab is a human CD38 IgGκ monoclonal antibody that demonstrated significant activity and a manageable safety profile in combination with bortezomib and dexamethasone. In a randomized phase 3 study, daratumumab in combination with bortezomib and dexamethasone (DVd) significantly prolonged progression-free survival (PFS) versus bortezomib and dexamethasone alone (Vd) in a pre-specified interim analysis of patients (pts) with relapsed or refractory multiple myeloma (RRMM; Palumbo A. N Engl J Med 2016; in press). Herein, we examine subgroups from this study to compare the efficacy of DVd vs Vd in bortezomib-naive and bortezomib-experienced pt populations. In addition, the efficacy of DVd vs Vd in pts who were refractory to lenalidomide at last prior line of therapy was also evaluated. Methods: Pts who received ≥1 prior line of therapy were randomized (1:1) to 8 cycles (q3w) of Vd (bortezomib: 1.3 mg/m2 SC on Days 1, 4, 8, 11; dexamethasone: 20 mg PO on Days 1, 2, 4, 5, 8, 9, 11, 12) with or without daratumumab (16 mg/kg IV qw in Cycles 1-3, Day 1 of Cycles 4-8, then q4w until progression). Pts who were refractory to bortezomib were not eligible. The primary endpoint was PFS. Bone marrow aspirate samples that had been prepared with Ficoll were evaluated for minimal residual disease (MRD) using three different thresholds (10-4, 10-5, and 10-6) based on the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA, USA). Results: Median follow-up was 7.4 months. Among bortezomib-naive pts (DVd, n=89; Vd, n=83), PFS was significantly improved with DVd vs Vd (median: not reached [NR] vs 7.5 months; HR, 0.25; 95% CI, 0.13-0.47; P&lt;0.0001); estimated 12-month PFS rates were 72% vs 28%, respectively. ORR was 88% with DVd vs 70% with Vd (P=0.0040), with ≥very good partial response (VGPR) rates of 72% vs 42% (P&lt;0.0001), and ≥complete response (CR) rates of 30% vs 20% (P=0.1199), respectively. For pts who previously received a bortezomib-containing regimen (DVd, n=162; Vd, n=164), PFS was also significantly longer with DVd vs Vd (median: 12.3 vs 6.7 months; HR, 0.46; 95% CI, 0.32-0.66; P&lt;0.0001). Estimated 12-month PFS rates were 55% vs 27%, respectively. ORR was significantly higher with DVd vs Vd (80% vs 60%; P=0.0001), along with significantly higher rates of ≥VGPR (52% vs 22%; P&lt;0.0001) and ≥CR (13% vs 3%; P=0.0019). Among pts who were refractory to lenalidomide at the last prior line of therapy (DVd, n=45; Vd, n=60), PFS was significantly longer in DVd vs Vd (median: 10.3 vs 4.4 mo; HR, 0.37; 95% CI, 0.21-0.65; P=0.0004; Figure). Within this subgroup, ORR was significantly higher for DVd vs Vd (81% vs 50%; P=0.0021), and the same trends were observed for rates of ≥VGPR (54% vs 12%; P&lt;0.0001) and ≥CR (20% vs 5%; P=0.0261). Updated efficacy and safety data, including MRD analyses across different sensitivity thresholds (10-4, 10-5, and 10-6), will be presented at the meeting. Conclusions: These analyses confirm that addition of daratumumab to Vd significantly improves outcomes for RRMM pts regardless of prior treatment with bortezomib. Importantly, this treatment benefit of DVd vs Vd was maintained in pts who were refractory to lenalidomide at the last prior line of therapy. These data lend further support to adding daratumumab to a standard-of-care regimen in RRMM. Figure Progression-free Survival in Patients Refractory to Lenalidomide at the Last Prior Line of Therapy Figure. Progression-free Survival in Patients Refractory to Lenalidomide at the Last Prior Line of Therapy Disclosures Lentzsch: BMS: Consultancy; Foundation One: Consultancy; Celgene: Consultancy, Honoraria. Quach:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Ovilla:Janssen: Consultancy. Qi:Janssen: Employment. Deraedt:Janssen: Employment, Equity Ownership. Schecter:Janssen: Employment, Equity Ownership. Amin:Janssen: Employment. Qin:Janssen: Employment. Casneuf:Johnson & Johnson: Equity Ownership; Janssen R&D, Beerse, Belgium: Employment. Chiu:Janssen: Employment. Sasser:Johnson & Johnson: Equity Ownership; Janssen Pharmaceuticals R&D: Employment. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding.

