ALBERT

Description: Background The epitome of cancer treatment personalization is N=1 segmentation where a custom therapy is designed for every patient. Because most cancer aberrations are not actionable mutations and tumors can have more than one actionable mutation, this one biomarker/one drug approach to cancer personalization has inherent limitations due to its over simplification. Personalization 2.0 methodology creates a patient simulation avatar incorporating a patient’s genomic profile information holistically. Methods Bone marrow samples from two myeloma patients (P1 and P2) refractory to most recent treatment was collected, and P1’s sample was sorted into CD138+ and CD138- cells. The patient cells were analyzed for chromosomal alterations using Comparative Genomic Hybridization (aCGH) arrays by GenPath Diagnostics and cytogenetic chromosome analysis by Washington University School of Medicine and New York University (NYU), respectively. Using this information, a predictive simulation avatar model of each patient was created by Cellworks based on genomic profile of patients. A digital functional library of over 80 FDA-approved drugs and agents currently in clinical trials were simulated individually and in combination using the two patient avatars to create a personalized treatment for each patient. The findings were prospectively validated using patient cells ex vivo as assessed by MTT assay at New York University. Results P1 aberrations included trisomy of CCND1 and deletion of TP53 along with single copy losses in different arms of chromosomes 1, 6, 8, 12, 13, 14, 16, 17 and 22 and gains in different arms and regions of chromosomes X, 1, 4, 7, 9, 17, 3, 5, 11, 15 and 19, indicating the presence of hyperdiploid clones. Using this information, 897 gene perturbations were included to model this patient simulation avatar. Simulation predicted high beta-catenin (CTNNB1) activity with increased hedgehog and NOTCH pathways that were inherent causes of Bortezomib resistance. Significant activation of STAT3 and STAT5 due to amplification of IL6 pathway, JAK2 and JAK3 was noted. Amplifications of MET, IGFR and FGFR converged at ERK and AKT signaling loops. Along with deletion of TP53, this profile had amplification of many anti-apoptotic genes including survivin, MCL1 and XIAP. Modeling predicted sensitivity to the JAK inhibitor Tofacitinib, a drug approved for rheumatoid arthritis. This was prospectively validated ex vivo, and the experimental data correlated with the prediction showing a reduction in viability. P2 aberrations include losses in chromosomes X and 9 and a chromosome 11:14 translocation that is a common occurrence in MM. This translocation results in an amplification of CCND1 expression. The genomic aberrations reported include knockdown of tumor suppressors RXRA, TGFBR1, TJP2 and TSC1. TSC1 regulates the mTOR pathway, and its deletion causes an aberrant activation of mTOR and its downstream targets. Reduced expression of RXRA and TJP2 both in different manners leads to increase in AP1 activation. NFkB is also activated due to RXRA reduction. TGFBR1 reduction decreases the expression of cell cycle inhibitors via SMAD2/3 down-regulation. In this patient avatar, modeling predicted sensitivity to a combination of Sirolimus and Trametinib. Ex vivo validation confirmed this prediction of additive synergy of these two drug agents in the context of this patient. Conclusions This study demonstrates and validates the personalization of treatment through two patient cases based on creating predictive simulation avatar models using genomic profile information. This modeling holistically incorporates all genomic aberration information and is not limited to associating drugs to actionable mutations. Disclosures Doudican: Cellworks: Research Funding. Vali:Cellworks: Employment. Basu:Cellworks: Employment. Kumar:cellworks: Employment. Singh:Cellworks: Employment. Sultana:Cellworks: Employment. Abbasi:Cellworks: Employment, Equity Ownership.

