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Abstract Abstract 479 Background: MLN9708 is an investigational, oral, potent, reversible, and specific 20S proteasome inhibitor, which immediately hydrolyzes to MLN2238, the biologically active dipeptidyl leucine boronic acid. In preclinical studies, MLN2238 has shown faster proteasome dissociation and greater tissue penetration than bortezomib. Current phase 1 data indicate that oral administration of single-agent MLN9708 was generally well tolerated, with no grade ≥3 peripheral neuropathy, and showed signs of antitumor activity in some patients with relapsed and/or refractory MM. Bortezomib in combination with lenalidomide and dexamethasone demonstrated a 100% partial response or better (≥PR) rate in patients with previously untreated MM, providing the rationale for evaluating oral MLN9708 in place of bortezomib in this combination. Here we report phase 1 data from the first combination study of MLN9708 (ClinicalTrials.gov: NCT01217957). Methods: Primary phase 1 objectives were to determine the safety, tolerability, and maximum tolerated dose (MTD) of weekly MLN9708 in combination with lenalidomide and dexamethasone; secondary objectives included characterization of the pharmacokinetic (PK)/pharmacodynamic (PD) profile of MLN9708, assessment of PK interaction and response. Adults aged ≥18 years with ECOG performance status of 0 to 2, and adequate renal, hepatic, and hematologic function were eligible. Patients with grade ≥2 peripheral neuropathy or prior/concurrent deep vein thrombosis (DVT)/pulmonary embolism were excluded. Patients received oral MLN9708 weekly on days 1, 8, and 15, lenalidomide 25 mg on days 1–21, and dexamethasone 40 mg on days 1, 8, 15, and 22, for up to twelve 28-day cycles. Patients received thromboprophylaxis with aspirin or low molecular weight heparin. Transplant-eligible patients could undergo stem cell transplant after six cycles. MLN9708 dose escalation, from a starting dose of 1.68 mg/m2, followed a 3+3 scheme based on the occurrence of dose-limiting toxicities (DLTs) in cycle 1. Adverse events (AEs) were evaluated according to NCI-CTCAE v4.0. Response was assessed according to modified EBMT criteria. Results: At data cut-off (June 29, 2011), 10 patients have been enrolled and treated: three each at 1.68, 2.23, and 2.97 mg/m2 and one at 3.95 mg/m2; median age was 66 years (range 59–77). Patients completed a median of 3 cycles (range 1–6), with three having received 6 cycles; treatment is ongoing in six patients. A DLT of grade 3 fainting was observed in a patient treated at 3.95 mg/m2. The MTD has not yet been reached; the current cohort is receiving 3.95 mg/m2. Drug-related AEs included rash in four patients (two maculopapular, two erythematous); vomiting and fatigue in three patients each; and diarrhea, constipation, and nausea in two patients each. Grade 1 treatment-related peripheral neuropathy was reported in one patient. Serious AEs were seen in four patients: one at 3.95 mg/m2 (DLT of grade 3 fainting), one at 2.23 mg/m2 (grade 3 DVT) unrelated to MLN9708, and two unrelated at 1.68 mg/m2 (grade 3 hypotension; grade 3 gastrointestinal hemorrhage resulting in discontinuation). Two patients required lenalidomide dose reductions to 15 mg due to erythematous rash; no dose reductions were required for MLN9708 or dexamethasone. There were no on-study deaths. Of nine response-evaluable patients, all nine achieved ≥PR, including three very good PR (VGPR) and one complete response. Time to response was rapid; all responders achieved a ≥50% decrease in M-protein in cycle 1, and best response was reached by the end of cycle 4. No patient has progressed to date. One patient with confirmed VGPR discontinued at cycle 6 to undergo stem cell transplant. Conclusions: MLN9708 administered weekly in combination with lenalidomide and dexamethasone appears to be generally well tolerated in previously untreated MM patients at the MLN9708 dose levels studied, with evidence of antitumor activity in the dose-escalation cohorts. Evaluation continues to determine the MTD of MLN9708 in this combination. Updated results, PK data, assessment of PK interaction, and PD data will be presented. Disclosures: Off Label Use: Use of the investigational agent MLN9708 for the treatment of previously untreated multiple myeloma. Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy. Niesvizky:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding. Hui:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Genzyme: Research Funding; Novartis: Research Funding.

