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Abstract Background: Patients with light chain amyloidosis (AL) often have delayed diagnosis and present with significant symptomatology; this may result in decreased quality of life (QOL). With improving treatment options providing longer survival, it is increasingly important to assess QOL. However there is paucity of data in the literature addressing QOL in AL patients. We prospectively employ a "Hematology Patient Reported Symptom Screen" (HPRSS) which consists of three questions about fatigue, pain and overall QOL. The aim of this study is to understand if HPRSS parameters predict various clinical outcomes. Methods: Eligibility for this retrospective study was as follows: 1) New diagnosis of AL between 2009-2014; 2) baseline HPRSS documented in the medical record; and 3) at least a year of follow-up, which included either death within or follow-up through 12 months after diagnosis. The HPRSS questions were rated on a 1-10 scale, with 10 being the worst for fatigue and pain, and 10 being the best for overall QOL. Scores were abstracted from visits at time of diagnosis, and at 12 months +/- 1 month post-diagnosis. We considered a 2-point difference in serial scores a "change" over time. Results: For the 302 patients in this study, the baseline median scores [interquartile range] for fatigue, pain, and QOL were 6 [3,7], 2 [0,5] and 5 [3,8], respectively. Median overall survival (OS) was 39.1 months, with 102 deaths in the first year. There were significant differences in baseline HPRSS between those who lived longer than one year and the early death patients in the domains of fatigue (5 [IQR 3, 7] vs. 7 [IQR 5, 8], p<0.0001) and QOL (6 [IQR 4, 8] vs. 5 [IQR 3, 7], p=0.006), but not in pain (2 [IQR 0, 5] vs. 2 [IQR 0, 5]). There were significant baseline differences in the early death group for alkaline phosphatase, bilirubin, creatinine, and Mayo stage. Patients who received ASCT had the best baseline fatigue 4 [2.5,6] and QOL 7 [5,8] scores and were significantly different from those who did not receive ASCT [fatigue p<0.0001) and QOL (p<0.0001)] On univariate analysis fatigue and QOL were prognostic for OS. On multivariate analysis Mayo 2012 staging, autologous stem cell transplant and baseline fatigue remained independently prognostic. When analyses were restricted to the 125 patients with HPRSS measurements at 12 months, we found that over time QOL scores improved significantly 6 [IQR 3.5, 8] to 7 [IQR 5, 8] (two sided Wilcoxon signed rank p=0.01), but fatigue (5 [IQR 2, 5] to 4.5 [IQR 3, 6]) and pain scores (2 [IQR 0 ,4] to 1.5 [IQR 0, 4]) did not. Patients with worse baseline parameters tended to have improvement in QOL by 12 months while those with the best baseline parameters tended to decline in QOL although not statistically significant. When we included the 102 patients who died within 12 months to the comparison, the early death patients had the worst baseline parameters and there were significant differences across all 4 groups for most characteristics (Table 1). There was no association between achieving hematologic or organ response with change in QOL. Conclusion: Asking patients with AL to rate their fatigue and QOL using a 10-point scale has predictive value. Patient reported fatigue at diagnosis is an independent prognostic factor for survival. Survival at one year was associated with significant improvement in QOL. Table 1. Baseline parameters between patients with early death and/or survive 12 months. Grouped by Patient Reported QOL at 12 months Relative to Baseline Dead by 12 months, n=102 Improved, n=44 Stable, n=55 Worsened, n=26 pa HPRSS scores [IQR] Baseline QOL Baseline fatigue Baseline pain 12 month QOL 12 month fatigue 12 month pain 5 [3,7] 7 [5,8] 2 [0,5] NA NA NA 4 [3-5] b,c,d6 [4-8] b,c2 [0-4] 7 [6-9] b,d4 [1.25-6] 1 [0-3] 7 [4-8] 4 [2-7] 2 [1-5] 7 [4-8] 5 [3-6] 2 [0-4] 8 [7-10] 2.5 [0-5.25] 2 [0-6.25] 5 [3-7] 5 [3-6] 2.5 [1-4] <0.0001 <0.0001 NS NS 0.001 NS dFLC, mg/dL 48 (2.89-726) 30 (1.1-494) 19 (36-455) 22 (0.2-2097) 0.008 Troponin, ng/mL 0.065 (<0.01-0.84) 0.02 (<0.01-1.6) 0.01 (<0.01-0.19) 0.01 (<0.01-0.14) <0.0001 NT-proBNP pg/mL 5222 (159-70,000) 1766 (26-16868) 1381 (24-19180) 496 (56-2973) <0.0001 Received Transplant (%) 4 (4) 13 (33) 36 (50) 13 (50) 0.0002 a Significant by Wilcoxon across all 4 categories; b Significant difference between Improved and Worsened; c Significant difference between Improved and Stable; d Significant difference between Worsened and Stable Disclosures Kumar: Millenium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Research Funding; Onyx: Consultancy, Research Funding. Thompson:Kite Pharma: Research Funding.

