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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 602 Although, MM remains the most common indication for ASCT in the US, a controversy exists about the timing of ASCT. Since early ASCT (eASCT) versus delayed ASCT (dASCT) results in similar progression free survival (PFS) and overall survival (OS) in the novel agent era, economic assessment of one strategy over the other may help both clinicians and policy makers in establishing guidelines in the MM treatment paradigm. Here we designed a study to model a decision tree of both the strategies and estimate their cost-effectiveness. A decision tree was developed to compare the outcomes of ASCT in newly diagnosed transplant eligible MM patients after chemotherapy with novel drug lenalidomide which formed the base case. The survival data was obtained from our published data on eASCT versus dASCT in MM patients who underwent initial therapy with dexamethasone + immunomodulatory agents (IMiDs). The initial decision node on the decision tree model was dichotomized based on the cutoff of 12 months for eASCT versus dASCT. The probabilities of events during the length of follow up (60 months) period which formed our base case were: (a) eASCT cohort: Induction chemotherapy for median of 6 months - ASCT - median 30 months to relapse (drug free interval) followed by median therapy of 24 months for relapsed MM; (b) dASCT cohort: Median initial therapy for 36 months - ASCT - median 24 months to relapse (drug free interval). The cost analysis was done from a US third party payer perspective. The cost data for MM ASCT was obtained from the published data in which direct hospital costs were obtained from Nationwide Inpatient Sample and were converted to Medicare cost-to-charge ratio for urban hospitals. Chemotherapy cost consisted of actual drug costs that calculated based on average wholesale prices AWP (2008), costs of medical oncology visits, and the costs of managing adverse events. Post-ASCT maintenance costs were not included in the analysis. TreeAge Pro 2012 software was used to perform a static decision analysis. The outcomes were expressed in the units of health utility values obtained from phase III HOVON trial which measured quality of life (QoL) using EORTC QLQ-C30 & EuroQoL-5D. All scales and items were linearly transformed to range from 0 to 100. The utilities measured by the EuroQol-5D ranged from 0.40 before induction therapy to 0.70 after ASCT and translated to QALYs using area under the curve method. Using a Consumer Price Index (CPI), the costs of ASCT and chemotherapy were converted into 2012 US$. The robustness of the decision model was tested through univariate analyses and tornado diagram to identify those variables which if varied across clinically relevant measures may result in difference in outcomes. The expected cost of providing treatment to newly diagnosed MM patients for a period of 5 years when they undergo eASCT after induction with IMiDs was calculated to be $211,869. This was $52,454 less than the expected cost of undergoing dASCT. Patients who underwent eASCT had an expected benefit of 2.06 QALYs following treatment, which was 0.19 QALYs more than the patients who received dASCT. This implies that eASCT is preferred over (dominates) dASCT. One-way sensitivity analysis was undertaken to identify factors that were found to be most influential and included OS, overall response rate (ORR) and 1 year ASCT related mortality rate (TRM). Specifically, eASCT showed dominance even if the probability of OS was lowered to 52.1% from the actual case base of 65%, or the probability of ORR was lowered to ≥ 75.8% from the actual case base of 92%, or the probability of 1 year TRM was increased to 11.5% from actual case base of 2%, indicating the robustness of the model favoring cost effectiveness of eASCT. In absence of a survival benefit, the cost savings of early ASCT as measured by ICER would favor this approach, and it would help clinicians, patients, policy makers and third party payers in decision making. Future prospective studies in MM ASCT should incorporate economic and QOL components in the analysis and also focus on the added cost of post-ASCT maintenance therapies with respect to ICER and QALYs. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3992 Little is known about the rare entities of heavy and light chain amyloidosis (AHL) and heavy chain amyloidosis (AH). In this study, we report the renal and hematologic characteristics, pathology, and outcome of 17 patients with renal AH/AHL including 5 with AH (4 IgG and 1 IgA) and 12 with AHL (7 IgGλ, 3 IgAκ, 1 IgAλ, and 1 IgMλ), and compare them with 202 patients with renal AL amyloidosis (AL) diagnosed during the same time period. All cases were diagnosed by kidney biopsy that showed Congo red-positive deposits. Amyloid typing was done by laser microdissection and mass spectrometry (LMD/MS) (12 patients) or by immunofluorescence (5 patients). All patients with renal AH/AHL were Caucasians, with a M:F ratio of 2.4 and a median age at biopsy of 63 years. Compared with patients with renal AL, those with renal AH/AHL had less frequent concurrent cardiac involvement, higher likelihood of having circulating complete monoclonal Ig, lower sensitivity of fat pad biopsy and bone marrow biopsy for detecting amyloid, higher incidence of hematuria, and better patient survival. The hematologic and renal responses to chemotherapy were comparable to renal AL. In 42% of patients, AH/AHL could not have been diagnosed without LMD/MS. In conclusion, renal AH/AHL is an uncommon but under-recognized form of amyloidosis, and its diagnosis is greatly enhanced by the use of LMD/MS for amyloid typing. The accurate histological diagnosis of renal AH/AHL and distinction from AL may have important clinical and prognostic implications. Table 1. Demographics and hematologic characteristics AH/AHL AL p value No. of patients 17 202 Gender: Male/female 12/5 (71%/29%) 126/76 (62%/38%) 0.61 Age, median (range) 63 (50–77) 62 (36–86) 0.73 Additional organ involvement 8 (47%) 126 (62%) 0.3 Cardiac involvement 3 (18%) 100 (50%) 0.01* % of plasma cells in bone marrow, median (IQR) 8 (5–15) 6 (5–10) 0.82 ≥30 plasma cells 4 (24%) 11/198 (6%) 0.02* Positive SPEP/SIF for paraprotein 15 (88%) 158/200 (79%) 0.53 Presence of whole monoclonal protein on SPEP 14 (82%) 108/200 (54%) 0.04* Positive UPEP/UIF for paraprotein 13/16 (81%) 158/189 (84%) 0.73 Presence of whole monoclonal protein on UPEP 10/16 (63%) 61/189 (32%) 0.03* Abnormal serum FLC ratio (<0.26 or >1.65) 9/12 (75%) 150/188 (80%) 0.71 Markedly abnormal FLC ratio (< 0.125 or > 8) 5/12 (42%) 100/188 (53%) 0.55 Positive bone marrow for amyloid 6/16 (38%) 135/183 (74%) 0.004* Positive fat pad biopsy for amyloid 2/14 (14%) 105/145 (72%) <0.001* IQR, interquartile range. Table 2. Renal characteristics at kidney biopsy AH/AHL AL p value No. of patients 17 202 24h urine protein in g, median (IQR) 5.1 (3.2–9.0) 6.0 (3.2–10.0) 0.9 Full nephrotic syndrome 9/16 (56%) 132/197 (67%) 0.42 Serum albumin in g/dl, median (IQR) 2.7 (2.2–3.3) 2.5 (1.9–2.9) 0.29 % albuminuria on UPEP, median (IQR) 68 (61–72) 70 (60–76) 0.47 Serum creatinine in mg/dl, median (IQR) 1.4 (1.1–2.1) 1.2 (0.9–1.8) 0.25 Serum creatinine >1.2 mg/dl 10/16 (63%) 92/201 (46%) 0.3 eGFR, median (IQR) 47 (27–67) 58 (36–75) 0.29 Decreased eGFR 10/16 (63%) 103/201 (51%) 0.44 Microscopic hematuria 9/16 (56%) 44/169 (26%) 0.02* IQR, interquartile range. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2059 Introduction: Two randomized trials have demonstrated a benefit in progression free survival (PFS) of 18–20 mofor maintenance treatment with lenalidomide after auto-PBSCT for multiple myeloma (MM). Although results on survival benefit are conflicting and quality of life (QOL) data is lacking, some have begun to recommend maintenance. No study has evaluated patient perceptions of maintenance. We conducted a systematic survey of MM patients (pts) regarding what constitutes a meaningful benefit that would make burdens of maintenance (toxicity and cost) acceptable. Methods: We mailed a brief self-administered survey in 3 waves to 1159 consecutive living pts evaluated at Mayo Clinic. The survey provided background on the standard of care for MM in transplant eligible pts and data on maintenance. Pts were asked to estimate the magnitude of OS benefit that would be acceptable for varying degrees of toxicity and cost. Results: Of the 1159 surveys sent, 886 pts (83.2%) responded, including 150 notifying us of a decision not to participate. 736 pts returned a completed survey (66% raw response rate). (56%) male, 407 (55%) had undergone auto-PBSCT, 467 (63%) had discussed maintenance with a physician, and 9 (1%) pts had received no treatment. 