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Abstract Background: Dexamethasone (dex) is an integral part of various anti-myeloma regimens both in the frontline and relapsed/refractory (RR) setting. Several clinical trials have shown that dex adds to the efficacy of novel therapeutic agents for multiple myeloma (MM). Yet, a substantial number of patients are intolerant to even the standard of care low-dose dex (40 mg weekly), especially in heavily pre-treated RRMM, possibly due to cumulative steroid toxicities and thus, require dex dose adjustments. There is a concern of compromising the efficacy of anti-MM regimens by adjusting the dex dose lower. We describe the frequency of dex dose adjustment, characteristics of patients who required it and its effect on patient outcomes in a large prospective clinical trial of pomalidomide (pom) and dex in RRMM (MC0789). Methods: We utilized data from the Pom-dex trial (MC0789), which treated RRMM patients in different cohorts of pom (2 vs. 4 mg; 21 vs 28 days cycle) with fixed dose dex (40 mg orally weekly). Patients were divided into 2 subgroups, with any dose adjustment/elimination of dex vs. not. Continuous and categorical variables were compared between the two groups using two-sample t-test/Wilcoxon rank sum test or Chi-squared test, respectively. Logistic regression and Cox regression models were used to find the univariate and stepwise multivariate predictors of response to treatment and overall mortality, respectively. Kaplan-Meier method was used to estimate overall survival (OS) at 1, 3, and 5 years. All statistical tests were two-sided with the alpha level set at 0.05 for statistical significance. Results: Results from the MC0789 clinical trial have been reported previously. Almost half of all treated patients in this trial had dex dose adjusted (n=175/343; 51%). The median number of cycles for the first dose adjustment in this group was 3 (range 1-62), with 46.5% of patients (n=82) having multiple dose adjustments and majority (58.3%, n=102) within the first 3 cycles of treatment. Patients in the dose adjustment group were significantly older (mean 65 vs 60 years; p=0.0001). Males, Whites and patients diagnosed before 2006 or with normal cytogenetics also had a higher incidence of dex dose adjustment, though this was not statistically significant. Patients with dex dose adjustment had a longer duration of treatment (mean 339 days) as compared to the non-adjusted cohort (mean 123.65 days) (95% CI 160.13, 270.58; p <0.0001). Dex dose adjustment was associated with a higher probability of responding in the clinical trial after a univariate (p<0.001) as well as multivariate (p<0.001) analysis. Patients with dex dose adjustment also had a significantly better OS at 1, 3 and 5 years by univariate (p<0.001) and multivariate (p<0.001) analysis. (Figure 1) The only other significant factor was lesser number of prior regimens (3 or less), associated with a higher probability of response (p=0.002) and survival (p<0.001). Conclusion: Our analysis established that in these heavily pre-treated RRMM patients, appropriate dose adjustment of dex did not compromise their response rates; patients remained on treatment significantly longer and had an improved survival. Majority of patients (58.3%) requiring dex dose adjustment had it instituted early during treatment (<3 cycles), suggesting that early disease progression was less likely to determine dex dose continuation or adjustment. Appropriate dex adjustments should be judiciously employed as they may ensure longer treatment duration with novel anti-MM therapeutic agents, conferring superior response and survival in this difficult to treat MM subgroup. This also paves the path to further optimize dex dose in various anti-MM regimens, especially in these patients who are more likely to be intolerant to it. Disclosures Kumar: Skyline, Noxxon: Honoraria; Celgene, Millennium, Onyx, Janssen, Noxxon, Sanofi, BMS, Skyline: Consultancy; Celgene, Millennium, Onyx, Novartis, Janssen, Sanofi: Research Funding.

