Citations

Abstract High‐dimensional mass cytometry data potentially enable a comprehensive characterization of immune cells. In order to positively affect clinical trials and translational clinical research, this advanced technology needs to demonstrate a high reproducibility of results across multiple sites for both peripheral blood mononuclear cells (PBMC) and whole blood preparations. A dry 30‐marker broad immunophenotyping panel and customized automated analysis software were recently engineered and are commercially available as the Fluidigm® Maxpar® Direct™ Immune Profiling Assay™. In this study, seven sites received whole blood and six sites received PBMC samples from single donors over a 2‐week interval. Each site labeled replicate samples and acquired data on Helios™ instruments using an assay‐specific acquisition template. All acquired sample files were then automatically analyzed by Maxpar Pathsetter™ software. A cleanup step eliminated debris, dead cells, aggregates, and normalization beads. The second step automatically enumerated 37 immune cell populations and performed label intensity assessments on all 30 markers. The inter‐site reproducibility of the 37 quantified cell populations had consistent population frequencies, with an average %CV of 14.4% for whole blood and 17.7% for PBMC. The dry reagent coupled with automated data analysis is not only convenient but also provides a high degree of reproducibility within and among multiple test sites resulting in a comprehensive yet practical solution for deep immune phenotyping.

Abstract BACKGROUND Adding intensive-procarbazine, lomustine, and vincristine (iPCV) to radiotherapy (RT) prolonged progression-free (PFS) and overall survival (OS) for patients with 1p19q codeleted anaplastic oligodendroglial tumors (AOTs); some benefit was also observed for IDH-mutant non-codeleted cases (Cairncross et al 2013, 2014, 2016). Now, 25 years after study activation, we updated survival, further assessed IDH as a predictive biomarker, and are exploring the benefit from vincristine. METHODS Eligible adults (KPS ≥ 60, adequate end-organ function) were randomized to pre-RT iPCV (4 cycles x 6 weeks each) vs. RT alone, stratified by age (< or ≥ 50), KPS (60–70 or ≥ 80), and level of anaplasia. Histology (anaplastic oligodendroglioma/oligo-astrocytoma required) and biomarkers (IDH and 1p19q, post-hoc) were determined centrally. Survival was estimated by Kaplan-Meier and Hazard Ratios (HRs) by Cox-regression. RESULTS Overall (n=289), median follow-up was 16.4 years vs. 11.3 years at last report. In codeleted cases, 40% randomized to iPCV remained alive vs. 53% at last report; 5, 10, and 14 year-PFS and -OS rates were 62%, 50%, 41% and 70%, 57%, 46%, respectively; and iPCV unequivocally prolonged PFS (median 9.8 vs. 2.9 years, HR 0.46, 95% CI 0.3–0.7, p< 0.001) and OS (median 13.2 vs. 7.3 years, HR 0.61, 95% CI 0.40–0.94; p=0.02). With IDH mutation but without codeletion (n=66), iPCV prolonged PFS (median 2.8 vs. 1.9 years, HR 0.58, 95% CI 0.34–0.99, p=0.046); OS was longer with a trend for significance (median 5.5 vs. 3.3 years, HR 0.6, 95% CI 0.34–1.03, p=0.06) on this underpowered exploratory post-hoc analysis. CONCLUSION For codeleted AOTs, long-term analyses confirmed that pre-RT iPCV produced meaningful and significant prolongations of PFS and OS. With IDH mutation but without codeletion, iPCV significantly prolonged PFS and showed a trend for prolonged OS. The value of vincristine is being assessed. Supported by NCI grants U10CA180868, U10CA180822, U24CA196067, and UG1CA189867.

