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Abstract Background Conflicting results have emerged, especially with respect to the impact on overall survival (OS), from trials evaluating lenalidomide maintenance (LM) therapy after induction therapy alone or post-autologous stem cell transplant (ASCT) in multiple myeloma (MM). We performed a systematic review and meta-analysis of existing outcome data from LM trials to evaluate role of lenalidomide as maintenance strategy in MM. Patients and methods A comprehensive search of electronic databases and abstracts through June 2013 was performed to identify randomized controlled trials (RCTs) that compared LM vs. placebo/no maintenance. Single arm studies were excluded. Pooled hazard ratio (HR) or odds ratio (OR) estimates with 95% confidence intervals (CIs) were calculated using the random-effects model for clinical endpoints of progression free survival (PFS), OS, response rate (RR) and adverse events (AEs), including second primary malignancies (SPMs). Analyses were performed using Comprehensive Meta-Analysis Software Version 2. We assessed between-study heterogeneity with the Cochran Q test and quantified its extent with the I2 statistic. Results Overall, five RCTs, with data extractable from four phase III trials (3 publications and 1 abstract) were identified (n= 1935). All studies were RCTs with an adequate randomization. MRC MM XI study was excluded from analyses as survival data are not available. Two placebo controlled trials (IFM 05-02, CALGB 100104) addressed the role of LM post-ASCT, one placebo-controlled trial (MM-015) studied LM therapy in the non-transplant setting and the remaining trial (RV-MM-PI209) had a 2 X 2 design comprising of both ASCT and non-transplant randomized arms followed by a second randomization of LM versus no maintenance. There was no heterogeneity for estimate of PFS results (Cochran Q, p=0.68; I2=0%), but considerable heterogeneity for estimate of OS (Cochran Q, p=0.09; I2= 55%), among the studies. There was significant prolongation of both PFS (HR 0.49, 95% CI, 0.41–0.58, p<0.001) and OS (HR 0.77, 95% CI, 0.62–0.95, p=0.013) with LM vs. placebo/no maintenance (Figure 1). Best response during maintenance was reported only in 2 studies and odds of responding (very good partial response or better) were not significantly different with LM (OR 1.28, p=0.3). Grade 3-4 AEs data were available from 3 trials for calculation of pooled OR with LM compared with placebo. We observed a nearly two-fold increase in the risk of SPMs with LM (OR 1.99; 95% CI, 1.31–3.04; p=0.001). Patients on LM were more likely to have grade 3-4 AEs than placebo: neutropenia (OR 4.9, p<0.001), thrombocytopenia (OR 2.7, p<0.001), fatigue (OR 2.3, p=0.01) and venous thromboembolism (OR 3.2, p=0.02). Odds of discontinuing treatment were also significantly higher in patients on lenalidomide (OR 2.9, p<0.001). Conclusions Meta-analysis of RCTs demonstrates significant improvement in PFS and modest improvement in OS with LM. There is an increased risk of grade 3-4 adverse effects, including SPMs with LM. Substantial heterogeneity for estimate of OS among protocols is a limitation of this analysis. Lack of uniform access to lenalidomide upon disease progression in the placebo/no maintenance arms of the constituent studies should be taken into account while interpreting aggregate effect estimates for OS in this meta-analysis. OS: Cochran Q p=0.09, I2=55%, substantial heterogeneity PFS: Cochran Q p=0.68, I2=0%, minimal heterogeneity Disclosures: Off Label Use: Lenalidomide for maintenance therapy in multiple myeloma. Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Novartis: Research Funding; Genzyme: Research Funding. Dispenzieri:Celgene, Millenium, Jansenn, Pfizer: Research Funding. Bergsagel:Onyx: Consultancy. Lacy:Celgene Corporation: Research Funding.

