Lacy, Martha Q.

Abstract BACKGROUND: Necrobiotic Xanthogranuloma (NXG) is a rare chronic granulomatous disorder of the skin associated with monoclonal gammopathies (MG). Due to its rarity, data on response to various therapies are largely limited to single case reports or small case series. Hence, we described the clinical features in patients with NXG and MG as well as their subsequent disease course and response to treatment. METHODS: This was a retrospective study evaluating 35 patients with NXG and coexisting MG from 1994-2015 who were evaluated in the Hematology Outpatient Clinic at the Mayo Clinic, Rochester. All patients had a biopsy proven diagnosis of NXG with the concurrent presence of a serum monoclonal gammopathy. RESULTS: The median age at diagnosis was 56 years (range: 26-88). Most patients had a plasma cell dyscrasia (28 MGUS; 5 Smoldering myeloma) while 2 had chronic lymphocytic leukemia. Themost common monoclonal (M) protein was IgG kappa (60%). The median M-spike was 1.1 g/dL (range: 0-3). The most common site of NXG was periocular (66%). All patients received treatment, with over half requiring >3 different lines of treatment. The treatments were heterogeneous and included excision, intra-lesional injection, radiotherapy as well as systemic treatment. The types of systemic treatment used and clinical response are reported in Table 1. The median follow up was 46 months (range: 4-234) and the median survival was not reached but at the time of analysis 80% were still alive. At last follow-up, 80% of patients had signs of either clinical improvement or stable skin disease. Eight patients (23%) had disease progression to multiple myeloma at a median of 67 months (Range: 21 - 107). CONCLUSIONS: We report the clinical findings and treatment outcomes of one of the largest series of patients with NXG associated with MG. The clinical course is generally indolent but malignant transformation is not uncommon. Cutaneous objective responses can be achieved with various systemic agents used in the treatment of lymphoproliferative malignancies. Table 1. Treatment Types and Clinical Response Rates Treatment No of patientsA Clinical Benefit Rate B Response rateC Chemotherapy - Chlorambucil +/- Steroids - Melphalan/Steroids - Cytoxan/Steroids - Cladribine - Vincristine/doxorubicin/dexamethasone - High dose therapy with stem cell rescue - Fludarabine/cyclophosphamide/rituximab 5 3 4 3 2 3 1 2/5 (40%) 0/3 (0%) 1/4 (25%) 1/3 (33%) 1/2 (50%) 2/3 (67%) 1/1 (100%) 1/5 (20%) 0/3 (0%) 0/4 (0%) 1/3 (33%) 0/2 (0%) 2/3 (67%) 1/1 (100%) Novel agents - Thalidomide +/- Steroids - Lenalidomide +/- Steroids - Bortezomib +/- Steroids - Bortezomib/Lenalidomide/Dexamethasone 11 14 4 1 5/11 (45%) 10/14 (71%) 2/4 (50%) 1/1 (100%) 4/11 (36%) 7/14 (50%) 1/4 (25%) 1/1 (100%) Intravenous immunoglobulin 4 3/4 (75%) 2/4 (50%) Systemic steroids alone 11 4/11 (36%) 4/11 (36%) Rituximab 6 2/6 (33%) 1/6 (17%) AntibioticsD 3 0/3 (0%) 0/3 (0%) ImmunosuppressantsE 6 1/6 (17%) 0/6 (0%) ANo of patients who underwent a particular therapy amongst the 35 patients in the study cohort. BClinical Benefit: Improvement or stable skin disease CResponse: Improvement in skin disease DAntibiotics: Fluoroquinolones, Tetracycline EImmunosuppressants: Cyclosporine, Methotrexate, Plaquenil Disclosures Kumar: Celgene, Millennium, Onyx, Novartis, Janssen, Sanofi: Research Funding; Celgene, Millennium, Onyx, Janssen, Noxxon, Sanofi, BMS, Skyline: Consultancy; Skyline, Noxxon: Honoraria.