Abstract Abstract 3053 Background: Patients with smoldering multiple myeloma (SMM) have a higher chance of progression to active MM than patients with monoclonal gammopathy of undetermined significance (MGUS). Since active MM remains incurable and since patients with SMM can have a long time to requiring treatment, observation remains an option for these patients. Bisphosphonates can prevent the bone complications of myeloma. The immunomodulatory (IMiD) drugs are well-tolerated and have documented anti-tumor activity in active MM. We hypothesized that treatment with the IMiD THAL and a bisphosphonate (ZLD) would prolong the time to progression (TTP) over the control arm of ZLD alone. This is the first report of this phase III trial of THAL/ZLD vs ZLD alone for patients with untreated SMM. Goals: The primary goal of this trial was to compare the TTP between patients treated with THAL/ZLD versus ZLD alone in asymptomatic MM. Secondary goals were progression rate at one year, response rate, duration of response, time to next therapy, and toxicity. Methods: Patients were required to have measurable disease as defined by either a serum monoclonal protein >1.0 g by protein electrophoresis or nephelometry or >200 mg of monoclonal protein in the urine on 24 hour electrophoresis or a measurable soft tissue plasmacytoma; >10% plasma cells as measured on the bone marrow aspirate, bone marrow biopsy, or labeling index; absolute neutrophil count >1500/μL; platelet count >100,000/μL; creatinine <2.0 mg/dL, and a performance status of 0, 1, or 2. Patients could not have symptomatic MM that required chemotherapy. The statistical plan was to accrue 120 eligible patients (60 per arm) over 4 years and after a minimum follow-up of 12 months the study would provide >90% power at a type I error rate of 0.05 to detect an increase in the median TTP from 12 months (ZLD) to 24 months (THAL/ZLD), and >80% power to detect an increase in median TTP from 12 to 21 months). Results: The study was activated in July 2003 and closed March 2009 due to slow accrual. Sixty-eight patients (35 Thal/ZLD; 33 ZLD) with a median age 63 years (range, 47–84) were randomized. The median TTP for Thal/ZLD versus ZLD was 2.4 years versus 1.2 years, respectively, P=0.02 one-sided log-rank. After adjusting for pre-specified stratification factors, the hazard ratio for TTP was 2.2 (one-sided p value = 0.01, univariate stratified Cox PH model) for ZLD compared to Thal/ZLD. 89% of patients on the Thal/ZLD arm were progression-free survival (PFS) at one year compared to 55% on ZLD alone (one-sided p<0.001, chi-square). Similar results were obtained (Table and Figures) when the CRAB (calcium, renal, anemia, bone) criteria were applied. Confirmed response was evaluated using the first 12 months of treatment. In the Thal/ZLD arm the response rate was 31% with a median duration of response of 5.1 years (95% CI: 1.9 - NA). There were no confirmed responses in the ZLD alone arm. The median overall survival has not been reached for either arm. In regards to toxicity, no grade 5 adverse events (AEs) have been reported. Thirty patients have reported grade 3+ AEs (17 Thal/ZLD; 13 ZLD, Fisher's exact p-value 0.47). Eight patients have reported grade 4 adverse events (5 Thal/ZLD; 3 ZLD, Fisher's exact p-value 0.71). Overall, only one grade 4 event was felt to be at least possibly related to study treatment – grade 4 neutropenia in Thal/ZLD. Conclusions: While the trial did not meet its planned accrual goals, there was a significant improvement in improved in outcomes in the Thal/ZLD arm compared to control (ZLD). Thal/ZLD produces anti-tumor responses that are quite durable with the median response duration of over 5 years. ZLD alone did not produce any anti-tumor responses. This study indicates that a non-chemotherapy approach can be effective in SMM and may be a useful strategy to test in future studies. Disclosures: Off Label Use: Thalidomide for smoldering myeloma. Lacy:Celgene: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Gertz:Celgene: Honoraria; Millennium: Honoraria.

