Citations

Abstract Background: Limited data exist regarding histological transformation in patients with Waldenström macroglobulinemia (WM). In this study, we present the disease characteristics, outcomes and risk factors for histological transformation in WM. Methods: Patients with WM seen at Mayo Clinic, Rochester, MN between January 1996 and December 2017 were included. Patients with aggressive non-Hodgkin lymphoma in the setting of WM were considered to have transformation. Univariate analysis for comparing baseline characteristics of transformed versus non-transformed WM was performed using Wilcoxon, Fisher's exact and Chi square tests, as appropriate. Multivariate analysis was performed using logistic regression analysis. Cox proportional hazard method was used to assess the impact on time-to-transformation. All time-to-event analyses were calculated by the Kaplan-Meier method. Results: Of 1014 patients with WM, 42 patients (4.1%) developed histological transformation. The median follow-up for the entire cohort was 9.5 years (95% CI: 8.8-10.5 years). The cumulative probability of transformation was 2.3% at 5 years, 5.3% at 10 years and 8.5% at 15 years from diagnosis of WM, respectively. There was no difference in the 5-year cumulative probability of transformation in patients with WM diagnosed between 1996-2000 (2.1%), 2001-2005 (2.9%), 2006-2010 (2.7%) and 2011-2015 (3.8%), p=0.61.The disease characteristics, laboratory parameters and histology at transformation are outlined in Table 1. In patients with DLBCL histology (n=39), Revised-International Prognostic Index was calculable in 28 patients, with 50% (n=14), 46% (n=13) and 4% (n=1) of DLBCL belonging to poor, good and very good risk groups, respectively. For DLBCL histology, 18 patients were classifiable using Hans algorithm into germinal center B-cell (GCB) type (n=3, 17%) and non-GCB type histology (n=15, 83%). The median lines of therapy received prior to transformation for the entire cohort was 2 (range 0-9), with 5 (11%) patients not having received any therapy for WM before transformation. Number of lines of alkylator-based therapy used prior to transformation [median 1 line (range 0-4)] was comparable to that used in patients in whom WM did not occur [median 1, (range 0-6); p=0.78]. The median time-to-transformation from diagnosis of WM was 4.8 years (95% CI: 2.6- 6.8 years). Overall survival (OS) from transformed disease was 3.2 years (95% CI 1.1-3.9 years). The 10-year OS of patients with WM who transformed was lower (46%) compared to patients without transformation (60%) with a trend towards statistical significance (p=0.08), Figure 1. The MYD88L265P mutation status was available in 333 patients in the entire cohort (22/42 pts in the transformed cohort and 311/972 in the non-transformed cohort. Of the 22 patients in the transformed WM cohort, 13 (59%) exhibited MYD88WT genotype and 9 (41%) exhibited MYD88L265P genotype. The risk of transformation was higher in patients with MYD88WT status [Odds ratio 6.3 (95% CI: 2.6-15.5); p<0.0001]. Additionally, serum lactate dehydrogenase (LDH) was higher at diagnosis of WM in patients who transformed, Table 2. On multivariate analysis, MYD88WT status remained an independent predictor of disease transformation [p=0.003; odds ratio 10 (95% CI: 2.1-48)]. On univariate Cox proportional hazard analysis for identifying predictors of time-to-transformation, only MYD88WT mutational status was associated with shorter time-to-transformation with a 5-year transformation rate of 15.5 % for MYD88WT versus 2.6 % with MYDL265P mutated patients [risk ratio 6.2 (95% CI: 2.5-16.4); p<0.0001]. Treatment-related details in the transformed cases were available for 37 (90%) patients; R-CHOP was the most common (41%) frontline therapy for transformation; 33% patients underwent autologous stem cell transplantation for transformed disease during their disease course. Conclusion: Histological transformation is an uncommon event in WM but confers poorer survival. MYD88WT genotype is independently associated with histological transformation a shorter time-to- transformation in patients with WM. Disclosures Ansell: Trillium: Research Funding; Pfizer: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Takeda: Research Funding; Celldex: Research Funding; Regeneron: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding. Gertz:Apellis: Consultancy; Alnylam: Honoraria; spectrum: Consultancy, Honoraria; janssen: Consultancy; annexon: Consultancy; Prothena: Honoraria; Abbvie: Consultancy; Amgen: Consultancy; celgene: Consultancy; Teva: Consultancy; Medscape: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy; Physicians Education Resource: Consultancy. 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.. 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:Merck: 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; 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; Roche: 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; Novartis: 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. Kapoor:Takeda: Research Funding; Celgene: Research Funding.

