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Abstract Background: The introduction of several novel agents has led to an improvement in response rates and survival outcomes in patients with newly diagnosed multiple myeloma. Despite significant therapeutic advances a subset of patients with multiple myeloma do not achieve a deep response to first-line treatment and biomarkers are needed to identify those at risk. Methods: We studied 472 patients with newly diagnosed multiple myeloma who were treated in clinical practice (n = 280, training cohort) or on prospective clinical trials (n = 192, validation cohort) at Mayo Clinic between 12/2003 and 12/2015. All patients had measurable disease (M-spike ≥ 1.0 g/dL) and received treatment with novel agents. Serum M-spike and free light chains (FLC) were measured before and after the first treatment cycle. The outcome of interest was the best response to first-line treatment (evaluated using the International Myeloma Working Group Uniform Response Criteria). Failure to achieve a deep response was defined as not achieving a very good partial response or better. The serum parameters of interest were the relative decrease in M-spike and absolute free light chain difference (ΔFLC). The Wilcoxon signed-rank test was used to compare the serum parameters before and after the first treatment cycle. Logistic regression models were used to assess the associations between the change in serum parameters after the first treatment cycle and best response to first-line treatment. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis in the training and the validation cohort were 67 (32 - 94) and 66 years (41 - 86), respectively. One hundred eighty one (65%) and 103 patients (54%) were male, respectively. The three most common regimens in the training cohort were lenalidomide + dexamethasone, lenalidomide + cyclophosphamide + dexamethasone, and bortezomib + lenalidomide + dexamethasone. In the validation cohort, the three most common regimens were carfilzomib + thalidomide + cyclophosphamide, lenalidomide + cyclophosphamide + dexamethasone, and ixazomib + cyclophosphamide + dexamethasone. In the two cohorts, the median baseline M-spike decreased from 3.1 g/dL (1.0 - 10.0) to 1.7 g/dL (0.0 - 6.6) and 3.2 g/dL (1.0 - 8.5) to 1.4 g/dL (0.0 - 4.5) after the first treatment cycle, respectively (p < 0.001 for both comparisons). The median baseline ΔFLC decreased from 31.1 mg/dL (0.0 - 2269.7) to 5.4 mg/dL (0.0 - 785.8) and from 23.3 mg/dL (0.1 - 3579.6) to 4.3 mg/dL (0.0 - 1139.3) after the first treatment cycle, respectively (p < 0.001 for both comparisons). M-spike reduction < 50% during the first treatment cycle was associated with failure to achieve a deep response: OR 4.54 (95% CI 2.72 - 7.58, p < 0.001) in the training cohort and OR 6.68 (95% CI 3.42 - 13.03, p < 0.001) in the validation cohort. Patients with reduction in M-spike < 10% during the first treatment cycle experienced failure to achieve a deep response in 86% (25/29) and 100% (10/10), respectively. ΔFLC reduction < 50% during the first treatment cycle was associated with treatment failure to achieve a deep response: OR 4.83 (95% CI 2.83 - 8.25, p < 0.001) in the training cohort and OR 5.09 (95% CI 2.37 - 10.92, p < 0.001) in the validation cohort. Patients with reduction in ΔFLC < 10% during the first treatment cycle experienced failure to achieve a deep response in 83% (34/41) and 91% (19/21), respectively. Conclusions: Early changes in M-spike and ΔFLC are strong predictors of response to treatment. We established and prospectively validated two readily available biomarkers that can identify patients at risk for treatment failure and may inform treatment decisions in newly diagnosed multiple myeloma. Disclosures Lacy: Celgene: Research Funding. Gertz:Physicians Education Resource: Consultancy; janssen: Consultancy; Teva: Consultancy; Alnylam: Honoraria; Research to Practice: Consultancy; Apellis: Consultancy; Medscape: Consultancy; annexon: Consultancy; Abbvie: Consultancy; celgene: Consultancy; Prothena: Honoraria; Ionis: Honoraria; Amgen: Consultancy; spectrum: Consultancy, Honoraria. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Russell:Vyriad: Equity Ownership. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Background: It is well known that the staging stratification at diagnosis predicts survival in immunoglobulin light chain (AL) amyloidosis, but there is a paucity of literature delineating the prognostic value of these systems at the time of 2nd-line therapy. Methods: We conducted a retrospective study to evaluate the prognostic value of AL staging among 563 patients with staging data, who initiated a 2nd-line therapy between 2000 and 2015. Both the Revised Mayo 2012 staging system and the European revision of the Mayo 2004 staging system were used. Results: The median time from initial treatment to 2nd-line therapy was 11.6 months. Median follow-up from institution of 2nd-line therapy was 54.1 months. The 1st-line therapy for patients was autologous stem cell transplant (ASCT) in 216 (38%) patients; and 2) non-ASCT therapies in 347 patients. Both staging systems were prognostic with a risk ratio of 9.4 (95%CI: 6.0, 15.1; p<0.0001) between stage IIIb and I, and of 12.2(8.1, 18.5; p<0.0001) between IV and I. At the time of 2nd-line therapy the staging systems' predictive values were independent of what the patients' 1st-line therapies had been despite the fact that the median time from initial treatment to 2nd-line therapy was 19.4 months in ASCT group and 8.0 months in non-ASCT group. Among the patients receiving 2nd-line therapy after ASCT, the 5-year overall survival (OS) from 2nd-line therapy for those with ≤ stage II versus >stage II was 65% and 31% (Mayo 2004) and 70% and 23% (Mayo 2012). The respective numbers for patients relapsing from a non-ASCT therapy were 57% and 26% (Mayo 2004) and 60% and 23% (Mayo 2012). Conclusions: This study indicates that the Mayo staging systems work well at the time of instituting 2nd-line therapy and is independent of whether 1st-line therapy was ASCT based. Figure. Figure. Disclosures Gertz: annexon: Consultancy; Medscape: Consultancy; Apellis: Consultancy; celgene: Consultancy; Prothena: Honoraria; Abbvie: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; spectrum: Consultancy, Honoraria; Ionis: Honoraria; Research to Practice: Consultancy; Teva: Consultancy; janssen: Consultancy; Alnylam: Honoraria. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lacy:Celgene: Research Funding. Dingli:Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Russell:Vyriad: Equity Ownership. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.

Abstract The use of soluble cardiac biomarkers such as NT-proBNP and troponin has revolutionized prognostication for patients with AL amyloidosis and led to their use in the Mayo 2004 and 2012 staging systems. Novel soluble markers with different phenotypic targets may further improve this approach. Soluble ST2 (sST2), which is the circulating form of the IL-33 receptor, has been shown to be a marker of cardiac remodelling and fibrosis, is predictive of mortality in patients with congestive heart failure, and is predictive of risk of GVHD and GVHD mortality. Samples of blood of patients with AL amyloidosis collected and frozen at -20C under a biobank IRB protocol were retrieved and sST2 measured. Patients were eligible for present study if they had a research sample collected within 90 days of their AL amyloidosis diagnosis. We have validated that values do not change significantly with storage at -20C over a 90 day period. Concentrations of sST2 were determined using a novel high-sensitivity sandwich immunoassay (Presagew ST2; Critical Diagnostics, San Diego, CA, USA). The sST2 assay had within-run and total coefficients of variation of <7.5% and 13.0% across its measurement range. Samples from 273 consecutive patients meeting diagnostic criteria for AL amyloidosis seen at our institution from 1/9/2010 to 12/22/2011 were evaluated. Median age was 63. 58% were male. One hundred and thirty have died over 33.9 months. Correlation between sST2 and the other biomarkers was modest with correlation coefficients of 0.48 and 0.20 for NT-proBNP and Troponin T, respectively. Patients with sST2 above and below the median of 27.2 ng/mL (6.3-596) had significant differences in 2 year overall survival: 71.2% to 39% (figure). In multivariate modeling sST2’s prognostic value was independent of the Mayo 2004 and the Mayo 2012 cardiac biomarker staging systems, the latter of which also includes prognostic information relating to plasma cell burden. In these multivariate models, sST2 median had a RR of 2.4, (95%CI 1.6, 3.6 p<0.001) with the Mayo 2004 Staging system (RR of 2.9, 95%CI 2.1, 4.1p<0.001); and sST2 median had a RR of 2.2 (95%CI 1.5, 3.4, p<0.001) with the Mayo 2012 staging system (RR 1.9, 95%CI 1.6, 2.3, p<0.001). A larger cohort including patients with longer follow up will be presented at the meeting as will gender specific cut off values and a comparison of our values with those previously used to prognosticate in patients with heart failure. sST2 appears to be a novel powerful prognostic factor for patients with AL amyloidosis. Because sST2 functions as a decoy receptor, which neutralizes the benefits of IL-33, it may play a role in the deleterious phenotype seen in patients with AL, i.e. myocardial hypertrophy and reduction of contractility. Disclosures: Saenger: Critical Diagnostics : Research Funding; Roche: Research Funding. Jaffe:Critical Diagnostics: Consultancy, Research Funding; Roche: Consultancy.

