Zeldenrust, Steven R.

Abstract Background: Patients with light chain amyloidosis (AL) often have delayed diagnosis and present with significant symptomatology; this may result in decreased quality of life (QOL). With improving treatment options providing longer survival, it is increasingly important to assess QOL. However there is paucity of data in the literature addressing QOL in AL patients. We prospectively employ a "Hematology Patient Reported Symptom Screen" (HPRSS) which consists of three questions about fatigue, pain and overall QOL. The aim of this study is to understand if HPRSS parameters predict various clinical outcomes. Methods: Eligibility for this retrospective study was as follows: 1) New diagnosis of AL between 2009-2014; 2) baseline HPRSS documented in the medical record; and 3) at least a year of follow-up, which included either death within or follow-up through 12 months after diagnosis. The HPRSS questions were rated on a 1-10 scale, with 10 being the worst for fatigue and pain, and 10 being the best for overall QOL. Scores were abstracted from visits at time of diagnosis, and at 12 months +/- 1 month post-diagnosis. We considered a 2-point difference in serial scores a "change" over time. Results: For the 302 patients in this study, the baseline median scores [interquartile range] for fatigue, pain, and QOL were 6 [3,7], 2 [0,5] and 5 [3,8], respectively. Median overall survival (OS) was 39.1 months, with 102 deaths in the first year. There were significant differences in baseline HPRSS between those who lived longer than one year and the early death patients in the domains of fatigue (5 [IQR 3, 7] vs. 7 [IQR 5, 8], p<0.0001) and QOL (6 [IQR 4, 8] vs. 5 [IQR 3, 7], p=0.006), but not in pain (2 [IQR 0, 5] vs. 2 [IQR 0, 5]). There were significant baseline differences in the early death group for alkaline phosphatase, bilirubin, creatinine, and Mayo stage. Patients who received ASCT had the best baseline fatigue 4 [2.5,6] and QOL 7 [5,8] scores and were significantly different from those who did not receive ASCT [fatigue p<0.0001) and QOL (p<0.0001)] On univariate analysis fatigue and QOL were prognostic for OS. On multivariate analysis Mayo 2012 staging, autologous stem cell transplant and baseline fatigue remained independently prognostic. When analyses were restricted to the 125 patients with HPRSS measurements at 12 months, we found that over time QOL scores improved significantly 6 [IQR 3.5, 8] to 7 [IQR 5, 8] (two sided Wilcoxon signed rank p=0.01), but fatigue (5 [IQR 2, 5] to 4.5 [IQR 3, 6]) and pain scores (2 [IQR 0 ,4] to 1.5 [IQR 0, 4]) did not. Patients with worse baseline parameters tended to have improvement in QOL by 12 months while those with the best baseline parameters tended to decline in QOL although not statistically significant. When we included the 102 patients who died within 12 months to the comparison, the early death patients had the worst baseline parameters and there were significant differences across all 4 groups for most characteristics (Table 1). There was no association between achieving hematologic or organ response with change in QOL. Conclusion: Asking patients with AL to rate their fatigue and QOL using a 10-point scale has predictive value. Patient reported fatigue at diagnosis is an independent prognostic factor for survival. Survival at one year was associated with significant improvement in QOL. Table 1. Baseline parameters between patients with early death and/or survive 12 months. Grouped by Patient Reported QOL at 12 months Relative to Baseline Dead by 12 months, n=102 Improved, n=44 Stable, n=55 Worsened, n=26 pa HPRSS scores [IQR] Baseline QOL Baseline fatigue Baseline pain 12 month QOL 12 month fatigue 12 month pain 5 [3,7] 7 [5,8] 2 [0,5] NA NA NA 4 [3-5] b,c,d6 [4-8] b,c2 [0-4] 7 [6-9] b,d4 [1.25-6] 1 [0-3] 7 [4-8] 4 [2-7] 2 [1-5] 7 [4-8] 5 [3-6] 2 [0-4] 8 [7-10] 2.5 [0-5.25] 2 [0-6.25] 5 [3-7] 5 [3-6] 2.5 [1-4] <0.0001 <0.0001 NS NS 0.001 NS dFLC, mg/dL 48 (2.89-726) 30 (1.1-494) 19 (36-455) 22 (0.2-2097) 0.008 Troponin, ng/mL 0.065 (<0.01-0.84) 0.02 (<0.01-1.6) 0.01 (<0.01-0.19) 0.01 (<0.01-0.14) <0.0001 NT-proBNP pg/mL 5222 (159-70,000) 1766 (26-16868) 1381 (24-19180) 496 (56-2973) <0.0001 Received Transplant (%) 4 (4) 13 (33) 36 (50) 13 (50) 0.0002 a Significant by Wilcoxon across all 4 categories; b Significant difference between Improved and Worsened; c Significant difference between Improved and Stable; d Significant difference between Worsened and Stable Disclosures Kumar: Millenium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Research Funding; Onyx: Consultancy, Research Funding. Thompson:Kite Pharma: Research Funding.