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 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: 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 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 Familial myeloid neoplasms are rare causes of myeloid malignancies. Over the last few years germline mutations involving RUNX1, JAK2, GATA1, GATA2 and CEBPA genes have been associated with myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML). We carried out this study to describe the spectrum of familial myeloid neoplasms seen at our institution. Methods After due IRB approval, the myeloid neoplasms data base (1990-2012) at the Mayo Clinic in Minnesota was queried for patients presenting with, or having a strong family history of myeloid neoplasms. Selective sequencing of germline DNA was done in appropriate patients. Germline mutations that were screened for included; RUNX1, JAK2, GATA1, GATA2 and CEBPA. In one family with none of the aforementioned gene mutations, exome sequencing was performed. Families with chromosomal breakage and primary telomere disorders were excluded. All patients had bone marrow and cytogenetic studies at diagnosis. Results We identified six families with familial myeloid neoplasms (table one). There were two with germline GATA2 mutations (no.1 and 2); one with a novel c1339A>C, pS447R, non-zinc finger gene abnormality. In this family nine members have developed MDS/AML. All members had profound B/NK cell deficiency, viral warts and one member had primary lymphedema (Embergers syndrome). Three of the 6 seen at the clinic have successfully undergone allo- SCT. The second GATA2 mutated family had a less extensive history of myeloid neoplasms. There was one patient (no.5) who presented with long standing thrombocytopenia, clinically diagnosed as ITP. She eventually developed MDS with trisomy 8. She had three first degree relatives with myeloid neoplasms. Germline sequencing identified a RUNX1 mutation. Platelet electron microscopy identified characteristic ultrastructural changes. There was one family (no.4) with a germline JAK2V617F mutation. The propositus was diagnosed to have primary myelofibrosis and then demonstrated clonal evolution to a concomitant BCR-ABL1 p190 driven chronic myeloid leukemia. His sister and mother have essential thrombocytosis (ET) and his brother has a detectable JAK2 mutation (no evidence for disease). The patient has successfully undergone an allo-SCT. The patient with a GATA1 mutation (no.3) presented with congenital anemia and had craniofacial anomaly, atrial septal defect and developmental delays. Red cell and platelet ultrastructural abnormalities lead to the diagnosis with an additional family member having chronic anemia and suspected MDS. One family (no.6) presented with seven first degree relatives affected by MDS/AML. Germline sequencing for the aforementioned genes was negative. Exome sequencing has been performed and results should be available at the time of the meeting. The prepositus has successfully undergone allo-SCT. Conclusion Familial myeloid neoplasms are uncommon but warrant early recognition. Clues to diagnosis include strong family history, associated primary immunodeficiency states, morphological/skeletal abnormalities and platelet ultrastructural defects (RUNX1, GATA2, and GATA1). Exome and whole genome sequencing is an exciting prospect for further discoveries. Disclosures: No relevant conflicts of interest to declare.

Abstract Background : Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor was approved for the treatment of Waldenstrom Macroglobulinemia (WM) in January, 2015 based on the results of a clinical trial of 63 previously-treated patients with WM. Data on outcomes with ibrutinib outside of clinical trials are limited. Methods : Medical records of patients with WM seen consecutively between 02/01/2015 and 06/01/2018 at Mayo Clinic, MN, FL and AZ were reviewed and those treated with ibrutinib at any point during their disease were included. Refractoriness to prior therapy was defined as disease progression on therapy or within 2 months of stopping treatment. The response rates were assessed by WM VI International Workshop Criteria. Adverse events were graded using National Cancer Institute Common Toxicity Criteria for Adverse Events (AEs) v4.03. All time-to-event analyses were performed from the time of initiation of ibrutinib. Results : Eighty patients [previously treated, n=67 (84%), treatment-naïve, n=13 (16%)] received ibrutinib for active WM. Median follow-up was 18 months (95% CI: 12-19) and the median overall survival (OS) was not reached (NR) (95% CI: 27-NR) for the entire cohort at the date of last follow-up. The median age was 67 years (range: 50-88) and the median ECOG performance score was 1 (range: 0-3) at the time of ibrutinib initiation. Median lines of therapies prior to ibrutinib for the previously-treated patients was 2 (range: 1-9) and 35 patients (44%) had received ≥3 prior lines of therapy. Of the 80 patients, 52 patients (43 previously treated, 9 treatment-naïve) had data for response assessment. The baseline characteristics and laboratory parameters at initiation of ibrutinib are outlined in Table 1a and prior therapies are mentioned in Table 1b. Overall response rate (ORR) was 90% (100% in patients with ibrutinib as primary therapy and 88% in salvage therapy setting); major-response rate (MRR) was 77%. Median time to first and best response was 2.1 months (95% CI: 1.5-3.5) and 5.4 months (95% CI: 3.5-13), respectively. Other clinically relevant endpoints and AEs related to ibrutinib therapy are outlined in Table 2 and 3, respectively. The median time-to-next therapy was 33 months (95% CI: 28-NR). At last follow-up, 25 (32%) patients had discontinued ibrutinib therapy. The reasons for discontinuation was progression (n=8), elevated liver enzymes (n=4), cognitive changes (n=1), inability to achieve better than MR (n=1), atrial fibrillation (n=3), consolidation with autologous stem cell transplantation after PR with ibrutinib (n=1), transition to hospice care due to progressive head and