10% of pts had MM for 3–12 mo, 14% for 1–2 yr, 13% for 2–3 yr, 20% for 3–5 yr, 44% for 5 yr or more. Pt age: 4% 18–49 yr, 24% 50–59 yr, 40% 60–69 yr, 27% 70–79 yr, and 6% >80 yrs. The most worrisome potential toxicity was identified as peripheral neuropathy by 27% of pts, cytopenias by 24%, LE DVT 20%, fatigue 15%, nausea 8%, diarrhea/constipation 7%. In response to a question about whether they would choose maintenance if there was a PFS benefit but no improvement in OS, 92% would opt for maintenance if it were known to cause mild toxicity, while 77% would opt for maintenance despite moderate toxicity. Subsequent questions included cost and toxicity considerations and required pts to identify minimum acceptable duration of OS benefit to estimate more precisely a meaningful clinical benefit. If treatment was free, had no toxicity, and the OS benefit was 1 yr or less, 49% would choose maintenance (see Figure). In the same scenario, if toxicities were mild, the proportion of pts who choose maintenance was similar (46%). If pts experienced moderate toxicity, 42% choose maintenance. With rising financial burden (out-of-pocket) and toxicity, the proportion of pts who choose maintenance declined (see Table). For example, if the cost was $25/mo, mild toxicity experienced, and the OS benefit was one year or less, 46% would choose maintenance, while 39% of pts would choose maintenance if it cost $250/month and there was moderate toxicity. If maintenance cost $10,000/mo and was associated with mild or moderate toxicity, 18% and 17% of pts would choose treatment, respectively. Conclusions: For the first time, we have described the broad range of patient perspectives regarding trade-offs in the treatment of MM with maintenance therapy. We found that willingness to be treated with maintenance declined when actual benefits were provided in concrete numeric terms compared with a general statement of PFS benefit. The discrepancy between the 92% of pts choosing to undergo maintenance if free and mild toxicity when there is a PFS benefit but no OS benefit, compared to 49% of pts choosing maintenance if free, mild toxicity, and associated with an OS benefit of 1 yror less; suggests pts have difficulty understanding the concept of PFS. We also found that the magnitude of benefit required to consider maintenance was affected by cost and toxicity. In our experience, pts typically incur a cost of approximately $25/mo and experience mild toxicity. In this study, nearly half (46%) of such pts would opt for maintenance if the OS benefit was 1 year or less while only 33% of pts would opt for maintenance if the OS benefit was 6 months or less. Our data implies that good care in MM requires detailed conversations about each and every patient's priorities and expectations prior to making recommendations for or against such treatments. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1861 Idiopathic Bence Jones Proteinuria (Smoldering Monoclonal Light-Chain Proteinuria), first reported in 1982, is an asymptomatic plasma cell proliferative disorder associated with an elevated risk of progression to symptomatic MM or amyloidosis (AL). We defined it as the presence of a monoclonal light chain in the urine ≥200 mg/24h, absence of an intact immunoglobulin M protein (IGH expression) in the serum and no evidence of MM, AL or other related plasma cell proliferative disorders. Following approval by our Institutional Review Board, we searched a computerized database and reviewed the records of all patients seen at Mayo Clinic within 30 days of the recognition of a monoclonal light chain (Bence Jones protein) in the urine from January 1, 1960 through June 30, 2004. Patients with end-organ damage at diagnosis resulting from the plasma cell proliferative disorder (including MM or AL), or who had received chemotherapy or had a nephrotic syndrome were excluded. Follow-up included review of each patient's medical record at Mayo Clinic, as well as review of death certificates for patients who died. Patients were sent letters of inquiry if they had not visited Mayo Clinic in the preceding year. The risks of progression to MM and AL were compared to those expected on the basis of Surveillance, Epidemiology and End Results (SEER) rates for MM in Iowa and the incidence of AL in Olmsted County, Minnesota. One-hundred and one patients fulfilled the criteria for diagnosis during the 44-year period (1960–2004). The median age at diagnosis was 67 years (range 