Abstract Background: Both MM specific and patient specific parameters place patients at risk for death. Patient frailty has been delineated primarily by age and ECOG performance score (PS) and secondarily with creatinine, eGFR, and the International Staging System (ISS), which reflect both renal function and disease burden. In an attempt to improve upon these commonly used measures, a frailty score for elderly patients that combines functional status [Activity of Daily Living (ADL) and Instrumental Activity of Daily living scores], comorbidities [Charlson comorbidity index (CCI)] and age has been developed by the IMWG. Incorporation of these tools into a busy clinical practice is challenging due to time constraints. Therefore, the identification of frail patients with an easily applicable, rapid and objective tool remains a challenge and an unmet need. A reliable, non-invasively assessable, biochemical marker of frailty would be an ideal tool to identify patients at higher risk of death. It was our goal to determine the role of NT-proBNP, a well-established cardiovascular risk biomarker, as a marker of frailty in patients with MM and in predicting overall survival (OS). Methods: Patients were elegible for this retrospective study if they were seen at the Mayo Clinic, Rochester, MN within 30 days of their myeloma diagnosis during the interval between 1/1/2007 and 12/31/2011. As part of the Mayo Clinic registration, all patients complete forms containing their past medical history, symptoms, and ADLs. Data from that first visit was abstracted and used to calculate a CCI. We excluded all patients with a concomitant diagnosis of light-chain AL amyloidosis. NT-proBNP concentration was measured in frozen sera collected within 30 days of diagnosis. NT-proBNP assay was run on the E170 Modular analyzer (Roche Diagnostics, Penzberg, Germany). We evaluated the prognostic role of NT-proBNP and these indices on OS using the Kaplan-Meier method. Results: Among the 351 consecutive patients satisfying entry criteria, median age was 65 years (range 22-95), 33% were ≥70 years, and 56% were male. Twenty-eight percent were ISS stage III, 13% had a creatinine ≥2 mg/dL, 19% had PS ≥2, and 11% had ADL score ≥2, and 30% CCI ≥2. The median value of NT-proBNP was 109 ng/L (interquartile range: 30-375 ng/L). NT-proBNP concentrations differed in the three ISS stages (median: 122 ng/L stage I, 190 ng/L stage II and 1822 ng/L stage III, P<0.0001). Median OS was 5.6 years. The best cutoff of NT-proBNP predicting OS at one year was 301 ng/L (sensitivity: 57.88%, specificity: 74.29%; AUC=0.668) and distinguished two groups with different OS (median not reached vs. 35 months, P<0.0001). Variables predictive for OS are shown in the Table and included PS, age, CCI, ISS, NT-proBNP. On multivariate analysis, ISS and NT-proBNP were independent of each other as long as age, PS and/or CCI were excluded from the model. NT-proBNP withstood these clinical variables better than did ISS (data not shown). We built two different models (table). In model 1, NT-proBNP >301 ng/L was an independent predictor of survival while age ≥70 and PS ≥2 and CCI were not significant. However, if we considered ISS stage instead of NT-proBNP in the same model, ISS stage was not significant. Conclusions: In this unselected cohort of patients with newly diagnosed multiple myeloma, NT-proBNP was a useful predictor of survival independent of age and PS. The threshold of 301 ng/L is remarkably similar to the well-established cutoff for heart failure of 300 ng/L. NT-proBNP outperformed the CCI and the ISS as risk factors. NT-proBNP is a widely available biomarker that could be added to the panel of laboratory tests of newly diagnosed MM patients and serve as a simple means of determining patient frailty in a busy clinical practice. Table. Results of univariate and multivariate analysis of various prognostic factors (NS, not significant; NI, not included). Univariate Multivariate