Dispenzieri, Angela

Abstract Introduction: Immunoglobulin light chain (AL) amyloidosis is associated with significant morbidity and mortality. Several models were developed to allow survival prediction, but head-to-head model comparison is lacking. Patients and Methods: Five prognostic models were compared: Mayo 2004; Mayo 2012; 2013 European modification of Mayo 2004 (where Mayo 2004 stage 3 is subdivided into 3 subgroups based on NT-proBNP at 8500 ng/L and systolic blood pressure at 100 mmHg); 2015 European modification of Mayo 2004 (where Mayo 2004 stage 3 is subdivided into 2 subgroups based on NT-proBNP at 8500 ng/L); and organ model (a model based on number of involved organs). All patients with available baseline data for the 5 models were included in this study (n=1005). Improvements in predictive accuracy of the various models were determined by calculating a net improvement in survival prediction for each pair of prognostic models. Net improvement was considered as the proportion where model A outperforms model B minus the proportion where model B outperforms model A. Results: For all models, there was increasing risk for death with increasing stage. The organ model was the least powerful system with a hazard ratio of 2.8 for ≥4 organs compared to 1 involved organ. The organ model was consistently outperformed by the other 4 systems. In the cohort as a whole, the biomarker models (Mayo 2004; Mayo 2012; European 2013; European 2015) were comparable in ability to predict survival (Figure). However, a slightly superior performance of the European 2013 modification of the Mayo 2004 system was seen over the Mayo 2004 system in the group as a whole (net improvement 4.1%, P=0.023) and when restricted to non-ASCT population (net improvement 6.3% P=0.014). The European 2015 modification performed slightly better than the Mayo 2004 system in the ASCT population (net improvement 3.4%, P=0.025). 1-year mortality was better predicted by the European models (net improvement 11-14%, P<0.05), while the Mayo 2012 had better survival prediction to all other biomarker models in 3-year landmark comparison (net improvement 7-9%, P<0.05). Conclusion: Using biomarker based staging is a clear improvement over the organ staging system. The different biomarker staging systems' abilities to predict for survival were relatively comparable, solidifying the importance of soluble cardiac biomarkers and free light chain measurement as prognosticators in AL amyloidosis. Mayo 2004-based models better predict for early death while Mayo 2012 model has a better prediction for long-term survival. Figure. Figure. Disclosures Gertz: Ionis: Honoraria; celgene: Consultancy; spectrum: Consultancy, Honoraria; janssen: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Medscape: Consultancy; annexon: Consultancy; Teva: Consultancy; Research to Practice: Consultancy; Apellis: Consultancy; Alnylam: Honoraria; Prothena: Honoraria; Physicians Education Resource: Consultancy. Lacy:Celgene: Research Funding. Dingli:Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Russell:Vyriad: Equity Ownership. Kumar: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; AbbVie: 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. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.