Abstract Background: High dose melphalan followed by autologous stem cell transplant (ASCT) is an effective treatment of immunoglobulin light chain amyloidosis (AL). However, the high treatment related mortality (TRM, death before day 100) remains a serious concern and is the major drawback of this therapy. A better understanding the risk factors contributing to TRM could help physicians choose the most appropriate therapy for these patients. We performed a retrospective study to identify risk factors that contribute to TRM after ASCT in AL patients. Methods: All patients who underwent ASCT for AL at our institution from 7/96 to 12/04 were studied. Data were collected on age, sex, septal thickness, glomerular filtration rate (GFR), B2M, CRP, proteinuria, albumin, cardiac troponin T (cTnT) and alkaline phosphate. Results: A total of 218 patients underwent ASCT for AL during this time period. One patient refused consent for this study. Pretransplant cTnT was available on 161 (73.9%) patients. The overall TRM rate for the 217 patients was 12.4%. By univariate analysis, septal thickness, GFR, albumin, alkaline phosphatase and cTnT were found to be associated with TRM. In the multivariate analysis, only albumin, alkaline phosphatase and cTnT remained independent predictors of TRM. Cutoffs were identified using receiver-operator characteristic (ROC) curve. The cutoff for albumin was 2.85 g/dL, 249 U/L for alkaline phosphatase and 0.02 ng/mL for cTnT. The percentage of patients with low albumin, elevated cTnT and alkaline phosphatase were 51.1%, 20.5% and 12.4% respectively. The TRM rate of patients with low albumin was 18.0%, 27.3% for elevated cTnT and 29.6% for high alkaline phosphatase. Risk of TRM increased significantly with each additional risk factor (Table). Discussion: In our AL population, low serum albumin, elevated alkaline phosphatase and cTnT were independent risk factors of TRM after ASCT. Patients with 2 or more risk factors are at significant risk of TRM during ASCT. In these high risk patients, alternative therapy should be considered in order to avoid excessively high incidence of TRM. Treatment Related Mortality by Number of Risk Factors Risk Factors 0 1 2 3 Rate of TRM 1.8% 8.4% 35.0% 66.0% Odds Ratio 5.0 29.1 108.0

Abstract Background: FLC is a valuable diagnostic tool to monitor response in patients with AL and oligosecretory MM. It is also prognostic in patients with MGUS. Its value in patients with non-oligosecretory myeloma has not been defined. Because of the short half-life of free-light chains, an early drop in free-light chain might be predictive for long term outcome post PBSCT. Methods: Between 8/1/03 and 12/10/04, 45 patients with multiple myeloma and abnormal FLC ratios (less than 02.6 or greater 1.65), who were undergoing PBSCT consented to have waste serum from routine post-transplant daily blood draws collected and frozen for future FLC analysis. The immunoglobulin FLC assay (Binding Site, U.K.) was run on samples collected from day +1 until patients were dismissed from our transplant center. Hematologic response was coded according to standard IBMTR criteria at approximately 3 months status post transplant (BJH 1998). Two types of immunoglobulin FLC response were coded: 50% reduction (FLC50) and 90% reduction (FLC90) of the difference of the involved and uninvolved FLC (Leukemia 2006). Two time periods of FLC response were analyzed: early (day 7); and delayed (day 19, range 13 to 24). Endpoints analyzed were overall response (>=PR), complete response rate (CR), progression free survival (PFS), and overall survival (OS). Results: The median age of the myeloma group was 59 years, and 53% were male. Thirty-three patients were monoclonal kappa, and 12 lambda. Forty-two percent were transplanted in response/plateau, 22% were primary refractory, and 36% relapsed disease. The overall hematologic response rate was 93% with a CR rate of 33%. Twenty-five patients have relapsed at a median of 14.2 months. Twelve patients have died, and median overall survival for the group has not been reached at a median follow-up of 24.6 months. Forty-nine and 58 percent of patients had early and delayed FLC90, respectively. Early FLC90, but not delayed FLC90, predicted for complete response (p<0.001). Neither early nor delayed FLC90 predicted for either PFS or OS. In addition, 89% and 96% of patients had an early and delayed FLC50, respectively. FLC50 at either time point did not predict for overall response, CR, PFS, or OS. Conclusion: Immunoglobulin free light chain responses are seen within the first weeks post high dose chemotherapy with peripheral blood stem cell transplant. A 90% reduction in FLC seen within the first seven days predicts for complete response. However, this does not yet translate into prolonged PFS or OS, but with longer follow-up separation of the survival curves may be seen.