Description: Introduction The incidence of multiple myeloma (MM) increases with age, yet some cytogenetic changes are actually more common in younger patients with MM (Avet-Loiseau J Clin Oncol 2013).  This suggests that a mechanism other than chromosomal changes underlies the increased incidence with age.  Senescent cells secrete a number of proinflammatory cytokines, chemokines, growth factors and proteases resulting in the senescence-associated secretory phenotype (SASP), which can promote tumor growth.  Preclinical data suggests that myeloma bone marrow stromal cells express the SASP (Andre PLOS ONE 2013). We hypothesized that SASP factors correlate with age in patients with MM. Methods Peripheral blood serum and matched bone marrow aspirate plasma from patients with multiple myeloma were evaluated for selected factors associated with the SASP using quantitative multiplex immunoassay (Rules Based Medicine, Austin TX USA).  SASP factors with a known role in MM [interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-15 (IL-15), granulocyte-macrophage colony-stimulating factor (GMCSF), intercellular adhesion molecule 1(ICAM1), osteoprotegerin (OPG), hepatocyte growth factor (HGF), insulin-like growth factor-binding protein(IGFBP-1), interleukin-1 beta (IL1b), monocyte chemotactic protein 1(MCP-1), macrophage inflammatory protein-1 alpha(MIP-1a), angiogenin, leptin,  vascular endothelial growth factor receptor 1(VEGFR1) and stem cell factor(SCF)] were selected. The relationship between age and SASP factors were analyzed using Kendall tau rank correlation coefficient. Results Samples from 25 patients (each with peripheral blood serum and matched bone marrow aspirate plasma) were analyzed.  The median age was 62 (range 47 - 74). Disease states were as follows: 36% newly diagnosed/untreated, 24% pretransplant and 40% relapsed.  ISS stage included 40% stage I, 28% stage II and 32% stage III.  Three of the selected SASP factors in the peripheral blood correlated   with age:  IL-8 (Kendall Tau 0.334, p=0.027), OPG (Kendall Tau 0.289, p=0.046) and MCP-1 (Kendall Tau 0.332, p=0.022).  No SASP factors tested in the bone marrow plasma were significantly correlated with age. Conclusions We demonstrated age-associated differences in the SASP factors IL-8, OPG and MCP-1 in the peripheral blood of myeloma patients.  Future research will examine differences between patients with myeloma and age-matched controls without cancer. Disclosures: Vij: Celgene : Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau. Stockerl-Goldstein:Celgene : Speakers Bureau; Celgene : Speakers Bureau; Millennium: Speakers Bureau; Millennium: Speakers Bureau.

Description: Background: Over the past two decades, peripheral blood stem cells (PBSC) have surpassed bone marrow as the preferred graft source for adult allogeneic transplantation due to its more rapid engraftment and potentially better graft-vs-tumor effects, and because PBSC collection is much less invasive for the donor. The optimal CD34+ PBSC dose is ≥ 4.0x106cells/kg, but doses ≥ 8.0x106cells/kg are suggested by some for reduced-intensity conditioning and haploidentical transplants. There is no established minimum CD34+ PBSC dose, but doses below 2.0x106cells/kg have been associated with a higher risk of engraftment delay and failure. There is significant inter-donor variability in the ability to mobilize PBSCs. Several factors have been identified as predictors of PBSC mobilization in healthy donors including: gender, age, weight, body mass index (BMI), and blood counts before and after mobilization. The impact of the donor’s comorbidities on mobilization is currently unknown. Patients/Methods: We performed retrospective chart review of 488 consecutive adult patients who underwent apheresis for allogeneic stem cell donation at Washington University School of Medicine from 2006 through 2013. Patients who received any collection regimen other than 10mcg/kg of G-CSF daily with 20 liters (+/-10%) apheresis on Day 5 were excluded. Patients who had undergone a previous apheresis for stem cell donation were excluded. Univariate analysis was performed to identify predictors of CD34+ PBSC collection in a single apheresis. Variables analyzed were: gender; age; weight; BMI; donor-to-recipient weight ratio; pre and post-mobilization blood counts (white blood count [WBC], hematocrit, platelets, neutrophils, lymphocytes, and monocytes); pre-mobilization glucose and triglyceride levels; post-mobilization peripheral blood (PB) CD34+count; and medical history significant for hypertension, hyperlipidemia, or diabetes mellitus. Subsequently, a linear regression multivariate analysis was performed with all variables found to be significant in the univariate analysis. 2-tailed tests for significance were used throughout the analysis. Results: 304 patients met the eligibility criteria for analysis. The median age was 53 years (range 18-76), 90% were Caucasian, and 50% were male. The median number of CD34+ cells collected was 7.4 x106/kg (range 0.8-27.1). 97% (295) collected ≥ 2.0x106 CD34+cells/kg, 81% (247) collected ≥ 4.0x106 CD34+cells/kg, and 44% (134) collected ≥ 8.0x106 CD34+ cells/kg. Post-mobilization PB CD34+ count (r= 0.841, p