Abstract Introduction: Light chain burden in light chain (AL) amyloidosis is often low, making accurate response assessment challenging. Methods: AL amyloidosis patients achieving very good partial or complete response to first line therapy and had serial sFLC studies during and after completion of therapy were included (n=396). Involved free light chain (iFLC), difference in involved-to-uninvolved free light chains (dFLC) and sFLC ratio (sFLCR) were assessed at the end of first line therapy and at nadir iFLC. Survival analysis was done using the Kaplan-Meier method. Hematological progression-free survival (hemPFS) was defined as the time from diagnosis until hematological progression or death, where patients known to be alive and progression-free at the end of follow-up were censored. Hematological progression was defined according to consensus criteria or upon initiation of second line therapy, whichever came first. Results: The median iFLC and dFLC at the end of therapy was 1.7 mg/dL and 0.5 mg/dL, respectively. sFLCR normalization occurred in 70% of patients. iFLC ≤2 mg/dL and dFLC ≤0.5 mg/dL were associated with a longer hemPFS compared to their counterparts (Figure). Only iFLC ≤2 mg/dL was associated with a significantly longer overall survival (Figure). sFLCR normalization did not predict hemPFS or overall survival. Organ response was predicted by iFLC ≤2 mg/dL and dFLC ≤0.5 mg/dL (Table), with best discrimination seen with iFLC ≤2 mg/dL. Organ response was not predicted by sFLC normalization (Table). The median nadir iFLC was 1.4 mg/dL and was reached 3.9 months from the end of therapy, longer in transplanted patients compared to patients treated with non-transplant regimens (7.3 vs 1.8 months, respectively; P<0.001). iFLC ≤2 mg/dL at the completion of therapy and nadir iFLC reached >12 months from the end of therapy were favorable predictors of hemPFS/OS in a multivariate analysis. Conclusion: iFLC at the end of first line therapy better predicts for organ response and survival than dFLC among deep responders. Normalization of sFLCR does not predict for organ response or survival and should not be used as measure of therapeutic efficacy. Figure. Figure. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Russell:Vyriad: Equity Ownership. Kumar: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; 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. Gertz:Alnylam: Honoraria; celgene: Consultancy; Ionis: Honoraria; Abbvie: Consultancy; annexon: Consultancy; janssen: Consultancy; spectrum: Consultancy, Honoraria; Research to Practice: Consultancy; Medscape: Consultancy; Apellis: Consultancy; Teva: Consultancy; Amgen: Consultancy; Prothena: Honoraria; Physicians Education Resource: Consultancy.

Abstract ATTRwt (formerly known as senile) amyloidosis and plasma cell disorders share a common demographic of occurrence with increasing prevalence with age. We aimed to identify the prevalence of plasma cell disorders in patients diagnosed with ATTRwt. We retrospectively reviewed all patients seen at Mayo Clinic Rochester between 1st January 2009 and 31st of December 2017 who were diagnosed with ATTRwt. The start date of the study was chosen to coincide with routine clinical availability of laser microdissection mass spectrometry (LCMS) for subtyping of amyloidosis. 492 patients with ATTRwt were evaluated during the study period. Serum immunofixation electrophoresis (SIFE), urine immunofixation electrophoresis (UIFE) and serum free light chain (FLC) assay testing was performed in 74% (n=362), 53% (n=261) and 79% (n=386) respectively. Of the 492 ATTRwt seen during this period, 139 (28%) had abnormal monoclonal protein studies, the vast majority (92%, n=128) of which were monoclonal gammopathy of undetermined significance (MGUS). Monoclonal protein testing in this cohort included SIFE, UIFE and FLC in 96% (n=134), 71% (n=99) and 99% (n=137) respectively. The non-MGUS diagnoses included smoldering multiple myeloma in <1%% (n=2), multiple myeloma (MM) in 6% (n=8), AL amyloidosis in 2% (n=3), and lymphoplasmacytic lymphoma (LPL) in 3% (n=4). MM and LPL developed after progression from MGUS in 2 and 3 patients respectively. Two patients with MGUS also had a diagnosis of low grade non Hodgkin lymphoma (chronic lymphocytic leukemia in one and marginal zone lymphoma in the other). The abnormal monoclonal protein studies included SIFE in 55%, UIFE in 26% and an abnormal serum free light chain ratio (FLCr) in 73%. The organ biopsied for the diagnosis of ATTRwt was heart in 43% (n=60), bone marrow in 24% (n=33), fat in 9% (n=12) and other sites in 5% (n=8, 3 lung, 2 lip, 2 bladder and 1 small bowel). LCMS confirmed the subtype of amyloidosis as ATTRwt in all patients with a biopsy positive for amyloidosis by congo red staining. 19% (n=26) of patients were diagnosed with ATTRwt based on clinical features and a strongly positive PYP scan. PYP scan was positive for ATTR in 55/56 patients in whom the test was performed. The most common monoclonal protein isotypes detected were light chain (45%) and IgG (28%). Light chain subtype was kappa in the majority of patients (80%). Plasma cell disorders are not uncommon in patients with ATTRwt amyloidosis. The diagnosis of a plasma cell disorder and ATTRwt are not mutually exclusive, and their coexistence can confuse the diagnosis if amyloid typing is not performed. Patients with ATTRwt may be misclassified as AL amyloidosis due to the presence of amyloid and a clonal plasma cell disorder with significant prognostic and therapeutic implications. Disclosures Kumar: Novartis: 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; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Merck: 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; 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; 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; Janssen: 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. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Gertz:Ionis: Honoraria; Research to Practice: Consultancy; Amgen: Consultancy; Prothena: Honoraria; Alnylam: Honoraria; Medscape: Consultancy; celgene: Consultancy; Teva: Consultancy; Abbvie: Consultancy; janssen: Consultancy; spectrum: Consultancy, Honoraria; annexon: Consultancy; Apellis: Consultancy; Physicians Education Resource: Consultancy. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.