Abstract Background: The optimal follow-up of MGUS patients, including frequency of visits and type of tests to order, is unknown because there are no evidence-based data available for guidance. Nevertheless, there are currently 4 clinical practice guidelines that are based on expert-consensus: UK-Nordic (2009), International Myeloma Working Group (IMWG; 2010), International Expert Consensus (IEC; 2010) and European Myeloma Network (EMN; 2014). Most guidelines recommend annual follow-up with laboratory tests until life expectancy becomes limited. How MGUS patients are followed in the US and whether clinical practice guidelines are being followed remain largely unknown. Methods: We conducted a retrospective analysis of adult (age >18 years) patients from 2006-2012 using theOptum Labs Data Warehouse,a large database including administrative claims information on >150 million privately insured and Medicare Advantage enrollees throughout the US. We identified patients with an incident diagnosis of MGUS (ICD9: 273.1) who had enrollment periods of>1 year pre- and>2 years post-diagnosis in order to exclude patients with a prior history or subsequent diagnosis of lymphoplasmacytic malignancy. We determined the overall outpatient follow-up practice patterns (visits or tests performed for MGUS), their variations over time and by geo-demographic subgroups, and concordance with current clinical practice guidelines Results: There were 10,349 MGUS patients who met the study criteria. The mean interval per MGUS follow-up visit was 13.1 months. The distribution of patients by mean interval between visits was: q<6 months (39.9%), q6-12 months (10.7%), q13-24 months (2.6%) and q>24 months (46.8%). There was a significant trend towards a higher proportion of patients being followed q<6 over time from 36.2% in 2006 to 43.7% in 2013 (P=0.01). Patients ≥70 years were more likely followed q<6 months, while those from the Northeast or ≤50 years were more likely followed q>24 months compared to their counterparts (P<0.01). Over half of patients≥80 years were being followed either q<6 (44.7%) or q6-12 (11.6%) months (Figure 1). Only about half of the patients diagnosed in 2013 were concordant with any of the available guidelines regardless of whether the guidelines were more aggressive (UK-Nordic/IEC) or more conservative (IMWG/EMN) in their follow-up recommendations (54.6% and 56.5%, respectively). The tests ordered during follow-up are shown in Figure 2. The most common tests were complete blood count, calcium, and creatinine as they were ordered in over half of the follow-up visits (56.5% to 68.4%). In 11.6% of the follow-up, a face-to-face visit was not associated with any ancillary test, while in 31.5%, the follow-up was comprised of ancillary tests only without a face-to-face visit. The test combination of complete blood count, calcium, creatinine, and serum protein electrophoresis with or without free light chain was ordered in 25.0% of the visits. Conclusions: In the US, the MGUS follow-up practice patterns varied demographically and geographically. Only half of the patients were followed according to current guideline recommendations. A large proportion of patients with limited life expectancy continued to undergo close follow-ups. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Prior studies on the risk of progression of monoclonal gammopathy of undetermined significance (MGUS) into lymphoplasmacytic malignancies (LPMs) were almost exclusively in the White populations, comprised of limited number of patients residing in relatively small geographic areas, or included patients mostly detected by serologic screening as part of clinical study (as opposed to detected clinically during evaluation of symptoms suspicious for LPMs). Similar epidemiologic studies in a large, racially diverse population are lacking. Methods: We conducted a retrospective analysis of incident MGUS patients diagnosed from 2006-2013 using theOptum Labs Data Warehouse, a large database including administrative claims information on >110 million privately insured and Medicare Advantage enrollees throughout the United States. We identified patients with a diagnosis of MGUS (ICD9: 273.1) with 1-5 years of continuous enrollment. Each enrollment cohort based on the duration of follow-up (1-, 2-, 3-, 4-, or 5-year) was analyzed individually to help estimate the progression to cancer. We excluded patients who were diagnosed with LPMs within three months of MGUS diagnosis. We calculated the rate of progression into LPMs (chronic lymphocytic leukemia [CLL], light chain amyloidosis [AL], multiple myeloma [MM], non-Hodgkin lymphoma [NHL], and Waldenström macroglobulinemia [WM]) expressed as number per 100 person-years. Results: There were 14,728 MGUS patients for a total of 21,288 person-years of follow-up. The distributions of the number of patients and events according to the cohorts classified by duration of follow-up were: 1-year (14,728 patients; 243 events), 2-year (10,644 patients; 307 events), 3-year (7,333 patients; 299 events), 4-year (4,497 patients; 237 events), and 5-year (2,960 patients; 191 events). The rates of progression to LPMs were consistently highest during the first year after MGUS diagnosis (~2.00), generally declined by half during the second year and remained fairly stable thereafter (~1.00; Table 1). The rates of progression into LPMs overall as well as by demographics are shown in Table 2. The risk of progression was significantly higher among men (P < 0.01) and older patients (>50 years; P = 0.03) compared to their counterparts but similar among races (P = 0.15). Of the 243 patients who progressed, the distribution of LPMs was MM (70.0%), NHL (13.2%), WM (12.3%), AL (4.1%), and CLL (0.4%). Conclusions: Among patients withMGUS, the risk of transformation into LPMs is continuous although twice as high during the first year after MGUS diagnosis compared to subsequent years. The risk of transformation was higher among men and those who were older but did not differ among the racial subgroups. Our findings can be used to develop an optimal risk-based MGUS follow-up strategy that incorporates not only serum biomarkers but also demographic factors. Disclosures No relevant conflicts of interest to declare.