Abstract Background: Lenalidomide (Len) is clinically active in CLL patients (pts). Robust anti-leukemic immune response from Len is truncated by dysfunctional immune system in CLL and anti-apoptotic bcl-2 protein. We hypothesized that therapeutic downregulation of Bcl-2 may help enhance the killing potential of immune effector cells that are activated by Len. AT-101 is a novel, orally active BH3-mimetic that binds to antiapoptotic Bcl-2 family proteins (Bcl-2, Mcl-1 and Bcl-xL) and induces CLL cell death ex vivo (Masood et al British Journal of Haematology 2012). Encouraging efficacy and safety results of AT-101 alone or in combination with rituximab in CLL have been reported in Phase I/II studies. We have previously demonstrated that bcl-2 downregulation in CLL cells enhanced the killing potential of Len-activated immune cells. Conversely, pretreatment of CLL cells with Len enhanced AT-101 cytotoxicity in an immune cell independent manner (Masood et al British Journal of Haematology 2012). These preclinical findings formed the basis of a phase I/II clinical trial testing the combination of AT-101 and lenalidomide in relapsed B-CLL patients. Methods: The phase I portion of this study (NCT 01003769) utilizes a standard cohort of three design to determine the maximum tolerated dose (MTD) of the combination regimen. The MTD is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients. Following the MTD determination, the phase 2 portion will assess the efficacy of this combination using a one-stage design with an interim analysis. Key inclusion criteria include adult CLL pts with relapsed disease who have received 1-4 prior lines of treatment (Rx) (phase I) or 1-2 lines of Rx (phase II), last dose > 4 weeks from enrollment, ECOG performance status 0-2, good renal/liver function, acceptable blood counts. Patients with known hypersensitivity to thalidomide/Len or prior use of gossypol/AT-101 were excluded. Cycle 1 Rx includes Len alone and cycles 2-12 includes Len and AT-101. Starting doses of Len and AT-101 are 5mg oral daily on days 1-21 and 40 mg oral twice daily (b.i.d) on days 1-3 of a 28-day cycle. Planned dose escalation is shown in Table 1. Three pts will be treated at each dose level and observed during the first cycle of the combination Rx. Dose limiting toxicity is defined as grade 4 anemia unrelated to disease, thrombocytopenia-grade 4 or grade 3 with bleeding/requiring platelets, ANC <500 for >14 days, febrile neutropenia , Grade 3/4 non-hematologic toxicity. Dose from Phase II will be based on MTD from phase I. Peripheral blood and bone marrow will be collected and analyzed for immune cellular microenvironment and effect of Len and AT-101 on molecular targets. Optional lymph node biopsy will be done at baseline and if tumor-flare reaction occurs. This study is expected to accrue a maximum of 26 pts in phase I and 34 pts in phase II, overall maximum sample size of 60 pts. Five pts in phase I have been accrued to date. Table 1 (* starting dose level) Table 1. (* starting dose level) Disclosures No relevant conflicts of interest to declare.

Abstract Objective: Allogeneic stem cell transplant (ASCT) is a potentially curative treatment for many hematologic malignancies. HLA match is the principal factor in donor selection but the total antigenic landscape as seen by the donor immune cells extends beyond the HLA and minor HLA antigens. Thus, despite "perfect" HLA match graft versus host disease (GVHD) caused by alloreactive donor immune cells reacting to disparate antigens in the recipient, remains a significant cause of morbidity and mortality. Whole exome sequencing (WES) which assays all the protein coding nucleotide sequences provides a powerful means to assess the entire antigenic makeup of the individual. We examined the WES of sibling donor-recipient pairs undergoing BMT to assess the influence of the extent of genetic disparity and specific gene polymorphisms on GVHD. Methods: Sixteen matched sibling donor-recipient pairs receiving allogeneic stem cell transplants between June 2008 and April 2013 had samples available for retrospective WES. Transplant data including conditioning regimen, age of donor and recipient at the time of transplant, development and type of GVHD and cause of death were recorded. The sequencing was performed using Illumina HiSeq2000 and the single nucleotide variants (SNVs) and small insertions and deletions (INDELs) were identified using the haplotype caller within the Genome Analysis Toolkit GATK v2.7. Functional variants including non-synonymous, frame-shift, truncating, and splice site SNVs and INDELs identified were compared between donor and recipient and among those with GVHD and those without GVHD (non-GVHD). One-sided Fisher's exact test was used to determine the statistical significance of the SNPs in GVHD and non-GVHD. Candidate genes with a p value of <0.05 were further