Abstract Background: Ixazomib is an experimental, orally bioavailable, proteasome inhibitor that has demonstrated anti-tumor activity in relapsed multiple myeloma (MM). In the dose escalation studies, ixazomib was tolerated up to a dose of 5.5 mg given every week as a single agent, while a dose of 4 mg was utilized in the combination studies with lenalidomide. We undertook this study to examine the efficacy and tolerability of the two doses of ixazomib in combination with dexamethasone in patients with relapsed MM. Patients and methods: This was a randomized phase 2 study of two doses of ixazomib (4mg; Arm A or 5.5 mg; Arm B) given weekly for three weeks with a week off along with weekly dexamethasone (40 mg) in patients with relapsed MM, who are proteasome inhibitor na•ve (including bortezomib) or have received less than 6 cycles of therapy with bortezomib and had a PR or better with no progression at the time of discontinuation. The primary objective was to determine the confirmed overall response rate (>=PR); secondary objectives included progression free and overall survival. A total of 71 patients were accrued from February 2013 to April 2015; one patient was ineligible. Results: Baseline characteristics were similar in the two arms; median age across the study was 70 years (46-84); 53% were male. Median number of prior therapies was 4 (range 2-6); 90% of the patients had prior IMiDs, 70% had prior transplant and 29% had prior bortezomib. At a median follow up of 10 months, 17 (49%) and 19 (54%) of patients had disease progression in arms A and B respectively with 12 (34%) patients in each arm still continuing on treatment. All patients in each arm were evaluable for response; the overall response rates were 31% in arm A (95%CI: 17-49) and 51% (95%CI: 34-69) in Arm B. The depth of response, event free survival and overall survival are outlined in Table 1. Among the patients with no prior bortezomib exposure the response rates were 38% for Arm A and 52% for Arm B. The treatment was well tolerated with 2 patients in each arm discontinuing treatment for adverse events; there were no on study deaths. A grade 3 or higher AE that was at least possibly related to treatment was seen in 21% and 54% in Arms A and B respectively; with 15% and 37% hematologic and 6% and 29% non-hematologic AEs. The most common attributable toxicities encountered included fatigue, thrombocytopenia, diarrhea and nausea with more grade 3 toxicities among Arm B. Peripheral neuropathy, possibly related to ixazomib, was seen in 55% (only grade 1 or 2) in arm A and 43% (2 patients with grade 3) in Arm B. Toxicities led to dose reduction of ixazomib in 17% and 43% of patients in Arm A and B respectively; the median number of cycles administered were 5 (1-24) and 5 (1-22) respectively. Conclusions: Ixazomib in combination with dexamethasone was well tolerated with significant anti-myeloma activity in this group of patients with relapsed MM. Deep responses including stringent CR were observed. The higher dose of ixazomib appears to be associated with a higher response rate but with higher rate of adverse events requiring dose reductions. Table 1. Treatment outcome in all patients Arm B (4 mg) (N=35) Arm C (5.5 mg) (N=35) Response Rate 31% (95%CI: 17-49) 51% (95%CI: 34-69) No. of Responders 11 18 sCR 0 1 CR 1 0 VGPR 7 8 PR 3 9 MR 5 1 Median Overall Survival1 NA NA 6 Months 100% 100% Median Event Free Survival1,2 8.4 mos (95%CI: 4.3-13.2) 8.2 mos (95%CI: 3.8-16.3) %Event Free at 6 Months 60% (95%CI: 45-81) 60% (95%CI: 45-81) Median Duration of Response1 16.7 mos (95%CI: 9.3-22.0) 16.3 mos (95%CI: 7.0-20.1) Median Time to Response 1.1 mos (range: 0.8-3.6) 1.0 mos (range: 0.8-7.5) CI: confidence interval; mo: month; NA: not attained 1Kaplan Meier 2Event-free survival time is defined as the time from registration to the first of disease progression, death due to any cause, or subsequent treatment for multiple myeloma. Disclosures Kumar: Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Consultancy, Honoraria; Onyx: Consultancy, Research Funding; Novartis: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy.