Abstract Abstract 1040 Introduction: Hemophagocytic syndrome (HPS) is a rare disorder characterized by fever, splenomegaly, cytopenias, hypofibrinogenemia, hyperferritinemia and hemophagocytosis in the bone marrow or lymph nodes. It is caused by pathologic activation of the immune system, and manifests clinically with signs and symptoms related to extreme inflammation. Primary HPS or familial hemophagocytic lymphohistiocytosis (HLH) occurs predominantly in children (<18 years) due to inherited defects in natural killer and cytotoxic T-cell function. Secondary HPS generally occurs in adults (>18 years) and is precipitated by autoimmune disorders, malignancy and a variety of infections. The results of HLH-94 trial, the largest prospective study in pediatric patients with HLH, reported an estimated 5-year survival of 54%. There is a paucity of information about HPS in adult patients. Methods: Records of all adult (≥ 18 years) patients with a diagnosis of “hemophagocytosis“ or “hemophagocytic syndrome” presenting from January 1996 through December 2011 at Mayo Clinic were reviewed. Our hematopathology database was also analyzed for patients bearing a diagnosis of HPS. Out of a total of 127 patients identified in the database, 50 adult patients were diagnosed to have HPS as per the diagnostic criteria of the HLH-1994 trial (for patients seen prior to 2004), and HLH-2004 trial (for patients seen after 2004). This study was approved by the Institutional Review Board at Mayo Clinic. Results: Baseline characteristics of all patients are shown in Table 1. The median time to diagnosis from the onset of symptoms was 38 days (4–158 days). Secondary HPS was diagnosed in 46 (92%) patients. The causes of secondary HPS are shown in Table 2. Twenty (40%) patients were treated with etoposide containing regimen, 26 (52%) were treated with therapeutic agents directed specifically to the underlying precipitating disease, and 4 (8%) patients did not receive any treatment. No patient in our study underwent a stem cell transplant (SCT). After a median follow-up of 43 months, 36 (72%) patients have died. The causes of death were infection (47%), malignancy (42%), bleeding (8%) and unknown (3%). The median overall survival (OS) for the entire cohort was 1.5 months (95% CI, 0.7–4.5 months). The median OS for patients with malignancy- related HPS was 0.8 months (95% CI, 0.4–2.4 months) compared to 11 months (95% CI, 0.7-not reached) for patients with non-malignancy related HPS (p-value:0.006; Figure). On univariableanalysis, factors associated with a worse survival were serum albumin <2 g/dL (hazard ratio, 8.3), malignancy-related HPS (hazard ratio, 7.3) and serum creatinine >1.3 mg/dL (hazard ratio, 3.8). Conclusion: In this large series of adult HPS patients treated at a single tertiary care center, most cases are secondary, and are associated with a worse survival compared to historical outcomes reported for children enrolled on the HLH-94 trial. This is likely related to a marked delay in referral to our institution, and high early mortality precluding consideration of SCT. Adult patients with malignancy- related HPS in this study had a markedly inferior outcome compared to patients with non-malignancy related HPS. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Previous studies have demonstrated inferior overall survival (OS) among patients with AL amyloidosis who have bone marrow plasmacytosis (BMPC) >10%. It is well recognized that AL patients who achieve the deepest hematologic responses have superior organ response and OS rate. Methods: We designed a study to determine if BMPC% affects CR rate post ASCT and whether pre-transplant induction therapy improves response rate and OS among patients with a higher baseline BMPC burden. Results: Among 415 AL patients who underwent ASCT at Mayo Clinic, Rochester within 12 months of diagnosis, 116 (28%) had BMPC>10% at diagnosis. The median age was 57.2 years. The median follow up for surviving patients was 67.3 months. There was no statistically significant difference in age, gender, time from diagnosis to transplant, or use of attenuated conditioning regimen between groups with high (>10%) and low (≤ 10%) bone marrow involvement. The high BMPC group tended to receive more induction chemotherapy before ASCT, and presented with greater value of albumin, beta-2 microglobulin and difference in serum free light chain (dFLC). A higher CR rate was observed in low BMPC group (44.6% versus 26.7%, p=0.0013). In patients with high BMPC, a higher CR rate (33.9% versus 17.7%, p<0.05) was seen in those who received pre-ASCT induction therapy compared with no induction therapy. Among 3 groups of patients who had: no pre-ASCT therapy; steroid only as induction; and induction chemotherapy, the 5-year OS rates were 50.5%, 40% & 67.5%, respectively, p<0.03. Conclusions: Lower bone marrow burden at diagnosis yielded a deeper response following ASCT. Compared to no therapy, patients who were treated with steroid only pre-ASCT had an inferior OS, but other induction regimens appeared to improve survival. These data would support the concept that using induction therapy prior to ASCT conditioning among patients with higher tumor burden may be of value. Figure 1. In BMPC > 10% at diagnosis, OS comparison between induction therapies pre-ASCT Figure 1. In BMPC > 10% at diagnosis, OS comparison between induction therapies pre-ASCT Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Kumar: Celgene: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Sanofi: Research Funding; AbbVie: Research Funding; Millenium/Takeda: Research Funding; Onyx: Research Funding; Skyline, Noxxon: Honoraria; Janssen: Research Funding. Gertz:Celgene: Honoraria; millenium: Consultancy, Honoraria; Onyx: Honoraria; Novartis: Honoraria; Smith Kline: Honoraria.