Abstract High-grade gliomas (HGGs) nearly always recur after standard initial treatment, and the resulting mixture of recurrent tumor and treatment-induced reactive changes presents major diagnostic challenges. Anatomical imaging, such as MRI, cannot adequately distinguish progressive disease from treatment effect (pseudo-progression). Furthermore, there is marked intra-tumoral heterogeneity, such that some areas of a tumor may demonstrate necrotic treatment effect and others frank recurrence. Due to this difficulty reliably differentiating between these two clinical findings, analytic methods using multiple modalities are necessary to further our understanding of this disease process. To this end, we sought to correlate radiographic, histopathologic and molecular features of surgically sampled post-treatment suspected recurrence to identify markers distinguishing tumor growth from treatment effect. We performed Stimulated Raman Histology (SRH) imaging and highly multiplexed RNA-sequencing (PLATE-seq) on 84 MRI-localized biopsies from 39 patients with clinically suspected recurrent HGG. The SRH images were classified as recurrent tumor or gliotic/reactive tissue using a convolutional neural network trained on an independent cohort including a large set of recurrent HGG, and an automated cell-counting algorithm was used to quantify cellularity from the SRH image of each sample. Differential gene expression analysis of the PLATE-seq data was used to identify gene sets that distinguish recurrent tumor from treatment effect, and single sample gene set variation analysis (GSVA) was used to further assess the molecular and cellular composition of each MRI-localized sample. The histopathologic and molecular features of each sample were also correlated with the MRI features of the corresponding biopsy sites, and this data is currently being used to train machine learning models that predict the distribution of recurrent tumor and treatment-induced reactive changes within a patient’s radiographic lesion. These predictive radiomic models will help to guide neurosurgical sampling, and improve our ability to monitor glioma progression and response to therapy.

Background: Adherence to surveillance guidelines in resected colon cancer has significant implications for patient morbidity, cost of care, and healthcare utilization. This study measured the underuse and overuse of imaging for staging and surveillance in stage I–II colon cancer. Methods: The OptumLabs database was queried for administrative claims data on adult patients with stage I–II colon cancer who underwent surgery alone in 2008 through 2016. Use of PET and CT imaging was evaluated during both initial staging (n=6,921) and surveillance for patients with at least 1 year of follow-up (n=5,466). “High use” was defined as >2 CT abdominal/pelvic (CT A/P) or PET scans per year during surveillance. Results: Overall, 27% of patients with stage I–II colon cancer did not have a staging CT A/P or PET scan and 95% did not have a CT chest scan. However, rates of staging CT A/P and CT chest scans increased from 62.0% (2008) to 74.8% (2016) and from 2.3% (2008) to 7.1% (2016), respectively. Staging PET use was overall very low (5.2%). During surveillance, approximately 30% of patients received a CT A/P or PET and 5% received a CT chest scan within the first year after surgery. Of patients who had surveillance CT A/P or PET scans, the proportion receiving >2 scans within the first year (high use) declined from 32.4% (2008) to 9.6% (2016) (P = .01). Conclusions: Although PET use remains appropriately low, many patients with stage I–II colon cancer do not receive appropriate staging and surveillance CT chest scans. Among those who do receive these scans during surveillance, high use has declined significantly over time.

OBJECTIVEScoliosis is frequently a presenting sign of Chiari malformation type I (CM-I) with syrinx. The authors’ goal was to define scoliosis in this population and describe how radiological characteristics of CM-I and syrinx relate to the presence and severity of scoliosis.METHODSA large multicenter retrospective and prospective registry of pediatric patients with CM-I (tonsils ≥ 5 mm below the foramen magnum) and syrinx (≥ 3 mm in axial width) was reviewed for clinical and radiological characteristics of CM-I, syrinx, and scoliosis (coronal curve ≥ 10°).RESULTSBased on available imaging of patients with CM-I and syrinx, 260 of 825 patients (31%) had a clear diagnosis of scoliosis based on radiographs or coronal MRI. Forty-nine patients (5.9%) did not have scoliosis, and in 516 (63%) patients, a clear determination of the presence or absence of scoliosis could not be made. Comparison of patients with and those without a definite scoliosis diagnosis indicated that scoliosis was associated with wider syrinxes (8.7 vs 6.3 mm, OR 1.25, p < 0.001), longer syrinxes (10.3 vs 6.2 levels, OR 1.18, p < 0.001), syrinxes with their rostral extent located in the cervical spine (94% vs 80%, OR 3.91, p = 0.001), and holocord syrinxes (50% vs 16%, OR 5.61, p < 0.001). Multivariable regression analysis revealed syrinx length and the presence of holocord syrinx to be independent predictors of scoliosis in this patient cohort. Scoliosis was not associated with sex, age at CM-I diagnosis, tonsil position, pB–C2 distance (measured perpendicular distance from the ventral dura to a line drawn from the basion to the posterior-inferior aspect of C2), clivoaxial angle, or frontal-occipital horn ratio. Average curve magnitude was 29.9°, and 37.7% of patients had a left thoracic curve. Older age at CM-I or syrinx diagnosis (p < 0.0001) was associated with greater curve magnitude whereas there was no association between syrinx dimensions and curve magnitude.CONCLUSIONSSyrinx characteristics, but not tonsil position, were related to the presence of scoliosis in patients with CM-I, and there was an independent association of syrinx length and holocord syrinx with scoliosis. Further study is needed to evaluate the nature of the relationship between syrinx and scoliosis in patients with CM-I.