Abstract Background Multiple myeloma (MM) is a heterogeneous disease with variable responses to different therapeutic regimens and wide spectrum of survival. Much of the heterogeneity in the outcomes appear to be related to the underlying primary genetic abnormality, which in the majority of patients consist of either translocations involving the heavy chain region on chromosome 14 (IgH translocation) or trisomies of odd numbered chromosomes. We hypothesized that the response to lenalidomide (Len) therapy would vary significantly based on the underlying molecular subtype of myeloma. Methods We examined a cohort of 518 patients with available FISH results, who had been exposed to Len-based regimens. Medical records were reviewed and data regarding the best response and time to next therapy following treatment with Len-based regimen was obtained. Data from the first use of Len was collected. Len was given in combination with dexamethasone (Dex) with or without alkylators in combination. Patients who received a combination of IMiD and bortezomib as their first exposure to Len were excluded. Patients were grouped according to whether FISH showed a trisomy or an IgH translocation. Results The median age was 62 (28-91), and the median estimated follow up from diagnosis was 52 months (95% CI; 50, 54) with 359 (69%) alive at the time of analysis. An IgH translocation was seen in 129 (30%) of patients and a trisomy in 268 (62%) of patients. IgH translocations included t(11;14) in 92 (18%), t(4;14) in 45 (9%), t(14;16) in 21 (4%); 34 (8%) had both translocations and trisomies. For the current analysis, we included only patients with either a translocation or trisomy (n=397) excluding those with neither or both of the abnormalities. The median time to start of Len from diagnosis was 0 months (range, 0-64). A PR or better was seen in 80% of patients with trisomy compared with 63% of the patients with translocation (p<0.001); and the response rate was similar among the different translocation types. The median TTNT was 28 months among trisomy pts compared with 17 months for translocated patients (p<0.001, figure). The median TTNT was similar across the different types of translocations (Figure). Among this group, 134 patients proceeded to an autologous SCT after Len induction. Among these patients, no difference was seen in terms of TTNT (29 months for patients with translocation vs. 28 months for those with trisomy (p=0.8). Finally, the TTNT was no different if Len was used with Dex or as part of an alkylator combination. Conclusion The current data supports the hypothesis that the underlying primary genetic abnormality can affect the response to a particular therapy. In this study response to Len was significantly higher in myeloma with trisomy compared with IgH translocated myeloma. Although the routine use of combinations of a proteasome inhibitor plus Len in frontline therapy in all patients with myeloma may overcome the lower response rate in IgH translocated patients, in most countries such a regimen is not approved or economically feasible. Based on our study, newly diagnosed patients with evidence of trisomy on FISH could be considered for a Len-based regimen such as lenalidomide-low dose dexamethasone. Additional studies should examine if use of bortezomib in patients with IgH translocation will lead to better outcomes compared with Len based therapies. Disclosures: Lacy: Celgene Corporation: Research Funding. Gertz:Celgene: Honoraria. Dispenzieri:Celgene, Millenium, Jansenn, Pfizer: Research Funding. Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Novartis: Research Funding; Genzyme: Research Funding.