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: While hematologic cancers comprise only 10% of all malignancies, they are divided into >100 distinct World Health Organization subtypes. It is known that higher volume of care is generally associated with better clinical outcomes. However, such a volume-outcome relationship in the medical management of hematologic cancers has not been rigorously explored. The American Society of Clinical Oncology (ASCO) National Census of Oncology Practices shows that the majority of hematologist-oncologists in the United States (US) have a combined hematology-oncology practice (J Oncol Pract 2013). In this study, we estimated the annual number of new and established patients with major hematologic cancers seen on average by a hematologist-oncologist in the US. METHODS: We estimated the number of hematologist-oncologists working in the US using the ASCO workforce information system data from 2011. We utilized statistics from the Surveillance Epidemiology and End Results (SEER) Program to determine the incidence and 37-year limited prevalence of hematologic cancers in 2011. We used 'first malignant tumor per site' statistics as the tumor inclusion method. For potentially curable hematologic cancers (acute lymphocytic leukemia, acute myeloid leukemia, Burkitt lymphoma, diffuse large b-cell lymphoma, Hodgkin lymphoma, and marginal zone lymphoma), we used the estimated 1-5 year survival rates from SEER and excluded patients who survived >5 years, since relapses are rare afterwards. Because prevalence estimates of chronic myelomonocytic leukemia, myelodysplastic syndromes, and certain subtypes of non-Hodgkin lymphoma are unavailable, we were unable to calculate the number of annual established cases. For myeloproliferative neoplasms, we obtained the prevalence estimate from Mehta J, et al (Leuk Lymphoma 2014). We derived the distribution of major non-Hodgkin lymphoma subtypes from the National Cancer Data Base (NCDB) Participant User File. RESULTS: The ASCO workforce information reported a total of 13,084 hematologist-oncologists working in the US in 2011. The Table summarizes the average number of specific hematologic cancer cases seen per hematologist-oncologist in 2011. CONCLUSION: Hematologic cancers are relatively rare but complex. In the US, a hematologist-oncologist on average cares for only 1-2 new patients of any subtype of hematologic cancers annually. The number of established patients is correspondingly low. These numbers are expected to vary by practice setting and disease specialization. As the diagnosis and management of hematologic cancers becomes more sophisticated, future research should explore the potential of a volume to clinical outcome relationship for these providers. Table. Hematologic Cancer Average Annual Number of Cases per Hematologist-Oncologist in the US New Cases Established Cases All Cases Acute lymphocytic leukemia 0.4 1.4 1.8 Acute myeloid leukemia 1 1.5 2.5 Chronic lymphocytic leukemia 1.1 10.7 11.8 Chronic myeloid leukemia 0.4 2.7 3.1 Chronic myelomonocytic leukemia 0.1 - - Hodgkin lymphoma 0.7 2.7 3.4 Multiple myeloma 1.6 6.3 7.9 Myelodysplastic syndromes 1.2 - - Myeloproliferative neoplasms 0.6 22.2 22.8 Non-Hodgkin lymphoma 5.1 - - Anaplastic large cell 0.1 - - Burkitt 0.1 0.3 0.4 Diffuse large B-cell 2 6 8 Follicular 1.1 - - Hairy cell leukemia 0.1 - - Lymphoplasmacytic 0.1 - - Mantle-cell 0.3 - - Marginal zone 0.5 2.1 2.6 Peripheral T-cell, not otherwise specified 0.1 - - Disclosures No relevant conflicts of interest to declare.