Multivariate RR (95% CI) P Model 1 P Model 2 P PS ≥2 3.4 (2.4-4.8) <0.0001 2.5 (1.7-3.6) <0.0001 2.8 (1.9-4.0) <0.0001 Age ≥70 2.7 (1.9-3.6) <0.0001 2.1 (1.5-2.9) <0.0001 1.9 (1.3-2.7) 0.0003 CCI >=2 1.9 (1.4-2.6) <0.0001 NS NS 1.5 (1.0-2.0) 0.03 ISS stage 1.1 (1.1-1.8) 0.0004 NI NI NS NS NT-proBNP >301 ng/L 2.3 (1.7-3.2) <0.0001 1.6 (1.1-2.2) 0.007 NI NI Disclosures Merlini: Janssen-Cilag: Honoraria; Prothena: Honoraria; Millennium-Takeda: Honoraria; Pfizer: Honoraria. Kumar:Janssen: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Millenium/Takeda: Research Funding; AbbVie: Research Funding; Onyx: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria.

Abstract Abstract 201 Background: Pomalidomide at doses of 2 or 4 mg/d has demonstrated excellent activity in patients with relapsed multiple myeloma (MM). Between November 2007 and March 2012, we opened 6 sequential phase 2 trials and treated 345 patients with relapsed MM with pomalidomide at differing doses with weekly dexamethasone (Pom/dex). Results of 164 of these patients have been previously published. Here we describe long term follow up of these patients as well as results of an additional 181 patients with relapsed MM treated with the Pom/dex regimen. Methods: The six cohorts consisted of: Cohort 1 (N=60): relapsed MM with 1–3 prior regimens, 2 mg dose; Cohort 2 (N=34): lenalidomide (LEN) refractory, 2 mg dose; Cohort 3 (N=35): BZ)/LEN refractory, 2 mg dose; Cohort 4 (N=35): BZ/LEN refractory, 4 mg dose; Cohort 5 (N=60) LEN refractory, 1–3 prior regimens, 4 mg dose; and Cohort 6 (N=120) LEN refractory, 4 mg dose. Pomalidomide was given orally 2 mg daily or 4mg daily on days 1–28(cohorts 1–5) or 1–21 (cohort 6) of a 28-day cycle with oral dexamethasone given 40 mg daily on days 1, 8, 15 and 22. Response was assessed by the International Myeloma Working Group Uniform Response criteria. All patients received aspirin 325 mg daily for deep venous thrombosis (VTE) prophylaxis or full dose anticoagulation. Results: A total of 345 patients were enrolled across all 6 cohorts. One patient was ineligible and excluded from analysis. The median age was 64 years (32–88). The median time since diagnosis was 53 months. The median number of prior therapies was 3 (1–14). 147 (44%) had high-risk molecular markers by mSMART criteria. Prior therapies consisted of thalidomide 52%, lenalidomide 87%, bortezomib 75%, autologous stem cell transplant 70% and allogeneic transplant 3%. The median follow-up is 10.4 months (5.4–34 months). Sixty-seven percent are alive and 32% remain progression free. 46 patients are continuing to receive treatment. The most common toxicities (grade 3 or higher) were neutropenia (31%), anemia (16%), thrombocytopenia (12%), pneumonia (8%) and fatigue (8%). VTE was seen in 10 patients (3%). Outcomes are shown in Table 1. Across all 6 cohorts confirmed responses of partial response (PR) or better were seen in 34%. The response rate in all patients with mSMART high risk status was 30.6%. Responses and duration of response (DOR) in those with high risk molecular markers include: 17p– 19 of 56 (34%) DOR 8.2 months; t(4;14) 6 of 24 (25%) and DOR 4.8 months; t(14;16) 7 of 11(64%) and DOR 9.5 months; deletion 13 by cytogenetics 13 of 37 (35%) with DOR 8.2 months. In a multivariate analysis, only LDH > ULN, number of prior regimens, and prior BZ therapy were predictive of a shorter TTP and factors associated with a poor OS following initiation of pomalidomide therapy included B2M > 5.5, LDH > ULN,number of prior regimens, and prior BZ therapy. Conclusions: Pom/dex is active and well tolerated even in heavily pretreated patients and those with high risk molecular markers. Remissions are durable. Response rates and toxicity are similar between the 2 mg and 4 mg doses. Disclosures: Lacy: Celgene: Research Funding. Stewart:Celgene: Consultancy, Honoraria. Reeder:Celgene: Mayo Clinic receives funding from Celgene to support clinical trials Other, Research Funding.