Abstract Limited experience with the use of urethane in the treatment of leukemia indicates that this substance presents a considerable promise as a palliative agent in chronic myelogenous leukemia. It has no apparent value in the treatment of acute leukemia. Further extensive observation will be necessary to provide a true measure of the clinical usefulness of this preparation.

Abstract Abstract 1795 Background: Waldenstrom's macroglobulinemia (WM) is an indolent B-cell lymphoma characterized by a heterogeneous population of lymphocytes, plasmacytoid lymphocytes and plasma cells with variable CD20 expression. Rituximab (R) achieves an overall response rate (ORR) of 25–50% in relapsed/refractory WM and is associated with IgM flares, manifested by a rapid rise in IgM, potentially leading to complications of hyperviscosity. Ofatumumab (OFA) is a fully human monoclonal antibody that targets an epitope encompassing both the large and small extracellular loops of CD20 and effectively induces complement-dependent cytotoxicity of B-lymphoma cells. OFA is approved for the treatment of fludarabine- and alemtuzumab-refractory chronic lymphocytic leukemia (CLL) and has demonstrated clinical activity in non-Hodgkin's lymphoma. Given the efficacy of OFA in CLL, with its decreased CD20 antigen density, similar to WM where CD20 is down-regulated with differentiation of cells into plasma cells, a Phase II, open-label, single-arm trial of OFA in patients (pts) with WM was initiated to examine the safety and efficacy of OFA in this population. We report data from a planned interim analysis, which was performed to examine IgM flare, toxicity and response data. Methods: Pts (age ≥18 years) with WM requiring therapy by 2nd International Workshop on WM criteria were eligible. Pts received OFA 300 mg week 1 and 1000 mg weeks 2–4. Premedication included acetaminophen and antihistamine (all infusions) and glucocorticoid (infusions 1 and 2). Pts who experienced grade 3–4 infusion-related adverse events (AEs) during weeks 1 and 2 also received glucocorticoid during weeks 3 and 4. The primary endpoint was ORR assessed by 3rd International Workshop on WM criteria, and toxicity was assessed according to NCI-CTCAE, v3.0. Results: Fifteen pts were enrolled between March 2009 and January 2010. Median age was 59 years (range 43–85), and 9 pts were male. Pts had a median IgM level of 3.70 g/dL (range 1.21–6.62) and median hemoglobin (hgb) of 9.8 g/dL (range 5.3–11.7). Three pts were previously untreated; 12 pts had received a median of 3 therapies (range 2–5), including 11 pts who had received R, and 7 pts who had received a purine analog. Fourteen pts completed all 4 infusions of OFA. One pt withdrew from study after infusion 3 due to a drug-related serious AE (SAE). One pt had cryoglobulinemia, which interfered with IgM assessment. Of the 14 pts with evaluable IgM levels, 3 achieved partial response (PR), and 3 achieved minor response (ORR=43%) 8 weeks to 5 months after start of OFA therapy. One of 3 previously untreated pts and 5 of 12 relapsed pts responded. Four of 11 pts who had received prior R and 2 of 4 R-naïve pts responded. Five of 9 pts with IgM <4 g/dL and 1 of 5 pts with IgM >4 g/dL responded. Four pts with a median hgb of 8.0 g/dL (range 5.3–9.2) experienced ≥2.8 g/dL increase in hgb, including 3 pts who had >5 g/dL increase; median time to reach hgb ≥11.0 was 4 weeks. Infusion-related events occurred with dose 1 (300 mg) in 12 pts and with dose 2 (1000 mg) in 7 pts; all infusion events were grade 1–2 except 2 grade 3 events (rash, serum sickness). Nine pts developed 11 infections: 7 URI, 2 UTI, 1 sinusitis, 1 oral candidiasis (all grade 2). One pt developed grade 3 febrile neutropenia. Two pts developed SAEs possibly related to OFA. One pt developed grade 3 Coombs-negative hemolytic anemia after infusion 3 resulting in study withdrawal, and 1 pt with a baseline IgM level of 6.62 g/dL developed grade 3 renal insufficiency due to a rapid rise in IgM and cast nephropathy 6 weeks after starting OFA. One additional pt, with a baseline IgM level of 4.69 g/dL, developed a rapid rise in IgM and hyperviscosity symptoms. Both pts with a rapid rise in IgM underwent plasmapheresis with resolution of symptoms. No other OFA-related hematologic toxicity was observed. Conclusions: OFA has an acceptable toxicity profile, although a rapid rise in IgM requiring plasmapheresis was observed in 2 pts with high baseline IgM levels. OFA shows clinical activity in pts with WM, including those who relapse after R therapy, with rapid improvement in hgb and slower reduction of IgM levels. Based on the acceptable safety profile in this study and the dose of OFA approved for refractory CLL, the study was amended to increase the OFA dose to 2000 mg and allow a 2nd cycle of therapy for pts who do not attain PR after cycle 1. Accrual to the amended study is ongoing. Disclosures: Furman: GlaxoSmithKline: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Cephalon, Inc.: Speakers Bureau; Celegene: Consultancy; Calistoga: Consultancy. Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Switzky:GlaxoSmithKline: Employment, Research Funding; Genmab: Employment, Research Funding. Leonard:GlaxoSmithKline: Consultancy. Liao:GSK: Employment. Shah:GlaxoSmithKline: Employment; Genmab: Research Funding. Brownell-Buttich:GlaxoSmithKline: Employment. Lisby:Genmab A/S: Employment. Lin:GlaxoSmithKline: Consultancy, Employment.