Abstract Background: Outcome studies for the unique cohort of young patients with multiple myeloma (MM) are sparse. In general, MM is a heterogenous disease with the genetic signature being one of the major determinants of prognosis. We have recently reported on improvement in overall survival (OS) of young patients with the use of novel agents, but the maximal survival gain has been achieved by integrating autologous stem cell transplant (SCT) to our current approach. Herein, we report on outcomes of patients with MM who were 50 years or younger at diagnosis and stratified by fluorescence in situ hybridization (FISH) results. Our study focuses on t(11;14) myeloma as its prognostic impact remains unclear with the use of novel agents upfront. Methods: Out of 1384 patients with MM, evaluated consecutively at Mayo Clinic, Rochester, MN between 1/1/2000 and 12/31/2011, 290 (21%) were 50 years or younger at diagnosis. Interphase FISH, performed within 100 days of diagnosis of MM, was utilized to stratify patients as high-risk [deletion 17p, t(14;16), t(14;20) or t(4;14)] or standard-risk [normal FISH, trisomies, t(11;14), t(6;14) or monosomy13/deletion 13q]. FISH results were available in 125 young patients that comprise the cohort of interest in the current study. OS from diagnosis was estimated by the Kaplan-Meier method. Results: Median age at diagnosis of MM was 47 years (range: 22 to 50 years) and 58% of the patients were male. At the time of data cut-off (7/31/2014), 45 (36%) patients had died with 90% of all known causes of deaths (n=39) being MM related. FISH abnormalities were noted in 114 (91%) patients. At diagnosis, 46%, 30% and 24% patients were categorized as International Staging System (ISS) stage I, II and III, respectively. The estimated median follow up was 60 months (95% CI: 54-67) and the 5-year OS rate was 69% [median 86 months (95% CI: 76-108)]. Standard (n=100; 80%) and high (n=25; 20%) risk patients had a median OS of 89 months (95% CI: 76-108) and 77.6 months (95% CI: 42-130), respectively (p=0.87). In order to further investigate the similar outcomes between these broad risk-groups with typically diverse disease course, we assessed the outcomes based on the common genetic abnormalities (Table 1) within each of the 2 categories. Presence of t(11;14) (n=37; 29%) was associated with a significantly shorter median OS (76 months) compared to patients with trisomic and normal FISH profile (n=46) (91 months, p=0.01; Figure 1). Patients with t(11;14) also had a significantly shorter median OS compared to those with other standard-risk FISH abnormalities (median OS 96 months, p=0.02). Presence of t(11;14) was not associated with higher plasma cell labeling index (PCLI, p=0.29) or worse ISS stage (p=0.99) compared to patients without t(11;14). OS survival of patients with t(11;14) was similar to those with high risk features (median 76.2 vs. 77.6 months, p=0.32). Of 24 (65%) patients with t(11;14) who underwent SCT, 79% had early SCT (within 12 months from diagnosis). Median OS was 79.4 months (95% CI: 36-108) vs. not reached (NR) (95% CI: 27-NR), respectively (p=0.79) in early versus late SCT. Twenty-one (57%) and 13 (35%) patients with t(11;14) received initial immunomodulatory drugs or bortezomib-based therapies, respectively. Those receiving frontline bortezomib had a higher median OS (76.2 months, 95% CI 76-79) compared to 64.8 months (95% CI 32-108) with other initial agents although it did not reach statistical significance (p=0.78). Conclusion: Presence of t(11;14) is associated with an inferior OS compared to patients with normal FISH, trisomies, or other standard risk abnormalities in young patients with MM. Given, the inherent biases associated with a retrospective study from a referral institution, our findings require external validation. However, our data suggest that our current therapeutic approaches in managing young patients with this unique genetic signature are inadequate. Table 1FISHn(%)Median OS in months (95% CI)t(11;14)37(29)76.2 (53.5-107.7)Trisomies35(28)91.3 (76.4-NR)13/del(13q)11(9)NR (32-NR)Normal11(9)95.5 (45.4-95.6)t(4;14)11(9)NR (40.1-NR)del(17p)/-1710(8)42 (19.2-129.6)t(14;16)4(3)77.6 (42.4-NR)Others6(5)NR (11.5-NR) Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Background:A goal of “post-genomic” cancer care is development of specific, affordable, reliable and rapid next-generation sequencing-based assays determining prognosis, therapeutic selection and minimal disease monitoring, replacing older technologies in the diagnostic and monitoring workup. In this regard, we designed and deployed a custom gene panel for identification of mutations, copy-number changes and clonal