Abstract Abstract 3972 Background: The treatment paradigm for myeloma has undergone a dramatic shift in the past decade with the introduction of the novel agents and their application at every stage of the treatment. We and others had previously shown that survival of patients with myeloma had improved in the earlier half of the last decade and attributed this to a combination of novel therapies as well as increased use of stem cell transplant. It is not clear if this momentum in improving survival has been maintained. We examined the survival trends of patients with newly diagnosed myeloma seen within the past decade to examine this question. Patients and Methods: We studied 1056 patients with newly diagnosed myeloma, who were seen at Mayo Clinic between January 1, 2001 and December 31, 2010; who were seen within 30 days of their diagnosis. For examination of the time trends, we grouped the time interval into two five year periods, 2001–2005 and 2006–2010. Survival was estimated using Kaplan Meier method and survival curves were compared by log rank test. Impact of various prognostic factors was evaluated using Cox proportional hazards test. Results: The median age at diagnosis was 65 (range; 22–92), and 59% were male. The median estimated follow up for the entire cohort was 4.6 years (95% CI; 4.4, 4.9) and 57% of the patients were alive at last follow up. The median overall survival (OS) for the entire cohort was 5.4 years (95% CI; 5, 6.3). The overall survival for patients in the 2001–2005 group was 4.6 years compared with not reached for the 2006–2010 cohort (P< 0.001). The five-year estimated OS was 48% for the earlier group compared with 66% for the latter group. The estimated 1-year survival was 90% for the recent cohort compared with 83% for the earlier cohort, suggesting improvements in the early mortality. Interestingly, the improvement was predominantly seen in the older age group (>65 years; 49%). The 5-year survival of the older patients improved significantly from 31% (2001–2005) to 56% (2006–2010) (P<0.001). In contrast, among younger patients (≤65 years of age), the 5-year survival improved only marginally from 63% (2001–2005) to 73% (2006–2010) (P=NS). One or more novel agents (Lenalidomide, thalidomide or bortezomib) were used as part of initial therapy in 631 (62% of 1021 in whom treatment data was available). The OS among of this group was 7.3 years (95% CI; 5.9, NR) compared with 3.8 years (95% CI; 3.1, 4.6). In a multivariate model that included both use of novel agent and the year group, only the novel agent use was associated with improved survival suggesting that the improvement in the survival is related to the increased use of novel agents in the initial therapy. No significant differences were observed between the groups in terms of conventional prognostic factors. Conclusions: The current results confirm continued improvement in the overall survival of patients, even within the last 10 year period, and highlight the impact of initial therapy with novel agents. Most importantly, we demonstrate that the improved survival has primarily benefited older patients. Our study highlights that urgent need for additional new agents to provide further survival improvement for younger patients, and in order achieve a cure for this disease. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Cephalon: Research Funding; Genzyme: Research Funding. Dispenzieri:Celgene: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Janssen Research & Development: Research Funding. Gertz:Binding Site: Honoraria.