Abstract Background Melphalan, prednisone and thalidomide (MPT) is a standard therapy for NDMM recognized worldwide based on a statistically significant advantage in overall survival (OS) and progression-free survival (PFS) vs. MP (Facon Lancet 2007; Fayers Blood 2011; NCCN 2013). The combination of lenalidomide and low-dose dexamethasone (Rd) increased OS with fewer adverse events (AEs) than treatment with lenalidomide and high-dose dexamethasone in NDMM pts (ECOG E4A03) (Rajkumar Lancet Oncol 2010). The FIRST trial is a multicenter, open-label, phase III trial comparing the efficacy and safety of Rd versus MPT in transplant-ineligible NDMM pts. Methods NDMM pts either ≥ 65 years of age, or not candidates for SCT were randomized to one of three arms: Rd in 28-day cycles until disease progression (Arm A), Rd in 28-day cycles for 72 weeks (18 cycles, Arm B), or MPT in 42-day cycles for 72 weeks (12 cycles, Arm C). Assessments by International Myeloma Working Group criteria were done after each cycle. Pts with renal impairment were enrolled; however, pts on dialysis were excluded. Starting doses of lenalidomide and dexamethasone were adjusted based on renal function and age, respectively. Melphalan starting dose was adjusted based on age, absolute neutrophil count, platelet count, and renal function; and thalidomide was adjusted for age. Dose adjustments were permitted for AEs. All pts were required to receive anti-thrombotic prophylaxis. Stratification factors included age, International Stage System, and country. The primary endpoint was a comparison of PFS in Arm A vs. Arm C. Secondary endpoints included OS, overall response rate (ORR), time to response, duration of response (DOR), safety, and quality of life (QOL). A preplanned additional analysis included time from randomization to second progression event or death (PFS2). The final preplanned analysis of independently adjudicated progressive disease (PD) events in Arm A vs. Arm C conducted after 960 events of death or PD, and an interim of OS in 64% of survival events (574/896 events) are presented in this abstract. Comparisons of PFS and all secondary endpoints, including OS for all three arms, will be presented at the meeting. Results A total of 1,623 pts were randomized 1:1:1 in three arms. As of today, 121 pts continue to receive lenalidomide on study (Arm A). The median age was 73 (40.0–92.0) years; 35% pts were aged ≥ 75 years; and 41% of pts had ISS stage 3 disease. After a median follow-up of 37 months, the trial met its primary endpoint (PFS), demonstrating a 28% reduction in risk of progression or death (HR=0.72; p= 0.00006). The preplanned interim analysis of OS demonstrated a 22% reduction in risk of death in favor of Arm A vs. Arm C (HR=0.78, p=0.01685); however, the pre-specified boundary (p<0.0096) was not crossed. All other secondary endpoints consistently showed improvement in favor of Arm A vs. Arm C; ORR (PR or better) 75% vs. 62% (p < 0.00001), DOR (HR=0.63; p<0.00001), and PFS2 (HR=0.78, p=0.0051). Relevant Grade 3/4 adverse events in Arm A vs. Arm C were neutropenia (28% vs. 45%), thrombocytopenia (8% vs. 11%), febrile neutropenia (1% vs. 3%), infection (29% vs. 17%), neuropathy (5% vs. 15%), and deep-vein thrombosis (5% vs. 3%). The incidence of secondary primary malignancies (SPM) was evaluated. Hematologic malignancies were 0.4% in Arm A vs. 2.2% in Arm C; the overall incidence of solid tumors was identical (2.8%). Conclusion Continuous treatment with the all oral doublet Rd significantly improved the primary endpoint of PFS compared with the standard triplet, MPT. All secondary endpoints support the clinical benefit of continuous Rd treatment. The safety profile of Rd was manageable, with reduced hematologic SPM compared to MPT. Disclosures: Facon: Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Lenalidomide as treatment for NDMM. Dimopoulos:Celgene, Orthobiotech: Honoraria. Dispenzieri:Celgene, Millenium, Jansenn, Pfizer: Research Funding. Catalano:Celgene, Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Hulin:Janssen: Honoraria; Celgene: Honoraria. Cavo:Celgene, Janssen, Millennium, Onyx, Brystol Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Pinto:Mundipharma: Consultancy, Honoraria; Roche: Honoraria; Celgene: Consultancy, Honoraria. Weisel:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Ludwig:Celgene: Honoraria, Research