evaluated for their biochemical pathway and possible role in inflammatory or immune responses. Results: Nine of 16 patients had a diagnosis of AML or high grade myelodysplastic syndrome, 3 had a diagnosis of non- Hodgkin lymphoma, 1 had Hodgkin lymphoma, 1 had multiple myeloma, and 2 had CML. Six patients were conditioned with a myeloablative regimen, others with a reduced intensity conditioning regimen. Eight of 16 patients were female and 7 of 16 donors were female. Nine of 16 patients developed stage II-IV acute and/or chronic GVHD with 7 of them developing GVHD of the skin. A total of 12,623 genes with 43,670 functional variants were identified using WES. 134 genes had a p value < 0.05 and enrichment analysis was performed on these genes. 12 out of 134 genes were associated with gene ontology (GO) term "immune system development" with an unadjusted enrichment p-value 0.0015. Three (IL31RA, OSMR, SIRPA) out of 134 genes were associated with "inflammation_Jak-STAT pathway" with an adjusted enrichment p-value 0.07. Variants of IL31RA, OSMR, and PTX3 were identified as genes with polymorphisms associated with GVHD (p= 0.003, 0.01, and 0.01, respectively) with 5 variants identified in IL31RA, 7 variants in OSMR, and 2 variants in PTX3. Further investigation of these three genes revealed their role in inflammatory or immune responses. Discussion: GVHD is a cytokine mediated immune-inflammatory process that can occur despite "perfect" HLA matching. WES identified the extensive genetic variability between donors and recipients implying large allo-reactivity potential that can lead to GVHD. Quantification of genetic variation may allow for more precise determination of GVHD risk and better selection of donors. In our cohort, WES identified polymorphisms in IL31RA, OSMR, and PTX3 as statistically significantly associated with development of GVHD. The protein products of these three genes have each been shown to be involved in inflammatory processes and are influenced by other cytokines. IL31RA and OSMR are found in many tissues including the skin and lungs. They function both independently and as a heterodimer receptor capable of binding multiple cytokines including IL-31, IL-6, and TNF-α. PTX3 is a reactive protein that increases in response to cytokine release related to systemic inflammation. Levels of this protein have been used as a prognostic marker in many disease processes with high levels correlating with poor outcomes. The small sample size of our cohort precludes any firm conclusions but provides promising hypotheses for further evaluation in larger studies. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Allogeneic Hematopoietic cell transplantation (HCT) is potentially curative therapy for MDS and AML. Although the median age at presentation is >65 years, most patients receiving HCT for these disorders are young (<60years). With the availability of Reduced Intensity Conditioning (RIC) many older patients are able to undergo HCT. The older age group is the most rapidly increasing cohort in CIBMTR registry. We analyzed the outcomes of AML and MDS patients' ≥ 60 years who received allogeneic sibling or unrelated donor HCT at our institution between 2009 and 2014. We also evaluated the influence of patient-, disease-, and transplant related factors on outcomes. Methods: Prospectively collected data available in the BMT databases at Mayo Clinic Florida, Arizona and Rochester as well as individual patient charts were reviewed after IRB approval. Patients with MDS or AML in complete remission at the time of transplant were included; those with active disease, induction failure, or prior transplant were excluded. HCT-specific comorbidity index (HCT-CI) and the disease risk index (DRI- Armand et al. Blood 2012) was noted. Survival estimates were calculated using the Kaplan Meier method. Associations with survival were explored using single variable Cox-regression modeling and log-rank tests. Results: 80 patients were included; 68 AML and 12 MDS. 31 (39%) were male. Median age 66 years (range 60-75). 33%, 52%, and 13% patients had ECOG status of 0, 1, >2, respectively. Thirty-seven patients (46%) had low or intermediate DRI and 43(54%) had high DRI. Twenty-two (28%), 24 (30%), and 34 (43%) patients had HCT-CI of 0, 1, or >2. There were equal number of sibling and unrelated donors; 85% were full HLA match and 15% with 1 or 2 mismatches; mean age of the donors was 52years (range18-74). Transplant conditioning was fludarabine-containing reduced intensity regimens in 78 (97%), 2 patients received myeloablative conditioning. The source of stem cells was peripheral blood in all patients. A median of 5.87 x10^6 CD34/kg donor cells were infused (range 1.58-10.92 X10^6). All patients received calcineurin inhibitor based GVHD prophylaxis (tacrolimus 56%, cyclosporine 44%); 6 patients also received ATG. The median follow