frequency in multiple myeloma (MM) samples. Methods: The MM Mutation Panel Version 2.0 (M3P 2.0)1 includes 1271 amplicons from 77 genes that are either mutated in MM (genes with a published mutation incidence ≥3%), represent critical pathophysiological pathways, are targetable with small molecule-based therapies and/or are associated with drug resistance (eg. XBP-1, CRBN, IZKF, IRF4). The amplicons are spread across 21 chromosomes, allowing the identification of copy-number changes in these regions. Results: We have sequenced 38 MM cases (150 will be presented) with paired tumor-germline DNA samples, using only 20ng of DNA for library preparation. Patients (Pts) included 29 untreated and 9 MM pts with multi drug refractory disease. Coverage depth averaged 964X. Hyperdiploid MM was successfully identified in 45% of cases, del(13q) in 34%, del(1p) in 18%, del(17p) in 8% and gain of 1q in 13%. Array CGH in representative cases confirmed concordance with semiconductor sequencing. Overall, 71 exonic missense and 3 nonsense mutations were detected, and 7 frameshift indels. In 89% of the pts a mutation in at least one M3P2.0 gene was identified (range 1-8). 92% of mutations were predicted damaging (Provean, Polyphene-2 or SIFT). Most commonly mutated were KRAS (37%), NRAS (21%), BRAF (13%), TP53, CDKN1B, DIS3 (each 11%), FAM46C, STAT3, and IRF4 (each 8%). The MEK-ERK pathway was mutated in 61% of cases and in 3 cases more than one gene in this pathway (NRAS, KRAS, BRAF) was simultaneously mutated. Six mutations in BRAF were identified in 5 untreated pts, 3 of them known to be activating and targetable (Val600E). Other commonly mutated pathways were the NFKB pathway in 24% of pts and the Cyclin D pathway, mutated in 16% of cases. Genes of the cereblon pathway (CRBN, IRF4, IKZF3), essential for the action of lenalidomide (len) were mutated in 5 Pts. One newly diagnosed and len refractory Pt harbored a subclonal CRBN mutation (Asn316Lys, allelic fraction [AF] 20%) as well as 4 clonal IRF4 mutations within the DNA binding domain of the gene (Lys89Asn (AF 78%), Lys77Glu, Ser48Arg and Cys49Ser (AF 80% each). Another IRF4 mutated (Lys123Arg, AF 90%) hemodialysis dependent Pt was responsive to dose adapted treatment of len and dexamethasone (dex). Mutations in the C2H2-type 3 region of IKZF3 in a len resistant (Gly191Arg, AF 48%) pt occured as well as in a len and dex responsive (Arg242Gly, AF 52%) Pt. Furthermore, we identified a truncating XBP1 mutation (p.Leu232*, 97% AF) in a Pt refractory to bortezomib. One patient harbored a mutation in the steroid receptor NR3C1 (Pro255Leu, 22% variant reads). Finally, integrated mutation and copy-number data identified biallelic deletions of CDKN2C and FAM46C in a multi drug refractory Pt. Mutation and/or copy-number losses in both alleles were found in DIS3 in 4 Pts, in CYLD, TP53 and TRAF3 in 2 Pts and in CARD11, CDKN2A, CDKN1B, RB1and STAT3 in one Pt each. Conclusion: In summary, we report the initial results from 38 MM Pts using a custom MM sequencing panel which employs small amounts of DNA requiring very few cells and providing deep coverage in clinically meaningful timeframes. Our findings frequently include prognostically significant information, actionable targets and mutations in genes related to drug resistance. Targeted mutation profiling will likely become part of the clinical workup in MM and our M3P2.0 mutation panel is a suitable tool to provide information needed to guide precision therapy and to set the basis for individually tailored treatment decisions. 1. Kortuem KM. et al. Development Of a 47 Gene Sequencing Panel For Common Mutations Present In Multiple Myeloma: Preliminary Results In 77 p53 Deleted Patients, ASH 2013. Disclosures Stewart: Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Array BioPharma: Consultancy; Sanofi: Consultancy; Takeda Pharmaceuticals International Co.: Research Funding; Novartis: Consultancy. Bruins:OncoSpire: Salary support Other. Vasmatzis:OncoSpire: Salary Support Other. Kumar:Celgene: Consultancy, Research Funding; Millennium: The Takeda Oncology Co.: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Sanofi-Aventis: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Skyline Diagnostics: Membership on an entity's Board of Directors or advisory committees. Fonseca:Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium, AMGEN: Consultancy, patent for the prognostication of MM based on genetic categorization of the disease. He also has sponsored research from Cylene and Onyx Other, Research Funding. Bergsagel:MundiPharma: Research Funding; OncoEthix: Research Funding; Constellation Pharmaceutical: Research Funding; Novartis: Research Funding.

Abstract Background: Both MM specific and patient specific parameters place patients at risk for death. Patient frailty has been delineated primarily by age and ECOG performance score (PS) and secondarily with creatinine, eGFR, and the International Staging System (ISS), which reflect both renal function and disease burden. In an attempt to improve upon these commonly used measures, a frailty score for elderly patients that combines functional status [Activity of Daily Living (ADL) and Instrumental Activity of Daily living scores], comorbidities [Charlson comorbidity index (CCI)] and age has been developed by the IMWG. Incorporation of these tools into a busy clinical practice is challenging due to time constraints. Therefore, the identification of frail patients with an easily applicable, rapid and objective tool remains a challenge and an unmet need. A reliable, non-invasively assessable, biochemical marker of frailty would be an ideal tool to identify patients at higher risk of death. It was our goal to determine the role of NT-proBNP, a well-established cardiovascular risk biomarker, as a marker of frailty in patients with MM and in predicting overall survival (OS). Methods: Patients were elegible for this retrospective study if they were seen at the Mayo Clinic, Rochester, MN within 30 days of their myeloma diagnosis during the interval between 1/1/2007 and 12/31/2011. As part of the Mayo Clinic registration, all patients complete forms containing their past medical history, symptoms, and ADLs. Data from that first visit was abstracted and used to calculate a CCI. We excluded all patients with a concomitant diagnosis of light-chain AL amyloidosis. NT-proBNP concentration was measured in frozen sera collected within 30 days of diagnosis. NT-proBNP assay was run on the E170 Modular analyzer (Roche Diagnostics, Penzberg, Germany). We evaluated the prognostic role of NT-proBNP and these indices on OS using the Kaplan-Meier method. Results: Among the 351 consecutive patients satisfying entry criteria, median age was 65 years (range 22-95), 33% were ≥70 years, and 56% were male. Twenty-eight percent were ISS stage III, 13% had a creatinine ≥2 mg/dL, 19% had PS ≥2, and 11% had ADL score ≥2, and 30% CCI ≥2. The median value of NT-proBNP was 109 ng/L (interquartile range: 30-375 ng/L). NT-proBNP concentrations differed in the three ISS stages (median: 122 ng/L stage I, 190 ng/L stage II and 1822 ng/L stage III, P<0.0001). Median OS was 5.6 years. The best cutoff of NT-proBNP predicting OS at one year was 301 ng/L (sensitivity: 57.88%, specificity: 74.29%; AUC=0.668) and distinguished two groups with different OS (median not reached vs. 35 months, P<0.0001). Variables predictive for OS are shown in the Table and included PS, age, CCI, ISS, NT-proBNP. On multivariate analysis, ISS and NT-proBNP were independent of each other as long as age, PS and/or CCI were excluded from the model. NT-proBNP withstood these clinical variables better than did ISS (data not shown). We built two different models (table). In model 1, NT-proBNP >301 ng/L was an independent predictor of survival while age ≥70 and PS ≥2 and CCI were not significant. However, if we considered ISS stage instead of NT-proBNP in the same model, ISS stage was not significant. Conclusions: In this unselected cohort of patients with newly diagnosed multiple myeloma, NT-proBNP was a useful predictor of survival independent of age and PS. The threshold of 301 ng/L is remarkably similar to the well-established cutoff for heart failure of 300 ng/L. NT-proBNP outperformed the CCI and the ISS as risk factors. NT-proBNP is a widely available biomarker that could be added to the panel of laboratory tests of newly diagnosed MM patients and serve as a simple means of determining patient frailty in a busy clinical practice. Table. Results of univariate and multivariate analysis of various prognostic factors (NS, not significant; NI, not included). Univariate Multivariate Multivariate RR (95% CI) P Model 1 P Model 2 P PS ≥2 3.4 (2.4-4.8) <0.0001 2.5 (1.7-3.6) <0.0001 2.8 (1.9-4.0) <0.0001 Age ≥70 2.7 (1.9-3.6) <0.0001 2.1 (1.5-2.9) <0.0001 1.9 (1.3-2.7) 0.0003 CCI >=2 1.9 (1.4-2.6) <0.0001 NS NS 1.5 (1.0-2.0) 0.03 ISS stage 1.1 (1.1-1.8) 0.0004 NI NI NS NS NT-proBNP >301 ng/L 2.3 (1.7-3.2) <0.0001 1.6 (1.1-2.2) 0.007 NI NI Disclosures Merlini: Janssen-Cilag: Honoraria; Prothena: Honoraria; Millennium-Takeda: Honoraria; Pfizer: Honoraria. Kumar:Janssen: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Millenium/Takeda: Research Funding; AbbVie: Research Funding; Onyx: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria.

Abstract Abstract 201 Background: Pomalidomide at doses of 2 or 4 mg/d has demonstrated excellent activity in patients with relapsed multiple myeloma (MM). Between November 2007 and March 2012, we opened 6 sequential phase 2 trials and treated 345 patients with relapsed MM with pomalidomide at differing doses with weekly dexamethasone (Pom/dex). Results of 164 of these patients have been previously published. Here we describe long term follow up of these patients as well as results of an additional 181 patients with relapsed MM treated with the Pom/dex regimen. Methods: The six cohorts consisted of: Cohort 1 (N=60): relapsed MM with 1–3 prior regimens, 2 mg dose; Cohort 2 (N=34): lenalidomide (LEN) refractory, 2 mg dose; Cohort 3 (N=35): BZ)/LEN refractory, 2 mg dose; Cohort 4 (N=35): BZ/LEN refractory, 4 mg dose; Cohort 5 (N=60) LEN refractory, 1–3 prior regimens, 4 mg dose; and Cohort 6 (N=120) LEN refractory, 4 mg dose. Pomalidomide was given orally 2 mg daily or 4mg daily on days 1–28(cohorts 1–5) or 1–21 (cohort 6) of a 28-day cycle with oral dexamethasone given 40 mg daily on days 1, 8, 15 and 22. Response was assessed by the International Myeloma Working Group Uniform Response criteria. All patients received aspirin 325 mg daily for deep venous thrombosis (VTE) prophylaxis or full dose anticoagulation. Results: A total of 345 patients were enrolled across all 6 cohorts. One patient was ineligible and excluded from analysis. The median age was 64 years (32–88). The median time since diagnosis was 53 months. The median number of prior therapies was 3 (1–14). 147 (44%) had high-risk molecular markers by mSMART criteria. Prior therapies consisted of thalidomide 52%, lenalidomide 87%, bortezomib 75%, autologous stem cell transplant 70% and allogeneic transplant 3%. The median follow-up is 10.4 months (5.4–34 months). Sixty-seven percent are alive and 32% remain progression free. 46 patients are continuing to receive treatment. The most common toxicities (grade 3 or higher) were neutropenia (31%), anemia (16%), thrombocytopenia (12%), pneumonia (8%) and fatigue (8%). VTE was seen in 10 patients (3%). Outcomes are shown in Table 1. Across all 6 cohorts confirmed responses of partial response (PR) or better were seen in 34%. The response rate in all patients with mSMART high risk status was 30.6%. Responses and duration of response (DOR) in those with high risk molecular markers include: 17p– 19 of 56 (34%) DOR 8.2 months; t(4;14) 6 of 24 (25%) and DOR 4.8 months; t(14;16) 7 of 11(64%) and DOR 9.5 months; deletion 13 by cytogenetics 13 of 37 (35%) with DOR 8.2 months. In a multivariate analysis, only LDH > ULN, number of prior regimens, and prior BZ therapy were predictive of a shorter TTP and factors associated with a poor OS following initiation of pomalidomide therapy included B2M > 5.5, LDH > ULN,number of prior regimens, and prior BZ therapy. Conclusions: Pom/dex is active and well tolerated even in heavily pretreated patients and those with high risk molecular markers. Remissions are durable. Response rates and toxicity are similar between the 2 mg and 4 mg doses. Disclosures: Lacy: Celgene: Research Funding. Stewart:Celgene: Consultancy, Honoraria. Reeder:Celgene: Mayo Clinic receives funding from Celgene to support clinical trials Other, Research Funding.

Abstract Background:The pathological behavior of Waldenströms macroglobulinemia (WM) cells relies on aberrant B-cell receptor (BCR), and Toll-like receptor (TLR) signaling and is intricately supported by malfunctions in initiation of apoptosis. In this dynamic, a complex shift between functionally active pro-apoptotic and anti-apoptotic proteins from the Bcl-2 family occurs and bestows the malignant cells with a significant survival advantage. This defective apoptotic signaling is associated with aggressive clinical behavior, chemoresistance, and a poor prognosis in many B-cell cancers, including WM. Thus, BCR/TLR induced proliferation and abnormal apoptotic signaling due to dysregulation of Bcl-2 signaling, act in concert for the assurance of the malignant WM cells survival. Clinically, mitigation of BCR signaling with the first in class BTK inhibitor, ibrutinib, has shown promising results in WM and other B-cell cancers. However, clinical responses to the BTK inhibitor alone are less than optimal and development of ibrutinib-resistant disease is being recognized as an important and impending dilemma. We have previously shown the utility of disrupting pro-apoptotic Bcl-2 protein interactions in WM, chronic lymphocytic leukemia and multiple myeloma and that this functional interference results in re-sensitization (or heightened sensitivity) of tumor cells towards chemoimmunotherapy. As such, we examined the effects of ABT-199, a Bcl-2 specific small molecule inhibitor, in preclinical models of WM. Importantly; we conducted this investigation in proprietarily developed WM cells that have acquired resistance mechanisms towards either ibrutinib (IR WM subclones) or bortezomib (BR WM subclones). Materials:WM cell lines (BCWM.1, MWCL.1 and RPCI-WM1; WT cells) including their bortezomib resistant (BR) or ibrutinib resistant (IR) subclones were used in this study. Results: An initial comparison of Bcl-2 family members, Bcl-2, Mcl-1, BCL-xL, A1 (anti-apoptotic members), Noxa, Puma, Bim (pro-apoptotic initiators) and Bak and Bax (pro-apoptotic effectors), revealed that BR WM cells express increased levels of pro-apoptotic Bcl-2 family members, particularly Bcl-2, relative to WT cells. Similarly, A1 and Bcl-2 levels were up regulated in IR cell lines suggesting that the Bcl-2 mediated survival pathway is involved in resistance to both bortezomib and ibrutinib. Cell growth (MTS) assays using ABT-199 indicated that both BR and IR cells were equally sensitivity to Bcl-2 inhibition, with an IC50 ranging between 2 – 4mM. ABT-199 induced a dose dependent increase in MOMP with concomitant induction of apoptotic cell death, the latter confirmed by observation of PARP-1 cleavage. ABT-199 induced an intrinsic apoptotic program with the activation of caspase 9 and caspase 3 in all the cells tested. This data indicated the Bcl-2 pathway as being relevant and essential in WM cell lines even under drug resistant conditions. To evaluate the priming effect of ABT-199 on bortezomib and ibrutinib induced cell death, MTS assays were performed with these drugs in presence of IC25 concentrations of ABT-199. The addition of ABT-199 significantly reduced the IC50of both bortezomib and ibrutinib in WT, BR and IR cells. This suggested that re-sensitization of BR and IR cells towards either bortezomib or ibrutinib, respectively, was possible in presence of ABT-199. Further, combined addition of ABT-199 with bortezomib or ibrutinib showed synergistic cell death (combination index range: 0.004 – 0.6, CalcuSyn, Biosoft UK) in BR or IR WM cells, respectively. Conclusion: Dysregulation of Bcl-2 signaling is associated with the pathogenesis and promotion of drug resistance in B-cell cancers, including WM. Our report is first to highlight in WM preclinically, the antiproliferative effect of disrupting Bcl-2, through use of ABT-199. Altogether, our data suggests that therapeutic interference of Bcl-2 function with ABT-199 complements the anti-WM activity of ibrutinib or bortezomib in a synergistic manner and can in fact restore sensitivity of either drug in WM cells that are resistant to proteasome or BTK inhibitors. Focused mRNA and protein profiling analyses are currently underway to delineate the mechanisms accounting for synergy observed between concomitant Bcl-2/BTK inhibition as well Bcl-2/proteasome inhibition. Disclosures Ansell: Biothera: Research Funding. Martin:Janssen: Honoraria. Coleman:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Speakers Bureau.

Abstract Abstract 600 Background: Both MM and AL are plasma cell neoplasms. The underlying clone in both diseases appears to be different not only in terms of “tumor burden” but also in terms of their underlying biology. The overall “fitness” of patients with these two diseases is also different, with AL patients having more major organ dysfunction. Therapy for both diseases is directed at killing the underlying clone. ASCT is one method of reducing the clone size and thereby improving overall survival. Post-ASCT outcomes between the two diseases have never been formally compared. Methods: We compiled all patients with a diagnosis of AL or MM who received ASCT at the Mayo Clinic Rochester between June 1996 and January 2011 to compare outcomes. Patients were retrieved from two prospectively maintained clinical transplant data bases (M.A.G.). Differences between groups were compared using Fisher's exact and Wilcoxon tests. Survival was calculated using the method of Kaplan-Meier, and differences between survival outcomes were calculated by log rank. Cox regression modeling was done to determine how non-disease specific variables—i.e. age, time period of ASCT, number of prior regimens, time to ASCT from diagnosis and acquisition of complete response (CR)—affected outcomes. All statistical analyses were performed using JMP (SAS, NC) software. This study was approved by the Mayo IRB. Results: The data set was comprised of 454 patients with AL and 1116 patients with MM. There were significant differences between the two respective groups of patients in terms of number of prior regimens (0 vs 1, p<0.0001), time to ASCT (3.95 months vs 7.20 months, p<0.0001), intensity of conditioning regimen (non-attenuated in 69.4% vs 89.1%, p<0.0001), serum creatinine (1.1mg/dl vs 1mg/dl p<0.0001), creatinine clearance (72.5 ml/minute vs 80 ml/minute p<0.0001), albumin (2.61g/dl vs 3.50g/dl, p<0.0001) CRP (0.40mg/dl vs 0.63mg/dl p<0.0001), LDH (196 U/l vs 182U/l, p<0.0001), and bone marrow plasmacytosis at transplant (6% vs 9%, p<0.0001). Hematologic response rates were also significantly different between the groups, with higher overall hematologic response in the MM group (90.9% vs 79.5%, p<0.0001) and higher complete response (CR) rates (40.1% vs 29.4%, p<0.0001) in the AL group. With a median follow-up of surviving patients of 68 months, the respective median overall survival (OS) for the AL and MM patients was 113 and 59.5 months, p<0.0001. Notably, the 5-year OS of AL and MM patients achieving CR were 91.4% and 57.7%, respectively, p<0.0001. If only those patients who were transplanted within 1 year of their diagnosis are included in the analysis, the respective 5-year OS of AL and MM patients achieving CR were 90.4% and 61.3%, p<0.0001 (Figure 1). To correct for imbalances in non-disease specific parameters, 3 multivariate analyses were performed using: 1) all patients; 2) only those achieving CR; and 3) only those who achieved a CR and were transplanted within 12 months of their diagnosis (Table 1). Among those patients achieving CR, MM patients had nearly a 4-fold risk of death as compared to patients with AL. Conclusion: Although ASCT is not available to all patients with either AL or MM, there is a significant difference in outcomes based on the diagnosis. Patients with AL who undergo ASCT enjoy a superior survival as compared MM patients undergoing the same procedure. This difference is most notable among those patients who achieve CR suggesting very different plasma cell biology between the two diseases. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 599 Purpose: This study was undertaken to develop selection guidelines for transplant centers to determine eligibility for stem cell transplantation in patients with light chain amyloidosis. Patients and Methods: Patients with biopsy-confirmed immunoglobulin light chain amyloidosis who underwent stem cell transplantation between March 8, 1996, and December 31, 2011, were reviewed in 2 cohorts: those who underwent transplantation between March 8, 1996, and June 30, 2009, and those who underwent transplantation between July 1, 2009, and December 31, 2011 (table 1). A second comparison was undertaken among patients who died before posttransplant day 100 to determine features predictive of early death (table 2). Results: A total of 499 patients were identified, 410 in the earlier group and 89 in the later group. After July 1, 2009, significantly fewer transplant recipients had Mayo stage III cardiac involvement. Mortality before posttransplant day 100 was 10.5% (43/410) in the earlier group and 1.1% (1/89) in the later group. In the earlier group, one-quarter of transplant recipients with N-terminal pro-brain natriuretic peptide (NT-proBNP) levels higher than 5,000 pg/mL died by 10.3 months (fig 1, left). When the serum troponin T level was > 0.06 ng/mL, 25% died at 3.7 months (fig 2, right). Conclusion: The Mayo staging system is highly predictive for overall survival but not useful for selecting transplant recipients. Patients with serum troponin T levels higher than 0.06 ng/mL or NT-proBNP levels >5,000 pg/mL (not on dialysis) should not be considered acceptable candidates for stem cell transplantation because of unacceptable early mortality. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3972 Background: The treatment paradigm for myeloma has undergone a dramatic shift in the past decade with the introduction of the novel agents and their application at every stage of the treatment. We and others had previously shown that survival of patients with myeloma had improved in the earlier half of the last decade and attributed this to a combination of novel therapies as well as increased use of stem cell transplant. It is not clear if this momentum in improving survival has been maintained. We examined the survival trends of patients with newly diagnosed myeloma seen within the past decade to examine this question. Patients and Methods: We studied 1056 patients with newly diagnosed myeloma, who were seen at Mayo Clinic between January 1, 2001 and December 31, 2010; who were seen within 30 days of their diagnosis. For examination of the time trends, we grouped the time interval into two five year periods, 2001–2005 and 2006–2010. Survival was estimated using Kaplan Meier method and survival curves were compared by log rank test. Impact of various prognostic factors was evaluated using Cox proportional hazards test. Results: The median age at diagnosis was 65 (range; 22–92), and 59% were male. The median estimated follow up for the entire cohort was 4.6 years (95% CI; 4.4, 4.9) and 57% of the patients were alive at last follow up. The median overall survival (OS) for the entire cohort was 5.4 years (95% CI; 5, 6.3). The overall survival for patients in the 2001–2005 group was 4.6 years compared with not reached for the 2006–2010 cohort (P< 0.001). The five-year estimated OS was 48% for the earlier group compared with 66% for the latter group. The estimated 1-year survival was 90% for the recent cohort compared with 83% for the earlier cohort, suggesting improvements in the early mortality. Interestingly, the improvement was predominantly seen in the older age group (>65 years; 49%). The 5-year survival of the older patients improved significantly from 31% (2001–2005) to 56% (2006–2010) (P<0.001). In contrast, among younger patients (≤65 years of age), the 5-year survival improved only marginally from 63% (2001–2005) to 73% (2006–2010) (P=NS). One or more novel agents (Lenalidomide, thalidomide or bortezomib) were used as part of initial therapy in 631 (62% of 1021 in whom treatment data was available). The OS among of this group was 7.3 years (95% CI; 5.9, NR) compared with 3.8 years (95% CI; 3.1, 4.6). In a multivariate model that included both use of novel agent and the year group, only the novel agent use was associated with improved survival suggesting that the improvement in the survival is related to the increased use of novel agents in the initial therapy. No significant differences were observed between the groups in terms of conventional prognostic factors. Conclusions: The current results confirm continued improvement in the overall survival of patients, even within the last 10 year period, and highlight the impact of initial therapy with novel agents. Most importantly, we demonstrate that the improved survival has primarily benefited older patients. Our study highlights that urgent need for additional new agents to provide further survival improvement for younger patients, and in order achieve a cure for this disease. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Cephalon: Research Funding; Genzyme: Research Funding. Dispenzieri:Celgene: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Janssen Research & Development: Research Funding. Gertz:Binding Site: Honoraria.

Abstract Abstract 602 Although, MM remains the most common indication for ASCT in the US, a controversy exists about the timing of ASCT. Since early ASCT (eASCT) versus delayed ASCT (dASCT) results in similar progression free survival (PFS) and overall survival (OS) in the novel agent era, economic assessment of one strategy over the other may help both clinicians and policy makers in establishing guidelines in the MM treatment paradigm. Here we designed a study to model a decision tree of both the strategies and estimate their cost-effectiveness. A decision tree was developed to compare the outcomes of ASCT in newly diagnosed transplant eligible MM patients after chemotherapy with novel drug lenalidomide which formed the base case. The survival data was obtained from our published data on eASCT versus dASCT in MM patients who underwent initial therapy with dexamethasone + immunomodulatory agents (IMiDs). The initial decision node on the decision tree model was dichotomized based on the cutoff of 12 months for eASCT versus dASCT. The probabilities of events during the length of follow up (60 months) period which formed our base case were: (a) eASCT cohort: Induction chemotherapy for median of 6 months - ASCT - median 30 months to relapse (drug free interval) followed by median therapy of 24 months for relapsed MM; (b) dASCT cohort: Median initial therapy for 36 months - ASCT - median 24 months to relapse (drug free interval). The cost analysis was done from a US third party payer perspective. The cost data for MM ASCT was obtained from the published data in which direct hospital costs were obtained from Nationwide Inpatient Sample and were converted to Medicare cost-to-charge ratio for urban hospitals. Chemotherapy cost consisted of actual drug costs that calculated based on average wholesale prices AWP (2008), costs of medical oncology visits, and the costs of managing adverse events. Post-ASCT maintenance costs were not included in the analysis. TreeAge Pro 2012 software was used to perform a static decision analysis. The outcomes were expressed in the units of health utility values obtained from phase III HOVON trial which measured quality of life (QoL) using EORTC QLQ-C30 & EuroQoL-5D. All scales and items were linearly transformed to range from 0 to 100. The utilities measured by the EuroQol-5D ranged from 0.40 before induction therapy to 0.70 after ASCT and translated to QALYs using area under the curve method. Using a Consumer Price Index (CPI), the costs of ASCT and chemotherapy were converted into 2012 US$. The robustness of the decision model was tested through univariate analyses and tornado diagram to identify those variables which if varied across clinically relevant measures may result in difference in outcomes. The expected cost of providing treatment to newly diagnosed MM patients for a period of 5 years when they undergo eASCT after induction with IMiDs was calculated to be $211,869. This was $52,454 less than the expected cost of undergoing dASCT. Patients who underwent eASCT had an expected benefit of 2.06 QALYs following treatment, which was 0.19 QALYs more than the patients who received dASCT. This implies that eASCT is preferred over (dominates) dASCT. One-way sensitivity analysis was undertaken to identify factors that were found to be most influential and included OS, overall response rate (ORR) and 1 year ASCT related mortality rate (TRM). Specifically, eASCT showed dominance even if the probability of OS was lowered to 52.1% from the actual case base of 65%, or the probability of ORR was lowered to ≥ 75.8% from the actual case base of 92%, or the probability of 1 year TRM was increased to 11.5% from actual case base of 2%, indicating the robustness of the model favoring cost effectiveness of eASCT. In absence of a survival benefit, the cost savings of early ASCT as measured by ICER would favor this approach, and it would help clinicians, patients, policy makers and third party payers in decision making. Future prospective studies in MM ASCT should incorporate economic and QOL components in the analysis and also focus on the added cost of post-ASCT maintenance therapies with respect to ICER and QALYs. Disclosures: No relevant conflicts of interest to declare.