Description: Background: The need to repeat peripheral blood stem cell (PBSC) mobilization and collection arises infrequently in healthy donors, but may be required due to insufficient initial collection, graft failure, or relapse of the recipient’s disease. Currently no published data exists on the efficacy of remobilization of healthy PBSC donors. Studies of remobilization in patients undergoing autologous transplantation (ASCT) have largely focused on the use of alternative mobilization agents such as chemotherapy or plerixafor. Boeve et al (Bone Marrow Transplant, 2004) reported that remobilization with G-CSF in patients undergoing ASCT who failed initial mobilization with G-CSF, resulted in higher numbers of CD34+ cells collected than the initial collection, though this required a doubling of the dose of G-CSF. Patients/Methods: We performed retrospective chart review of 977 consecutive adult (〉18 yrs) donors who underwent apheresis for PBSC donation at Washington University School of Medicine from 1995 through 2013. We identified 66 donors who had undergone more than one mobilization. Two cohorts of donors were identified for analysis: Group 1 included donors mobilized initially and again subsequently with G-CSF (10 ug/kg/day), or GM-CSF (5 ug/kg/day) + G-CSF (10 ug/kg/day). Group 2 consisted of donors mobilized with a CXCR4 antagonist, plerixafor (240-320 ug/kg) or POL6326 (1000-2500 ug/kg), and subsequently were remobilized with G-CSF (10 ug/kg/day). Statistical Analysis: Spearman correlations were performed to analyze the relationship between peak peripheral blood (PB) CD34+/uL level; the number of CD34+ cells collected per kg (recipient weight); and the number of CD34+ cells per L of apheresis collected during initial mobilization (MOB1) and remobilization (MOB2); and the interval (days) between MOB1 and MOB2. One-way ANOVA with repeated measures analyses were performed to determine the relationship of PB CD34+/uL, CD34+/kg and CD34+/L during MOB1 and MOB2. Results: Group 1 included 30 donors. The median age was 49 years (range 18-75) and 15 were male. The median number of days between MOB1 and MOB2 was 140 (range 26-2238). All 30 donors were remobilized due to graft failure or relapse of the recipient’s disease. PB CD34+/uL, CD34+/kg and CD34+/L all correlated between MOB1 and MOB2. The mean PB CD34/uL at MOB1 was 69 compared to 37 at MOB2 (p= 0.029); the mean CD34/kg collected at MOB1 was 5.6x106 compared to 3.3x106 at MOB2 (p= 0.002); and the mean CD34/L collected at MOB1 was 24.0x106 compared to 17.6x106at MOB2 (p= 0.023). The interval between MOB1 and MOB2 did not correlate with any of the MOB2 variables. Results from the analysis are summarized in Table 1. Group 2 included 32 donors. The median age was 51 years (range 21-67) and 18 were male. The median number of days between MOB1 and MOB2 was 20 (range 4-1123). 18 donors were remobilized due to mobilization failure, while 14 were remobilized due to graft failure or relapse of the recipient’s disease. The mean PB CD34/uL at MOB1 was 15 compared to 68 at MOB2 (p〈 0.001); the mean CD34/kg collected at MOB1 was 2.5x106 compared to 7.1x106 at MOB2 (p〈 0.001); and the mean CD34/L collected at MOB1 was 10.6x106 compared to 30.1x106at MOB2 (p〈 0.001). The interval between MOB1 and MOB2 did not correlate with any of the MOB2 variables. Results from the analysis are summarized in Table 2. Conclusion: Remobilization with G-CSF or GM-CSF and G-CSF after initial successful mobilization with the same regimen results in poorer mobilization while remobilization with G-CSF after initial mobilization with a CXCR4 antagonist results in dramatically improved mobilization. The reason for this remains unclear, but in this study the interval between collections was not associated with successful remobilization. Abstract 850. Table 1 Group 1 MOB 1 MOB 2 One-way ANOVA Spearman Correlation PB CD34/ul 69 (13-417) 37 (1-115) F(1.0, 29.0) = 5.26, p= 0.029 r= 0.615, p〈 0.001 CD34/kg (x106) 5.6 (0.8-13.8) 3.3 (0.3-10.6) F(1.0, 29.0) = 11.77, p= 0.002 r= 0.483, p= 0.007 CD34/L (x106) 24.0 (4.5-72.0) 17.6 (2.8-41.3) F(1.0, 29.0) = 5.74, p= 0.023 r= 0.566, p〈 0.001 Abstract 850. Table 2 Group 2 MOB 1 MOB 2 One-way ANOVA Spearman Correlation PB CD34/ul 15 (2-54) 68 (14-358) F(1.0, 31.0) = 23.16, p〈 0.001 r= 0.433, p= 0.013 CD34/kg (x106) 2.5 (0.2-19.7) 7.1 (1.7-42.4) F(1.0, 31.0) = 33.84, p〈 0.001 r= 0.769, p〈 0.001 CD34/L (x106) 10.6 (1.4-67.1) 30.1 (6.0-165.0) F(1.0, 31.0) = 34.70, p〈 0.001 r= 0.774, p〈 0.001 Disclosures No relevant conflicts of interest to declare.