Abstract Purpose: The surface receptor MET is highly expressed on primary uveal melanoma; MET inhibitors demonstrated early clinical signals of efficacy in slowing uveal melanoma growth. The primary objective of our study was to compare the progression-free survival rate at 4 months (PFS4) of patients with uveal melanoma treated with cabozantinib or chemotherapy. Patients and Methods: Patients with metastatic uveal melanoma and RECIST measurable disease were randomized 2:1 to receive either cabozantinib (arm 1) versus temozolomide or dacarbazine (arm 2) with restaging imaging every two cycles. Cross-over from arm 2 to cabozantinib after progression was allowed (arm 2X). Available tumor specimens were analyzed by whole-exome sequencing (WES) and results were correlated with outcome. Results: Forty-six eligible patients were accrued with 31, 15, and 9 in arms 1, 2, and 2X, respectively. Median lines of prior therapy, including hepatic embolization, were two. Rates of PFS4 in arm 1 and arm 2 were 32.3% and 26.7% (P = 0.35), respectively, with median PFS time of 60 and 59 days (P = 0.964; HR = 0.99). Median overall survival (OS) was 6.4 months and 7.3 months (P = 0.580; HR = 1.21), respectively. Grade 3–4 Common Terminology Criteria for Adverse Events were present in 61.3%, 46.7%, and 37.5% in arms 1, 2, and 2X, respectively. WES demonstrated a mean tumor mutational burden of 1.53 mutations/Mb and did not separate OS ≤ or &gt;1 year (P = 0.14). Known mutations were identified by WES and novel mutations were nominated. Conclusions: MET/VEGFR blockade with cabozantinib demonstrated no improvement in PFS but an increase in toxicity relative to temozolomide/dacarbazine in metastatic uveal melanoma.

Objective: The aim of this study was to develop and externally validate the first evidence-based guidelines on minimally invasive pancreas resection (MIPR) before and during the International Evidence-based Guidelines on Minimally Invasive Pancreas Resection (IG-MIPR) meeting in Miami (March 2019). Summary Background Data: MIPR has seen rapid development in the past decade. Promising outcomes have been reported by early adopters from high-volume centers. Subsequently, multicenter series as well as randomized controlled trials were reported; however, guidelines for clinical practice were lacking. Methods: The Scottisch Intercollegiate Guidelines Network (SIGN) methodology was used, incorporating these 4 items: systematic reviews using PubMed, Embase, and Cochrane databases to answer clinical questions, whenever possible in PICO style, the GRADE approach for assessment of the quality of evidence, the Delphi method for establishing consensus on the developed recommendations, and the AGREE-II instrument for the assessment of guideline quality and external validation. The current guidelines are cosponsored by the International Hepato-Pancreato-Biliary Association, the Americas Hepato-Pancreato-Biliary Association, the Asian-Pacific Hepato-Pancreato-Biliary Association, the European-African Hepato-Pancreato-Biliary Association, the European Association for Endoscopic Surgery, Pancreas Club, the Society of American Gastrointestinal and Endoscopic Surgery, the Society for Surgery of the Alimentary Tract, and the Society of Surgical Oncology. Results: After screening 16,069 titles, 694 studies were reviewed, and 291 were included. The final 28 recommendations covered 6 topics; laparoscopic and robotic distal pancreatectomy, central pancreatectomy, pancreatoduodenectomy, as well as patient selection, training, learning curve, and minimal annual center volume required to obtain optimal outcomes and patient safety. Conclusion: The IG-MIPR using SIGN methodology give guidance to surgeons, hospital administrators, patients, and medical societies on the use and outcome of MIPR as well as the approach to be taken regarding this challenging type of surgery.