Abstract Abstract 747 Background: Light chain amyloidosis is a monoclonal plasma cell proliferative disorder characterized by multiorgan deposition of monoclonal light chain derived amyloid fibrils. The diffuse organ infiltration by the amyloid fibrils leads to various AL related clinical features. Therapy of AL has been primarily aimed at elimination or control of the monoclonal plasma cells, thus decreasing the light chain available for amyloid formation. Assessment of response to therapy has been grouped into hematological response demonstrating elimination or reduction of the monoclonal population and organ response demonstrating actual improvement in its structure or function. Given the potentially long delay in observing organ improvement, hematological response has been the surrogate short term marker for long term outcome given the relatively rapid decline seen in the monoclonal protein with effective therapy, as well as studies showing improved long term outcome with a hematological response, especially complete response. However, conventional hematological response criteria give priority to the intact monoclonal protein rather than the light chain, which is the amyloidogenic protein. We hypothesized that a light chain response will correlate better with outcome than changes in the intact monoclonal protein levels. Methods: We identified 348 patients who had undergone stem cell transplant (SCT) for AL from among a large group of patients undergoing different treatments for AL, and in whom serial tests results were available. We identified the lowest value attained following SCT for various hematological response parameters (intact serum M-protein [MP], the difference between involved and uninvolved serum free light chain [FLC-diff], and urine M-protein [UP]) before an alternate therapy was instituted. We first estimated the best cutoff for the degree of change in each parameter that predicted 5-year survival from SCT. Cox proportional hazards model was used for multivariable analysis of factors influencing overall survival (OS). Results: We first examined the relative contribution of the MP and the FLC-diff on the overall survival following transplant. The best cutoff for reduction in FLC-diff to predict OS at 5 years from SCT was 88% if all patients were considered and 90% if only those with a baseline FLC diff > 7.5 mg/dL were considered. The best cutoff for MP reduction was 40% for 5 year survival for all patients and 67% for those with a baseline MP > 1.0 gm/dL. We then looked at the impact of FLC reduction and MP reduction in a multivariable analysis using OS as endpoint. For all patients, FLC reduction, but not MP reduction significantly impacted outcome, and results were similar when considering patients with MP>1.0 gm/dl and FLC-diff > 7.5 mg/dl at baseline. Among those with a baseline FLC-diff >7.5 mg/dL (n=125), the overall survival was 35 mos from SCT for those with less than 90% decrease in FLC-diff (45 pts) compared to not reached for those with at least 90% decrease (80 pts); P < 0.001 (Figure). Conclusions: The current study supports the notion that reductions in the free light chain parameters represent a more useful measure of hematological response that translates into better overall survival and possible better chance at organ improvement. A reduction in the FLC difference of 90% appears to correlate best with prolonged survival. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lacy:celgene: Research Funding.

Abstract Abstract 946 Background: The emerging therapies directed at the plasma cell clone have dramatically increased overall survival (OS) for both myeloma and amyloidosis patient populations. As more treatment trials are done in patients (pts) with AL, benchmarks for outcomes among previously treated AL pts are required, especially for those pts who are not candidates for high-dose chemotherapy with peripheral blood stem cell transplantation (ASCT). Inadequate information is available about the number of non-transplant pts who go on to receive second line treatment for AL amyloidosis. Methods: To ascertain the outcomes of pts who did not receive ASCT as primary therapy but who required a second line of therapy, we reviewed the experience of pts seen at Mayo Rochester between 1990 and 2010 according to an IRB approved retrospective review protocol. 1828 pts had their first Mayo visit for AL during this time period. Pts were excluded from this study for the following reasons: 571 had upfront transplant; 907 pts had received only one line of treatment for their amyloid; 91 had longstanding other associated malignancy [Waldenstrom's macroglobulinemia (8), lymphoma (15), CLL (6), multiple myeloma (62)]; and 93 had inadequate follow-up information. One-hundred and sixty-six pts received 2 or more lines of therapy for their AL amyloid and are the subject of these analyses. Statistical analyses were done using JMP statistical software (SAS, Carey, NC). Results: Of the 166 pts, the median age was 64 years (range 34, 84). 