Abstract Introduction: The role of surveillance imaging in diffuse large B-cell lymphoma (DLBCL) after treatment with curative intent is debated. In 2013, the American Society of Hematology (ASH) Choosing Wisely® campaign (Hicks LK, et al. Blood 2013) released a recommendation to "limit surveillance CT scans in asymptomatic patients following curative-intent treatment for aggressive lymphoma." This was based on previous studies demonstrating a lack of survival benefit as well as a significant impact on the patient in terms of cost, anxiety, incidental findings and radiation exposure. Similar findings have been described regarding the use of PET imaging, especially in low risk patients. We aimed to study the changes in practice patterns of surveillance imaging for DLBCL survivors treated with curative intent before and after the publication of the ASH Choosing Wisely® campaign. Methods: Administrative claims data from a large U.S commercial insurance database (OptumLabs Data Warehouse) were used to retrospectively identify adult patients with an incident diagnosis of DLBCL between 2008 and 2016 and at least one year of follow-up. We excluded those who did not receive treatment with curative intent: RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) x 6 cycles or RCHOP x 3-5 cycles plus radiation. Patients were also excluded if they had a co-existing or second cancer, or if they received any chemotherapy/radiation during their surveillance period, as to exclude anyone with a recurrence of their lymphoma. The surveillance period started 90 days after the last chemotherapy or radiation and continued for the duration of follow-up. Surveillance imaging was defined as any PET, PET-CT, CT chest, CT abdomen, and/or CT pelvis. To examine trends over time, three time periods were defined: 2008-2010, 2011-2013 and 2014-2016. The Cochran Armitage test was used to test the trend hypothesis. Results: A total of 1,472 patients were included. Cohort characteristics by time period are described in Table 1. Surveillance imaging frequency decreased from 84% in Year 1 of surveillance to 43% in Year 5 (Figure 1). Overall, surveillance imaging during the first 3 surveillance years significantly decreased over the three time periods (Figure 2) (P<0.01 for Years 1 and 2, P=0.04 for Year 3). Imaging surveillance for the first two years of surveillance did not significantly decrease from 2008-2010 to 2011-2013 (P>0.05), but significantly decreased from 2011-2013 to 2014-2016 (P<0.01). Of the groups that received imaging surveillance during year 1, the median number of scans during the first year was 2 (inter-quartile range, 1-2) and did not significantly change over time. In addition, PET/PET-CT surveillance decreased from 49% in Year 1 to <10% in Year 5. PET/PET-CT also decreased over the three time periods, from 62% (2008-2010) to 48% (2011-2013) to 43% (2014-2016) during the first year of surveillance and 40% to 31% to 25% during the second year. Younger age (<65 years versus ≥65 years) was associated with higher imaging utilization (86% versus 81%, respectively), and specifically PET/PET-CT utilization (55% versus 43%, respectively), during the first year of surveillance. However, race (white versus non-white) did not significantly affect imaging (85% versus 83%) or PET utilization (50% versus 47%) during the first year of surveillance. Conclusions: Our study demonstrates that the rate of surveillance CT and PET imaging in DLBCL patients treated with curative intent decreased significantly in the years after the publication of the ASH Choosing Wisely® campaign. However, over half of the DLBCL patients diagnosed in 2014-2016 continued to undergo surveillance imaging, indicating either incomplete guideline dissemination or ongoing debate regarding optimal surveillance practice. Future studies are necessary to determine whether such a decline in surveillance imaging is sustained and to examine factors (patient, provider, and payer) associated with surveillance imaging in DLBCL. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 3701 Background: Waldenstrom's macroglobulinemia (WM) is an indolent B-cell non-Hodgkin's lymphoma (B-NHL) characterized by production of a monoclonal IgM paraprotein and variable CD20 expression due to the downregulation of CD20 as B cells differentiate into plasma cells. Rituximab monotherapy (R) achieves an overall response rate (ORR) of 25–50% in therapy naïve and relapsed WM and is associated with IgM flares in 25–75% of patients (pts) that potentially lead to hyperviscosity due to a rapid rise in IgM. Ofatumumab (OFA) is a fully human monoclonal anti-CD20 antibody approved for the treatment of fludarabine and alemtuzumab-refractory chronic lymphocytic leukemia (CLL) and has demonstrated activity in indolent B-NHL. Since OFA is active in CLL, with its low CD20 expression, we initiated a phase II single-arm trial of OFA in pts with WM. We report primary endpoint data from this study. Methods: Pts (age ≥ 18 years) with WM requiring therapy by 2nd International Workshop on WM (IWWM) criteria were eligible. Cycle 1 (C1) of therapy consisted of OFA 300 mg week 1 and 1000 mg weeks 2–4 (Treatment Group A [TGA]) or OFA 300 mg week 1 and 2000 mg weeks 2–5 (TGB). Premedication included acetaminophen and antihistamine (all infusions) and glucocorticoid (infusions 1 and 2). Pts with grade 3–4 infusion-related adverse events (AEs) during weeks 1 and 2 also received glucocorticoid during weeks 3–5. Pts with stable disease (SD) or a minor response (MR) at week 16 of cycle 1 were eligible to receive a re-dosing cycle (C2) consisting of OFA 300 mg week 1 and 2000 mg weeks 2–5. The primary endpoint was ORR assessed by 3rd IWWM criteria. Toxicity was assessed according to NCI-CTCAE, v 3.0. Results: Thirty-seven pts were enrolled between March 2009 and February 2011. Median age was 63 years (range 43–85); 22 pts were male. Median IgM level was 3.11 g/dL (range 0.81–8.64); median hemoglobin (hgb) was 9.8 g/dL (range 5.3–13.2). Nine pts were treatment naïve; 28 pts had received a median of 3 prior therapies (range 1–5) including R (25 pts) and purine analog (14 pts). The first 15 pts were enrolled in TGA and the next 22 pts in TGB; pt characteristics were similar in both groups. Thirty-four pts completed C1; 1 pt withdrew after 1 dose and 2 pts received only 3 doses due to serious AEs (SAEs). Eleven pts achieved partial response (PR) and 7 achieved MR after C1 (ORR=49%; 95% CI [32%, 66%]). Twelve pts received C2, after which 4 pts improved their response (1 MR to PR, 1 SD to PR, 2 SD to MR) and 1 nonevaluable pt attained MR. After C1 and C2, the ORR was 59% (13 PR, 9 MR; 95% CI [42%, 75%]). Responses were seen in 67% (6/9) of therapy naïve pts, 57% (16/28) of relapsed pts, 52% (13/25) of pts who had prior R, 75% (9/12) of R-naïve pts, 64% (16/25) of pts with IgM < 4 g/dL and 50% (6/12) of pts with IgM ≥ 4 g/dL. ORR was 47% (7/15) in TGA and 68% (15/22) in TGB. ORR in TGA was negatively affected by prior R exposure and IgM ≥ 4 g/dL, whereas ORR in TGB was not affected by prior therapy, prior R or IgM level. Fifteen of 26 (58%) pts with hgb < 11.0 g/dL experienced ≥ 3.0 g/dL increase in hgb (range 3.0–7.1). Infusion-related events occurred with dose 1 in 30 (81%) pts and with dose 2 in 21 (57%) pts; all infusion events were grade 1–2 except 4 grade 3 events (1 rash, 1 chest pain, 1 chest discomfort, 1 back pain). Fifteen pts developed 22 infections including 8 upper respiratory tract, 4 urinary tract (UTI) and 4 sinus infections; all infections were grade 1–2 except 1 grade 3 UTI. One pt developed grade 3 febrile neutropenia. In total, there were 14 grade 3–4 AEs (all grade 3). Five pts developed 8 SAEs possibly related to OFA. One pt withdrew due to grade 3 hemolytic anemia. Two pts with baseline IgM of 6.63 and 4.75 g/dL required plasmapheresis for grade 3 renal insufficiency and hyperviscosity symptoms, respectively, with resolution of symptoms and were able to complete C1. Two pts developed IgM flare, defined as > 25% rise in IgM followed by subsequent MR or PR. Conclusions: OFA is clinically active in pts with WM, with an acceptable toxicity profile and a lower incidence (5%) of IgM flare. The ORR to OFA was 59% (TGA 47%, TGB 68%) including a 50% ORR (TGA 17%, TGB 83%) in pts with IgM ≥ 4.0 g/dL. Pts' anemia responded to OFA with 58% of pts with baseline hgb < 11.0 g/dL experiencing ≥ 3.0 g/dL increase in hgb. TGB achieved ORR > 60% in all pt groups regardless of prior therapy or baseline IgM level. A higher dose of OFA appeared to be more effective in pts previously exposed to R or with baseline IgM ≥ 4.0 g/dL. Further study of OFA in WM is warranted. Disclosures: Furman: Genentech: Speakers Bureau; GlaxoSmithKline: Speakers Bureau. Off Label Use: • Ofatumumab is an anti-CD20 monoclonal antibody approved for the treatment of fludarabine- and alemtuzumab-refractory chronic lymphocytic leukemia, and is 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). Eradat:Millennium: Speakers Bureau; Genentech, A Roche Company: Speakers Bureau. DiRienzo:GlaxoSmithKline: Employment. Leonard:GlaxoSmithKline: Consultancy. Advani:GSK: Research Funding. Switzky:GlaxoSmithKline: Employment. Liao:GlaxoSmithKline: Employment. Shah:GSK: Employment. Lisby:Genmab A/S: Employment. Lin:GlaxoSmithKline: Employment.

Abstract Introduction: Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoma characterized by lymphoplasmacytic cell infiltration of bone marrow and elevated serum levels of immunoglobulin M (IgM) protein. Despite recent advances in treatment the disease relapses in most patients. About 90% of WM patients harbor the MYD88 L265P oncogenic mutation. MYD88 is an adapter protein in the Toll-like receptor (TLR) pathway. The MYD88 L265P oncoprotein has been shown to amplify TLR 7 and 9 signaling, leading to downstream activation of NF-κB and cytokine signaling pathways that promote tumor cell survival and proliferation (Lim, AACR 2013). IMO-8400 is an investigational oligonucleotide antagonist of endosomal TLRs 7, 8 and 9. In preclinical studies in a human cell line and animal models of WM, IMO-8400 inhibited key cell signaling pathways, including NF-κB, BTK, STAT-3 and IRAK-4, and inhibited tumor growth and tumor IgM production. In Phase 1 and 2 clinical trials in healthy subjects (N=30) and in patients with autoimmune disease (N=35), IMO-8400 was generally well tolerated and demonstrated evidence of clinical activity. Based on these data, we initiated a Phase 1/2 clinical trial of IMO-8400 in WM, the first study of a drug candidate specifically targeting the MYD88 L265P mutation. Methods: This Phase 1/2 multicenter, open-label, dose-escalation clinical trial continues to recruit adult patients with relapsed or refractory WM (NCT Identifier: NCT02092909). In a classic 3x3 dose escalation scheme, patients are enrolled in one of three sequential escalating dose cohorts and receive subcutaneous IMO-8400 at dosages of 0.6, 1.2 or 2.4 mg/kg per week, respectively, for 24 weeks. The presence of the MYD88 L265P mutation is assessed by PCR-based genetic screening following enrollment. Patients who complete the 24-week treatment period are eligible to enroll in an extension trial. The primary study objective is to evaluate the safety and tolerability of escalating IMO-8400 dosages. Secondary objectives include preliminary evaluation of clinical response based on international guidelines and identification of an optimal dose for further evaluation (Kimby, Clin Lymphoma Myeloma 2006). Results: Overall, 17 patients (6 female, 11 male) have been enrolled in three dose cohorts to date. Median baseline characteristics include: age 66 years, prior therapies 4 (range 1-13), serum IgM 2,225 mg/dL, serum M protein 0.96 g/dL, and B2-microglobulin 3.42 mg/L. IMO-8400 has been generally well tolerated across all dose cohorts to date, with patient exposure ranging from 2-46 weeks in the Phase 1/2 and extension trials. The most common adverse events reported to date include transient flu-like symptoms and injection site reactions. One serious adverse event of worsening grade 3 arthritis, deemed possibly related to study drug, was reported in a patient with a pre-existing history of arthritis in the 2.4 mg/kg dose