Funding, Speakers Bureau. Bahlis:Celgene: Consultancy, Honoraria. Delforge:Celgene: Honoraria. Chen:Celgene: Consultancy, Research Funding; Lundbeck: Consultancy; Johnson & Johnson: Consultancy, Research Funding; Roche: Honoraria; GlaxoSmithKline: Research Funding. Oriol:Celgen: Consultancy. White:Celgene: Honoraria, Research Funding. Binder:Celgene: Research Funding. Anderson:Acetylon, OncoPep: Equity Ownership; Celgene, Onyx, Sanofi Aventis, Gileod: Consultancy. Moreau:Celgene Corporation: Honoraria, Speakers Bureau. Attal:Janssen: Lectures, Lectures Other, Membership on an entity’s Board of Directors or advisory committees; Celgene Corporation: Lectures Other, Membership on an entity’s Board of Directors or advisory committees. Knight:Celgene: Employment, Equity Ownership. Chen:Celgene: Employment. Van Oostendorp:Celgene: Employment. Jacques:Celgene: Employment. Ervin-Haynes:Celgene: Employment, Patents & Royalties. Benboubker:Celgene: Consultancy.

Abstract Aim: The autonomic nervous system plays an essential role in homeostasis and the response to stress. The peri-transplant period can be a challenging time for homeostatic responses due to the fluid shifts, sepsis and cardiac dysrhythmias that can occur. Patients with AL amyloidosis may have significant autonomic neuropathy (AN) that renders the peri-transplant care problematic. The purpose of this study was to compare a cohort of patients with AL amyloidosis complicated by AN with a matched cohort without AN to determine the outcome of patients with AN during and after stem cell transplantation (PBSCT). Methods: We performed a nested case-control study by searching the Mayo Clinic dysproteinemia transplant database for all patients with AL amyloidosis who underwent autologous PBSCT. Patients with proven AN were identified and compared to a large cohort of matched controls. We have complete follow-up on all the patients. The main outcome variables were overall survival (OS), the duration of hospitalization, incidence of sepsis, peri-transplant atrial fibrillation (AF) and engraftment kinetics. Comparisons between groups were performed with the Mann Whitney U test for continuous variables and the chi squared test for nominal variables. Overall survival was determined by the Kaplan-Meier method. A stepwise Cox proportional hazards model was used to evaluate the impact of various parameters on OS. Results: We identified 13 patients with AN who underwent PBSCT and compared them to a control group of 94 patients. The two cohorts were well matched for many of the relevant clinical and laboratory characteristics prior to PBSCT. Notable differences included (i) patients with AN tended to have more organs involved (2.5 versus 1, p<0.001) and as a result (ii) the conditioning dose of melphalan was often reduced (p=0.0015). There was no difference in the number of apheresis sessions required for CD34+ cell collection (2.5 versus 2.0, p=0.99), or the number of CD34+ cell collected (6.75 versus 8.15 x106/kg, p=0.99) between the two cohorts. The median hospital duration was 10 (1 – 78) and 8 (0 – 78) days (p=0.99) respectively. Engraftment kinetics, as measured by the time to reach a neutrophil count > 500/ml (p=0.85), a platelet count > 20,000/ml (p=0.99) and a platelet count > 50,000/ml (p=0.99) were similar in the two cohorts. Culture positive sepsis was more common in patients with AN (75% versus 47%, p=0.014). Atrial fibrillation occurred in all patients with AN but in only 1 patient from the control group (p<0.0001). The median OS from PBSCT was 45.2 months for all the combined groups. However, the median OS for patients with AN was 29 months but not yet reached for the controls (p<0.0001). On univariate analysis, cardiac involvement (p=0.0132), AN (p=0.0011), GFR (p=0.038), number of organs involved (p=0.0064) and NT-pro-BNP (p=0.039) all had an impact on OS. On multivariate analysis, AN remained an independent adverse determinant of OS. Conclusion: Patients with autonomic neuropathy secondary to AL amyloidosis can undergo PBSCT safely with similar engraftment kinetics. They are at a higher risk of peri-transplant atrial fibrillation and sepsis although their hospitalizations are not longer compared to controls. Patients with AN generally have more organ involvement by AL amyloidosis. However, AN is an independent, adverse determinant of OS in AL amyloidosis.