up of survivors was 13 months. Kaplan Meier estimate of overall survival at 100 days, 1 year, and 2 years was 90%, 64%, and 55%. Cumulative incidence of relapse at 6 months, 1 year, and 2 years was 19.5%, 22.3%, and 27.1%. Relapse free survival at 2 years was 50%. The non-relapse/ treatment related mortality at 6 months, 1 year and 2 years was 11.7%, 15.9% and 15.9%. The rate of acute grade 2-4 GVHD was 30% and chronic GVHD was 39%. Univariate analysis identified secondary disease (compared to de novo) and high DRI(compared to low/intermediate) to be associated with worse mortality - HR 2.54 (1.31-4.93; P = 0.006), and 2.31 (1.13-4.73; P = 0.021), respectively. Probability of overall survival at 6 months, 1 year, and 2 years for patients with de novo disease (n=57) vs. secondary disease (n=23) was 87.1% vs. 64.5%, 71.1 vs. 45.6%, and 63.2 vs. 32.6%, respectively; P= 0.006. There was no effect of donor age, donor type or degree of mis-match on the survival. Conclusion: Allogeneic HCT is feasible in older patients with MDS and AML utilizing reduced intensity conditioning regimens with acceptable outcomes that are comparable to published results in younger patients. Patients with high DRI and secondary disease have poorer overall survival as compared to those with de novo disease and low/intermediate disease risk index. These data support other studies that age alone does not negatively influence transplant outcomes. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 3047 Background: There is concern about the increased incidence of extramedullary plasmacytomas among patients with multiple myeloma (MM) in recent years (Varettoni et al Annals of Oncology 21: 325–330, 2010). There is controversy about whether novel agents increase the risk of extramedullary disease (EMD). EMD may be associated with decreased overall survival in MM. The purpose of this study was to determine the incidence of true, treatment-emergent EMD in MM among a cohort of patients who have been previously exposed to novel agent (thalidomide, lenalidomide, or bortezomib) therapy, and to evaluate the activity of pomalidomide in patients with EMD. Methods: We examined 174 consecutive patients with relapsed refractory multiple myeloma that were enrolled on a phase II clinical trial of pomalidomide plus low-dose dexamethasone. The study cohort was chosen since all patients had previously been exposed to novel agents, and were followed systematically. We adopted a strict definition of EMD which required that in order to be considered extramedullary, plasmacytomas must not have risen from any bone. Thus, masses arising from the bone with a soft tissue component were not considered extramedullary. Results: Of 174 patients studied, 16 patients (9.2%) had EMD prior to enrollment. In 3 of the 16 patients, EMD was present at time of diagnosis and was therefore not considered as treatment-emergent disease for this analysis. In 13 of 174 patients (7.5%) EMD developed during the course of MM, after starting therapy. All 13 patients by inclusion criteria were exposed to novel agents prior to the onset of EMD, including 100% to immunomodulatory agents (thalidomide or lenalidomide); and 78% (10 patients) were exposed to bortezomib prior to developing EMD. The median number of lines of prior therapy in these patients was 6, range 1–12). EMD occurred a median of 48 months following diagnosis (range, 16–183 months); the rate of EMD in the first 3 years following diagnosis of MM was 3%. Since all patients had prior exposure to immunomodulatory agents in this cohort, we were able to calculate the median length of time from initiation of immunomodulatory agents to onset of EMD as 24 months (range 7–119 months). The EMD sites involved included the temporal area soft tissue (3), muscle (3 [1 pt with 10 different areas of involvement, 1 pt with 5 muscles involved]), chest wall not attached to bone (3), abdominal/pelvic masses (3), kidney (2), scrotum (2), sinus (1), paraspinal (1), hilar/pleural based (1), paraesophageal (1), subcutaneous tissue (1), pancreas (1), spleen (1), mediastinum (1), pleural fluid (1), liver (1). Per protocol, all patients received pomalidomide (2-4 mg per day) and low dose dexamethasone (40 mg once a week). Of the 13 patients, there were 2 CR (with complete disappearance of EMD), 2 PR, 2 stable disease, 3 with progressive disease, and 4 patients who did not have their EMD re-evaluated. Thirty percent (n=4) of patients had a 50% or greater reduction in size of the EMD including one patient who received concomitant radiation. Overall survival from measured from trial entry was significantly shorter for patients who presented with EMD compared to those who did not have EMD, median 16 months versus not reached, p=0.002 (log-rank). Conclusion: We found that 7.5% of patients with relapsed refractory myeloma in the era of novel agents develop EMD during the course of their myeloma, including 3% within 3 years of diagnosis. The underlying reasons for the possible increased incidence of EMD may include better radiographic detection (the role of PET/CT scans and MRI), improved overall survival of patients in recent years, and the possibility that novel agents may increase the risk for strictly defined, true EMD among patients who did not have EMD at time of initial MM diagnosis. These need further study. Disclosures: Dispenzieri: Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Gertz:Celgene: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