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 Background: The combination of a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and dexamethasone is the current standard induction therapy for myeloma. Daratumumab, a monoclonal antibody directed against CD38, is highly effective in treating myeloma and improves response rates and progression free survival (PFS) when added to PI or IMiD. Ixazomib, lenalidomide and dexamethasone (IRd) is an effective, all oral, induction regimen that has been studied in phase 2 and 3 trials. We designed this trial to examine the feasibility and efficacy of adding daratumumab to the IRd regimen. Patients and Methods: Patients with previously untreated MM, with measurable disease and adequate organ function were enrolled irrespective of their transplant eligibility. The primary objective was to determine the rate of complete response to the IRD-Dara combination in patients with NDMM. Treatment consisted of Ixazomib 4mg days 1, 8, 15; lenalidomide 25 mg days 1-21, dexamethasone 40 mg, weekly and daratumumab 16 mg/kg, weekly for two cycles, every other week during cycles 3-6 and then every 4 weeks after that. Overall, 40 patients were accrued; data on 38 patients were available for analysis as of July 02, 2018 (Table 1). Results: The median age was 62 (41-81); 52.6% female. All patients were alive and progression free at last assessment with a median follow up of 5.2 (2.0-12.9) months (median 5 cycles, range 2-13). One patient had gone off for alternate therapy. Responses were rapid with 90% partial response or better (32% VGPR) after 2 cycles, and 100% PR or better (50% VGPR) for 32 patients who have completed 4 cycles. The overall best confirmed response rate among the 38 patients was 95% including 11% CR and 47% VGPR. Overall, 231 cycles have been administered across the study, with dose modifications/ hold required for ixazomib, lenalidomide, daratumumab and dexamethasone in 3 (8%), 11 (29%), 2 (5%), and 8 (21%) patients respectively, the most common reasons being hematologic and skin rash. A grade 3 or higher adverse event at least possibly attributed to the study drugs was seen in 42% of patients, hematologic in 37% and non-hematologic in 11% (Figure). 11 patients have so far proceeded to stem cell collection, all have collected adequate numbers of stem cells for one or two intended transplants(median CD34+ collected 8.4 million/kg; range 3.8-12.3). Updated results with additional 6 months of follow up and MRD testing will be presented at the meeting. Conclusion: This represents the first reported results of this combination for treatment of newly diagnosed myeloma. The early results from the use of IRd-Dara in newly diagnosed myeloma suggests excellent efficacy with rapid responses that deepen quickly over the initial cycles of therapy. The regimen was well tolerated with limited dose modifications and no discontinuation for toxicity and no influence on the ability to collect stem cells. Figure. Figure. Disclosures Kumar: Janssen: 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; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding. Lacy:Celgene: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Prothena: Honoraria; Amgen: Consultancy; Abbvie: Consultancy; Teva: Consultancy; annexon: Consultancy; janssen: Consultancy; celgene: Consultancy; Alnylam: Honoraria; Medscape: Consultancy; Apellis: Consultancy; spectrum: Consultancy, Honoraria; Physicians Education Resource: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy.

