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Abstract Background: Peripheral blood biomarkers of tumor microenvironment and immune surveillance such as absolute lymphocyte (ALC) and monocyte (AMC) counts are independent prognostic factors in several hematologic malignancies including multiple myeloma. The timing and prognostic impact of immune reconstitution has been studied after autologous hematopoietic stem cell transplantation, less is known about its significance in newly diagnosed multiple myeloma prior to transplantation. Methods: We studied 771 patients with newly diagnosed multiple myeloma who were treated with novel agents at Mayo Clinic between 01/2004 and 12/2015. Peripheral blood absolute lymphocyte and monocyte counts were measured at the time of treatment initiation and one month thereafter in all patients (including data obtained between 14 and 42 days after treatment initiation). The outcome of interest was overall survival. The peripheral blood parameters of interest were abnormal ALC (reference range 800-2400/µL) and AMC (reference range 500-1500/µL) at baseline and at one month. Immune dysregulation was defined as both abnormal ALC and AMC. Immune reconstitution was defined as recovery of both normal ALC and AMC. The Wilcoxon signed-rank test was used to compare the peripheral blood parameters before and after the first month of treatment. Multivariable-adjusted proportional hazards regression models were used to assess the associations between changes in peripheral blood parameters and overall survival. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis was 65 years (27 - 90) and 459 patients were male (60%). The three most common first-line regimens were lenalidomide + dexamethasone, bortezomib + cyclophosphamide + dexamethasone, and bortezomib + lenalidomide + dexamethasone. Two hundred and eighty patients (36%) went on to undergo autologous hematopoietic stem cell transplantation as part of their first-line therapy. The median ALC decreased from 1100/µL (range 60 - 5590) at baseline to 850/µL (range 60 - 5590) at one month (p < 0.001). The median AMC increased from 330/µL (range 0 - 1840) at baseline to 420/µL (range 0 - 1840) at one month (p < 0.001). The median time between re-assessment of ALC and AMC was 25 days (range 15 - 42). Two hundred and thirty-four patients (31%) had evidence of immune dysregulation at baseline (both abnormal ALC and AMC). Eighty-seven of these 234 patients (37%) recovered normal ALC and AMC at one month (early immune reconstitution). One hundred and thirty-seven of the 537 patients with normal ALC and AMC at baseline (26%) developed new immune dysregulation at one month. The absence of immune dysregulation at baseline (compared to the presence thereof) was associated with better overall survival (HR 0.77, 95% CI 0.61 - 0.97, p = 0.025, n = 771). The absence of immune dysregulation at one month (compared to the persistence or development thereof) was associated with better overall survival (HR 0.63, 95% CI 0.50 - 0.80, p < 0.001, n = 771). Early immune reconstitution (compared to the persistence or development of immune dysregulation) was associated with better overall survival (HR 0.62, 95% CI 0.43 - 0.92, p = 0.016, n = 771). Both associations remained statistically significant after adjusting for age at diagnosis, sex, International Staging System stage, and eligibility for transplantation: HR 0.70 (95% CI 0.54 - 0.90, p = 0.006, n = 612) and HR 0.59 (95% CI 0.39 - 0.90, p = 0.014, n = 612), respectively. Conclusions: Peripheral blood biomarkers of immune dysregulation vary over time and have prognostic significance both at baseline and during follow-up. The presence or development of immune dysregulation in newly diagnosed multiple myeloma is an independent risk factor. The favorable impact of early immune reconstitution suggests that immune dysregulation is a potentially modifiable risk factor that may be exploited for therapeutic benefit. Figure. Figure. Disclosures Lacy: Celgene: Research Funding. Gertz:celgene: Consultancy; Medscape: Consultancy; janssen: Consultancy; Prothena: Honoraria; Apellis: Consultancy; Ionis: Honoraria; annexon: Consultancy; spectrum: Consultancy, Honoraria; Amgen: Consultancy; Physicians Education Resource: Consultancy; Abbvie: Consultancy; Research to Practice: Consultancy; Teva: Consultancy; Alnylam: Honoraria. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Russell:Vyriad: Equity Ownership. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Introduction: Thrombocytopenia is a major dose-limiting hematologic toxicity of anti-myeloma therapy. Clinical trial data in the relapsed/refractory setting have linked the development of thrombocytopenia during therapy with bortezomib with improved response to treatment. Less is known about the prognostic significance of early treatment related thrombocytopenia during initial therapy for newly diagnosed multiple myeloma (MM) using novel agents. Aims: The aim of this study was to characterize the effect of new, treatment related thrombocytopenia during initial therapy for newly diagnosed MM with novel agents on survival and clinical response. Methods: We identified 690 patients with newly diagnosed MM treated at Mayo Clinic, Rochester from January 2004 to December 2015 through a retrospective record review. All patients received novel agents including proteasome inhibitors (PI) and/or immunomodulatory drugs, were evaluable using the International Myeloma Working Group uniform response criteria, and had platelet counts greater than 150,000/µL prior to initial treatment. Survival outcomes and response were compared in patients who became thrombocytopenic within two cycles of first line treatment, defined as a nadir platelet count less than 150,000/µL, and in patients who did not develop thrombocytopenia. Survival estimates were calculated using the Kaplan-Meier method, and the log-rank test was used to compare survival in subgroups. Multivariable-adjusted proportional hazards regression models were fit to adjust for known prognostic factors including age, sex, International Staging System (ISS) stage, and the presence of cytogenetic high-risk abnormalities. Logistic regression was performed to evaluate for differences in response between groups. P-values less than 0.05 were considered statistically significant. Results: Of the 690 patients treated with novel agents, 495 patients (72%) received a PI as initial therapy. Median follow up was 3 years (0.1-13.2), median overall survival (OS) was 6.6 years (95% CI 5.9-8.0), and median progression free survival (PFS) was 4.84 years (95% CI 3.53-8.98). 123 patients (18%) developed thrombocytopenia within two cycles of first line therapy; two patients developed platelet counts less than 20,000/µL and none developed counts less than 10,000/µL. Differences in survival estimates for OS and PFS for patients who did not develop thrombocytopenia and those who became thrombocytopenic are illustrated in Figure 1. Median OS in patients who did not develop thrombocytopenia was 7.4 years (95% CI 5.9-8.9), compared to 4.6 years (95% CI 4.1-6.0) in those who became thrombocytopenic (p = 0.003), while median PFS was 5.4 years (95% CI 3.63-NR) and 3.53 years (95% CI 0.49-NR), respectively (p = 0.008). Similar results for both OS and PFS were observed when using a platelet nadir of less than 100,000/µL. These relationships remained statistically significant when adjusting for the effect of known prognostic factors including age, sex, ISS stage, and high-risk cytogenetics, for both OS and PFS (HR = 1.70, 95% CI 1.12-1.59, p = 0.013, n = 387 and HR = 1.56, 95% CI 1.03-2.37, p = 0.036, n = 387, respectively). Multivariable-adjusted estimates were similar for the subset of patients receiving PI containing regimens. Development of thrombocytopenia within two cycles was not associated with very good partial response or better (VGPR+) (p = 0.588) or with complete response (CR) (p = 0.968). This was also true for the subset of patients receiving PIs (p = 0.827 and p = 0.772, respectively). Conclusions: Our results suggest that the development of new, treatment related thrombocytopenia within two cycles of first-line therapy with novel agents is independently associated with inferior survival in newly diagnosed MM. This was also true in the subset of patients receiving PI containing regimens. In contrast to prior studies, there was no association between early treatment-related thrombocytopenia and response to treatment for either novel agents in general or PI based therapies. Figure 1: Kaplan-Meier progression free and overall survival estimates stratified by platelet count ≥ 150,000/µL (no thrombocytopenia) and <150,000/µL (new thrombocytopenia) within two cycles of initial therapy with novel agents. Figure 1. Figure 1. Disclosures Lacy: Celgene: Research Funding. Gertz:Prothena: Honoraria; Teva: Consultancy; Ionis: Honoraria; Alnylam: Honoraria; Research to Practice: Consultancy; Apellis: Consultancy; Physicians Education Resource: Consultancy; janssen: Consultancy; spectrum: Consultancy, Honoraria; Amgen: Consultancy; Abbvie: Consultancy; Medscape: Consultancy; annexon: Consultancy; celgene: Consultancy. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Background: The introduction of novel therapeutics has led to improved outcomes in patients with multiple myeloma (MM). MM and its precursor lesion smoldering multiple myeloma (SMM) have traditionally been associated with increased mortality despite treatment. We aimed to assess the impact of a diagnosis of SMM and MM compared to the general population in the context of established prognostic factors. Methods: We studied the overall survival of 1697 patients with smoldering multiple myeloma (SMM, n = 582) and multiple myeloma (MM, n = 1115) diagnosed at Mayo Clinic between 01/2005 and 12/2015. Expected survival accounting for age and sex was calculated using the United States general population (US) as the reference group. Observed and expected overall survival was expressed as the standardized mortality ratio (SMR) of observed to expected deaths. Kaplan-Meier overall survival estimates were calculated and the log-rank test was used to compare overall survival in subgroups. The subgroups of interest were based on the International Staging System (ISS) and the presence of fluorescence in situ hybridization (FISH) high-risk cytogenetics: t(4;14), t(14;16), t(14;20), and del(17p). Proportional hazards regression models were used to assess the associations between the aforementioned prognostic factors and overall survival. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis in patients with SMM and MM was 65 (32 - 92) and 63 years (24 - 90), respectively. Two hundred forty-nine patients (57%) and 663 (60%) were male. The median follow-up in patients with SMM and MM was 4.7 (0.1 - 11.0) and 2.6 years (0.2 - 9.5). The median overall survival for patients with SMM and MM was 9.0 (95% CI 8.4 - 9.7) and 7.9 years (6.4 - 8.7). With age- and sex-matched population controls as the reference, the SMRs in patients with SMM and MM were 2.6 (95% CI 2.2 - 3.0) and 4.6 (4.1 - 5.2). Among those MM patients with available data on ISS staging and FISH cytogenetics, 30% (236/780) had ISS III and 21% (188/878) had high-risk cytogenetics. Patients with MM (compared to SMM) experienced worse overall survival (HR 1.5, 95% CI 1.2 - 1.8, p < 0.001, n = 1697). Patients with ISS I/II MM (compared to SMM) experienced similar survival (HR 1.0, 95% CI 0.8 - 1.3, p = 0.698, n = 1131). Patients with ISS III MM (compared to MM with high-risk cytogenetics) experienced similar survival (HR 1.3, 95% CI 0.9 - 2.0, p = 0.128, n = 329). Conclusions: Patients with SMM and MM in this cohort experienced excess mortality compared to the general population. In the absence of universal screening the true morbidity and mortality of patients with SMM and MM remains unknown and is likely overestimated in hospital-based cohorts. Overall survival in patients diagnosed with SMM and patients with ISS I/II MM receiving contemporary anti-myeloma therapy was clinically indistinguishable. Patients treated for ISS III MM experienced overall survival similar to patients with cytogenetic high-risk disease. MM remains associated with excess mortality, the magnitude of which varies considerably based on the presence of additional tumor and host factors. The outcomes with modern therapy among the ISS I/II patients highlight the potential for improving outcomes of SMM by early intervention, especially for the higher risk patients. Figure. Figure. Disclosures Lacy: Celgene: Research Funding. Gertz:Medscape: Consultancy; Alnylam: Honoraria; janssen: Consultancy; spectrum: Consultancy, Honoraria; Ionis: Honoraria; annexon: Consultancy; celgene: Consultancy; Teva: Consultancy; Prothena: Honoraria; Apellis: Consultancy; Abbvie: Consultancy; Physicians Education Resource: Consultancy; Amgen: Consultancy; Research to Practice: Consultancy. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Russell:Vyriad: Equity Ownership. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Background: The introduction of several novel agents has led to an improvement in response rates and survival outcomes in patients with newly diagnosed multiple myeloma. Despite significant therapeutic advances a subset of patients with multiple myeloma do not achieve a deep response to first-line treatment and biomarkers are needed to identify those at risk. Methods: We studied 472 patients with newly diagnosed multiple myeloma who were treated in clinical practice (n = 280, training cohort) or on prospective clinical trials (n = 192, validation cohort) at Mayo Clinic between 12/2003 and 12/2015. All patients had measurable disease (M-spike ≥ 1.0 g/dL) and received treatment with novel agents. Serum M-spike and free light chains (FLC) were measured before and after the first treatment cycle. The outcome of interest was the best response to first-line treatment (evaluated using the International Myeloma Working Group Uniform Response Criteria). Failure to achieve a deep response was defined as not achieving a very good partial response or better. The serum parameters of interest were the relative decrease in M-spike and absolute free light chain difference (ΔFLC). The Wilcoxon signed-rank test was used to compare the serum parameters before and after the first treatment cycle. Logistic regression models were used to assess the associations between the change in serum parameters after the first treatment cycle and best response to first-line treatment. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis in the training and the validation cohort were 67 (32 - 94) and 66 years (41 - 86), respectively. One hundred eighty one (65%) and 103 patients (54%) were male, respectively. The three most common regimens in the training cohort were lenalidomide + dexamethasone, lenalidomide + cyclophosphamide + dexamethasone, and bortezomib + lenalidomide + dexamethasone. In the validation cohort, the three most common regimens were carfilzomib + thalidomide + cyclophosphamide, lenalidomide + cyclophosphamide + dexamethasone, and ixazomib + cyclophosphamide + dexamethasone. In the two cohorts, the median baseline M-spike decreased from 3.1 g/dL (1.0 - 10.0) to 1.7 g/dL (0.0 - 6.6) and 3.2 g/dL (1.0 - 8.5) to 1.4 g/dL (0.0 - 4.5) after the first treatment cycle, respectively (p < 0.001 for both comparisons). The median baseline ΔFLC decreased from 31.1 mg/dL (0.0 - 2269.7) to 5.4 mg/dL (0.0 - 785.8) and from 23.3 mg/dL (0.1 - 3579.6) to 4.3 mg/dL (0.0 - 1139.3) after the first treatment cycle, respectively (p < 0.001 for both comparisons). M-spike reduction < 50% during the first treatment cycle was associated with failure to achieve a deep response: OR 4.54 (95% CI 2.72 - 7.58, p < 0.001) in the training cohort and OR 6.68 (95% CI 3.42 - 13.03, p < 0.001) in the validation cohort. Patients with reduction in M-spike < 10% during the first treatment cycle experienced failure to achieve a deep response in 86% (25/29) and 100% (10/10), respectively. ΔFLC reduction < 50% during the first treatment cycle was associated with treatment failure to achieve a deep response: OR 4.83 (95% CI 2.83 - 8.25, p < 0.001) in the training cohort and OR 5.09 (95% CI 2.37 - 10.92, p < 0.001) in the validation cohort. Patients with reduction in ΔFLC < 10% during the first treatment cycle experienced failure to achieve a deep response in 83% (34/41) and 91% (19/21), respectively. Conclusions: Early changes in M-spike and ΔFLC are strong predictors of response to treatment. We established and prospectively validated two readily available biomarkers that can identify patients at risk for treatment failure and may inform treatment decisions in newly diagnosed multiple myeloma. Disclosures Lacy: Celgene: Research Funding. Gertz:Physicians Education Resource: Consultancy; janssen: Consultancy; Teva: Consultancy; Alnylam: Honoraria; Research to Practice: Consultancy; Apellis: Consultancy; Medscape: Consultancy; annexon: Consultancy; Abbvie: Consultancy; celgene: Consultancy; Prothena: Honoraria; Ionis: Honoraria; Amgen: Consultancy; spectrum: Consultancy, Honoraria. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Russell:Vyriad: Equity Ownership. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Background: Cytogenetic evaluation, especially using fluorescence in situ hybridization (FISH), at the time of diagnosis is essential for initial risk stratification and the employment of risk-adapted treatment strategies in multiple myeloma. Little is known about the occurrence and prognostic significance of cytogenetic evolution during follow up. Methods: We studied 433 patients who were diagnosed with multiple myeloma between January 2000 and December 2011 and had at least two FISH evaluations at Mayo Clinic Rochester, including the diagnostic specimen. Bone marrow aspirates were evaluated for deletions, monosomies, trisomies, and tetrasomies using chromosome- or centromere-specific FISH probes. IGH rearrangements were evaluated using an IGH break-apart probe and up to five potential partners (FGFR3, CCND1, CCND3, MAF, and MAFB). Cytogenetic evolution was defined as a new deletion, monosomy, trisomy, tetrasomy, or translocation during follow up. Multivariable-adjusted logistic regression models were used to assess the associations between the parameters of interest and the presence of cytogenetic evolution in follow-up specimens. Multivariable-adjusted Cox proportional hazards models were used to assess the effect of cytogenetic evolution on overall survival. All models were adjusted for sex, age, the presence of high-risk FISH abnormalities, and the number of abnormalities at the time of diagnosis. Likelihood ratio tests were used to assess the goodness of fit of nested models. The χ2 or Fisher's exact test was used to assess the distribution of cytogenetic abnormalities in subgroups. Results: The median age at diagnosis was 60 years (32 - 82), 264 (61%) of the patients were male. The median overall survival for the entire cohort was 7.0 years (6.2 - 7.8). At the time of diagnosis, 150 (35%) and 57 (13%) of the 433 patients presented with a hyperdiploid karyotype and cytogenetic high-risk abnormalities, respectively. Independent of each other, the presence of a translocation at the time of diagnosis was associated with decreased odds of cytogenetic evolution during follow up (OR 0.39, 95% CI 0.24 - 0.63, p < 0.001) while the presence of at least one trisomy or tetrasomy at the time of diagnosis was associated with increased odds (OR 2.53, 95% CI 1.37 - 4.70, p = 0.003). A greater proportion of patients presenting with a hyperdiploid karyotype experienced cytogenetic evolution during follow up. Those patients more frequently evolved additional trisomies and tetrasomies, while translocations were more common in those presenting with a non-hyperdiploid karyotype (Table 1). The development of additional abnormalities during the three years following diagnosis (compared to no new abnormalities) was associated with increased subsequent mortality in those who survived at least three years (HR 3.22, 95% CI 1.82 - 5.68, p < 0.001). Including the time between first and last cytogenetic evaluation as a covariate did not significantly change the parameter estimates or improve model fit (p = 0.727). Conclusions: Demographics, risk profile, and overall survival of this cohort reflect the fact that patients had to survive long enough to undergo repeated cytogenetic evaluation. Hyperdiploid and non-hyperdiploid genotypes were associated with distinct behavior regarding cytogenetic evolution during follow up. The identification of cytogenetic evolution was an adverse prognostic factor in those who survived at least three years after diagnosis. These findings emphasize the importance of the dynamics of the underlying clonal disease process for accurate risk assessment and suggest that selected subgroups of patients may benefit from risk stratification during follow up. Table 1. Cytogenetic evolution during follow up in 433 patients with multiple myeloma stratified by karyotype at the time of diagnosis Hyperdiploid (n = 150) Non-hyperdiploid (n = 283) p New abnormality 76 (51%) 108 (38%) 0.012 New monosomy 8 (5%) 24 (8%) 0.243 New trisomy 48 (32%) 55 (19%) 0.004 New tetrasomy 37 (25%) 27 (10%) < 0.001 New deletion 17 (11%) 27 (10%) 0.557 New translocation 1 (1%) 11 (4%) 0.065 Most common new abnormality [type (percent of type in each group)] Monosomy mono(13) (75%) mono(13) (62%) Trisomy tri(11) (22%) tri(3) (22%) Tetrasomy tetra(15) (48%) tetra(15) (30%) Deletion del(17p) (79%) del(17p) (63%) Translocation t(11;14) (100%) t(11;14) (36%) Data are given as count (percent) unless denoted otherwise. Disclosures Binder: American Society of Hematology: Research Funding. Kumar:AbbVie: Research Funding; Onyx: Research Funding; Sanofi: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria; Millenium/Takeda: Research Funding; Janssen: Research Funding; Celgene: Research Funding.

