ALBERT

Description: We have measured the fully carboxylated (native) prothrombin antigen and the undercarboxylated (abnormal) prothrombin antigen in patients treated with sodium warfarin using specific immunoassays to evaluate a new approach for monitoring oral anticoagulant therapy. Plasma and serum samples (391) were assayed for the prothrombin time, native prothrombin antigen, and abnormal prothrombin antigen. The results were correlated with the presence of bleeding or thromboembolic complications at the time of phlebotomy. The native prothrombin antigen correlated with the occurrence of complications in 95% of samples. Of 13 samples from patients with bleeding complications, 13/13 (100%) had a native prothrombin of 12 micrograms/mL or lower. Of seven samples from patients with thromboembolic complications, 6/7 (86%) had a native prothrombin of 24 micrograms/mL or greater. By comparison, a prothrombin time index of 1.5 to 2.5, 1.5 to 2.2, 1.5 to 2.0, or 1.3 to 1.8 identified 6/20 (30%), 9/20 (45%), 11/20 (55%), or 12/20 (60%) patients at risk, respectively. Although the prothrombin time index did correlate with the presence of bleeding complications, the native prothrombin antigen correlated closely with the presence of bleeding and thromboembolic complications. According to these results, the native prothrombin antigen, maintained in a range of 12 to 24 micrograms/mL by regular adjustment of the warfarin dosage, may be associated with a reduced risk of complications due to excessive or insufficient warfarin therapy. On the basis of these preliminary data, we recommend that the native prothrombin antigen be considered to monitor warfarin therapy.

Description: Hemoglobin (Hb) Suan-Dok (alpha 109Arg) is a rare alpha-globin structural mutation that is linked to an alpha-thalassemia (alpha-thal) determinant. When inherited in trans to an alpha-thal-1 mutation (-), it results in Hb H disease associated with low levels (9%) of the Suan- Dok Hb. The nature of the thalassemic defect associated with the alpha SD mutation has been investigated by structural and functional studies. Sequence analysis of the cloned Suan-Dok allele showed a missense mutation (T----G) at codon 109 in an otherwise normal alpha 2-globin gene. When the alpha 2SD-globin gene was introduced into mouse erythroleukemia cells, the steady state alpha-globin messenger RNA (mRNA) level was equivalent to the alpha A-globin gene control. Although in vitro translation of a synthetic alpha 2SD-globin mRNA generated levels of alpha globin equivalent to alpha 2A-globin mRNA at early time points, the ratio of alpha SD to alpha A globin decreased markedly at later time points. These data suggest that the thalassemic defect associated with the Suan-Dok mutation results from a significant instability of the alpha SD globin.

Description: Key Points C1q can form a multimolecular signaling complex with HMGB1, RAGE, and LAIR-1 in lipid rafts. C1q and HMGB1 together promote monocytes to differentiate to an anti-inflammatory phenotype.

Description: A 34% response was obtained in 202 evaluable patients in the terminal phase of chronic granulocytic leukemia using combinations of hydroxyurea, 6-mercaptopurine, and corticosteroids. Twelve percent of responses were complete and 22% partial. Overall median survival was 12 wk. A 30 wk median survival for responding patients was statistically superior to the 7-wk survival for nonresponders (p less than 0.001). Response was inversely correlated with toxicity. No responses were obtained in patients sustaining both severe infectious and bleeding complications. No benefit could be demonstrated from the addition of vincristine in induction and daunorubicin for consolidation. Although the response frequency and duration of survival with this combination chemotherapy were generally superior to those previously reported by our group, the terminal phase of chronic granulocytic leukemia still remains a formidable and generally refractory disease.