Abstract Abstract 3468 Engraftment syndrome (ES) is a complication of hematopoietic stem cell transplantation classically characterized by fever, rash, diarrhea, weight gain and non-cardiogenic pulmonary edema. Renal failure has been observed but is not considered to be a major part of the syndrome. We have noted that acute renal failure (ARF) is common around the time of leukocyte engraftment in light chain amyloidosis (AL) patients after autologous stem cell transplant (ASCT). We suspect this is due to ES and this retrospective review was conducted to further study this entity. Data were collected from 377 AL patients who underwent ASCT from 7/1997 to 10/2009. Patients who experienced an elevation of serum creatinine (Scr) > 0.5 mg/dl within 4 days of leukocyte engraftment were selected. Patients who carried a diagnosis of ES were also included regardless of Scr elevation. Nephrotoxic insults were reviewed. Vitals were collected. Forty-one patients met criteria. Four patients were found not to have ES, 2 sepsis, 1 allergic interstitial nephritis (AIN), 1 acute cellular rejection. ES was noted in 37 (9.8%) patients, 2 presented with mainly pulmonary ES and 8 had both pulmonary and renal involvement. The degree of renal failure varied from mild and self-limited to severe and requiring dialysis. The renal failure is usually preceded by fever, rash, increasing edema, relative hypotension and low urine sodium (Figure 1). Treatment with glucocorticoids (60 mg/d) was successful in reversing the renal failure in most patients but those with pulmonary involvement required higher doses. Our study showed that ES presents more commonly with renal failure than pulmonary involvement in AL patients. Further complications may be prevented by early treatment with corticosteroids once infection is ruled out. Dosing depends on concurrent pulmonary findings. Distinguishing ES with AIN is difficult as presentations are similar but AIN will continue until the offending drug is removed while ES generally responds quickly to steroids alone. Figure 1. Figure 1. Disclosures: Dispenzieri: Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

Abstract Abstract 3572 High dose melphalan and autologous stem cell transplantation (ASCT) is an effective treatment for light chain amyloidosis (AL) but high treatment related mortality (TRM) limits its use. Both cardiac troponin T (cTnT) and N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) are sensitive predictors of high risk patients. Aim of this study is to compare two models of TRM, one using cTnT and the other BNP. Patients who underwent ASCT between 7/1996 and 7/2009 at the Mayo Clinic were analyzed retrospectively. Variables were chosen for ease of measurement and reproducibility thus echocardiographic parameters were excluded. Each additional risk factor must contribute to a significant increase in TRM. Also, since NT-pro-BNP and cTnT are already highly associated with mortality, the other risk factors must be independent predictors. Univariate analysis revealed serum albumin, B-2-microglobulin, cTnT, NT-pro-BNP, and uric acid were associated with TRM while age, sex, alkaline phosphatase, serum creatinine, CRP, proteinuria were not (Table 1). Multivariate analysis showed albumin and uric acid were independent risk factors to cTnT and NT-pro-BNP (Table 2). Of the 412 patients, 347 (8.9% TRM) could be evaluated by the cTnT, albumin and uric acid (TAU) model and 282 (9.2%) TRM could be evaluated by the NT-pro-BNP, albumin, uric acid (BAU) model. Both models showed increasing TRM with additional risk factors beyond 1 risk factor (Table 3 and 4). Albumin and uric acid were found to be significant contributors in both models. Patients with elevated cTnT alone had a 0% TRM vs 23.4% if they