Description: Background: Bone lesions and extramedullary plasmacytomas, present in ~70% and ~15% of multiple myeloma (MM) patients at diagnosis, respectively, are a major source of morbidity. Extensive bone or extramedullary disease is often associated with severe pain, fracture, or spinal cord compression requiring immediate medical attention. Palliative radiation to the afflicted area(s) can provide relief or reduction of the associated symptoms. The presence of bone lesions or extramedullary plasmacytomas at MM diagnosis have been linked to poorer prognosis, but to date, the prognosis of patients with extensive bone or extramedullary disease requiring radiotherapy during front-line treatment is unclear. In a single institution retrospective study of 162 newly diagnosed MM patient’s, including 87 who received front-line radiotherapy, Yaneva, et al (J Buon, 2006) found no survival difference between patients who received radiotherapy during front-line treatment and those who did not. Methods: Using the SEERStat software, we extracted the case listings of 85,115 patients diagnosed with MM from 1973 through 2010 in Surveillance Epidemiology and End Results (SEER)-18 registries database based on the November 2012 submission. Children (under 18 years old) were excluded. Autopsy or death certificate only cases were excluded. As non-black minorities have been historically underrepresented in the SEER databases, patients identified as any race other than white or black were excluded. Patients were followed for OS through December 2011. Disease-specific-survival was defined as death from myeloma. Patients were classified as having radiotherapy during front-line treatment or not. Patients who refused radiotherapy (n = 184) or for whom radiotherapy status was unknown (n = 973) were excluded. Results: 77,714 patients were eligible for analysis. The median age at diagnosis was 70 years (range 18-85+); 54% were male; 19% were black. The median follow-up was 22 months (range 0-441). 25% (n = 19,295) of patients received radiotherapy during front-line treatment. Radiotherapy during front-line treatment was more common among patients under the age of 60 at diagnosis (30.9% vs 21.4%; p 〈 0.001), white patients (25.5% vs 21.8%; p 〈 0.001), and male patients (26.2% vs 23.2%; p 〈 0.001). The frequency of radiotherapy during front-line treatment decreased in the most recent decade (22.8% vs 27.3%; p 〈 0.001). Patients who received radiotherapy during front-line treatment had an estimated median disease-specific-survival of 38 months compared to 46 months for patients without (p 〈 0.001). In a multivariate cox regression model of age, race, sex, and radiotherapy during front-line treatment, all four variables were independently significant (Table 1). Radiotherapy was associated with a 17% (95% CI 15-20) increase in disease-specific mortality. The impact of radiotherapy was relatively stable over the time frame studied (Table 2). Conclusions: Radiotherapy during front-line treatment, a surrogate for extensive bone or extramedullary disease at MM diagnosis, is independently associated with increased disease-specific mortality. It has remained a relatively stable predictor of poorer prognosis throughout the timeframe tested, suggesting that MM treatment advances have not overcome the poor prognosis associated with extensive bone lesions or extramedullary disease at MM diagnosis. Table 1 Multivariate Overall Survival Analysis Overall Age HR1 (95% CI) p value