Abstract Background Waldenströms macroglobulinemia (WM) is a lymphoplasmacytic subtype of Non-Hodgkins lymphoma in which specific molecular changes lead to unrestricted cell proliferation and overproduction of immunoglobulin-M. These processes require exquisite coordination between growth promoting transcription factors (NFkB) and cell homeostatic systems. The bioavailability of various transcription factors and cell cycle proteins is primarily regulated by the ubiquitin proteasome system (UPS). Moreover, the proteolytic machinery ensures proper elimination of unwanted or misfolded proteins, which when disrupted leads to protein accumulation and apoptotic cell death. The 26S proteasome is a barrel shaped structure with a 20S catalytic core that is flanked by 19S caps on either side. 26S proteasomes are critical for WM cell survival, which is clinically evident, as up to 80% of WM patients treated with the proteasome inhibitor (PI) bortezomib have derived significant benefit. Traditional PI such as bortezomib and carfilzomib have been designed to target the B5 catalytic core within the 26S proteasome. However, proteasomes are capable of altering conformation of their proteolytic subunits in response to inflammation and stress, which can lower the effectiveness of these PI. The 19S cap is the regulatory complex and functions in unfolding and deubiquitinating the proteins before their entry into the 20S complex using constitutive deubiquitinating enzymes (DUBS). Recently, it has been demonstrated that inhibition of the DUBS, UCHL5 and USP14 results in cell death in a variety of tumor types but more so in cancer cells that rapidly divide or have a high protein turnover rate. Aim To define the anti-WM activity of the novel DUB inhibitor, b-AP15 in preclinical models of WM. Methods The WM cell lines BCWM.1, RPCI-WM1 and MWCL-1 were used for experiments in this analysis. Proteasomal activity was measured using synthetic fluorogenic peptide substrates. Apoptosis was determined by annexin-V/PI staining and mitochondrial membrane permeability (MOMP) was assessed using TMRM followed by flow cytometry. Protein profiling was done via immunoblot analysis. Results As reported by D’Arcy et al in their characterization of the b-AP15 molecule, inhibition of UCHL5 and USP14 by b-AP15 does not disrupt proteasomal activity conferred by the b-catalytic subunits. We confirmed these findings by treating WM cells with single agent bortezomib (10nM), carfilzomib (10nM), b-AP15 (100nM) or all three agents in combination to assess chymotrypsin-like, caspase-like and trypsin-like proteasomal activity using fluorogenic peptide substrates. Further, when used in combination with the other PI, PI-mediated chymotrypsin-like activity remained inhibited in the presence of b-AP15. Next, we sought to determine if b-AP15 treatment could induce WM cell death. Annexin-v staining showed that b-AP15 (500uM) induced apoptosis in all WM cell lines (28 – 60% cell death) with variable responses noted among the 3 models. Treatment with b-AP15 increased MOMP while also inducing the cleavage of caspases-9 and 3 and PARP-1 suggesting that the anti-WM activity of b-AP15 is mediated through the intrinsic apoptotic pathway. As components of the NFkB signaling cascade lie downstream to the UPS, we examined the effects of b-AP15 on this pathway. When treated with the DUB-inhibitor, nuclear translocation of NFkB was reduced in a time dependent manner. Interestingly, treatment with b-AP15 increased the phosphorylation of the mitogen activated protein kinase-p38 (p38) in all the WM cell lines tested. Treatment of WM cells with b-AP15 in presence of the p38 inhibitor, SB203580, resulted in a synergistic induction of cell death. Conclusion b-AP15 is a novel DUB inhibitor that disrupts two regulatory enzymes (UCHL5 and USP14) present in the 19S proteasomal cap. Results presented here demonstrate that b-AP15 induces apoptosis in in vitro models of WM and with in vivo analysis underway, is a potential therapeutic in WM. We would like to acknowledge the Waterfall Waldenström Macroglobulinemia Research Fund, the Leukemia and Lymphoma Society and the International Waldenström Macroglobulinemia Foundation for their continued support. Disclosures: No relevant conflicts of interest to declare.