had 1 additional risk factor, p = 0.03. Similarly, TRM was 3.7% in patients with elevated NT-pro-BNP alone but 18.0% if they had 1 other risk factor, p = 0.05. NT-pro-BNP and cTnT could not be used in the same model because cTnT becomes non-significant. Both models were superior to visceral organ involvement which had TRM of 5.3% with 1, 9.2% with 2 and 16.7% with 3 organ involvement. Both models were also predictive of overall survival (Figure 1 and Figure 1b). Our results show that these models show that albumin and uric acid with either cTnT or NT-pro-BNP can accurately predict TRM in AL patients undergoing ASCT. Multivariate analysis shows that the NT-pro-BNP containing model may be superior since cTnT loses it significance when added to the model. Our results suggest these models could be very helpful in identifying high risk patients not suitable for ASCT. Figure 1a Overall survival evaluated by Kaplan-Meier method on 347 patients using the TAU model. Mortality increased significantly with the number of risk factors, p < 0.001. Solid line represents patients with 0 risk factors, dotted line represents patients with 1 risk factor, dashed line represents those with 2 risk factors and dotted dashed line represent those with 3 risk factors. Figure 1a. Overall survival evaluated by Kaplan-Meier method on 347 patients using the TAU model. Mortality increased significantly with the number of risk factors, p < 0.001. Solid line represents patients with 0 risk factors, dotted line represents patients with 1 risk factor, dashed line represents those with 2 risk factors and dotted dashed line represent those with 3 risk factors. Figure 1b Overall survival evaluated by Kaplan-Meier method on 282 patients using the BAU model. Overall survival was significantly longer in patients with less risk factors, p < 0.001. Solid line represents patients with 0 risk factors, dotted line represents patients with 1 risk factor, dashed line represents those with 2 risk factors and dotted dashed line represent those with 3 risk factors. Figure 1b. Overall survival evaluated by Kaplan-Meier method on 282 patients using the BAU model. Overall survival was significantly longer in patients with less risk factors, p < 0.001. Solid line represents patients with 0 risk factors, dotted line represents patients with 1 risk factor, dashed line represents those with 2 risk factors and dotted dashed line represent those with 3 risk factors. Table 1. Patient characteristics Control TRM p-value N 318 29 Age 58 (25–73) 55 (35–75) 0.54 Sex (male) 58.2% 72.4% 0.13 Albumin (g/dl) 2.7 (0.8–4.4) 2.2 (0.8–3.7) 0.02 Alkaline phosphatase (U/L) 89 (28–1014) 86 (31–1394) 0.22 b2m (mg/ml) 2.6 (1.0–35.1) 3.2 (1.3–15.2) 0.007 NT-pro-BNP (pg/ml) 564 (12–35000) 1661 (21–35001) 0.03 CRP (mg/L) 0.3 (0.01–16.6) 0.3 (0.05–3.2) 0.34 cTnT (ng/ml) 0.01 (0–1.0) 0.03 (0.01–0.22) <0.001 Scr (mg/dl) 1.1 (0.4–12) 1.2 (0.8–2.3) 0.09 Proteinuria (g/d) 3.4 (0.01–35.4) 5.1 (0.1–20.5) 0.10 Uric acid (mg/dl) 6.2 (1–14.8) 7.5 (3.7–13.2) 0.02 Organ Involvement 1 94.7% 5.3% 0.04 2 90.7% 9.3% 3 83.3% 16.7% Table 2. Multivariate analysis using proportional hazard model cutoffs >Risk Ratio >p-value Model TAU cTnT 0.04 ng/ml 2.78 0.01 Albumin 3.3 g/dl 3.11 0.03 Uric acid 8.5 mg/dl 2.69 0.02 Model BAU NT-pro-BNP 1270 pg/ml 3.77 0.003 Albumin 3.3 g/dl 3.53 0.04 Uric acid 8.5 mg/dl 3.11 0.03 Table 3. Model of cTnT, albumin and uric acid TAU Risk Factors n TRM p-value Risk Ratio 0 69 2.9% 1 205 5.9% 0.33 2 61 16.4% 0.009 2.98 3 12 41.7% 0.05 8.52 Table 4. Model of NT-pro-BNP, albumin and uric acid BAU Risk Factors >n >TRM >p-value >Risk Ratio 0 28 0% 1 161 5.6% 0.20 2 82 14.6% 0.02 2.7 3 11 45.5% 0.01 10.8 Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Lacy:Celgene: Research Funding.