Abstract Abstract 2877 Poster Board II-853 Background and Objective: In newly diagnosed multiple myeloma (MM) patients, treatment with lenalidomide plus high-dose dexamethasone (RD) was superior to high-dose dexamethasone in terms of both response rates and 1-year progression-free survival (PFS) (Zonder JA et al, Blood 2007;110:77). Preliminary results suggest that the combination lenalidomide plus low-dose dexamethasone (Rd) compared to the RD regimen yields significantly better 2-year overall survival (OS) (Rajkumar SV et al, J Clin Oncol 2008;26:8504). The combination of melphalan, prednisone, and lenalidomide (MPR) has been investigated in a phase I/II study showing promising results (Palumbo A et al, J Clin Oncol 2007; 25:4459-4465). The goal of this case –control study was to compare the efficacy and the toxicity of the lenalidomide/dexamethasone (len/dex) combination vs MPR as primary therapy for newly diagnosed elderly MM patients, to determine the additive value of melphalan compared to a regimen of lenalidomide plus corticosteroid. Patients and methods: Data from 51 newly diagnosed MM patients enrolled in Italy in a phase I/II dose-escalating trial, from January to October 2005, with MPR, were analyzed. For comparison of their outcome, 37 patients were identified among newly diagnosed patients seen at the Mayo Clinic from March 2005 to December 2008 who received len/dex as primary therapy and were enrolled in phase II or III trials. Patients treated with MPR received 9 monthly cycles of oral melphalan (doses ranging from 0.18 to 0.25 mg/kg on days 1-4), prednisone (2 mg/kg on days 1-4) and lenalidomide (doses ranging from 5 to 10 mg/day on days 1-21). After 9 cycles, patients started maintenance with lenalidomide alone (10 mg, days 1-21) until relapse or progression. Patients treated with len/dex received oral lenalidomide (25 mg/day, days 1-21) plus dexamethasone, either at low-dose (n=17) (40 mg orally days 1, 8, 15, 22) or at high-dose (n=21) (40 mg orally on days 1-4, 9-12, and 17-20). Treatment was continued until progression, relapse or unacceptable toxicity, or could be stopped at the physician's discretion. Patients (n=13) were allowed to receive transplant if they wished and were deemed eligible. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method and comparisons were determined by the log-rank test and the Cox proportional hazards model. Results: On intention-to-treat analysis, 15.7% versus 23.7% patients, respectively in the MPR and in the len/dex group, (p=0.342) achieved a complete response, and 43.2% vs 47.4%, (p=0.691) achieved at least a very good partial response. Time-to-progression (TTP) (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.04; 95% CI 0.55-1.98; p=0.903), PFS (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.03; 95% CI 0.55-1.92; p=0.926) and OS (2-year OS: 86.2% in MPR group vs 89.1% in len/dex, HR 0.86; 95% CI 0.38-1.98; p=0.730) were not significantly different between the 2 groups. No significant differences in TTP, PFS and OS were reported when MPR patients were compared with the subgroup of patients treated with low-dose dexamethasone plus lenalidomide. Similar results were found when the analysis was restricted to MPR patients and len/dex pair mates receiving lenalidomide plus low/dose dexamethasone, matched according to age and sex, and who did not received transplant. The toxicity profile was different in the two groups. Hematologic grade 3-4 toxicities were more common with MPR compared with len/dex, in particular neutropenia (66.7% vs 21.1%, p < 0.001) and thrombocytopenia (31.4% vs 2.6%, p < 0.001), respectively. Grade 3-4 gastrointestinal events (13.2% vs 2.0%, p= 0.080), thrombotic events (13.2 vs 5.9, p= 0.279) and fatigue (10.5% vs 3.9%, p= 0.395) were more common with len/dex compared with MPR. Conclusion: Results of this case-control study show that both MPR and Rd are efficacious regimens for elderly MM patients. Data need however to be carefully evaluated and randomized control trials are needed to confirm these results. Disclosures: Off Label Use: research drug in combination to standard of care. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; novartis: Research Funding; genzyme: Research Funding. Dispenzieri:celgene: Research Funding. Gertz:celgene: Honoraria; genzyme: Honoraria; millenium: Honoraria; amgen: Honoraria. Lacy:celgene: Research Funding. Musto:celgene: Honoraria. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Petrucci:celgene: Honoraria; Janssen Cilag: Honoraria. Greipp:celgene: Research Funding. Boccadoro:jansen Cilag: 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, Speakers Bureau; pharmion: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria.