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: 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 Background: Oprozomib (OPZ) is an oral epoxyketone proteasome inhibitor that has shown promising antitumor activity in patients (pts) with hematologic malignancies (HM), including WM (Kaufman, EHA 2013, P223; Ghobrial, ASH 2013, 3184). Updated safety and efficacy results from the subset of pts with WM enrolled in this ongoing phase 1b/2 study in pts with HM are presented. Methods: This open-label, multicenter, phase 1b/2 study (NCT01416428) is enrolling adult pts with HM who have relapsed after receiving ≥1 line of therapy. The primary objectives of the phase 1b portion of the study are to determine the maximum tolerated dose (MTD) and the safety and tolerability profile of OPZ. The primary objective of the phase 2 portion of the study is to determine the best overall response rate (ORR; ≥minimal response [MR]). In the phase 1b portion, single-agent OPZ is being administered once daily on days 1, 2, 8, and 9 of a 14-day cycle (2/7 schedule) or on days 1–5 of a 14-day cycle (5/14 schedule). The starting dose was 150 mg/day (mg/d); doses were escalated in 30-mg increments. In the phase 2 study, pts have received 240 mg/d on the 5/14 schedule, which was the initial phase 2 schedule opened to enrollment. For this report, all enrolled patients with HM are included in the description of the MTD while only the subset of patients with WM is included in the safety and efficacy results. Results: As of July 21, 2014, 106 pts with HM (including 36 pts with WM) were enrolled and treated with the OPZ tablet. Enrollment and baseline demographic information for pts with WM are presented in Table 1. For WM patients in the phase 1b portion, median treatment duration was 17.1 weeks (range, 3.1–51.4; 2/7 schedule) and 51.7 weeks (range, 3.9–74.9; 5/14 schedule); preliminary median treatment duration in the ongoing phase 2 portion was 8.1 weeks (range, 0.7–22.0). In all pts with HM, the MTD for the 2/7 schedule was 300 mg/d and 240 mg/d for the 5/14 schedule. None of 3 dose-limiting toxicities (DLTs) on the 2/7 schedule occurred in patients with WM. Two of the 4 DLTs observed on the 5/14 schedule occurred in pts with WM (grade 4 tumor lysis syndrome [240 mg/d, n=1] and grade 3 vomiting [270 mg/d, n=1]). The most common adverse events (AEs) in pts with WM are shown in Table 2. Grade 4 AEs were thrombocytopenia (n=1; phase 1b; 2/7 schedule) and influenza and tumor lysis syndrome (n=1 each; phase 1b; 5/14 schedule). No on-study deaths occurred in pts with WM. In the phase 1b portion, two pts (25%) in the 2/7 schedule and 1 pt (9%) in the 5/14 schedule discontinued treatment due to an AE; 6 pts (35%) discontinued treatment due to an AE in the phase 2 portion. In the phase 1b portion, 3 pts (38%) (2/7 schedule) and 6 pts (55%) (5/14 schedule) had their dosage reduced at least once due to an AE; 10 pts (59%) in the phase 2 portion had their dosage reduced at least once due to an AE. In the phase 1b portion, all 19 pts were eligible for response and were carfilzomib (CFZ)-naïve. The ORR in 8 pts enrolled on the 2/7 schedule was 38% (3 pts had a partial response [PR]). Among 11 pts enrolled on the 5/14 schedule, the ORR was 73% (1 complete response, 1 very good partial response, 5 PRs, and 1 MR); the ORR for BTZ-refractory pts (n=4) was 75%. All 17 pts enrolled on the phase 2 portion were response-eligible. The ORR in the phase 2 portion was 59% (there were 5 PRs and 5 MRs). The ORR among CFZ-naïve pts (n=16) in the phase 2 portion was 56; the ORR among BTZ-refractory pts (n=3) was 67%. Conclusions: The MTD of OPZ was 300 mg/d in the 2/7 schedule and 240 mg/d in the 5/14 schedule; these MTDs were determined from all pts with HM. In pts with WM who received single-agent OPZ, the most common grade 3 AEs were neutropenia and diarrhea; grade 4 AEs were infrequent. Additional measures will be taken to improve gastrointestinal tolerability. Single-agent OPZ continues to have promising antitumor activity in pts with WM. Enrollment of patients on the 2/7 schedule is continuing; the target enrollment for the phase 2 portion of the study is 66 patients. Extended-release OPZ tablets will be introduced and assessed for safety, activity, and pharmacokinetics. Updated results will be presented at the meeting. Disclosures Siegel: Celgene: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Off Label Use: Monoclonal antibody/toxin fusion protein. For treatment of multiple myeloma. Kaufman:Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; Merck: Research Funding. Raje:Celgene: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Onyx: Consultancy; Acetylon: Research Funding; Ely Lilly: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding. Kapoor:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Treon:Onyx: Consultancy, Research Funding. Neuman:Onyx: Employment. Lee:Onyx Pharmaceuticals, an Amgen subsidiary: Employment. Ghobrial:BMS: Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Millennium: Advisory Board, Advisory Board Other; Onyx: Advisory Board, Advisory Board Other.