49% were male. Baseline organ involvement was as follows: cardiac 84/166 (50%); renal 118/166 (71); liver 23/166 (13.8%); peripheral nerves 19/166 (11.4%); and gastrointestinal 14/166(8.4%). Thirty-one percent (52/16) had both cardiac and renal involvement. Only 73 pts had cardiac biomarkers (NT pro BNP and Troponin T) done at baseline. Of these pts, 26% were stage 1, 49.3% were stage 2, and 24.6% were stage 3 according to original Mayo cardiac biomarker staging system. By inclusion criteria definition, all 166 pts received 1st and 2nd line therapies; 53 (32%) pts received 3rd line of treatment; 20 (12%) received 4th line of treatment; and 10 (6%) received 5th line of treatment. For first line therapy, the most common drugs given either singly or in combination were corticosteroid (147/166; 88.5 %), alkylator (99/166; 59.6%), IMID (34/166; 20.4 %), and bortezomib (19/166; 11.4%). The median time from diagnosis to 2nd line therapy was 10.3 months. Second line regimens received included: corticosteroid, 108/166 (65.1%); alkylator, 76/166 (45.8 %); IMID, 46/166 (27.7%); and bortezomib, 46/166 (27.8%). The median time from diagnosis to 3rd line therapy was 19.8 months. For the 53 pts who received 3rd line treatment, regimens included: corticosteroid, 41/53 (77.3%); IMIDs, 17/53 (32.1%); alkylator, 17/53 (32.1%); bortezomib, 12/53 (22.6%). The median time from diagnosis to 4th line therapy was 31.8 months. For the 20 pts receiving 4th line treatment, regimens included: corticosteroids, 15/20(75%); alkylator, 12/20 (60%), bortezomib, 7/20 (35%); and IMIDs, 4/20(20%). Eighty-three pts have died. The 1 year mortality of our study population was only 8%. The median follow-up of surviving pts was 47.6 months. Figure 1 demonstrates Kaplan-Meier estimates of overall survival (OS) from initiation of each successive therapy. The median OS from initiation of 1st, 2nd, and 3rd lines of treatment were 65, 49.5 and 36.7 months respectively. The median OS after the 4th line of treatment was not reached. The 4 year OS rates from initiation of 1st, 2nd, 3rd and 4th lines of therapy were 58%, 50.8 %, 50 % and 53.4% respectively. Conclusion: Outcomes among relapsed or refractory AL pts are better than what one might expect. Multiple publications have demonstrated that the 1 year mortality of newly diagnosed AL is in the vicinity of 40%. Thereafter, the rate at which pts die dramatically decreases. Our study provides explicit data characterizing the fate of pts unfortunate enough to require additional therapy but fortunate enough to survive past the exceedingly high risk period of death that occurs within 6–12 months of diagnosis. These data provide useful information for benchmarking future trials for treatments of AL amyloidosis. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1988 Background With the utilization of novel agent-based combination therapies and autologous stem-cell transplantation (ASCT) in multiple myeloma (MM), the rigorous response category of stringent complete remission (sCR) in the international uniform response criteria is increasingly becoming attainable. In addition to the standard criteria for complete remission (CR), sCR requires normalization of the free light chain ratio and disappearance of clonal cells as determined by the marrow immunofluorescence or immunohistochemistry. We have previously validated the new response category of sCR created in by the International Myeloma Working Group and demonstrated that sCR represents a deeper level of response, translating into a superior OS. Herein we report the survival outcomes of patients attaining sCR or standard CR, from a 2-year landmark after ASCT in a cohort of patients with extended follow-up. Additionally, we report the outcome of patients who remained in sCR for at least 6 months (sustained-sCR) after ASCT. Patients and Methods Maximal response rates of four hundred and forty-five consecutive patients who underwent ASCT within 12 months of diagnosis of MM were determined. The population achieving varying degrees of complete remission (n=237) is the focus of this study. We performed a landmark analysis 2 years after ASCT to ensure that all the patients attaining at least CR had sufficient time to reach the response levels being studied. Patients were categorized as having sustained sCR (sus-sCR) if the duration of sCR was at least 