Abstract Abstract 2848 Poster Board II-824 Background: Multiple myeloma remains incurable with current therapies and novel approaches based on disease biology are needed. IL-6 is a critical cytokine involved in myeloma cell proliferation and survival and exerts its activity primarily through the JAK/STAT pathway. In addition to IL6, other cytokines are also believed to cross talk with the JAK/STAT pathway, making it a crucial interface for survival signals. It has been implicated in myeloma cell interaction with the microenvironment and resistance to apoptotic stimuli from different drugs, and represents a potential therapeutic target. We examined the pre-clinical activity of a novel JAK2 tyrosine kinase inhibitor TG101209. Methods: TG101209 (N-tert-butyl-3-(5-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino)-benzenesulfonamide) was synthesized by TargeGen Inc. (San Diego, CA, USA). Stock solutions were made in DMSO, and subsequently diluted in RPMI-1640 medium for use. MM cell lines were cultured in RPMI 1640 containing 10% fetal bovine serum (20% serum for primary patient cells) supplemented with L-Glutamine, penicillin, and streptomycin. Cytotoxicity was measured using the MTT viability assay and proliferation using thymidine uptake. Apoptosis was measured using flow cytometry upon cell staining with Annexin V-FITC and propidium iodide (PI) for cell lines and using Apo2.7 in primary patient cells. CD45 expression was estimated using flow cytometry and cells were gated by their CD45 expression to assess differential effects of the drug. Immunoblotting was done on cell extracts at various time points following incubation with the drug in order to study the cell signaling pathways. Results: TG101209 resulted in a dose and time dependent inhibition of cell growth in the MM cell lines tested. Most of the cytotoxicity was evident by 48 hours, with minimal increase seen up to 96 hours of incubation. At 48 hours of incubation, the median inhibitory concentration was between 2 and 4uM with similar IC50 seen for myeloma cell lines sensitive or resistant to conventional therapies. The IC50s were maintained when the cells were treated in co-culture with stromal cells or in the presence of IL6, IGF or VEGF. Increasing doses of IL6 was not able to rescue the cells from the drug. Dose dependent decrease in proliferation of the cell lines was evidenced by decreased thymidine incorporation. Apoptotic changes in cells following drug treatment was confirmed by flow cytometry for Annexin and PI. Cleavage of caspases 3, 8 and 9 were confirmed on flow cytometry. Addition of the pan-caspase inhibitor zvad-fmk did not prevent drug-induced apoptosis confirming non-caspase mediated mechanisms of cell death as well. Primary myeloma cells from several patients were treated with increasing doses of the drug and IC50 similar to cell lines were seen in 8/10 patient samples tested. Interestingly, evaluation of U266 cell lines, which have a mix of CD45+ and negative cells as well as primary patient cells demonstrated more profound cytotoxicity and anti-proliferative activity of the drug on the CD45+ population relative to the CD45- cells. Immunoblotting studies demonstrated significant down regulation of IL-6 induced pSTAT3 with minor effects on the pERK and pAkt. The effect on pSAT3 was sustained compared to that on pERK and pAkt. This was accompanied by significant down regulation of Bcl-xL. Studies in a mouse model of myeloma are planned. Conclusion: These studies demonstrate significant in-vitro activity of JAK2 inhibition in multiple myeloma. In particular, the preferential targeting of CD45 cells, considered to reflect the proliferative compartment in myeloma holds out the promise for more sustained impact on the disease from a therapeutic standpoint. This is likely explained by the increased sensitivity of the CD45 cells to cytokines as a result of higher expression of different cytokine receptors as has been previously shown. This leads to increased activity of and dependence of the cells on the JAK-STAT pathway and likely explains the increased effect of the pathway inhibition. These studies form the framework for clinical evaluation of the drug in the setting of myeloma. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding.

