Hwa, Yi L.

Abstract Background: Cardiac involvement is integral in staging and prognosis of immunoglobulin light chain (AL) amyloidosis. The N-terminal prohormone of brain natriuretic peptide (NT proBNP) is a cardiac biomarker used in screening for cardiac involvement and staging the disease. Transthoracic echocardiogram (TTE) and cardiac magnetic resonance (CMR) are the imaging modalities recommended to determine cardiac involvement and function. Methods: We conducted a retrospective review of all patients with biopsy proven systemic AL amyloidosis seen at the mayo clinic between Jan 1, 2006 and Dec 30, 2015. The aim of the study is to identify the nature of abnormalities in cardiac biomarkers and echocardiographic features in patients with AL amyloidosis and the ability of these investigations to diagnose cardiac involvement. We first identified all patients with AL amyloidosis that underwent endomyocardial biopsy for suspicion of cardiac involvement (Cohort 1). We then analyzed a cohort (Cohort 2) which consisted of patients who had serum NT proBNP and a comprehensive echocardiographic evaluation at time of diagnosis. Results: 179 patients with AL amyloidosis underwent endomyocardial biopsy (Cohort 1) of whom 173 had evidence of amyloid deposition. In this cohort, 159 patients had NT proBNP performed at the time of the procedure. The NT proBNP was elevated (>300) in all 159 patients with a median NT proBNP of 4917 (range 355-69541). The median left ventricular ejection fraction (LVEF), interventricular septal (IVS) thickness and strain rate were 54 (range 10-77), 15 (range 8-30) and -9 (range -21 to 0) respectively. CMR findings were consistent or suggestive of light chain amyloidosis in 38/42 patients, yielding a sensitivity of 90 percent. The LVEF, IVS thickness and strain rate were abnormal in 89/168 (53%), 102/64 (61%) and 92/95 (97%) respectively. 95 patients with biopsy proven cardiac amyloidosis had complete echocardiogram data available on LVEF, IVS thickness and strain rate, with 97% (n=92) presenting with an abnormality in at least one of these variables . CMR findings were consistent or suggestive of light chain amyloidosis in 38/42 patients, yielding a sensitivity of 90 percent. Patients with a normal NT proBNP and normal echocardiogram were considered disease free (true negative), based on our initial analysis of these investigations in Cohort 1. Cohort 2 consisted of 342 consecutive patients. The median NT pro BNP was 1878 (25-48214). The median LVEF, IVS thickness and strain rate were 63 (22-90), 14 (6-25) and -13 (-25 to -3) respectively. 259 (76%) patients had a positive NT proBNP (above 300), of whom 237 (92%) had an abnormality detected on TTE. 83 patients had a negative NT proBNP, of whom 27 (33%) had an abnormality in either LVEF, IVS thickness or strain rate. 19 of these 27 patients had a borderline reduced strain rate between -17 and -18, whilst the remaining 8 patients had a strain between -14 and -15. Only 6/27 patients were considered to have possible early cardiac involvement and none have any other diagnostic or classical features of amyloidosis on TTE. Conclusion: The combination of NT proBNP and comprehensive echocardiographic evaluation provides substantial information to diagnose cardiac amyloidosis in a significant portion of patients negating the need for endomyocardial biopsy. A negative NT proBNP rules out clinically meaningful cardiac involvement and may obviate the routine use of TTE in patients with a low clinical suspicion of cardiac amyloidosis. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Research to Practice: Consultancy; Physicians Education Resource: Consultancy; Ionis: Honoraria; celgene: Consultancy; spectrum: Consultancy, Honoraria; Teva: Consultancy; Amgen: Consultancy; Medscape: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Abbvie: Consultancy; annexon: Consultancy; Apellis: Consultancy; Prothena: Honoraria. 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:Takeda: Research Funding; Celgene: Research Funding. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: 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; 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; 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; 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; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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 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 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 Background: As our healthcare system faces increasing complexity, it is important for all healthcare providers to practice at the full scope of their training. However, there are limited current options for subspecialty training in hematology for advanced practice providers (APPs), a group of health care providers including both nurse practitioners and physician assistants. We are unaware of any existing postgraduate fellowship for APPs focused on education in both malignant and nonmalignant hematologic disorders. We hope that by creation of the first such fellowship, we can better prepare APP graduates with the subspecialty-specific knowledge required to become highly skilled and competent clinicians in hematology. Methods: Using surveyhero.com, we conducted a web-based needs assessment survey which was distributed to 68 APPs currently working in the hematology and blood & marrow transplant (BMT) teams at three Mayo Clinic sites (Rochester, Scottsdale, and Jacksonville). This survey included questions regarding hematology-specific education the respondents had received in their APP schools, as a way to assess participant's perceptions about the readiness to practice in hematology after completion of APP education, and to identify the learning/training needs that are most important for APPs to practice in hematology. Results: Of 68 APPs, 49 (72%; 34 NPs,15 PAs) completed the survey. 57% of respondents were new APP graduates when hired and 35% had no prior work experience in hematology/BMT. All APPs held a Master's or higher degree (doctorate 31%). Thirty-nine (80%) reported <5% of their APP school curriculum was hematology-focused. The majority (92%) felt that the level of subspecialty training they received in APP schools did not adequately prepare them with the full confidence to practice in hematology. Forty-four (90%) APPs believed subspecialty training could help them to become more competent providers for patients with hematologic disorders. Forty-seven (96%) APPs agreed that being confident and knowledgeable in their practice positively impacted their job satisfaction, and most APPs (84%) felt structured hematology training would attract them to stay within the specialty. The educational subjects that APPs identified as most important included variety of malignant and benign hematologic disorders as well as hematopathology, bone marrow transplant, palliative care, transfusion medicine, infectious disease and pharmacology related to hematology practice. The top three effective learning strategies reported by the APP respondents were active learning from direct patient care, cased based teaching, and educational experience during hospital rounds. Conclusions and Discussions: This needs-based assessment educational project revealed to us the significant gaps in subspecialty training of APP education in hematology and confirmed the necessity of this fellowship. The findings of the survey helped us to optimize the fellowship curriculum in order to meet the learning needs of future APP trainees. Development of the subspecialty fellowship program is a step forward in the future training of APPs. We believe our fellowship has the potential to serve as the postgraduate training model for other institutions nationwide. Disclosures Lacy: Celgene: Research Funding.