6 months. Overall survival (OS) was estimated by the Kaplan Meier method and the survival curves were compared by log-rank test. Results The median follow-up of the entire cohort was seventy-seven months (95% CI: 73–82 months). The sCR rate after ASCT was 24% (n=109). Median time to progression (TTP) of patients attaining sCR was 50 months from ASCT, and median overall survival (OS) is not reached, in contrast to those attaining standard CR (n=37, TTP=20 months, OS=81 months) or near CR/nCR (n=91; TTP= 19 months, OS=60 months, p<0.0001 for both TTP and OS). OS of patients surviving at least 2 years from ASCT (Figure 1a) continued to remain superior for those attaining sCR (n=105, median: not reached) versus 70 months for the CR group (n=32; p=0.004). Among patients achieving sCR (n=109), OS of patients with sus-sCR (n= 75) at 6 months from ASCT is not reached (5-year OS=91%, 7-year OS=86%) versus median OS of 66 months (5-year OS=49%, 7-year OS=37%; p<0.0001) for those who had non-sustained-sCR (n=34) after ASCT (Figure 1b). Conclusion In our landmark analysis of patients with MM who survived at least 2 years from ASCT, those attaining sCR have a markedly superior outcome compared to those attaining standard CR. However, among patients attaining sCR, those with sustained sCR of 6 months or greater had the best outcome. Myeloma trials reporting response rates should identify patients achieving sCR and CR separately owing to markedly disparate outcomes of the two categories. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1831 Poster Board I-857 IL-1 Antagonists Are More Effective at Inhibiting IL-6 Production than Apoptosis Inducing Agents: Implications for Targeting the Myeloma Proliferative Component. John A. Lust, MD,PhD1, Steven R. Zeldenrust, MD, PhD1, Laurie L. Moon-Tasson1*, and Kathleen A. Donovan, PhD1*. 1Division of Hematology, Mayo Clinic, Rochester, MN, United States, 55905. Background Multiple myeloma patients with an elevated growth rate have a shortened duration of response and survival. IL-6 is a central myeloma growth factor and we have shown that abnormal production of IL-1beta in the myeloma microenvironment stimulates the generation of paracrine IL-6 and myeloma cell growth in vivo. Dexamethasone and IL-1Ra both have the ability to inhibit IL-1 induced IL-6 production in vitro however their ability to inhibit IL-6 production and myeloma cell growth have not been investigated in a comparative fashion. Methods In vitro, IL-1 (100, 10, 1 pg/ml) was added to stromal cell cultures in the presence or absence of IL-1Ra (1 and 0.1 μg/ml) or dexamethasone (100 and 10 μM). IL-6 levels were quantitated by ELISA. In vivo, a patient with smoldering myeloma (≥ 10% bone marrow plasma cells) received 100 mg of IL-1Ra SQ qd for 6 months, low dose dexamethasone (20 mg qweek) for 6 months, followed by the combination of IL-1Ra and dexamethasone for 6 months. The bone marrow plasma cell percentage (BMPC), serum IgG, the plasma cell labeling index (marker of myeloma cell proliferation) and the C-reactive protein (marker of IL-6 production) were monitored serially. Results The effects of IL-1Ra and dexamethasone on IL-1 induced IL-6 production by marrow stromal cells are detailed in Figure 1. The results showed that IL-1Ra at 1 μg/ml was able to inhibit IL-1 induced IL-6 production back to baseline at all IL-1 concentrations tested. The inhibitory effect was less pronounced at 0.1 μg/ml IL-1Ra but still superior to dexamethasone. Dexamethasone was less effective at IL-6 inhibition compared to IL-1Ra using 100 and 10 pg/ml of IL-1 but similar at 1 pg/ml of IL-1. Of interest, the patient treated with IL-1Ra alone, dexamethasone alone, and the combination appeared to mimic these results in vivo. Anakinra alone induced a reduction of the PCLI and CRP. Dexamethasone alone decreased the M-protein; however the PCLI and CRP values increased. The PCLI increased from 0% to 0.8% and the CRP increased from 0.18 up to 1.48 indicating increased levels of IL-6 and a more active proliferative component of the disease. Subsequently, the combination of dexamethasone and IL-1Ra led to a further decrease in the IgG and the PCLI and CRP decreased again; PCLI decreased from 0.8% to 0.2% and CRP decreased from 1.48 down to 0.40. Conclusion The above results suggest that agents such as IL-1Ra are more effective at IL-6 inhibition and targeting the proliferative myeloma component than apoptosis inducing agents such as dexamethasone. Combination therapy with IL-1 inhibitors and apoptosis inducing agents may be useful in patients with active myeloma that have an elevated PCLI at diagnosis. Disclosures No relevant conflicts of interest to declare.