neck cancer (n=1), infection in lower extremity (n=1), transformation to DLBCL (n=1), blistering rash which resolved after ibrutinib discontinuation (n=1), obscure GI bleed that resolved after ibrutinib discontinuation (n=1), fatigue (n=1) and for unclear reasons recorded as treatment intolerance (n=1). Following discontinuation of ibrutinib, 21 patients received salvage therapy. Of these, data regarding the response to salvage therapy was available in 9 (43%) patients (VGPR=2, PR=3, SD=3 and progressive disease=1); median PFS from the salvage therapy following ibrutinib discontinuation was 18 months (95% CI: 2-25). Of the 4 patients who were not treated following ibrutinib discontinuation; 1 elected hospice care due to concurrent head and neck cancer progression, and the other 3 patients elected to be monitored off therapy (one had achieved SD and two had PR from ibrutinib). Fourteen patients were evaluable for IgM rebound following ibrutinib discontinuation. Of those, 5 (36%) had sudden increase in IgM level [median: 158% from the IgM level after ibrutinib discontinuation (range: 22%-1368%)] within a median of 2 months (range: 1-3 months) and 1 patient required plasmapheresis for symptomatic hyperviscosity. Four of 5 patients received salvage therapy between 0-15 months. At last follow-up, 11 patients (14%) had died of whom 3 were on ibrutinib at the time of death [CNS involvement, (n=1), causes unrelated to WM, (n=2)]. Conclusions : Ibrutinib is an effective agent in WM patients with MYD88L265Pmutation. Our data regarding outcomes in non-trial setting appear comparable to the results observed in the pivotal clinical trial. Hematologists should be aware of unique ibrutinib associated toxicities and clinically relevant IgM rebound phenomenon following abrupt discontinuation of ibrutinib. Disclosures Ailawadhi: Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy. Gertz:janssen: Consultancy; Prothena: Honoraria; Medscape: Consultancy; Teva: Consultancy; celgene: Consultancy; annexon: Consultancy; Alnylam: Honoraria; Physicians Education Resource: Consultancy; spectrum: Consultancy, Honoraria; Apellis: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy. Kumar:Novartis: 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; 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; 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; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lacy:Celgene: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dingli: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.; Millennium Takeda: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding.

Abstract We retrospectively reviewed all patients receiving bortezomib, lenalidomide and dexamethasone induction followed by autologous stem cell transplantation (ASCT) within 12 months of diagnosis for multiple myeloma at the Mayo Clinic. 243 patients treated between January 2010 and April of 2017 were included in the study. Median age was 61 (interquartile range, 55-67) with 62% of patients being male. High risk cytogenetic abnormalities (HRA) were present in 34% of patients. 166 (68%) patients received some form of maintenance/other therapy post transplant (no maintenance (NM, n=77), lenalidomide maintenance (LM, n=108), bortezomib maintenance (BM, n=39) and other therapy (OT, n=19)). Overall response rate was 99% with complete response (CR) rate of 42% and 62% at day 100 and time of best response post transplant respectively. The four cohorts categorized by post transplant therapy were well matched for age, gender and ISS stage. HRA were more common amongst patients receiving bortezomib maintenance or other therapy post transplant (NM 18% vs LM 22% vs BM 68% vs OT 79%, p<0.0001). Two year and five year overall survival rates were 90% and 67% respectively with an estimated median overall survival (OS) and progression free survival (PFS) of 96 months and 28 months respectively for the whole cohort. OS was not significantly different when stratified by post-transplant therapy (Median OS 96 months for NM vs not reached for LM vs 62 months for BM vs not reached for OT, p=0.61), however post-transplant therapy was predictive of PFS (median PFS 23 months for NM vs 34 months for LM vs 28 months for BM vs 76 months for OT, p=0.01). High risk cytogenetics was associated with a worse OS but not PFS when compared to patients with standard risk (median OS: not reached for standard risk vs 60 months for HRA, p=0.0006; median PFS: 27 months for standard risk vs 22 months for HRA, p=0.70). In patients that did not receive maintenance therapy presence of HRA was a strong predictor of OS and PFS (median OS: not reached for standard risk vs 36 months for HRA, p<0.0001; median PFS: 24 months for standard risk vs 7 months for HRA, p<0.0001). Patients receiving maintenance therapy appeared to have a similar PFS and OS irrespective of cytogenetics (median OS: not reached for standard risk vs 62 months for HRA, p=0.14; median PFS: 35 months for standard risk vs 34 months for HRA, p=0.79).On multivariable analysis ISS stage III and achieving CR/stringent CR predicted PFS whilst the only independent predictors of OS were presence of HRA and achieving CR/stringent CR. The combination of bortezomib, lenalidomide and dexamethasone followed by ASCT is a highly effective regimen producing deep and durable responses in many patients. Maintenance therapy in this cohort may overcome the poor prognostic impact of high risk cytogenetic abnormalities. Table Table. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: 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:Celgene: Research Funding; Takeda: Research Funding. 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; 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. Gertz:Abbvie: Consultancy; Apellis: Consultancy; annexon: Consultancy; Medscape: Consultancy; celgene: Consultancy; Prothena: Honoraria; spectrum: Consultancy, Honoraria; Amgen: Consultancy; janssen: Consultancy; Ionis: Honoraria; Teva: Consultancy; Alnylam: Honoraria; Research to Practice: Consultancy; Physicians Education Resource: Consultancy.