18–90 years), and only 2% were < 40 years old. Seventy-three percent were male. The urine M protein ranged from 200 mg/24h to 4.7 g/24h (median value, 500 mg/24h); 29% had > 1 g/24h. Kappa light chain accounted for 50% while the remaining 50% were lambda. Fifty-seven (56%) had a monoclonal light chain in the serum on immunofixation. Concentrations of uninvolved (normal, polyclonal or background) immunoglobulins were reduced in 62%. Eighty-eight percent of patients died during follow-up. During 900 person years of follow-up, 29 patients developed symptomatic MM (relative risk, 140.3; 95% CI, 93.9–201.5) and an additional 9 patients developed AL (relative risk, 104.4; 95% CI, 47.8–198.4). Four patients had both multiple myeloma and AL amyloidosis. The cumulative probability of progression to active MM or AL was 19% at 5 years, 31% at 10 years and 42% at 15 years. The factors associated with progression to MM or AL included size of urine M protein, percentage of bone marrow plasma cells, serum free light chain ratio < 1/100 or > 100, serum creatinine and reduction of all 3 uninvolved immunoglobulins. We conclude that patients with Idiopathic Bence Jones Proteinuria (Smoldering Monoclonal Light-Chain Proteinuria) are at risk for the development of MM or AL and must be followed indefinitely. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 956 Background: Autologous SCT has been an integral part of myeloma therapy since randomized trials demonstrated improved survival for SCT compared to conventional therapy. However, the conventional treatment of MM has changed with the introduction of novel therapies such as IMiDs and there is an increasing trend towards delaying SCT. While trials in the pre-novel agent area have shown equivalent outcomes with early or delayed SCT, it is not clear if this holds true with novel agent induction. Patients and methods: We reviewed the outcome of patients seen at Mayo Clinic between 2001 and 2008, who received initial therapy with thalidomide-dexamethasone (TD) or lenalidomide-dexamethasone (LD) (n=410). All patients in whom a stem cell harvest was attempted (started on growth factor irrespective of collection success; n=292, 71%) were included as a method to identify transplant eligible patients. Patients undergoing SCT within 12 months of diagnosis and in whom the SCT was performed within 2 months of stem cell harvest were considered in the early SCT group vs. delayed SCT for the remaining patients irrespective of whether an SCT was actually done (immediate vs. collect and store approach). Variables were compared between the groups using a chi-square or t-test as appropriate. Survival curves were generated using Kaplan Meier method and compared using log rank test. Results: Among the 292 transplant eligible patients, 125 (43%) received TD and 167 (57%) received LD as initial therapy. An early SCT approach was undertaken in 174 patients 60%, with the remaining 118 in the delayed group, 46 of whom have been transplanted to date. The median estimated follow up for the entire group was 54 months from diagnosis, 52 and 61 months respectively for the early and delayed groups. The median estimated time to SCT was 5.3 months among the early group compared to 39 months in the delayed group COMMENTS/* MERGEFORMAT . 83 (66%) patients receiving TD had an early SCT compared to 91 (55%) patients in the LD group; p =0.04. At baseline, the groups were comparable for age and gender. The median overall survival from diagnosis was 86 months for the early SCT compared to NR for the late SCT; P=0.3. The median OS was similar between the Early and Delayed group in the TD group (86 vs. 64 months respectively) as well as in the LD group (NR for either group; 82% vs. 86% at 4 years respectively). Conclusion: In this group of newly diagnosed patients treated with thalidomide or lenalidomide as initial therapy, an approach of continued initial therapy and delayed transplant at the time of first relapse appears comparable to upfront transplant. This is consistent with the findings of randomized trials in the setting of alkylator based initial therapies. The timing of transplant in the era of novel agents remains the top question on the mind of physicians and patients, and this is the first study to examine this very important question. The rationale governing the decision to go forward with an early SCT or delayed transplant is difficult to ascertain for any particular patient in this retrospective study. These findings should be confirmed in prospective randomized trials. Disclosures: Kumar: celgene: Research Funding; millenium: Research Funding. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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 1802 Poster Board I-828 Background Heterogeneity in multiple myeloma (MM) leads to disparate outcomes with a wide variation in overall survival (OS). Based upon the evidence predominantly gathered from newly diagnosed patients treated with standard chemotherapy and/or transplantation, the current Mayo (mSMART) prognostic model uses a combination of metaphase cytogenetics, fluorescence in-situ hybridization (FISH) and plasma cell labeling index (PCLI) for risk-stratification at diagnosis of MM. The objective of our study was to evaluate the significance of this stratification model in the era of novel therapies, and to assess the independent prognostic value of each of the components in the model. Methods Data were abstracted from a cohort of 1556 consecutive patients with MM who presented to our institution between January 1999 and March 2009 within ninety days of diagnosis of MM A total of three hundred and eighty six patients had been evaluated with conventional cytogenetics near diagnosis in addition to interphase FISH. Out of this cohort, three hundred and sixty six patients had availability of all the three tests, including the slide-based PCLI. High-risk MM was defined as presence of any one or more of the following: cytogenetics: hypodiploidy, monosomy of chromosome 13 or deletion 13q ; FISH: deletion of p53 (locus 17p13) or immunoglobulin heavy chain (IgH) translocations, t(4;14) (p16.3;q32) or t(14;16)(q32;q23); PCLI ≥3%. Survival estimates were created using the Kaplan-Meier method and compared by log-rank tests. The impact of each of the three tests was assessed by a multivariate (MV) analysis using Cox proportional hazards model. Results The median OS of the cohort of 366 patients was 65 months from presentation. One hundred and twelve (31%) patients were deemed high risk by any one or more of the three tests: Metaphase cytogenetics, FISH or PCLI (current mSMART definition of high-risk MM). The median OS of high risk patients was 52 months versus 71 months for standard-risk (P=0.007). We then studied the prognostic value of the three tests separately. Patients classified as high risk by FISH had a median OS of 35 months versus 65 months for the standard risk, HR= 2.3, P<0.001. Similarly, cytogenetics alone was also able to classify patients into high and standard risk with a comparable HR of 2.1 (P=0.008, median survival 37 vs. 64 months). In contrast, PCLI did not have a significant prognostic value (HR =1.41, P=0.32). This was confirmed on multivariate analysis in a model that included all 3 tests. FISH (HR=2.36, P=0.001) and cytogenetics (HR=1.99; P=0.017) emerged as independent determinants of prognosis in the multivariable analysis, while PCLI (HR=1.03, P=0.93) did not provide additional prognostic value. We then examined whether the prognostic value of FISH contributed additionally in patients classified into high and standard risk by conventional cytogenetics, and vice versa. Those classified as high risk by cytogenetics (n=44, 11 %), were further categorized into 2 groups by additional prognostic information obtained by FISH (median survival 18 vs. 52 months; P=0.005). Similarly, those classified as standard risk by cytogenetics (n=342, 89 %), were further categorized into 2 groups (median survival 52 vs. 71 months; P=0.017) by additional FISH-based stratification. Similarly, high-risk patients defined by FISH (n=65, 17 %) were further classified into 2 groups with significant difference in median OS (18 vs. 52 months, P=0.004), based on the presence or absence of high-risk features on cytogenetics. In contrast, no additional prognostic information was gained by cytogenetics in patients who were stratified as standard risk by FISH alone (n=321, 83%). Conclusion Our study validates high risk features defined by FISH and conventional cytogenetics in the mSMART risk stratification model among patients treated after the introduction of novel therapies. Either test identifies a high risk cohort with a hazard ratio of approximately 2 (median survival ∼37 versus ∼65 months). In patients known to have high risk disease by one of the two tests, knowledge of the other appears to add additional prognostic value. Disclosures Fonseca: Amgen, BMS, Celgene, Otsuka, Genzyme and Medtronic: Consultancy. Gertz:celgene, millennium: Honoraria. Dispenzieri:celgene: Research Funding. Kumar:celgene, genzyme, millennium, novartis, bayer: Research Funding; genzyme: Membership on an entity's Board of Directors or advisory committees.