Description: Background: The use of autologous stem cell transplants (ASCT) for multiple myeloma (MM) has greatly improved overall survival (OS), however, not all patients have benefited equally. Several studies have indicated that patients over the age of 65 or 70 at diagnosis had no immediate improvement in OS following the use of ASCT for MM, which is intuitive as ASCT was not covered by Medicare until 2001 and today is still often reserved for patients under 70. In addition, Waxman, et al (Blood, 2010) reported that ASCT for MM, resulted in nearly a two-fold improvement in OS in white patients compared to black patients. This suggests that white patients had better access to ASCT as retrospective studies of MM patients who undergo ASCT have failed to show an OS difference between the two races. Disparities in the OS benefit of ASCT among patients of different socioeconomic groups have not been reported on to date. It is also unclear if these disproportional improvements in outcomes have continued following the approvals of bortezomib and lenalidomide. Methods: Using the SEERStat software, we extracted the case listings of 85,115 patients diagnosed with MM from 1973 through 2010 in Surveillance Epidemiology and End Results (SEER)-18 registries database based on the November 2012 submission. Children (under 18 years old) were excluded. Autopsy or death certificate only cases were excluded. Patients identified as any race other than white or black were excluded. Patients were followed for OS through December 2011. Patients were divided into three cohorts based on the year of diagnosis, era 1 those diagnosed from 1973 to 1994, era 2 those diagnosed from 1995-2002 (to coincide with ASCT), and era 3 those diagnosed from 2003-2010 (to coincide with bortezomib’s approval). Socioeconomic status (SES) was approximated by median household income (MHI) of each patient’s county of residence from the 1990 US census; patients were divided into tertiles within their era of diagnosis based on MHI and classified as low-SES, middle-SES, or high-SES. Results: 78,681 patients were eligible for analysis. The median age at diagnosis was 70 years (range 18-85+); 54% were male; 18% were black. The median follow-up was 22 months (range 0-441). The OS of white patients increased from 23 months in the era 1 to 27 months in era 2, to 36 months in the era 3 (p

Description: Abstract 2965 Background: Alkylating agents have been the mainstay of multiple myeloma (MM) therapy for decades and despite introduction of several new therapies, it continues to play a significant role in its management as part of various drug combinations. While melphalan has been the most commonly used alkylator in MM, recent studies have suggested significant activity for bendamustine, a bifunctional alkylator. The combination of lenalidomide and melphalan has been associated with high response rates in relapse and newly diagnosed MM. Based on these promising results we designed a trial to evaluate the maximally tolerated dose of lenalidomide and bendamustine when used in combination as well as the efficacy of the combination in relapsed disease. Patients and Methods: Patients with relapsed MM and measurable disease were enrolled on this phase 1/2 trial provided they had not more than 4 prior lines of therapy for MM, had adequate performance status and organ and hematological function. Patients refractory to lenalidomide were allowed to enroll. The primary objectives were to (i) to determine the MTD of bendamustine and lenalidomide in combination with dexamethasone in subjects with relapsed MM (phase 1) and (ii) to evaluate the confirmed response rate of bendamustine in combination with lenalidomide and dexamethasone in patients with relapsed MM (phase 2). Bendamustine (B) was administered on days 1 and 2 of a 28-day cycle at doses of 50–100 mg/m2. Lenalidomide (R) was given days 1–21 at doses of 15–25 mg daily. Dexamethasone (D) was administered at 40 mg weekly. Dose escalation was done using a 3+3 design and MTD was defined as one dose level below that resulted in 〉=2 DLTS among 6 patients. The primary end point for this trial was the proportion of patients with confirmed hematologic response (sCR, CR, VGPR, or PR) over the first 6 cycles of treatment. Results: A total of 72 patients were accrued to this study from March 2010 to May 2012: 21 patients in phase 1 and 51 in phase 2. The 6 patients from the MTD dose level of phase 1 were also included in phase 2. The median age of all 72 patients was 62.1 (range, 40–86) and 57% were male. Majority (75%) of patients had previously been exposed to lenalidomide and 69% had prior exposure to bortezomib. Median # of prior therapies was 3 (range, 1–5) and 74% of patients had a prior autologous stem cell transplant. Patients have received a median of 4 cycles (range, 1–25), with 27 patients still continuing on active treatment. Disease progression led to study discontinuation in 22 (49%) and adverse events were the reason for discontinuation in 14 (31%). In phase I, two DLTs (Grade (Gr) 2 neuropathy and Gr 4 neutropenia) were seen at the highest dose level (100 mg/m2 B, 25 mg R), and the MTD was determined as 75 mg/m2 of B given days 1 and 2 and 25 mg of R days 1–21, along with D 40 mg weekly. Overall patients, 12/21 (57%) had a PR or better. In phase 2, 17 (40%) confirmed responses (〉=PR) were seen among the 43 patients evaluable for response (received at least 6 cycles of treatment or have gone off study prior to 6 cycles); including 9 (21%) VGPR and 8 (19%) PR. An additional 5 patients had a minor response. Over all dose levels, a gr 3 or higher adverse event at least possibly attributed to the study was seen in 75% of patients. The most common toxicities were all hematological (thrombocytopenia and leukopenia), and most common non-hematological toxicity was infection. Prolonged time to recovery of blood counts was seen in a few patients, but majority of patients were able to tolerate the regimen with adequate dose reductions. Conclusion: The recommended dose of the combination for further studies is bendamustine at 75 mg/m2 days 1 and 2, lenalidomide 25 mg daily on days 1–21 and dexamethasone days 1, 8, 15, 22; with cycles repeated every 28 days. The regimen is well tolerated with hematological toxicity being the most common and manageable with dose reductions. The regimen is effective with high response rates and durable responses seen. Updated results with response rates and time to event analyses will be available for the entire cohort at the time of meeting. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Cephalon: Research Funding; Genzyme: Research Funding. Krishnan:celgene: Consultancy, Speakers Bureau. Zimmerman:Celgene: Honoraria; Millennium: Honoraria; Novartis: Expert Testimony, Expert Testimony Other. Vij:Teva: Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Millennium: Speakers Bureau; Onyx: Honoraria, Research Funding.

Description: Background: Despite improvements in overall survival (OS) and progression free survival (PFS), the prognosis of patients with relapsed/refractory multiple myeloma (RRMM) remains poor. Carfilzomib (CFZ), a second generation proteasome inhibitor, is active as a single-agent or in combination with lenalidomide and/or dexamethasone (DEX) in RRMM. Pegylated liposomal doxorubicin (PLD) combined with bortezomib has been shown to prolong PFS and OS and is FDA approved as combination therapy in MM. We investigated the combination of CFZ with PLD in RRMM in a Phase I study. Objective: To determine the maximum tolerated dose (MTD) of CFZ combined with PLD. Patient/Methods: Patients with RRMM after ≥ 1 lines of therapy, with measureable disease, and good performance status, organ function and hematological reserve were eligible. Prior CFZ or PLD/doxorubicin exposure was not exclusionary. CFZ was given on days 1, 2, 8, 9, 15 and 16 at escalating doses of 27-56mg/m2 and PLD was given on day 8 in 28 day cycles at a dose of 30mg/m2. All dose levels included a lead-in dose of 20mg/m2 of CFZ on days 1 and 2 of cycle 1. Following 6 cycles of combination therapy, PLD was discontinued and patients were treated with maintenance CFZ (once weekly). Dose escalation was performed using a 3+3 design; MTD was defined as the highest dose level where dose limiting toxicity (DLT) occurred in less than 2 of 6 patients. Disease response was determined using International Myeloma Working Group (IMWG) criteria. Results: 16 patients were enrolled from May 2012-March 2014. Median age was 66 years (range 53-79) and 11 were female. Seven patients were ISS stage 3, 9 were stage 1. 3 patients had 〉 50% plasma cells present on bone marrow aspirate, 8 had 〈 20%. By mSMART criteria, 2 patients were high-risk, 2 were intermediate-risk, and 12 were standard-risk. Most patients were IgG Kappa subtype (12); while 3 patients had Kappa light chain subtype, and 1 had IgG Lambda subtype. Median number of prior therapies was 3 (range 1-12). Median time from diagnosis to start of protocol was 42 months (range 9-236). 100% had prior exposure to lenalidomide; 87.5% had prior exposure to bortezomib; 75% had undergone autologous transplantation; 6% had prior PLD or doxorubicin exposure; and 6% had prior CFZ exposure. No DLTs were observed in any cohort. Two patients were unable to complete the first cycle of treatment due to early progressive disease, and were replaced. Grade 3/4 non-hematologic adverse events were rare, but included: UTIs (3), sepsis (2), pneumonitis (2), dyspnea (2), syncope (1), pleural effusion (1). Grade 3/4 hematologic AEs were limited to: anemia (7), thrombocytopenia (4), neutropenia (5), lymphopenia (4), and hemolysis (2). Most of the neutropenia (60%) and thrombocytopenia (75%) occurred in the 56mg/m2 cohort. The median number of cycles completed was 3.5 (range

Description: Background High-dose melphalan (HDM) has been the standard conditioning regimen for autologous stem cell transplantation (ASCT) in multiple myeloma (MM) for decades. Second ASCT is often offered as salvage therapy for patients who relapse after a first ASCT, but while response rates are similar, the progression free survival (PFS) is rarely comparable with that of the first ASCT when HDM conditioning is used for both. BEAM (carmustine, etoposide, cytarabine, and melphalan) is one of the most commonly used conditioning regimens for lymphoma patients undergoing ASCT and all of the components have been shown to be effective in refractory MM, but it has not been tested as a conditioning regimen for ASCT in MM. Bortezomib has been incorporated with HDM as a conditioning regimen for initial ASCT, with promising outcomes and limited toxicities. Based on these findings, we proposed a new conditioning regimen, V-BEAM (bortezomib-BEAM), administered prior to a second ASCT for relapsed/progressive MM, aiming to improve the response rates and PFS of the second ASCT. Objectives To evaluate the safety and efficacy of a new conditioning regimen, V-BEAM, prior to a second ASCT in patients with relapsed/progressive MM after a first ASCT with HDM conditioning. Patient/Methods Patients with relapsed/progressive MM after a previous ASCT with HDM conditioning were enrolled after 2 to 6 cycles of induction chemotherapy with a bortezomib or carfilzomib based regimen. Patients who had progressive disease on induction chemotherapy were excluded. V-BEAM was administered as the following: Bortezomib 1.3 mg/m2 on days -6, -3, +1, and +4, carmustine 300 mg/m2 on day -7, etoposide 100 mg/m2 and cytarabine 100 mg/m2 each twice daily on days -6 through -3, and melphalan 140 mg/m2 on day -2. On day 0, autologous stem cells (〉 2.0x106/kg) were infused. No maintenance or consolidation therapy was given post-transplant. Results A total of 10 patients were enrolled from October 2012 to May 2013 at the Siteman Cancer Center. The median age was 64.5 years old (range, 48-68) and 50% were male. Seventy percent of patients were Durie-Salmon stage IIIA at diagnosis, while the remaining 30% were stage IIA. The median time to progression following previous autologous stem cell transplant was 29 months (range, 17-97). The median number of prior therapies (including first ASCT) was 4 (range, 3-6). At the time of abstract submission, one patient has not reached day +100 and two patients expired within 30 days of transplant. For the remaining seven patients, the day +100 response rates include five complete responses (CR) and two very good partial responses (VGPR). To date, no patients have had subsequent disease progression after a median follow-up of 5.0 months (range, 2.3-9.3). Two patients suffered from treatment related mortality (one from neutropenic colitis [Day +18] and the other from sepsis [Day +2]). Serious complications included: neutropenic fevers (100%), diarrhea (grade 3-4, 100%), oral mucositis (all grade, 100%; grade 3-4, 20%), sepsis (30%), Clostridium difficile colitis (30%), and neutropenic colitis without Clostridium difficile (30%). Two patients (20%) had new or worsening peripheral neuropathy, both of which were grade 2 and easily controlled. The median duration of hospitalization was 23 days (range, 19-29). The median duration of neutrophil engraftment and platelet engraftment (〉20x109/L) were 10 days (range, 9-11) and 22.5 days (range, 17-36), respectively. The median duration of intravenous antibiotics was 14 days (range, 2-23). Two patients were readmitted shortly following discharge for neutropenic fevers and candida esophagitis, respectively. In June 2013, eight months after study initiation, the decision was made to terminate the study due to excessive toxicity. Conclusion While the new conditioning regimen V-BEAM prior to a second ASCT produced promising response rates for relapsed/progressive MM, it resulted in unexpected treatment related mortality and should not be investigated further without modifications. Disclosures: Off Label Use: BEAM regimen as a conditioning regimen for relapsed multiple myeloma. Abboud:Ariad, Alexion, Novartis, Teva: Honoraria, Speakers Bureau. Stockerl-Goldstein:Millennium: Speakers Bureau; Celgene : Speakers Bureau. Vij:Celgene : Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau.