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

Abstract Abstract 1958 Vaccines may offer additional benefit as consolidation therapy after plateau phase or autologous stem cell transplant (ASCT) for multiple myeloma (MM). We have reported previously the results of another phase II trial showing that using APC8020 (Mylovenge™) after ASCT improved the overall survival (OS 5.3 yrs, 95% CI 4.0 yrs – NA) compared to ASCT alone (3.4 yrs, 95% CI 2.7 – 4.6 yrs; p = 0.02; Lacy, AJH (84): 799). We now report the results from a randomized, phase II trial using the same vaccine plus adjuvant cytokines in MM patients in plateau phase after either chemotherapy or ASCT. Twenty patients were enrolled between 2001 and 2003 and were randomized to receive APC8020 and adjuvant cytokine of either interferon-g (IFNg, arm A, n = 10) or interleukin-2 (IL2, arm B, n = 10). Each cycle of treatment included five days of daily subcutaneous injections of either IFNg (106 IU, arm A) or IL2 (200 mg, arm B) followed by APC8020 injection. Each patient received a cycle of treatment every 2 weeks for 4 cycles. One patient in each arm was in plateau phase post-chemotherapy. Time from diagnosis to treatment was 11.9 mos for the patient in arm A and 16.2 mos for arm B. Time to progression (TTP) was 3.7 and 68 months respectively the patient in arm A and B. Both patients were alive at five years. For the 9 post-ASCT patients in each arm, no statistically significant differences were seen in the baseline characteristics between the 2 arms. The median time from diagnosis to treatment was 15.4 months. No grade 4 or 5 adverse events (AEs) were reported. Two patients in each arm had grade 3 AE, including lymphopenia, thrombocytopenia, hemorrhage, infection, and fatigue. One patient in arm B had grade 3 autoimmune disorder that was deemed possibly related to study treatment. The most common AEs were grade 1 fatigue (n = 7) and anemia (n = 5) in arm A and grade 1 anemia (n = 7) and injection site reaction (n = 5) in arm B. The median TTP was 9.3 months (95% CI: 3.9 – 19.3 months) for arm A and 6.6 months for arm B (95% CI: 6.3 – 29.6 months) with no statistically significant difference between the two arms (p = 0.89). The median OS had not been reached for either arm; the 5-year OS rate was 67% and 56% for arms A and B respectively (p = 1.0). Interestingly, similar to our previous study where TTP was not different while OS was improved with vaccine, when we compared the clinical outcome for all patients in this vaccine trial to that of 78 matched control patients who only received ASCT during the same time frame, we did not see significant improvement in TTP (Figure 1). However, the 5-year overall survival for all patients in this trial is significantly improved at 71% (95%CI: 51–96%) compared to ASCT control patients (41%, 95% CI: 31 – 54%; p = 0.03; Figure 1). This trial suggests improved OS with vaccine plus cytokine. It is possible that modulation of patients’ immunity may help them live longer with multiple myeloma. Further investigation is needed to compare the approach in this trial with dendritic cell vaccine alone to better understand optimal strategy for vaccine therapy in MM. Figure 1. Kaplan-Meier curves for time to progression and overall survival Figure 1. Kaplan-Meier curves for time to progression and overall survival Disclosures: Dispenzieri: Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Lacy:Celgene: Research Funding.

Abstract Background: Dexamethasone (dex) is an integral part of various anti-myeloma regimens both in the frontline and relapsed/refractory (RR) setting. Several clinical trials have shown that dex adds to the efficacy of novel therapeutic agents for multiple myeloma (MM). Yet, a substantial number of patients are intolerant to even the standard of care low-dose dex (40 mg weekly), especially in heavily pre-treated RRMM, possibly due to cumulative steroid toxicities and thus, require dex dose adjustments. There is a concern of compromising the efficacy of anti-MM regimens by adjusting the dex dose lower. We describe the frequency of dex dose adjustment, characteristics of patients who required it and its effect on patient outcomes in a large prospective clinical trial of pomalidomide (pom) and dex in RRMM (MC0789). Methods: We utilized data from the Pom-dex trial (MC0789), which treated RRMM patients in different cohorts of pom (2 vs. 4 mg; 21 vs 28 days cycle) with fixed dose dex (40 mg orally weekly). Patients were divided into 2 subgroups, with any dose adjustment/elimination of dex vs. not. Continuous and categorical variables were compared between the two groups using two-sample t-test/Wilcoxon rank sum test or Chi-squared test, respectively. Logistic regression and Cox regression models were used to find the univariate and stepwise multivariate predictors of response to treatment and overall mortality, respectively. Kaplan-Meier method was used to estimate overall survival (OS) at 1, 3, and 5 years. All statistical tests were two-sided with the alpha level set at 0.05 for statistical significance. Results: Results