Description: Background: Carfilzomib (Cfz), lenalidomide, and dexamethasone synergize to provide an impressive overall response rate (ORR) in upfront treatment of multiple myeloma (MM) (Jakubowiak et al 2012). The ORR to Cfz+dexamethasone (Cfz-Dex) as first-line therapy is unknown. We hypothesized that sequential treatment with Cfz-dex and BiRD would improve provide similar ORR and improve tolerability. A protocol of Cfz-Dex, consolidation with BiRd (Clarithromycin(Biaxin¨), Lenalidomide/(Revlimid¨), dexamethasone), and lenalidomide maintenance (Len) was conducted to evaluate ORR and safety as induction therapy for MM. Methods: Forty patients (pts) with symptomatic untreated MM were enrolled in a phase 2 study of Car-BiRd. Car-BiRd therapy is: Cfz IV over 30 min on Days 1, 2, 8, 9, 15, 16 of a 28-day cycle at a dose of 20mg/m2 on days 1, 2 of the 1st cycle only and 45mg/m2 for each dose thereafter and dex 40mg on D1, 8, 15, 22. After the first 26 pts were enrolled, the protocol was amended to increase the Cfz from 45 to 56mg/m2. Echocardiography and spirometry were performed prior to study entry and serum brain natriuretic peptide (BNP) was followed monthly to evaluate for heart or lung toxicity. Cfz-dex was continued until plateau in disease response, defined as unchanged M-protein for 2 cycles. Elective stem cell collection was then performed in transplant eligible pts and consolidation with BiRd initiated. Transplant ineligible pts proceeded directly to BiRd. BiRd is: Clarithromycin 500mg BID, lenalidomide 25mg daily on D1-21, and dex 40mg on D1, 8, 15, 22 of 28-day cycle. BiRd was continued until a 2nd response plateau after which lenalidomide maintenance (Len) at 10mg daily D1-21 of 28 day cycle was continued until disease progression or intolerability. Results: 36 pts completed at least 1 cycle and were evaluable for response. 58% of pts were ISS II/III. High-risk cytogenetics and unfavorable MyPRS score were found in 62% and 21% of pts, respectively. Median study follow-up was 66.2 weeks (range 3.7-114.7). Maximum response to the Cfz-dex, BiRd, and Len is shown in Table 1. Median time to PR was 1 cycle. Median time to maximum response with Cfz-dex, BiRD, and Len was 2, 2, and 4 cycles respectively. At last audit, 8 (22%) pts remain on Cfz-Dex; 21 (58%) reached plateau and received BiRd. Of the pts that received BiRd, 9 (43%) improved categorical response and 19 (90.5%) received Len. Two (11%) pts deepened response to CR while on Len. 97.5% of pts are alive and 82.5% without progression at last follow-up. One pt died after coming off study (withdrew consent) from sepsis during elective autologous stem cell transplant. Pts with high risk cytogenetics had a trend towards a shorter progression free survival (PFS), with median 71.7 weeks vs not reached (NR) (P = 0.058). Similar results were seen with unfavorable MyPRS score with a shorter median PFS at 71.7 weeks vs NR (P = 0.094). 17 pts had stem cell harvest following Cfz-dex. All collected stem cells to support at least two transplants, with median 14.5 x 10^6 (range 7.06-27) CD34/kg in a median of 1 (range 1-2) apheresis session. 18 pts (46.2%) have come off study, 6 (15%) for disease progression (2 during CfzDex , 1 during BiRD, 3 during Len) and 5 pts (12.5%) due to toxicity: 3 pts for renal failure [2 Grade 2, I grade 3, all with renal recovery after discontinuation, all attributable to Cfz]; 1 pt due to Grade III CHF [attributable to Cfz with recovery]; 1 pt with Grade III Thromboembolic [attributable Len]. There was no correlation between pre-study cardiac and lung function, or serial BNP, with toxicities. Seven (17.9%) pts came off study for noncompliance, lost to follow up, investigator discretion, or withdrew consent (Cfz-dex: 4, BiRD: 1, Len: 2). Discussion: This is