Abstract Monoclonal gammopathies, including multiple myeloma (MM), represent a group of plasma cell (PC) disorders that comprise of mostly incurable hematopoietic malignancies with an increasing incidence in the US. Previous epidemiological studies demonstrated a 2-3 fold higher incidence of monoclonal gammopathy of undetermined significance (MGUS) and a similarly higher incidence of MM along with a ~4-year younger age of onset among African Americans (AA) compared to European Americans (EAs) (Fonseca, Leukemia, 2017). This suggests a possible ancestral-associated genetic predisposition of AAs to the development of monoclonal gammopathies (Landgren, Blood, 2006). When access to care is equal, AAs have a better overall survival compared to EAs suggesting that AAs may have a genetic predisposition that renders them better responders to treatment or have more favorable cytogenetic subtypes of MM (Waxman, Blood, 2010). Previous efforts to understand this disparity have relied on self-reported race rather than genetic ancestry. We hypothesize that quantifying genetic ancestry is necessary to fully understand the genetic mechanisms of racial disparities of monoclonal gammopathies. We describe our study of 881 patients with monoclonal gammopathies who had undergone uniform testing to identify MM-specific cytogenetic abnormalities. DNA from the bone marrow samples was genotyped on the Precision Medicine Research Array. Biogeographical ancestry was assessed using the Geographic Population Structure Origins tool, which provides the ancestral breakdown of 36 admixture components for each individual representing different geographic regions and outputs admixture proportions corresponding to those ancestries (Elhaik, Nat Commun, 2014). We evaluated whether an increase in the percentage of African Ancestry altered the odds of any primary cytogenetic abnormality. We demonstrated that a 10% increase in the percentage of African ancestry was associated with a 6% increase in the odds of detecting either an t(11;14), t(14;16) or t(14;20) (odds ratio = 1.06, 95% CI: 1.02 - 1.11; p-value = 0.05). Although we observed an increase in the odds of each of the individual translocations with 10% increase in African ancestry, l t(11;14) (OR=1.03) t(14;16) (OR=1.11) and t(14;20) (OR=1.10), these three abnormalities were combined to achieve greater statistical power. The differences in cytogenetic abnormalities were most striking among individuals with ≥80.0% African (n=120) compared to individuals with <0.1% African ancestry (n=235). Using these cutoff values comparing the ≥80.0% and <0.1% African ancestry cohorts, there was a higher prevalence of t(11;14), t(14;16) and t(14;20) (51% vs. 33%, respectively, p-value=0.008) and a lower prevalence of trisomies (with or without IgH translocations) (48.3% vs. 61.3%, respectively, p-value=0.066). In addition, the ≥80% African ancestry cohort also displayed a slightly lower prevalence of monosomy 13/13q deletion compared to the cohort with <0.1% African ancestry (34.2% vs. 38.7%, respectively, p-value=0.021). Further, we observed a significantly higher prevalence in the proportion of females with monoclonal gammopathies among the ≥80% African ancestry cohort compared to the cohort with <0.1% African ancestry (56.7% vs. 42.1%, respectively, p-value=0.028). We complement our past studies that relied on self-reported race and characterized patients' demographic and uniformly collected cytogenetic data in relation to genetically defined African ancestry. We demonstrate the prevalence of having one of three specific subtypes (i.e., t(11;14), t(14;16), or t(14;20)) was significantly higher in those with highest (≥80%) compared to lowest (<0.1%) African ancestry demonstrating African ancestry is associated with a subtype distribution of MM that differs from non-African individuals. These differences were only revealed after analysis of individuals with the highest and lowest percentage of African ancestry. Since 38.3% of the individuals with ≥80% African ancestry have the favorable t(11;14) translocation (in comparison to 26.8% of <0.1% African individuals), this finding may explain improved survival with equal access to care. Understanding the genetic mechanisms of this disparity is a fundamental step to understanding differences in incidence and outcomes of patients with monoclonal gammopathies. Disclosures Elhaik: DNA Diagnostics Center: Consultancy. Baird:DNA Diagnostics Center: Employment. Cerhan:Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding; Celgene: Research Funding. Stewart:Amgen Inc., BMS, Celgene, Takeda, Roche, Seattle Genetics, Janssen, Ono: Consultancy; Amgen Inc., Celgene, Roche, Seattle Genetics: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Kumar:Novartis: 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; Takeda: Membership on an entity's Board of Directors or advisory committees; 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; 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; Merck: 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; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: 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 Aims: Autologous stem cell transplantation (ASCT) is an important component in the treatment of newly diagnosed multiple myeloma (MM). However, relapse following ASCT is considered almost inevitable, with a median time to progression (TTP) of approximately 23-26 months (without maintenance) and 40-46 months (with maintenance)(Attal MA et al. N Engl J Med 2012; 366:1782-1791; McCarthy PM et al. N Engl J Med 2012; 366:1770-1781). However, some patients can experience a prolonged period of remission with ASCT. The purpose of this study was to identify and characterize patients who have an exceptional response to upfront ASCT without maintenance therapy, and to determine the frequency of relapse in such patients. Methods: We searched the Mayo Clinic Multiple Myeloma bone marrow transplant database for patients who were diagnosed with MM between Aug 1, 1988 to Jan 3, 2006, and underwent ASCT within 12 months of initial diagnosis. For the purposes of this study, we defined exceptional responders as patients who were free of progression for 96 months or more, which is 2-3 fold more than the median TTP expected in this population. Since maintenance therapy was not standard of care at the time, only a small minority (6) of patients with prolonged TTP had received maintenance therapy; these patients were excluded since the study was focused on exceptional response with ASCT alone. One patient who had a tandem autologous transplant was excluded. Results: 509 patients underwent transplant during the study period. Of those, 46 (9%) met criteria for exceptional response. Twenty seven (59%) were female, 19 (41%) were male. Median age was 57.28 years, range, 31.9-73.0. Of 45 patients with response data available, the best response status was complete response or better in 32 patients (73.3%), VGPR in 4 patients (8.9%), and PR in 8 patients (17.7%). FISH data were available during the disease course for 41 patients. Of these, the majority, 28 patients (68.3%), had no abnormalities detected by the probes used; 3 patients (7.3%) had high risk cytogenetics (t(4;14) in 2 patients and t(14;16) in one patient) , 4 (9.8%) had trisomies; 6 patients had other isolated abnormalities. At last follow up, 23 patients have progressed (50%); 14 (30.4%) have died, including one who died without progression to MM. The median overall survival from time of diagnosis of the exceptional responders was 18.5 years, range 9.2-22 years. From the landmark time of 96 months, the median TTP was 6.2 years, range, 0.4-10.6 years (Figure 1); No plateau was seen in the TTP curve. From the landmark time of 96 months, the median OS was 10.5 years, range, 0.4-14 years. Conclusions: We conclude that approximately 10% of patients with newly diagnosed myeloma have an exceptional response to a single ASCT without maintenance therapy. These patients have a remarkable overall survival, both from diagnosis and from the landmark time point where they are classified as having achieved an exceptional response. Although TTP from the landmark time point is excellent, with median TTP of 6.2 years, there appears to be no plateau in the curve indicating ongoing risk of relapse despite a prolonged period of disease stability. Exceptional responders tended to have normal FISH studies (likely an indicator of responsive, low-tumor burden disease), and nearly 20% achieved this state despite not attaining a complete response. Figure. Figure. Disclosures Gertz: Research to Practice: Consultancy; Apellis: Consultancy; spectrum: Consultancy, Honoraria; Medscape: Consultancy; celgene: Consultancy; janssen: Consultancy; Teva: Consultancy; Abbvie: Consultancy; annexon: Consultancy; Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Amgen: Consultancy; Physicians Education Resource: Consultancy. Kumar:KITE: 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; 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; 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; Merck: 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; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; 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. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Dingli:Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Russell:Vyriad: Equity Ownership. Kapoor:Takeda: Research Funding; Celgene: 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 Introduction Recent advances in the understanding of the WM pathobiology led to the expansion of our therapeutic options in this disease. A number of targeted drugs are either available or under investigation and are poised to change the chemo-immunotherapy paradigm in the treatment of WM. Now more than ever, an individualized treatment approach for patients with WM is possible, where patient characteristics and preferences can be matched by different treatment goals and side effect profiles. While deep responses have been associated with longer disease-free survival in other hematologic malignancies, data on patients with WM are sparse. We report the impact of depth of response in disease-free and overall survival (OS) in WM. Methods WM patients consecutively seen at Mayo Clinic between 01/1998 and 12/2016 were reviewed for response to therapy and disease burden. The best response achieved after the treatment of interest (TOI) was classified using the IWWM-7 Response Criteria. The included TOI were: BR, DRC, BDR and high-dose chemotherapy followed by ASCT. All time-to-event analyses were performed from the TOI initiation date using the Kaplan-Meier method and the log-rank test. A landmark analysis from the date-of-best response was also performed for OS to prevent immortal-time bias. Univariate and multivariate analyses of progression-free survival (PFS) and time-to-next therapy (TTNT) were performed using the Cox regression method. Results A total of 181 patients had disease response assessed after the TOI. Baseline characteristics at time of diagnosis are summarized in table 1. The median follow up from TOI was 3.8 years (95% CI: 3-4), the majority of patients received TOI as salvage therapy [n=112 (63%); median 2nd line (rage 1-11)]. Best response rates with the corresponding 5-year PFS and TTNT are summarized in table 2. The median OS from TOI was longer in patients who achieved at least a PR [median 7.2 years (95% CI: 5-NR) vs 3.7 years (95% CI: 1.6-NR), p=0.01]. A trend towards a longer OS was also seen with deeper responses (PR or better) achieved with frontline therapy [median 5.8 years (95% CI: 5.8-NR) vs 3.4 years (95% CI: 1.6-NR), p=0.24]. Figure 1 shows the correlation between deeper responses with PFS and TTNT. Among patients achieving a PR or VGPR, those with a normal FLC ratio post TOI demonstrated a longer PFS and TTNT [PFS: median NR (95% CI: 3.4-NR) vs 4.9 years (95% CI: 2.8-8.7), p=0.01; TTNT: median NR (95% CI: 3.5-NR) vs 5.2 years (95% CI: 4.2-9.4), p=0.04], figure 2. In a multivariate analysis including normal FLC ratio, normal IgM level and minimal BM involvement (<5%) post TOI, normal FLC ratio remained an independent prognostic factor for longer PFS and TTNT. Similar trends were seen when considering treatment naïve and relapsed/refractory patients independently (data not shown). Discussion Our results not only suggest an association between depth of response with PFS and TTNT, but also with OS in patients with WM. A normal FLC ratio (not part of the IWWM-7 response criteria) seems to predict a longer disease-free interval in patients achieving a PR or VGPR. Disclosures Gertz: Ionis: Honoraria; Apellis: Consultancy; annexon: Consultancy; Prothena: Honoraria; janssen: Consultancy; Physicians Education Resource: Consultancy; Alnylam: Honoraria; Teva: Consultancy; spectrum: Consultancy, Honoraria; Medscape: Consultancy; celgene: Consultancy; Research to Practice: Consultancy; Amgen: Consultancy; Abbvie: Consultancy. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Ailawadhi:Amgen: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy. Reeder:Affimed: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Kumar:Janssen: 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; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Seattle Genetics: Research Funding; Celldex: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Regeneron: Research Funding.