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 1802 Poster Board I-828 Background Heterogeneity in multiple myeloma (MM) leads to disparate outcomes with a wide variation in overall survival (OS). Based upon the evidence predominantly gathered from newly diagnosed patients treated with standard chemotherapy and/or transplantation, the current Mayo (mSMART) prognostic model uses a combination of metaphase cytogenetics, fluorescence in-situ hybridization (FISH) and plasma cell labeling index (PCLI) for risk-stratification at diagnosis of MM. The objective of our study was to evaluate the significance of this stratification model in the era of novel therapies, and to assess the independent prognostic value of each of the components in the model. Methods Data were abstracted from a cohort of 1556 consecutive patients with MM who presented to our institution between January 1999 and March 2009 within ninety days of diagnosis of MM A total of three hundred and eighty six patients had been evaluated with conventional cytogenetics near diagnosis in addition to interphase FISH. Out of this cohort, three hundred and sixty six patients had availability of all the three tests, including the slide-based PCLI. High-risk MM was defined as presence of any one or more of the following: cytogenetics: hypodiploidy, monosomy of chromosome 13 or deletion 13q ; FISH: deletion of p53 (locus 17p13) or immunoglobulin heavy chain (IgH) translocations, t(4;14) (p16.3;q32) or t(14;16)(q32;q23); PCLI ≥3%. Survival estimates were created using the Kaplan-Meier method and compared by log-rank tests. The impact of each of the three tests was assessed by a multivariate (MV) analysis using Cox proportional hazards model. Results The median OS of the cohort of 366 patients was 65 months from presentation. One hundred and twelve (31%) patients were deemed high risk by any one or more of the three tests: Metaphase cytogenetics, FISH or PCLI (current mSMART definition of high-risk MM). The median OS of high risk patients was 52 months versus 71 months for standard-risk (P=0.007). We then studied the prognostic value of the three tests separately. Patients classified as high risk by FISH had a median OS of 35 months versus 65 months for the standard risk, HR= 2.3, P<0.001. Similarly, cytogenetics alone was also able to classify patients into high and standard risk with a comparable HR of 2.1 (P=0.008, median survival 37 vs. 64 months). In contrast, PCLI did not have a significant prognostic value (HR =1.41, P=0.32). This was confirmed on multivariate analysis in a model that included all 3 tests. FISH (HR=2.36, P=0.001) and cytogenetics (HR=1.99; P=0.017) emerged as independent determinants of prognosis in the multivariable analysis, while PCLI (HR=1.03, P=0.93) did not provide additional prognostic value. We then examined whether the prognostic value of FISH contributed additionally in patients classified into high and standard risk by conventional cytogenetics, and vice versa. Those classified as high risk by cytogenetics (n=44, 11 %), were further categorized into 2 groups by additional prognostic information obtained by FISH (median survival 18 vs. 52 months; P=0.005). Similarly, those classified as standard risk by cytogenetics (n=342, 89 %), were further categorized into 2 groups (median survival 52 vs. 71 months; P=0.017) by additional FISH-based stratification. Similarly, high-risk patients defined by FISH (n=65, 17 %) were further classified into 2 groups with significant difference in median OS (18 vs. 52 months, P=0.004), based on the presence or absence of high-risk features on cytogenetics. In contrast, no additional prognostic information was gained by cytogenetics in patients who were stratified as standard risk by FISH alone (n=321, 83%). Conclusion Our study validates high risk features defined by FISH and conventional cytogenetics in the mSMART risk stratification model among patients treated after the introduction of novel therapies. Either test identifies a high risk cohort with a hazard ratio of approximately 2 (median survival ∼37 versus ∼65 months). In patients known to have high risk disease by one of the two tests, knowledge of the other appears to add additional prognostic value. Disclosures Fonseca: Amgen, BMS, Celgene, Otsuka, Genzyme and Medtronic: Consultancy. Gertz:celgene, millennium: Honoraria. Dispenzieri:celgene: Research Funding. Kumar:celgene, genzyme, millennium, novartis, bayer: Research Funding; genzyme: Membership on an entity's Board of Directors or advisory committees.