Introduction With the introduction of novel agents, survival in multiple myeloma has successively increased in the past decade. This improved survival increases the risk for late complications. Patients continue to receive melphalan therapy as a standard induction for those over the age of 65. Lenalidomide is considered a standard component of induction therapy in the United States for patients who are transplant candidates. Stem cell transplantation remains the standard of care for patients eligible to receive it. As a consequence of exposure to lenalidomide, stem cell transplant, and melphalan, the risk of late myelodysplasia and acute leukemia remains significant. We reviewed the Mayo Clinic experience with therapy-induced myelodysplasia beginning with the advent of novel agents. Patients and Methods All patients that carry the diagnosis of multiple myeloma between January 1, 2000, and September 1, 2011, were included. Patients with a synchronous diagnosis of a myeloproliferative or a myelodysplastic disorder or those who developed the myelodysplastic disorder within 15 months of first chemotherapy exposure were excluded. The date of diagnosis for the purpose of this abstract was based on first exposure to chemotherapy and not first detection of a monoclonal protein or smoldering multiple myeloma. All patients had to have morphologic verification in the bone marrow of dysplastic change consistent with therapy-related myelodysplasia. Results Of 3111 patients who had a myeloma diagnosis and first treatment after January 1, 2000, through September 1, 2011, 22 patients were identified to fulfill the criteria of myelodysplasia. There were 13 men and 9 women with a median age of 67 (46 to 82). At the time of this report, 17 have died. Prior to the development of myelodysplasia, exposure to an alkylating agent, lenalidomide, or an auto stem cell transplant was seen in 13, 15, and 10, respectively. Only one patient had been exposed to lenalidomide alone. Eighteen patients were classified as myelodysplasia. Four had acute non-lymphocytic leukemia. Metaphase cytogenetics was available in 19 and only one was normal. Twelve were hypodiploid. Trisomy 8 or abnormalities of chromosome 5 and 7 were present in 13. Seven patients received a hypomethylating agent with no clear evidence of response in any. Four patients had an allotransplant to manage the MDS/AML and only one survives 487 days after a matched-related donor allogeneic transplant. The median time from initial therapy of multiple myeloma to recognition of MDS or AML was 50.9 months (range: 15.2-146.5 months) fig 1. The median overall survival of the 22 patients is 6.5 months. Fig 2 Six of the 22 had active myeloma at the diagnosis of MDS/AML. Conclusion Myelodysplasia during the era of novel agents is a devastating complication of therapy with a very short survival and low response rate. As a time-dependent complication, the overall risk cannot be accurately estimated but has occurred in <1% of our patient population to date. Hypomethylating agents were ineffective in the seven that received it. One of four allotransplant patients remains alive. Ongoing surveillance for MDS/AML in this population is warranted and more effective therapies are needed. Disclosures: Kumar: Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Abstract Background: Autologous stem cell transplantation is an effective therapy for patients with multiple myeloma. We and others have previously reported the influence of lenalidomide based regimens on the ability to harvest adequate number of stem cells for successful transplantation. In order to identify factors predicting for poor mobilization we studied a large group of patients who underwent an attempt at stem cell mobilization after receiving lenalidomide and dexamethasone as primary therapy for myeloma. Methods: We identified sequential patients who received lenalidomide and dexamethasone as initial therapy for their myeloma and then underwent stem cell mobilization for immediate or future stem cell transplantation. Patients who received any other regimen prior to the stem cell mobilization were excluded. Between July 2004 and May 2008, 106 patients, satisfying the above criteria were identified from the Mayo Clinic transplant database. Medical records and collection sheets were examined for the data. Results: The median (range) age at mobilization was 60 yrs (29–75); 34 (32%) were over 65 yrs and 59 (55%) were males. The median duration of lenalidomide therapy was 4 months (range; 1–13). The strategy for stem cell mobilization was GCSF alone in 92 patients (87%), cyclophosphamide (CTX) and GCSF in 11 pts and 3 pts received AMD3100 and GCSF. Among the GCSF mobilized patients, 10 pts (11%) failed to collect at least 2.5 million cells required for one transplant, including 8 patients who never achieved the minimum peripheral count threshold to initiate the collection. Two of the 11 pts undergoing primary mobilization with CTX/GCSF failed to collect any cells, while all of the 3 pts mobilized with AMD3100 were successful. Five of these pts subsequently underwent successful salvage mobilization with CTX/GCSF, 1 with AMD3100, one failed to mobilize with CTX and the rest did not repeat mobilization. Given that the total CD34 collection and the number of days of collection are influenced by the CD34 goal, we examined patient characteristics that correlated with the CD34 collections over the first 2 days. Increasing patient age and the duration of lenalidomide therapy, both correlated with decreasing 2-day CD34 collection, while the time between last dose of lenalidomide and the start of GCSF had no effect. We then performed ROC analysis to find best cut-off points that predicted the inability to collect adequate (2.5 million) CD34 cells in 3 days. Lenalidomide therapy of more than 4 months (P =0.03) and age > 63 yrs (P = 0.04) best predicted inability to achieve this endpoint. In addition, a peripheral blood CD34 count < 5/uL on day 5 after start of GCSF was highly predictive of failure to reach this endpoint. Conclusions: Inability to collect adequate stem cells with lenalidomide appears to be related to patient age and the duration of lenalidomide therapy. We recommend early stem cell collection and storage, if a delayed transplantation approach is taken. Patients receiving more than 4 cycles of therapy and those over 65 years should undergo mobilization with CTX+G-CSF, rather than G-CSF alone. Majority of the patients who fail G-CSF based collection can be mobilized using CTX and G-CSF. Early identification of failures after G-CSF administration using the peripheral CD34 counts can potentially allow salvage using strategies such as AMD3100.

Abstract Abstract 824 There is no standard therapy for MM relapsing after autologous hematopoietic cell transplantation (AHCT). A second AHCT can result in additional progression-free survival (PFS). Nonmyeloablative/reduced intensity conditioning (NST/RIC) allogeneic transplantation (AlloHCT) has the advantages of a tumor-free graft and the potential of a graft-versus-myeloma (GVM) effect. Few studies have compared second AHCT vs. NST/RIC AlloHCT. We compared the outcome of second AHCT or NST/RIC AlloHCTafter relapse from prior AHCT in patients with MM reported to the CIBMTR from 1995–2008. Recipients of planned tandem transplants, AlloHCT for graft failure or second malignancies and myeloablative alloHCT were excluded. 137 patients underwent second AHCT and 152 underwent NST/RIC AlloHCT (32 HLA-identical sibling and 120 unrelated donor). The table below illustrates clinical characteristics and patient outcomes. AlloHCT recipients were significantly younger (median 53 years [yrs] of age vs. 56 yrs in the AHCT cohort (p < 0.001). The groups were similar in Karnofsky performance score (KPS) and gender. Conditioning regimens differed between groups. In the AHCT cohort, 85% were melphalan based. In the NST/RIC alloHCT cohort, 38% received melphalan + other drugs and 24% received total body irradiation +/− other drugs but no melphalan (p <0.001). Time from 1st to 2nd transplant was significantly shorter for the AlloHCT cohort (30 vs. 23 months, p = 0.014). Acute graft-versus-host disease (GVH) was 35% at 60 days while chronic GVHD was 44% at 36 months.Patient CharacteristicsAutologousAllogeneicP-valueNumber of patients137152Age at 2nd transplant, median (range), years56 (28–65)53 (32–65)0.001*Gender Male84 (61)90 (59)0.720Karnofsky Score pre-transplant ≥90%68 (50)76 (50)0.884Time from 1st to 2nd transplant, months, median (range)30 (6–122)23 (6–78)0.014* 6–24 months44 (32)78 (51)0.001* >24 months93 (68)74 (49)OutcomesTreatment-related Mortality (TRM)12 months2 (1–5)13 (8–19)<0.001*60 months4 (2–8)15 (10–21)<0.001*Relapse/Progression12 months51 (43–58)72 (64–79)<0.001*36 months82 (76–88)80 (73–86)0.655Progression-free survival12 months47 (40–54)15 (10–21)<0.001*36 months13 (9–19)6 (3–10)0.038*Overall Survival (OS)12 months83 (77–89)51 (42–58)<0.001*36 months46 (37–54)20 (14–27)<0.001*60 months29 (21–38)9 (5–15)<0.001**Significant difference The most common cause of death in both cohorts was progression of MM. On multivariate analysis risk of death was higher for alloHCT (HR 2.38, p < 0.001), KPS < 90 (HR 1.96, p < 0.001), and year of transplant (2004 or earlier, HR 1.77, p = < 0.001). AlloHCT was associated with significantly higher risk of TRM (HR 7.14, p < 0.001). Durie-Salmon Stage III was associated with a higher risk of relapse (HR 2.70, 95% CI: 1.93–3.80, P<0.001) and treatment failure in the alloHCT group (HR 3.05, 95% CI: 2.20–4.22, p < 0.001). We conclude that patients with MM who underwent NST/RIC alloHCT after AHCT failure experienced higher TRM and lower probability of survival compared with those who received second AHCT. Because genetic risk data were not available for these patients, we cannot exclude the possibility that the alloHCT population was a higher risk population. Despite this limitation, our data demonstrate that the value of alloHCT after relapse from prior AHCT is limited. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 636 Cellular vaccine may offer additional benefit as consolidative therapy after autologous stem cell transplant (ASCT) for multiple myeloma (MM). We have reported previously from two phase II studies the survival of MM patients who received APC8020 (autologous antigen presenting cell vaccine) after ASCT (Lacy, AJH '09, (84): 799; Lin, ASH annual meeting 2010, abstract 1958). To determine if there was an outcome advantage for additional consolidative vaccine therapy after ASCT, we performed this matched case control analysis comparing the survival of patients who received ASCT only (control) at Mayo Clinic to those who received APC8020 after ASCT in the same time period. Forty-three study patients accrued between July 1998 and March 2002 were eligible for matching. To reduce bias from disease risks and transplant-related mortality, control patients were required to be alive and progression free six months after transplant and have a M-spike value of < 2g/dL at 4 mos (1st study) or 9 mos (2nd study) after transplant, similar to post-ASCT patients who were enrolled in the two APC8020 studies. A total of 111 control patients were eligible for matching. Control patients were matched to study patients by age (+/− 5 yrs), ISS (International Staging System) stage, and plasma cell labeling index (PLCI, either >= 3 or < 3). A matched control was not identified for one study patient. Of the remaining 42 study patients, all had at least one matched control patient. Thirty-two patients had 2 matched controls. Cox proportional hazards analysis showed that there was no statistically significant difference in time to progression between the study and control patients (HR 1.54, 95% CI 0.92 – 2.58, p = 0.1). However the overall survival is significantly improved among the study patients (HR 0.54, 95% CI 0.30 – 0.99, p = 0.05). This analysis is the only known report of long-term follow-up of the largest group of MM patients treated with APC8020 vaccine. While many current prognostic tests were not available at the time of the initial vaccine studies, the control patients in this analysis were matched by known disease risks that are still in use today. The survival advantage in study patients remained statistically significant compared to matched controls. Interestingly, the time to progression is unchanged between study and control patients. This is similar to other reports of vaccine therapy such as in sipuleucel-T (Provenge™) in prostate cancer where an overall survival benefit is seen without change in progression-free survival. A larger, randomized phase III study is needed to confirm the encouraging survival benefit of this treatment modality in MM. Further insight into the mechanisms of action of APC8020 is needed to improve our understanding of the role of this therapy in the context of current practice of MM maintenance therapies. Disclosures: Sims: Dendreon Corporation: Employment.