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 591 Background: Survival of patients with MM has improved over the past two decades, in part due to the use of AHCT. Increasingly, second primary malignancies (SPMs) are observed in MM survivors. Determining the baseline incidence and risk factors associated with SPMs after AHCT is important to assess risk and to evaluate the risk-benefit ratio of newer therapies. Methods: We analyzed the incidence of SPMs in 3784 MM patients receiving (“upfront”) AHCT for MM within 18 months of diagnosis between 1990 and 2010 and reported to the CIBMTR. Cumulative incidence rates of SPMs were estimated taking into account the competing risk of death. For each transplant recipient, the number of person-years at risk was calculated from the date of transplantation until date of last contact, death, or diagnosis of SPM, whichever occurred first. Incidence rates for all invasive cancers in the general population were obtained from the SEER database. Age-, sex-, and race- specific incidence rates for overall SPMs and particular anatomical sites were applied to the appropriate person-years at risk to compute the expected numbers of cancers. Observed–to –expected (O/E) ratios were calculated, and Poisson distribution 99% confidence intervals (CIs) were generated. Poisson regression model was used to analyze risk factors for overall SPMs and AML/MDS. Results: Pre-transplant therapy included novel agents in 56% including thalidomide (35%), lenalidomide (9%), bortezomib (16%) or their combinations (11%). Majority (80%) received high dose melphalan conditioning. Post-transplant maintenance therapy included thalidomide (16%), lenalidomide (8%), bortezomib (9%) and interferon (6%). Median follow-up of survivors was 52 months (range 3 to 192 months).With 12707 person years of follow up, 153 new malignancies were reported with a crude rate of 1.2 SPM per 100 person years of follow up. Observed/Expected [O/E] ratio for all SPMs was 0.99 (99% CI, 0.80–1.22). Cumulative incidence of SPM overall was 2.48% (95% CI, 1.96–3.05) at 3 years and 6.0% (95% CI, 4.96–7.10) at 7 years [Figure 1]. Individual SPMs observed significantly more frequently than expected are summarized in Table 1. The cumulative incidence of MDS/AML was 0.5% (95% CI, 0.28–0.78) at 3 years and 1.3 (95% CI, 0.85– 1.9%) at 7 years. Majority had MM progression prior to diagnosis of SPM (65 of 102 patients overall and 15 of 23 patients for MDS/AML). In multivariate analysis, significant risk factors for development of SPMs included: obesity [Hazard ratio = HR 1.89(95%CI, 1.21–2.93), p=0.0047 for BMI>30 vs. BMI<25], older age: [HR10.53 (95%CI, 1.46–75.82), p=0.0195] for 60–69 year olds and HR14.4 (95%CI, 1.89–109.75), p=0.01 for 70+ year olds compared to the 18–39 year old group. Specific conditioning regimens did not correlate with the risk of SPM. The low number of MDS/AML (33 events out of 3784 cases) limited the power of multivariate analysis. Increasing age was significantly associated with development of MDS (HR10.77, (95%CI,92.09–55.51), p=0.004 for 70+ year old vs. 40–49 year olds). Conclusion: In this large cohort of AHCT recipients for MM, the incidence of MDS/AML, melanoma and other skin cancers was significantly higher compared to age and sex matched general population. However the overall risk of SPM was similar to that expected for age and sex matched population. It was also similar to the placebo arms of recent reports by McCarthy Pl et al and Attal M et al (N Engl J Med. 10; 366(19):1770–91). Lenalidomide (8%) or thalidomide maintenance (16%) used in a small subset of patients with comparatively short follow up, was not associated with risk of SPM in the analysis of the overall cohort. Disclosures: Gale: Celgene: Employment. Brandenburg:Celgene: Employment, Equity Ownership. Lonial:Millennium, Celgene, Novartis, BMS, Onyx, Merck all Consultancy. Krishnan:Celgene and Millennium: Consultancy, Speakers Bureau. Dispenzieri:Celgene and Millennium: Research Funding. Hari:Celgene: Consultancy, Honoraria.