Abstract Abstract 2868 Poster Board II-844 Background and Objective: In newly diagnosed multiple myeloma (MM), the combination of lenalidomide plus high-dose dexamethasone (RD) is superior to high-dose dexamethasone (Zonder JA et al, Blood 2007;110:77). Preliminary results show that lenalidomide plus low-dose dexamethasone (Rd) has better 2-year overall survival (OS) compared with RD (Rajkumar SV et al, J Clin Oncol 2008;26:8504). The addition of clarithromycin (Biaxin) to lenalidomide and low-dose dexamethasone (BiRd) has been investigated in a phase II study, demonstrating a high response rate and 2-year OS (Niesvizky R at al, Blood 2008;111:1101-1109). However, the additive value of clarithromycin is not known. No randomized trials have compared Rd versus BiRd, none are planned. The objective of this case–matched study was to compare the efficacy and the toxicity of BiRd vs Rd as initial therapy for newly diagnosed MM. Patients and methods: Data from 72 newly diagnosed MM patients treated at the New York Presbyterian Hospital–Cornell Medical Center, from December 2004 to December 2006, with BiRD, were analyzed. For comparison, an equal number of pair mates were selected among newly diagnosed patients seen at the Mayo Clinic who received Rd, from March 2005 to December 2008. Case matching was performed with respect to age, gender, and transplant status. Patients treated with BiRd received oral lenalidomide (25 mg/day, days 3-21 of cycle 1; days 1-21 of subsequent cycles); dexamethasone (40 mg days 1, 2, 3, 8, 15, 22 of cycle 1; days 1, 8, 15, and 22 of each subsequent cycle); clarithromycin (500 mg twice daily, from day 2 of cycle 1). Patients treated with Rd received oral lenalidomide (25 mg/day, days 1-21) plus low-dose dexamethasone (40 mg days 1, 8, 15, 22). In both groups patients were allowed to discontinue treatment to pursue transplant, but treatment until progression, relapse or unacceptable toxicity was permitted at the physician's discretion. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method; comparisons were determined by the log-rank test and the Cox proportional hazards model. Results: Median duration of treatment was 11.8 months in the BiRd group vs 6 months in the Rd group. On intention-to-treat analysis, complete response was significantly higher with BiRd compared to Rd (45.8% vs 13.9%, respectively, p<0.001); similarly very good partial response (VGPR) or better was higher with BiRd (73.6% vs 33.3%, p<0.001). Rates of VGPR or better, after 6 months and 1 year of therapy, were significantly higher in BiRd patients. Both time-to-progression (TTP) (median 48.3 months vs 27.5 months; HR 0.51; 95% CI 0.25-1.06; p=0.071) and PFS (median 48.3 months vs 27.5 months, HR 0.50; 95% CI 0.25-0.98; p=0.044) were higher with BiRd. Median time to next treatment (TTNT) was not reached in BiRd group compared to 29.9 months in Rd patients (HR 0.37 95% CI 0.20-0.66, p<0.001). There was a trend toward better OS with BiRd, (3-year OS: 89.7% vs 73.0%), but the difference was not statistically significant (HR 0.48; 95% CI 0.17-1.37; p=0.170). Thirty-two patients in each group received transplant; median time to transplant was longer in BiRd group (13.5 vs 5.9 months). Results of survival, for patients who received transplant and patients who did not, were similar to those of the total population. On subset analysis, among patients presenting with International Staging System (ISS) stage I/II at diagnosis, TTP, PFS and TTNT were significantly longer in BiRd patients; no significant differences were found among patients with ISS stage III. Main grade 3-4 toxicities of BiRd were hematological, in particular thrombocytopenia (23.6% vs 8.3%, p=0.012); rate of neutropenia was similar between the 2 groups (19.4% vs 16.7%, p=0.665). Infections (16.7% vs 9.7%, p=0.218) and dermatological toxicity (12.5% vs 4.2%, p=0.129) were higher in patients who received Rd. Rate of venous thromboembolism was similar in the 2 groups (9.7% vs 12.5%, respectively in Rd and BiRd patients, p=0.596). Conclusion: Results of this case-control analysis suggest superiority of BiRd in terms of response rate and survival, compared with Rd, and suggest that there may be a significant additive value when clarithromycin is added to Rd. These data indicate the need for randomized prospective phase III studies to evaluate BiRd versus Rd in the treatment of MM. Disclosures: Off Label Use: research drug in combination to standard of care. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; novartis: Research Funding; genzyme: Research Funding. Mark:celgene: Research Funding. Dispenzieri:celgene: Research Funding. Gertz:celgene: Honoraria; genzime: Honoraria; millenium: Honoraria; amgen: Honoraria. Leonard:celgene: Consultancy. Lacy:celgene: Research Funding. Witzig:celgene: Research Funding. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Greipp:celgene: Research Funding. Niesvizky:celgene: Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau; Proteolix: Research Funding, data monitoring committee.

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.

Abstract Background: Patients with AL and congestive heart failure have a median survival of less than one year. Methods: Between 1994 and 2005, 11 patients underwent sequential heart transplant followed by autologous peripheral blood stem cell transplant (SCT) for treatment of AL. Patients had heart dominant AL with minimal/no other organ impairment and no evidence of multiple myeloma. Results: Patients ranged in age from 35 to 63 years (median 54). All had biopsy proven amyloidosis and monoclonal protein detectable in serum (73%) or urine (100%). Free light chain assay was available prior to SCT in 6 and was abnormal in all. All patients presented with NYHA Class III or IV heart failure. All but two patients had no other organ involved at the time of heart transplant. One patient had his heart transplant at another facility and had renal involvement at the time of heart transplant. One patient had peripheral nerve involvement documented prior to heart transplant. Five patients had progression of amyloid to involve other organs by the time of SCT. These included: renal (6), peripheral nerve (2), macroglossia (3), gastrointestinal (2). The median time from diagnosis to heart transplant was 3 months (range 1 to 5). The median time from heart transplant to SCT was 8 months, (range 3 to 24). Conditioning chemotherapy consisted of melphalan 200 mg /m2 (6 patients) or melphalan 140 mg/m2 (5 patients). Two patients died of complications before day +100, (TRM of 18%). Hematologic remissions were seen in 8 and organ responses in 3. Five were unable to be evaluated for organ response due to the heart transplant. Three died from progressive amyloidosis at 66, 56.7, and 55 months following SCT. The median survival is 56.7 months from SCT. Six are alive with a median follow-up of 24 months, range 9 to 90 months. Among the 6 surviving patients, one patient relapsed and one patient has failed to improve, but 4 patients are in continued remission. One patient developed secondary myelodysplastic syndrome. Conclusions: Heart transplant followed by SCT is feasible and offers durable remissions for carefully selected patients with cardiac AL. Figure Figure

Abstract Background: High dose therapy (HDT) and stem cell transplant has been shown to improve survival in patients with myeloma and remains the standard of care. However, the reported results of initial HDT in these patients reflect the combined effect of the initial therapy and the HDT. The contribution of HDT on its own is often difficult to analyze in this group of patients with varying degree of response to initial therapy. In this single institution retrospective study, we have analyzed the results of HDT in a group of patients with measurable disease at the time of HDT. Methods: We identified patients from our transplant database, who had measurable disease at the time of initiation of transplant as defined by a serum M protein of ≥ 1.0 g/dL, 24 hour urine M-protein ≥ 200 mg or a bone marrow plasma cell % of ≥ 30. Details regarding the clinical outcome were obtained from the database and from patient clinical records. Chi square test was used for comparison of nominal variables and t-test for continuous variables. Kaplan Meier analysis was used for comparing survival and Cox proportional hazards was employed to identify predictors of progression free and overall survival. Responses were defined by the EBMTR criteria, using the measurements at the time HDT and the lowest measurement obtained. VGPR required a 90% reduction in the serum M component with urine protein &lt; 100 mg/24 hours. Results: A total of 440 patients were studied; 271 (61.5%) of whom had a transplant within one year of their diagnosis. Among the 271 patients, 140 (52%) were in the initial plateau, 99 (36%) failed to achieve a PR to initial therapy and 32 (12%) were in their first relapse. Given the known differences in the outcome between these groups of patients, those receiving an early transplant were analyzed separately. The response rates included CR (24%), VGPR (7%), PR (52%), MR or less (17%) and among the late transplants CR (23%), VGPR (8%), PR (61%) and MR or less (8%). The median progression free survival was 23.6 mos and the overall survival from HDT was 62 