Abstract Introduction: Prognosis of AL amyloidosis has improved in recent years; however for many patients prognosis remains poor. We aimed to define patient-, disease- and treatment characteristics which are associated with long-term survival. Method: A retrospective chart review of all patients with biopsy-proven systemic AL amyloidosis, who were seen within 90 days of the confirmed diagnosis. Long-term survival was defined as 5-year and 10-year survival from the time of diagnosis. For 5-year survival we selected patients seen between January 1, 2000 and December 31, 2012 (allowing a minimum of 5-year follow-up, n=1331) and for 10-year survival we screened patients seen between January 1, 2000 and December 31, 2007 (allowing a minimum of 10-year follow-up; n=779). Treatment allocation was defined as the first regimen given, irrespective of subsequent treatment modifications. Results: Of the screening population, 498 patients survived ≥5 years from diagnosis (37% of the 5-year screening cohort) and 168 patients survived 10 years or more (22% of the 10-year screening cohort). Five-year survivors and 10-year survivors as compared to their counterparts were (Table): younger, higher proportion of women, more likely to have single organ involvement, less heart/liver/nerve involvement and more kidney involvement. Long-term survivors also had lower bone marrow plasma cell percentage at the time of diagnosis and lower tumor burden measured by the difference between involved to uninvolved light chain (dFLC). Similarly, long-term survivors had lower Mayo stages and higher systolic blood pressure. No difference in light chain isotype was observed between long-term survivors to long term non-survivors. Long-term survivors were less likely to be seen within 30 days of diagnosis compared to their counterparts (52% among 5-year survivors vs 67% among 5-year non-survivor; P<0.001). FISH abnormalities (data available for 555/1331 patients, 42%) were comparable between groups with regard to t(11;14) (50% among 5-year survival compared to 50% among 5-year non-survivors; P=0.93) and 13q abnormalities (34% vs 36%, respectively; P=0.53). However, trisomies were less frequently encountered in the 5-year survivor group (20% vs 29%, respectively; P=0.01), and far less common among 10-year survivors (11% vs 26%, respectively; P=0.04). Autologous stem cell transplantation (ASCT) was more likely to be associated with long-term survival. Of all patients who underwent ASCT, 74% survived more than 5 years and 49% survived more than 10 years. In comparison, among the standard-intensity therapies, 5-year survival rates for melphalan-dexamethasone, bortezomib-based regimens, immunomodulatory drug-based regimens and single agent dexamethasone/ melphalan-prednisone were 29%, 28%, 30% and 10%, respectively. The corresponding 10-year survival rates were 15%, 20%, 20% and 5%, respectively. Conclusions: Long-term AL survivors have distinct favorable baseline characteristics (including those introduced by referral bias) and ASCT as their initial therapy. Identification of these patients, especially the Mayo 2004 stage III and the Mayo 2012 stage III-IV patients who unexpectedly survived 10 years, will allow for further study and insights. Disclosures Gertz: Teva: Consultancy; Prothena: Honoraria; Alnylam: Honoraria; celgene: Consultancy; Ionis: Honoraria; Physicians Education Resource: Consultancy; Research to Practice: Consultancy; Amgen: Consultancy; janssen: Consultancy; Apellis: Consultancy; Medscape: Consultancy; Abbvie: Consultancy; spectrum: Consultancy, Honoraria; annexon: Consultancy. 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. Russell:Vyriad: Equity Ownership. Kumar: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; Novartis: 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; AbbVie: 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; Roche: 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; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.