Post-transplant lymphoproliferative disorders (PTLD) are B-cell disorders characterized by abnormal lymphoid proliferation due to immunesuppression mediated T-cell dysfunction after organ transplantation, and carry a poor prognosis. Reduction of immunesuppression is the first line of therapy but involves the risk of allograft rejection. Anti-viral agents like acyclovir, intravenous immunoglobulin, interferon-α, anti interleukin -6 antibodies, chemotherapy and rituximab are other treatments that have been tried with limited success. EBV-specific adaptive immunetherapy is promising but only available in a few centers. Prognosis is poorer in patients with relapsed disease. We report the case of a 46 year-old liver transplant recipient, with recurrent PTLD after liver transplantation, who was successfully treated with high dose chemotherapy followed by autologous bone marrow transplant (ABMT). He had undergone an orthotopic liver transplant (OLT) 13 years ago for primary sclerosing cholangitis. PTLD (EBV related, Hodgkin like, CD20+ and CD30+) developed 7 years ago, and initially resolved with ganciclovir and reduction of immunesuppression. The patient relapsed 5 years later. Immunesuppression was discontinued and 3 cycles of rituximab with CHOP (R-CHOP) followed by 4 doses of R at weekly intervals were given leading to complete response. Four months later, he again relapsed and responded to 4 more cycles of R-CHOP. He was referred to our center for transplant evaluation. Progenitor cell mobilization with filgrastim was unsuccessful. He underwent an unstimulated bone marrow harvest yielding 1.02 × 10 6 CD34 cells/kg. Transplant conditioning was with R-BEAM. Because of abnormal liver function tests and concern for further hepatotoxicity, carmustine dose was reduced by 50%. Immunesuppression for OLT was withheld during the transplant period. He tolerated the chemotherapy well but had delayed neutrophil and platelet engrafment (days +31 and +50 respectively). Liver functions deteriorated in the post transplant period, but responded to reinitiation of prednisone and tacrolimus on days +41 and +50, respectively. Post transplant PET/CT imaging performed on day+45 revealed complete resolution of his lymphadenopathy. He continues to be asymptomatic with no evidence of relapse days+ 72 after transplant, at the time of this writing. ABMT is the standard of care for chemotherapy-sensitive relapsed lymphomas. However, the complexity of ABMT after a prior solid organ transplant limits its use for relapsed PTLD. There is a higher likelihood of regimen-related toxicity, and immunesuppression needs to be carefully managed. While it is desirable to reduce immunesuppression during the transplant period to minimize infections and to control PTLD, this has to be balanced against the risk of solid organ graft rejection. This is particularly critical in patients with liver transplantation in whom (unlike renal graft) loss of liver graft may be fatal. There are only 6 previous cases of PTLD treated with stem cell transplant, but none of these patients had a prior OLT. Our experience with this case suggests that autologous bone marrow transplant can be a potential treatment option for patients with recurrent PTLD in selected patients. Appropriate dose modification of conditioning regimen and careful management of peritransplant immunesuppression appears important for successful outcome.

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 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.