Description: Abstract 809 Immunoglobulin light chain amlyloidosis (AL) is a rare plasma cell disorder characterized by deposition of misfolded light chains in various organ systems with an average survival of 1–2 years. AL is also the most common form of systemic amyloidosis with 1200–3200 newly diagnosed cases reported annually in the United States. Very little is known regarding specific genomic aberrations associated with AL-amyloidosis. Aside from the light chain selection, no phenotypic or genetic features have been identified that distinguish AL amyloidosis from other plasma cell dyscrasias. Understanding the genetics of AL and the molecular mechanisms involved in amyloid formation may lead to early diagnosis and the identification of novel drug targets and therapies. We therefore have attempted to study the genomic landscape of AL patients and MM for comparison. Genomic copy number and loss of heterozygosity (LOH) analyses were performed on DNA derived from tumor (CD138 sorted cells) and matched germline (skin) from biopsy proven AL patients using Affymetrix single nucleotide polymorphism (SNP) 6.0 arrays. Numerous genomic changes with gains in chromosome 1q, 6, 9, 11q, 15, 19 and 21 and loss on chromosome 1p, 2q, 8, 10, 12, 13, 14, 16, 18, 20 and 22 were observed in more than 10% of the patients. Recurrent genomic changes in about 249 segments involving 457 genes were present in about 1/3 of AL patients. In particular, deletion of IGK, IGH, PIK3CA, FLT3, RB1, PCDH9, GPC6, RASA3, ADAM6 genes and amplification of CFHR1, JAK2, GCNT1, TSC1, PGR genes were observed. Gene network analysis showed five distinct major modules consisting of 51 distinct elements and involving PDGF, TP53, interleukin signaling, TRKA signaling, cell cycle and mitotic pathways were enriched. Allele specific copy number analysis in tumor (ASCAT) profile showed increased ploidy status of the AL genome in 47% of the assessed patients. LOH was observed in chromosomes 4, 5, 6, 8, 9, 12, 13, 18 and 22 in 30% of patients, ranging from 5Mb to entire chromosome. Furthermore, genomic comparisons of AL with multiple myeloma (MM) showed the typical archetype of myeloma's signature with exception of gain of chromosomes 3, 5, 7 and loss of chromosome 6q and 8p. Interestingly deletion of IGH, IGK locus and PIK3CA gene were observed at a higher frequency in AL patients. Categorical analysis using isotype specific classification in AL showed a significantly higher frequency of deletion in chromosome 14, 13, 8 and amplification of chromosome 9q in the kappa type than lambda isotype. To the best of our knowledge, this is the first ultra-high resolution study of the genomic landscape of AL amyloidosis. In this study, we have found several novel genes and pathways associated with this rare disease. The numerous copy number alterations of AL thus reflect the genomic complexity and the heterogeneity of this disease. Additional genome-wide analysis in a larger panel with target organ stratified patients is under way and may further our understanding of genetic changes specifically associated with AL. Disclosures: No relevant conflicts of interest to declare.