Abstract Introduction: Hypocellular myelodysplastic syndrome (h-MDS) represents only a small portion of MDS, of which, the clinical significance and outcomes are not well understood. Both laboratory and clinical evidence suggests that h-MDS shares immune-mediated pathogenic mechanisms similar to acquired aplastic anemia. As a result, immunosuppressive therapy (IST) has been the mainstay treatment. Since h-MDS is poorly understood and reported response rates to IST vary, we retrospectively reviewed the outcome of our patients with hypocellular MDS and identified the effectiveness of alternative therapy using hypomethylating agents (HMA). Methods: AllMDS patients over a 13-year period (June 1997 to May 2010) were captured after an IRB approval was obtained. Patients' demographics, labs, bone marrow aspirates and biopsies as well as cytogenetic data were collected. We used the currently accepted age-adjusted criteria to define hypocellularity as ≤ 30% in patients <70 years old, and ≤20% in >70 years old. Only patients with available response data were included in the final analysis. Survival estimates were calculated using Kaplan-Meier curves. Results: We identified 65 (8%) h-MDS patients from a cohort of 827 adult MDS. Median age was 68 years (range, 20-90), with 69% males. The largest group of patients were RAEB-1 at 9 (14%) and RAEB-2 at 14 (22%) along with RCMD at 18 (28%) and 15 (23%) MDS-U, 2 (3%) MDS 5q, 4 (6%) RARS and 2 (3%) were considered atypical. Cytogenetic analysis was normal in 17 (26%) with 7 (11%) having trisomy 8, and 11 (16%) and 14 (22%) having abnormalities of chromosome 7 and 5, respectively. IPSS-R were very low, low, intermediate, high, and very high in 4%, 30%, 28%, 21% and 17%, respectively. Leukemic transformation (LT) occurred in 6 (9%). The 4 year overall survival and progression free survival was 35% and 34%, respectively. Median overall survival and progression free survival was 30.2 and 29.7 months, respectively. Nine out 65 h-MDS patients were treated with a HMA, azacitidine (4) or decitabine (5). The median age of patients was 71 years (range, 66-85) with 6 (66%) being males. The median cellularity of the diagnostic bone marrow was 15% with the majority of patients presenting with RAEB-1 (11%) and RAEB-2 (55%) classification and 2 (22%) cases of RCMD as well as 1 (11%) case of MDS with isolated 5q. Cytogenetic analysis was normal in 3 (33%). IPSS-R were low in 1 (11%), intermediate in 4 (44%), high in 1 (11%) and very high risk in 3 (33%). The median time to initiation of a HMA from diagnosis was 5 months with response assessed at a median of 4.2 months. Two patients had received prior therapy including lenalidomide (for MDS 5q) and one had 1 cycle of trial therapy. Two patients (22%) achieved a marrow complete remission at a median time of 2.95 months; with one case of relapse at 9.8 months using HMA. Three patients (33%) had LT at a median time of 7.9 months post initiation of HMA. Median overall survival of patients with LT was 20 days. A total of 4 (44%) patients remain alive with a leukemia free survival of 67% at 2 years. In comparing to h-MDS patients without HMA treatment versus HMA treated, median OS was 28.2 vs 50.9 months (p=0.41) and PFS was 28.1 vs 40.6 months (p=0.69), respectively. Conclusions: The results from our clinical experience confirm that hypocellular MDS is a rare variant and that it is distinct from normocellular/hypercellular MDS. Two thirds of h-MDS received HMA for the treatment of higher risk disease (RAEB1-2). HMA has some efficacy in h-MDS. Further studies are warranted to better understand the clinical significance and outcomes of hypocellular MDS. Disclosures Binder: American Society of Hematology: Research Funding. Al-Kali:Celgene: Research Funding.