the first prospective study evaluating induction response to Cfz/Dex in MM. Cfz/Dex is safe and active, with ORR of 91.7% and rate of 〉=VGPR of 55.6%, despite the majority with a high-risk cytogenetics. Cfz-dex did not hinder stem cell harvest. ORR improved with lenalidomide-based consolidation and maintenance, with CR rate 〉 50%. Baseline heart/lung function or serial BNP change did not predict emerging toxicities. Table 1: Maximum Response For Car-BiRD Phase: Response Category Car-Dex BiRD Lenalidomide N = 36 N = 21 N = 19 PD 0 1 (4.8) 0 SD 3 (8.3) 0 0 PR 13 (36.1) 1 (4.8) 1 (5.3) VGPR 17 (47.2) 12 (57.1) 8 (42.1) CR 1 (2.8) 0 0 SCR 1 (2.8) 5 (23.8) 8 (42.1) ICR 1 (2.8) 2 (9.5) 2 (10.5) 〉=PR 91.7 95.2 100 〉=VGPR 55.6 90.4 94.7 〉=CR 8.4 33.3 52.6 Disclosures Mark: Onyx: Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Carfilzomib is not approved for first-line treatment of myeloma. . Rossi:Celgene: Speakers Bureau. Pekle:Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perry:Celgene: Speakers Bureau. Coleman:Onyx: Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niesvizky:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Description: Background: Pomalidomide is the newest IMiD approved for the treatment of patients with relapsed/refractory multiple myeloma (MM). Pomalidomide undergoes hepatic metabolism, and as such is not expected to accumulate as its predecessor lenalidomide, in patients with impaired renal function. Renal insufficiency is common in patients with myeloma, and is generally associated with poor outcomes. Previous studies have shown that renal dysfunction is not associated with increased toxicity in these patients. Here we evaluate the impact of renal and hepatic function on dose level of pomalidomide in our cohort of patients receiving ClaPD (clarithromycin, pomalidomide, dexamethasone). Methods: One hundred twenty patients with relapsed/refractory MM were enrolled in a phase II trial of ClaPD: clarithromycin 500mg PO BID, pomalidomide 4mg PO daily, dexamethasone 40mg PO weekly. We evaluated renal and hepatic function, as well as bone marrow involvement in all patients at baseline and throughout the study, and evaluated how this correlated with dose reduction requirement. Results: Renal function was evaluated based on creatinine clearance. Hepatic function was evaluated by albumin, bilirubin, and transaminases. At baseline renal dysfunction was seen in 37 (31%) patients, and hepatic dysfunction was seen in 7 (6%) patients. Neither was significantly associated with pomalidomide dose reductions. Treatment emergent cytopenias and dose reduction were not associated with baseline neutropenia. However, thrombocytopenia at baseline did correlate significantly with dose reduction (p ULL x2 6/81 (7%) 6/39(15%) Disclosures Rossi: millenium: Speakers Bureau; celgene: Speakers Bureau. Mark:Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Pekle:Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perry:celgene: Speakers Bureau. Coleman:Onyx: Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niesvizky:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Description: Background: While B-cell receptor (BCR) signaling is essential for the development, of normal B cells, its aberrant hyper-activation results in neoplastic transformation of B-lymphocytes. Recent investigations using small molecule inhibitors validate the BCR pathway as a valuable target. Bruton’s tyrosine kinase (BTK) is one of the components of a signaling hub that transduces signals from the BCR into the cell for its activation and has been shown to be a therapeutic target. Ibrutinib (PCI-32765), an irreversible BTK inhibitor has shown clinical efficacy in CLL, mantle cell lymphoma (MCL) and Waldenströms macroglobulinemia (WM). Ibrutinib binds to