cohort. This patient discontinued study treatment. To date, no other patients have discontinued treatment due to treatment-related adverse events. Preliminary evidence of clinical activity for IMO-8400 has been observed in all dose cohorts. In June 2015, an independent Data Review Committee reviewed 4-week safety data from the highest dose cohort and agreed that 2.4 mg/kg was safe for further evaluation. Safety, pharmacokinetics and preliminary activity for all three dose cohorts will be presented. Conclusions: IMO-8400 is a mutation-targeted therapy in development for the treatment of patients with relapsed or refractory WM. In an ongoing Phase 1/2 clinical trial in WM, IMO-8400 has been generally well tolerated and has demonstrated preliminary evidence of clinical activity. Safety results support continued evaluation of IMO-8400 at 2.4 mg/kg/week in this patient population. Disclosures Thomas: Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Beck:Idera Pharmaceuticals: Research Funding. Nashat:Idera Pharmaceuticals: Research Funding. Ansell:Idera Pharmaceuticals: Research Funding. Eradat:Idera Pharmaceuticals: Research Funding. Libby:Idera Pharmaceuticals: Research Funding. Hajdenberg:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau; AbbVie: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Heffner:Idera Pharmaceuticals: Research Funding. Hoffman:Idera Pharmaceuticals: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Simov:Idera Pharmaceuticals: Employment. Wyant:Idera Pharmaceuticals: Employment. Brevard:Idera Pharmaceuticals: Employment. O'Leary:Idera Pharmaceuticals: Employment. Agrawal:Idera Pharmaceuticals: Employment.

Abstract The time in cellular differentiation at which the expression of an oncogene is dysregulated is thought to determine the phenotype of the resulting neoplasia. We tested this assumption in C57BL6/J transgenic mice expressing an HA-tagged c-myc oncogene in B cells under the control of kappa light chain regulatory elements. Two transgenes were engineered that differed by only one nucleotide. The first set of mice carries a wild type HA-MYC transgene, develops pro-B cell tumors, and succumbs rapidly to pronounced lymphosplenomegaly. In the second set of mice, a point mutation in the HA-tag portion of the transgene creates a stop codon that abrogates HA-MYC translation. This stop codon was engineered to be a hotspot for somatic hypermutation. Thus sporadically, in a germinal center B cell, somatic hypermutation may revert the stop codon, allowing translation of HA-MYC. In two independently derived lines, mice spontaneously develop monoclonal gammopathies (50% incidence at 30 weeks (n=35), 80% at 40 weeks (n=35)). Serum protein electrophoresis detects M-spikes that increase in intensity over time, and 6 out of 7 cases tested so far were of IgG1 isotype. Unlike other mouse models of plasma cell neoplasia, no lymphosplenomegaly nor ascites were detected. In analogy to human multiple myeloma, that is a disease of isotype-switched and hypermutated cells homing to the bone, large populations of plasma cells were found in the bone marrow. Bone marrow (but not spleen) lysates reacted for HA and human MYC proteins by western blot and immunohistochemistry, thus indicating that reversion of the stop codon occurred. Remarkably, in two young mice, monoclonal spikes appeared 2 weeks after vaccination with NP-CGG. These spikes were sustained and the monoclonal protein was reactive to the NP antigen. Together, comparison of the two sets of mice demonstrates that activation of the same transgene at distinct B cell developmental stages results in dramatically different tumor phenotypes. In addition, and opposite to most engineered mice, we have created a system where the oncogene is turned on sporadically, as occurs in the human disease. Furthermore, we have developed a model that faithfully reproduces important clinical aspects of monoclonal gammopathy of undetermined significance (MGUS) and its progression to multiple myeloma. This model will be useful to develop immunologic and chemoterapeutic approaches.