Abstract Background: Cytogenetic evaluation using fluorescence in situ hybridization (FISH) at the time of diagnosis is essential for initial risk stratification in multiple myeloma. Despite the absence of cytogenetic high-risk abnormalities a subset of patients does experience poor overall survival comparable high-risk disease (i.e. median overall survival less than three years after diagnosis). We aimed to identify demographic, clinical, and cytogenetic characteristics predicting poor three-year overall survival in patients with standard-risk cytogenetics. Methods: We studied 428 patients who were diagnosed with multiple myeloma between July 2004 and July 2014 at Mayo Clinic Rochester, underwent FISH evaluation within six months of diagnosis, and received treatment with novel agents (immunomodulator, proteasome-inhibitor, or a combination thereof). Patients with high- and intermediate-risk cytogenetics as well as patients lost to follow-up within three years were excluded. High-risk cytogenetics were defined as del(17p), t(14;16), and t(14;20). Intermediate-risk cytogenetics were defined as t(4;14) and gain(1q). Bone marrow aspirates were evaluated for deletions, monosomies, trisomies, and tetrasomies using chromosome- or centromere-specific FISH probes. IGH rearrangements were evaluated using an IGH break-apart probe and evaluating up to five potential partners (FGFR3, CCND1, CCND3, MAF, and MAFB). A multivariable-adjusted logistic regression model was used to assess the associations between the parameters of interest and three-year overall survival. Discrimination and calibration of the model were evaluated using the c-statistic and the Hosmer-Lemeshow test, respectively. The odds ratios of the identified predictors were rounded up to the next integer and assigned as points in a scoring system. Receiver operating characteristic analysis was used to determine the optimal cut-point and associated test performance characteristics. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis was 65 years (31 - 95), 259 (61%) of the patients were male. The median overall survival was 7.4 years (6.1 - 8.6) for the entire cohort (n = 428), 10.5 years (8.3 - NR) for those who survived at least three years (n = 327, 76%), and 1.6 years (1.2 - 1.7) for those who did not survive three years after diagnosis (n = 101, 24%). The factors associated with poor three-year overall survival and the derived scoring system are summarized in Table 1. Conclusions: Patients with multiple myeloma and standard-risk cytogenetics are a heterogeneous group. One fourth of the patients are experiencing less than three years of overall survival after diagnosis. Stage, age, extent of bone marrow involvement, karyotype, and platelet count at the time of diagnosis were helpful in identifying patients at risk for poor three-year overall survival. These findings emphasize the importance of further risk stratification in this patient population and warrant external validation. Disclosures Dispenzieri: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen: Research Funding; pfizer: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Alnylam: Research Funding. Kapoor:Takeda: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Kumar:AbbVie: Research Funding; BMS: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon: Consultancy, Honoraria; Janssen: Research Funding; Skyline: Consultancy, Honoraria.

AbstractHypomethylating agents (HMA) are currently the only FDA approved therapy for patients with chronic myelomonocytic leukemia (CMML). In the current retrospective study, we assessed response rates as adjudicated by the IWG (International Working Group) MDS (myelodysplastic syndrome) and MDS/MPN myeloproliferative neoplasm overlap syndrome response criteria, in 121 CMML patients treated with Azacitidine (AZA, n = 56) and Decitabine (DAC, n = 65). The overall response rates were 41% by the IWG MDS (AZA‐ 45%, DAC‐39%), and 56% by the IWG MDS/MPN (AZA‐56%, DAC‐58%) response criteria, with CR (complete remission) rates of <20% for both agents, by both criteria. There were no significant differences in response rates between proliferative and dysplastic CMML. Moreover, 29% of CMML patients in a CR with HMA progressed to AML (blast transformation), underscoring the limited impact of these agents on disease biology. Progression after HMA response was associated with a median overall‐survival (OS) of 8 months, while median OS in patients with primary HMA failure was 4 months. Lower serum LDH levels (<250 Units/L) were associated with HMA responses by both criteria; while ASXL1 and TET2 mutational status had no impact. HMA treated patients had a longer median OS (31 vs 18 months; P = .01), in comparison to those treated with conventional care regimens (excluding observation only patients), without any differences between AZA vs DAC (P = .37). In conclusion, this study highlights the inadequacies of HMA therapy in CMML, retrospectively validates the IWG MDS/MPN response criteria and underscores the need for newer, rationally derived therapies.