mos. In a multivariate analysis, presence of cytogenetic abnormalities (RR: 2.5) and high plasma cell labeling index (≥ 1%) (RR: 2.4) at HDT and failure to achieve a CR or VGPR (RR: 1.7) were prognostic for decreased progression free survival post HDT. In a similar model, only high PCLI (RR: 2.8) and abnormal cytogenetics (RR: 2.5) at HDT predicted for poor overall survival after transplant. Conclusion: This study provides a sense of the contribution of HDT, independent of the initial therapy, by determining responses based on the immediate pre-transplant disease measurements and the best values observed post transplant. In this group of patients with residual measurable disease after the initial therapy, HDT therapy leads to complete responses in nearly a quarter of the patients and a VGPR in another 7%, an outcome associated with better progressin free survival. While measurements at transplant do not correlate strictly with response to initial therapy, the aim of this study was to understand the individual contribution of HDT in these patients. Thus some of the patients who would have been classified as having a partial response to induction and HDT may be classified as non-responders in this analysis. These numbers will provide a historical comparison for trials evaluating novel consolidation therapies for myeloma.

Abstract Background: Epigallocatechin-3-gallate (EGCG) is a polyphenol extracted from green tea that has been studied for cancer prevention and treatment. Green tea and its extracts have been an integral part of traditional medicines from Asia and are thought to have considerable medicinal value. EGCG has been studied in many tumor types and in vitro studies have been encouraging. It is currently in Phase I/II clinical trial in the treatment of chronic lymphocytic leukemia. Here we examined the activity of EGCG in the setting of myeloma and its potential mechanisms of action. Methods: MM cell lines were cultured in RPMI 1640 containing 10% fetal bovine serum supplemented with L-Glutamine, penicillin, and streptomycin. The KAS-6/1 cell line was also supplemented with 1 ng/ml IL-6. Cytotoxicity of EGCG was measured using the MTT viability assay. Apoptosis was measured using flow cytometry upon cell staining with Annexin V-FITC and propidium iodide (PI). Fresh myeloma cells were obtained from bone marrow aspirates and subjected to ACK lysis to remove red cells. These cells were cultured in RPMI1640 with or with out EGCG and apoptotic rates were determined by Apo 2.7 expression on gated plasma cells. Flow cytometry was used for determining the phosphorylation state of various signaling proteins. Anti-angiogenic activity of EGCG was measured using a human in vitro angiogenesis kit (Angiokit). Results: EGCG treatment of myeloma cell lines resulted in dose- and time-dependent cytotoxicity to the cells. EGCG was cytotoxic to several myeloma cell lines, including IL-6 dependent cell lines KAS-6/1 and ANBL-6 as well as drug resistant cell lines MM1.R, Dox40 and LR5. The effect was maintained when the cells were grown in co-culture with marrow stromal cells, indicating the ability to overcome microenvironment mediated resistance. EGCG induced apoptosis of myeloma cell lines, apoptotic cells being measured as Annexin (+)/PI (−) cells by flow cytometry. It induced a dose-dependent apoptosis of freshly isolated myeloma cells with increased effect seen on the CD45+ myeloma cells compared to CD45- cells, reflecting increased activity on the proliferative fraction. Down regulation of Akt phosphorylation was seen following treatment of myeloma cells with EGCG. Using the Angiokit, we were able to demonstrate inhibition of tubule formation by EGCG at concentrations lower than those cytotoxic to myeloma cells. It was also able to overcome the angiogenic activity of VEGF. Conclusion: We demonstrate potent anti-myeloma activity of EGCG in vitro. In vivo studies in animal models of myeloma are ongoing. We demonstrate, as in other cell lines, inhibition of Akt pathways as a potential mechanism of action of EGCG. Ongoing studies are exploring other mechanisms. Most importantly, we demonstrate anti-angiogenic activity of this compound in the setting of myeloma, a finding in concordance with the inhibition of VEGF activity seen with other tumor systems.