from the MC0789 clinical trial have been reported previously. Almost half of all treated patients in this trial had dex dose adjusted (n=175/343; 51%). The median number of cycles for the first dose adjustment in this group was 3 (range 1-62), with 46.5% of patients (n=82) having multiple dose adjustments and majority (58.3%, n=102) within the first 3 cycles of treatment. Patients in the dose adjustment group were significantly older (mean 65 vs 60 years; p=0.0001). Males, Whites and patients diagnosed before 2006 or with normal cytogenetics also had a higher incidence of dex dose adjustment, though this was not statistically significant. Patients with dex dose adjustment had a longer duration of treatment (mean 339 days) as compared to the non-adjusted cohort (mean 123.65 days) (95% CI 160.13, 270.58; p <0.0001). Dex dose adjustment was associated with a higher probability of responding in the clinical trial after a univariate (p<0.001) as well as multivariate (p<0.001) analysis. Patients with dex dose adjustment also had a significantly better OS at 1, 3 and 5 years by univariate (p<0.001) and multivariate (p<0.001) analysis. (Figure 1) The only other significant factor was lesser number of prior regimens (3 or less), associated with a higher probability of response (p=0.002) and survival (p<0.001). Conclusion: Our analysis established that in these heavily pre-treated RRMM patients, appropriate dose adjustment of dex did not compromise their response rates; patients remained on treatment significantly longer and had an improved survival. Majority of patients (58.3%) requiring dex dose adjustment had it instituted early during treatment (<3 cycles), suggesting that early disease progression was less likely to determine dex dose continuation or adjustment. Appropriate dex adjustments should be judiciously employed as they may ensure longer treatment duration with novel anti-MM therapeutic agents, conferring superior response and survival in this difficult to treat MM subgroup. This also paves the path to further optimize dex dose in various anti-MM regimens, especially in these patients who are more likely to be intolerant to it. Disclosures Kumar: Skyline, Noxxon: Honoraria; Celgene, Millennium, Onyx, Janssen, Noxxon, Sanofi, BMS, Skyline: Consultancy; Celgene, Millennium, Onyx, Novartis, Janssen, Sanofi: Research Funding.

Abstract Abstract 3557 Introduction: Autologous stem cell transplantation for patients with amyloidosis results in high reported hematologic and organ response rates compared with conventional chemotherapy. Patients: Four-hundred and thirty-four patients have undergone transplantation between March 8, 1996, and April 13, 2010 Table 1. Clinical parameters seen in patients with amyloid are given in Table 2. The overall day-100 mortality seen in this group of patients is 44 of 434 patients (10%). Results: The most important determinant of outcome is stage defined by BNP and troponin levels. Figure 1 demonstrates the survival for patients for all 3 cardiac stages. Troponin <.035; NT-proBNP <332. Stage 1 both low, Stage 3 both elevated. The survival of all patients based on whether they achieved a complete response, a partial response (>50%), or no response was analyzed. Median survival has not been reached for the complete response group, is 107 months for the partial response group, and is 32 months for the no response group (p<0.0001). Figure 2, divides the patients at the median dFLC level of 13.5 mg/dL demonstrating that for patients with a higher level of free light chain, the median survival is 87.6 months and has not been reached for those with a lower level of free light chain. A proportional hazards model for variables that impact on survival was done in all patients, and the only relevant predictor of outcome was stage (p<0.0001). When the same analysis was performed using a landmark of 6 months, the only predictor of outcome was stage (p=0.0005). When best response was incorporated into the landmark model, it was the strongest predictor of survival. The amyloid stage predicted survival (p= 0.0005), and the best response to therapy (p <0.0001). When the same analysis was performed in the entire group of 434, stage and best response each remained significant (p<0.0001). Discussion: There is a high response rate associated with high-dose therapy that was not observed in the melphalan and prednisone era. For eligible patients who can be transplanted safely, high-dose melphalan is an effective therapy for many patients with amyloidosis. Best response and stage at diagnosis are the best predictors of overall survival. Disclosures: Lacy: Celgene: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