cysteine-481 of the BTK protein and blocks its phosphorylation, resulting in termination of BCR-mediated activation of cells with a concomitant induction of death. Despite the clinical success of ibrutinib, a high percentage of patients achieve only partial response and eventually acquire resistance to the drug, resulting in aggressive relapse of the disease. A mutation of Cys481-Ser in BTK (ibrutinib-BTK binding site) has been reported to be one of the reasons for the development of ibrutinib resistance (IR). To understand the mechanisms resulting in acquisition of IR, we developed preclinical models of IR in WM and MCL. Materials: Ibrutinib was obtained from Pharmacyclics, CA. Validated human WM models (BCWM.1, RPCI-WM1 and MWCL.1 cell lines) and human MCL models (Jeko-1 and Maver cell lines) were used for the study. Results: BTK was constitutively phosphorylated at Y223 and Y551 in all the cell lines tested and this was inhibited by ibrutinib in a dose dependent manner. Phosphorylation of other kinases in the cascade such as SYK (Y323 and Y525/526) and PLCg2 (Y759 and Y1217) were also inhibited while AKT phosphorylation at both Ser473 and Thr308 was consistently increased in presence of ibrutinib. Treatment with ibrutinib induced cell cycle arrest in the G1 phase by 24h followed by apoptosis. Cell growth assays (MTS assay) showed that BCWM.1 was the most sensitive cell line followed by MWCL-1, RPCI-WM1, Maver and Jeko-1. Exposure of WM and MCL cells for prolonged periods of time with progressively increasing concentrations of ibrutinib resulted in outgrowth of clones (IR WM and MCL cell lines) that were resistant to apoptosis with a slow growth rate as compared to wild type parental cells. IR cells attained 2 – 20 fold resistance to ibrutinib as compared to the respective parental lines as determined by MTS assay. Sequence analysis of the BTK gene in all the cell lines revealed no mutation in IR cells at Cys481 suggesting that in an acquired IR state, resistance to ibrutinib can be developed independent of BTK Cys481 mutation. Interestingly, we found p-BTK levels to be markedly reduced in IR cells. Ibrutinib reversal experiments suggested that while a continuous presence of ibrutinib is needed for inhibition of BTK phosphorylation, a stable IR state could be maintained (for 〉1 month) in the absence of ibrutinib. This suggested the cells reliance on a parallel survival pathway, independent of BTK phosphorylation. Focused mRNA (Nanostring nCounter assay) and immunoblot analysis revealed significant changes in the expression profiles of several cellular elements. These included transcription factors such as PU.1, IRF4, BLIMP1, BCL-6 b-catenin as well as the phosphorylated ERK1/2, STAT1 and 3 suggesting a reprogramming of critical cellular networks, which IR tumor cells might be utilizing to overcome ibrutinib-induced cytotoxicity. Importantly, we observed that IR cells retained high levels of p-AKT and showed an increase in expression of BCL2 family members, as well as BCL-2 itself. Treatment of IR cells with ibrutinib +/- MK2206 (AKT inhibitor), or ABT-199 (BCL-2 inhibitor), synergistically induced cytotoxicity in IR cells, suggesting the importance of these parallel survival pathways (AKT/BCL2) in maintaining an IR state. Conclusion: Here we demonstrate that in the absence of BTK Cys481 mutation, an IR state is associated with reprogramming of transcriptional networks countering ibrutinib-induced toxicity by activation of AKT and BCL-2. Our current data exposes multiple vulnerabilities within IR cells, which can be therapeutically exploited to potentially delay onset of IR, by targeting alternative oncogenic mechanisms that are activated in presence of sustained BTK inhibition. Disclosures No relevant conflicts of interest to declare.

Description: Background: Autologous stem cell transplantation (ASCT) performed early in the disease course or at first relapse leads to improved progression-free and overall survival in transplant-eligible patients with multiple myeloma (MM). Filgrastim, a recombinant granulocyte colony-stimulating factor (G-CSF), when used after ASCT has been shown to accelerate time to neutrophil engraftment (TNE), and in some studies, it has been associated with reduced length of hospitalization, infectious complications, and antibiotic use. Strategies that reserve G-CSF administration to when neutrophil recovery is delayed, have attempted to show that there is no difference in infectious complications, length of hospitalization or TNE when compared to early administration of G-CSF on the day after stem cell infusion (DOT). However, the optimal timing for administering G-CSF has not yet been determined in patients with MM undergoing ASCT. Methods: This is a retrospective, single-center analysis of patients with MM undergoing ASCT from mobilized peripheral blood stem cells. Patients enrolled in a clinical trial of high-dose lenalidomide and melphalan as conditioning therapy which mandated the administration of filgrastim from day +1 after DOT (Lenalidomide Plus Melphalan as a Preparative Regimen for Autologous Stem Cell Transplantation in Relapsed Multiple Myeloma, NCT01054196) were assigned to the early strategy group (ES). Patients receiving filgrastim as per our institutional guideline (starting on day +12 if ANC 〈 1000 cells/uL, or at the physician's discretion) were included in the delayed strategy group (DS). Patients were excluded from the analysis if their conditioning regimen included a different agent other than melphalan or lenalidomide. DOT was defined as the day of stem cell infusion. Date of neutrophil engraftment was defined as the first of three consecutive days with an ANC ≥ 500 cells/uL. TNE was calculated as the time from DOT to the date neutrophil engraftment. Total duration of neutropenia was defined as the time from onset of neutropenia (ANC 〈 500 cells/uL) to date of neutrophil engraftment. Length of hospitalization was defined as the time from DOT to the day of discharge. Results: We identified 59 patients in the ES group and 39 patients in the DS group from 08-16-2010 to 05-22-2019, for a total of 98 included in this analysis. Median age was 60 and 65 years in the ES and DS groups, respectively. Patients received a comparable dose of CD34+ cells, 5.05x106/kg in the ES group vs 4.66x106/kg in the DS group (p = 0.48). The ES group started filgrastim administration earlier (day +1 vs +9, p 〈 0.001) and received a greater median number of doses (10 vs 4, p 〈 0.001) as compared to patients in the DS group. Median time to neutrophil engraftment was shorter in the ES group compared to the DS group (10 vs 12 days, p 〈 0.001), as was the total duration of neutropenia (5 vs 6 days, p 〈 0.001). Documented infections were just as likely in both groups, 37% in the ES group and 39% in the DS group (p = 1). Length of hospitalization was shorter in the ES group as compared to the DS group (15 vs 17 days, p = 0.01). Discussion: Filgrastim use guided by an ES decreased the time to neutrophil engraftment, the duration of neutropenia and the length of hospitalization compared to a DS. Further analyses to identify predictive factors associated with a reduction in infectious complications and length of stay are underway, with the aim of developing a risk-adapted strategy for the use of filgrastim in patients with MM undergoing ASCT. Disclosures Van Besien: Miltenyi Biotec: Research Funding. Coleman:Kite Pharmaceuticals: Equity Ownership; Merck: Research Funding; Pharmacyclics: Speakers Bureau; Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau. Rosenbaum:Janssen: Research Funding; Honoraria Akcea: Other: Accordant Health. Rossi:Janssen, Celgene, Amgen: Consultancy; BMS: Research Funding. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding.

Description: Background: Deubiquitinating enzyme (DUB) inhibitors are an emerging class of compounds, which are increasingly being regarded for their anti-cancer activity and therapeutic potential. The 19S regulatory particle of the proteasome contains two DUBs, USP14 and UCHL5, which are critical for the proper unfolding and deubiquitination of proteins prior to their entry into the 20S proteasome β-catalytic core. In B/plasma cell malignancies such as Waldenströms macroglobulinemia (WM) and multiple myeloma (MM), protein homeostasis and optimal proteasome functionality are paramount for tumor survival. This is evidenced by the success of 20S proteasome inhibition with bortezomib and carfilzomib, which have demonstrated remarkable clinical benefit in patients with WM or MM. As such, the proteasome degradation pathway represents a highly attractive and clinically validated, yet still largely unexplored therapeutic target. Here, we provide first evidence of the cytotoxic effects and molecular sequelae associated with a novel 19S proteasome DUB inhibitor, VLX1570, which selectively targets USP14 and UCHL5, in preclinical models of B/plasma cell cancers and their drug resistant tumor subclones. Materials: VLX1570 was obtained from Vivolux AB, Sweden. Bortezomib was purchased from Sellekchem, Houston TX. Human myeloma cell lines (OPM2, U266, KMS11), human WM cell lines (BCWM.1, MWCL-1 and RPCI-WM1), their respective bortezomib-resistant (BR) subclones as well as ibrutinib-resistant (IR) derivatives of BCWM.1 and RPCI-WM1 were used in experiments (total n=12). Peripheral blood mononuclear cells (PBMCs) from healthy donors were used to assess for cytotoxicity of VLX1570 in non-tumor cells. Results: A 72hr MTS assay first established sensitivity of plasma cell cancer models towards VLX1570, including drug resistant subclones (EC50 range, 20 – 90nM). Next we assessed whether loss of viability was due to apoptosis and observed dose-dependent annexin-V staining in ~50 – 70% of wild-type MM and WM cells, ~45 – 55% in corresponding BR models and ~50% in IR subclones when exposed to VLX1570 (100nm – 500nM) for 24hrs. VLX1570 was tested at similar concentrations in PBMCs and induced minimal cell death. To understand if VLX1570-induced apoptosis was mitochondrial mediated, we assessed mitochondrial outer membrane permeability (MOMP) in all plasma cell cancer models treated with the DUB inhibitor (100 – 500nM) and found a dose-dependent increase in MOMP (p

Description: Abstract 4919 Waldenstrom's macroglobulinemia (WM) is characterized by the presence of lymphoplasmacytic cells in the bone marrow and the secretion of IgM monoclonal antibody in the serum. Several conventional therapies are available but the disease remains incurable. Recently, bortezomib (a proteasomal inhibitor) has shown promising anti-WM activity with enhanced responses when combined with traditional therapies. Resistance to bortezomib therapy is an important event that is associated with continued treatment. In order to understand the mechanism of bortezomib resistance in WM we exposed BCWM.1 (a known WM cell line) in vitro to increasing concentrations of bortezomib over prolonged periods of time and isolated the bortezomib resistant clone (BCWM.1/BR). This clone was compared with its parent wild type cell line (BCWM.1/WT). Investigation to understand the susceptibility of BCWM.1/Br cells to various therapeutic agents showed that these cells are resistant to many of the agents such as melaphalan, fludarabine or doxorubicin. Interestingly, verapamil, a broad spectrum inhibitor of multidrug resistance, failed to reverse the resistance induced by bortezomib indicating that bortezomib resistance is not because of an activation of multidrug resistance in these cells. While BCWM.1/WT cells showed an IC50 of 7.8nM when treated for 72h with bortezomib, the BCWM.1/BR cells were not inhibited at any concentration of the compound up to 100nM. Furthermore, the cells with the acquired resistance showed a 4 fold increase in the proteasomal activity as measured by the release of a fluorescent product (7-Amino-4-methylcoumarin (AMC)) from its peptide substrate, suc-LLVY-AMC. Biochemical analysis further revealed that many of the proteasomal components are altered in BCWM.1/BR cells as compared to their parental control cells. Interestingly, protein levels of two of the proteasomal catalytic subunits, PSMB5 and PSMB9 are upregulated in resistant cells suggesting a reason for the enhanced proteasomal activity of these cells. The resistant cells showed an altered gene expression profile that indicates a transformation of the parental wild type cell line to acquire resistance. A comparative analysis of the signal transduction pathways operated in these cells showed that many of the activation and cell survival pathways that are present in BCWM.1 cells are inhibited in the resistant cells. For example, BCWM.1 cells show a constitutive activation of AKT and ERK1/2 which are inhibited in the resistant cells thus making them insensitive to the inhibitors of these pathways. Similarly, HSP27 which was earlier shown to contribute to bortezomib induced resistance was completely inhibited in BCWM.1 resistant cells. Interestingly, there is an increase in Bcl-2 protein in BCWM.1/BR cells as compared to WT cells indicating that the resistant cells might be dependent on Bcl-2 family for their survival. Inhibition of Bcl-2 induced potent apoptosis in BCWM.1/BR cells. Thus the results presented here indicate that acquired bortezomib resistance in BCWM.1 cells alters their proteasomal activity, cellular signaling pathways to make them resistant to many of the known therapies but these cells retain the Bcl-2 mediated pathway for targeting thus inhibitors of Bcl-2 may be used in therapy against bortezomib-resistant WM. Disclosures Chanan-Khan: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immunogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.