Abstract Background Clinical practice guidelines for MM list many alternative therapeutic options with an equivalent category of evidence but lack recommendations on the best approaches for individual patient cases. To provide clinicians with expert guidance on treatment options for defined patient scenarios, we developed and updated an interactive, online decision aid that allows users to enter specific disease and patient characteristics, enter their planned treatment, and then compare their choice of therapy with those of an MM expert panel for that scenario. Here we report data from the most recent version (2015) of this tool, capturing changes in expert recommendations and treatment trends for MM over time and evaluating the impact of this online tool on clinical care. Methods Each of 3 annual updates to the tool were developed with input from a panel of 5 MM experts. The individual experts provided treatment recommendations for multiple patient scenarios across the settings of induction therapy, maintenance therapy, and therapy for relapsed/refractory MM. A series of pull-down menus allowed users to select individual patient and disease characteristics identified by experts as important to consider when making treatment choices. These characteristics included: eligibility for autologous stem cell transplantation (for induction therapy only), results of chromosome analysis (cytogenetics/FISH), ECOG performance status, risk of renal insufficiency or peripheral neuropathy, previous therapy and depth of response (for maintenance and relapsed/refractory settings), and cardiac or pulmonary dysfunction (for relapsed/refractory setting). Users were then asked to state their intended management approach for that particular patient scenario. Once completed, recommendations for that scenario from each of the experts were displayed, and users were asked to indicate the impact of the expert recommendations on their treatment choice. Results Expert recommendations spanning the continuum of care were compiled in October 2012, November 2013, and March 2015 for the 3 different MM tool updates. As for earlier versions of the MM tool, each of the experts in the 2015 update provided recommendations for 32 case scenarios for induction therapy, for a total of 160 possible induction recommendations. Comparing overall induction therapy recommendations the use of bortezomib/lenalidomide/dexamethasone was approximately 40% in both 2013 and 2015, whereas the use of carfilzomib-containing regimens increased from 5% to 17%. None of the experts chose regimens with melphalan as induction therapy in 2015. In the relapsed/refractory setting, the use of newer therapeutic approaches continued to grow especially in the setting of patients who did not respond to induction therapy or relapsed within 6 months. For example, in those with prior proteasome inhibitor (PI) therapy, the selection of carfilzomib/lenalidomide/dexamethasone by experts rose from 11% to 38% from 2013 to 2015 with pomalidomide and lenalidomide selected for 20% to 25% of cases in the most recent tool. For prior IMiD and PI, the experts selected a new combination of pomalidomide with a PI (either bortezomib or carfilzomib) and dexamethasone in 55% of the case scenarios in 2015. To date, 170 different clinicians sought guidance on more than 259 patient case scenarios using the 2015 decision support tool. In the subset of cases (n = 104) in which users reported how the tool affected their management of patients with MM, 68% indicated the expert recommendations either confirmed or changed their intended treatment (22% changed; 46% confirmed), whereas 17% indicated that there would be barriers to implementing the expert recommendations, and 5% said they disagreed with the experts' recommendations. Conclusions Expert opinions regarding optimal MM therapy continue to evolve with new evidence. Our data show that interactive online therapy decision aids that provide expert recommendations to clinicians for specific case scenarios can aid decision making and capture practice trends in this rapidly evolving environment. Preliminary data suggest that most clinicians using the online decision aid either confirmed or changed their treatment approaches for specific MM patient case scenarios based on expert recommendations. A detailed and updated analysis of expert and user data will be presented. Disclosures Kumar: Janssen: Consultancy, Research Funding; Novartis: Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Skyline: Consultancy, Honoraria; BMS: Consultancy; Sanofi: Consultancy, Research Funding. Lentzsch:BMS: Consultancy; Novartis: Consultancy; Axiom: Honoraria; Janssen: Consultancy; Celgene: Consultancy. Lonial:Novartis: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Roodman:Amgen: Consultancy; Eli Lilly: Research Funding. Mortimer:AstraZeneca: Other: spouse is an employee of and has equity ownership in.