Abstract Abstract 1893 Background: Recent data has shown that the level of immunoglobulin free light chain (FLC) is a prognostic factor for patients with AL amyloidosis. Approximately 25% of patients with AL amyloidosis have coexistent multiple myeloma (MM) with myeloma-related end-organ damage and patients may also present with 310% plasma cells (PC) in the bone marrow (BM) in the absence of any MM features. The goal of this study was to determine the effect of increased BM plasmacytosis in the absence of MM end-organ damage on early mortality. Methods: We performed a retrospective study of 263 consecutive patients with AL amyloidosis seen at Mayo Clinic within 30 days of diagnosis from July 2002 – April 2009, to compare the effect of PC burden among those who died within 90 days of diagnosis (n=88) and those who survived more than 90 days after diagnosis (n=175). Only those patients with documented BM PC were included in this study. MM end-organ damage was defined according to the CRAB criteria. Results: In those who died <90 days after diagnosis and patients who lived beyond 90 days, the proportion of patients with 310% BM PC were 57% and 55%, respectively. Overall survival (OS) was significantly shorter in the early mortality group when there was 310% BM PC present at diagnosis (25 vs. 54 days, p=0.006), but this was not observed in the group who survived beyond 90 days (Figure 1). In patients with 310% BM PC, troponin-T, ejection fraction (EF), and hemoglobin (Hgb) were significantly worse in the early mortality cohort but patients who survived beyond 90 days had significant increase in intraventricular septal (IVS) thickness and beta-2 microglobulin (Table 1). As expected, patients with 310% BM PC in both cohorts had significantly higher serum M-spike and involved FLC (Table). The same cohort of patients were analyzed substituting MM-related end-organ damage for 310% BM PC and similar results were observed with the exception of uric acid and calcium being significantly higher in the early mortality cohort with MM (results not shown). Conclusion: This study demonstrated that an excess of early—but not late—deaths occur in AL amyloidosis patients with 310% BM PC at diagnosis. In our cohort, this finding can be attributed to higher troponin-T levels, indicating more severe cardiac involvement as observed by worse cardiac function. These findings warrant additional investigation. Disclosures: Lacy: Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.

Abstract Background: Light chain Amyloidosis (AL) is characterized by deposition of light chain derived amyloid fibrils in major organs and/or soft tissue. An observational study on natural history and outcome of localized immunoglobulin light-chain amyloidosis without vital organ (liver, heart, kidney, peripheral and autonomic nervous system) involvement has shown extremely low rate of progression (1%) to systemic amyloidosis at a median follow-up of 74.4 months (Mahmood S et al. The Lancet Haematology; 2015; 6:e241-e250). There is, however, limited evidence in published literature on natural history of AL amyloidosis confined to fat and/or bone marrow biopsy, without involvement of vital organs or other soft tissues. Methods: We retrospectively identified patients with AL amyloidosis limited to fat and/or bone marrow aspirate in a single-institution database. Patients were evaluated for progression to systemic amyloidosis. Statistical analysis was done using JMP 10.0.0 (SAS Institute Inc.). Results: We identified 117 patients, with a median age of 70 years, who had light chain amyloidosis detected in abdominal fat aspirate and/or bone marrow biopsy, without systemic involvement. Amyloid was seen in fat only in 39%, marrow only in 54% and in both sites in 7%. The median follow up was 45.6 months (95% CI-38.1-57.7) from detection of amyloid. Of these, 64% were alive at the time of analysis. Among 117 patients, 65 were treated for a diagnosis of another plasma cell disorder made prior to or concurrent with detection of amyloid. The remaining 52 patients only had isolated fat or marrow amyloid. Among 65 patients with another diagnosis of plasma cell disorder requiring treatment, 3 progressed to systemic amyloidosis, one each with cardiac, renal and lymph node (LN) involvement detected at 32, 42 and 65 months respectively from the detection of amyloid. The first 2 patients had underlying multiple myeloma, and the third patient with LN involvement had underlying Waldenström macroglobulinemia. Among 52 patients without another diagnosis of a plasma cell disorder requiring treatment, at a median follow up of 32 months, no progression to systemic amyloidosis was observed. Median overall survival (OS) in 117 patients from detection of amyloid, using Kaplan-Meier survival estimates, was 60.2 months (95% CI-48.9-146.1). Conclusion: Our study highlights the fact that isolated amyloidosis detected in fat and/or bone marrow aspirate, in the absence of another plasma cell dyscrasias that require therapy, is unlikely to progress to systemic amyloidosis. Watchful waiting might be considered in such patients after a thorough evaluation to rule out systemic involvement. Disclosures Gertz: Smith Kline: Honoraria; Novartis: Honoraria; Onyx: Honoraria; millenium: Consultancy, Honoraria; Celgene: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Abbvie: Research Funding; Millenium: Consultancy, Research Funding; Novartis: Research Funding; Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding.