Dingli, David

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

Abstract Abstract 2970 Background: Over a quarter of patients (pts) with symptomatic multiple myeloma (MM) have some degree of renal insufficiency at the time of diagnosis. Multiple studies show that presence of renal failure is strong predictor of inferior overall survival in MM. With effective therapy, renal function improves in a considerable number of patients. It is not clear if the return of renal function to normal levels will improve their outcome to that expected for patients without renal dysfunction. Methods: We evaluated 1478 patients with newly diagnosed myeloma seen at Mayo Clinic within 90 days of diagnosis, between January 1999 and January 2009. We examined these patients for improvement in renal function and identified the lowest serum creatinine obtained during the disease course. The outcomes were analyzed with respect to the renal function improvements. Results: The median age at diagnosis was 64 years (range; 22–93) and 50% were male. The median estimated follow up for the entire cohort was 53 months, with 781 patients alive at the time of analysis with a median follow of 3 years. The serum creatinine was over 1.5 mg/dL at diagnosis in 333 (22.5%) pts and over 2.5 mg/dL in 148 (10%) pts. The median overall survival for the 333 patients was 37 mos (95% CI; 28, 40) compared to 56 mos (95% CI; 51, 63) for those < 1.5 mg/dL; P < 0.001. Among the 333 pts with baseline Cr > 1.5 mg/dl, any improvement in Cr was seen in 263 (79%) including an improvement of at least 0.5 mg/dL in 208 (62%) pts. Among the 263 pts with any improvement, the median time to lowest Cr was 4 months (range; 1–13). The median survival of the group of patients with Cr <= 1.5 mg/dl, over 1.5 mg/dL at diagnosis but improved to <= 1.5 mg/dL, or remained >1.5 mg/dL were 56., 40 and 27 mos respectively; P < 0.001, Figure). We then examined the impact of renal function improvement in the group of patients where the baseline Cr was >2.5 mg/dL. The median OS for the 42 (out of 148 pts with Cr > 2.5 at diagnosis) who had improved to <=1.5 mg/dL was 40 mos compared to 56 mos for those with a Cr <= 1.5 mg/dL at diagnosis and 27.4 mos for the 106 pts whose Cr did not decrease to <= 1.5 mg/dL; P < 0.001. Conclusion: The results of this study point toward improved outcome among patients with renal dysfunction in whom renal function improves. However, it shows that this improvement in renal function does not necessarily improve survival to that observed for the patients with a comparable level of serum creatinine at diagnosis. While early treatment of asymptomatic myeloma has been shown to have little impact on overall survival, a strategy of waiting for serious features of target organ damage to appear before initiation of treatment may have a negative impact on survival in some patients, especially patients with high light chain production who have a higher predilection for renal insufficiency. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Lacy:Celgene: Research Funding.

Abstract Background: Amyloidosis is a multisystem disease with extracellular deposition of pathological insoluble beta-fibrillar proteins. Involvement of the heart is seen in more than one-half of the patients with systemic AL amyloidosis and it is the most important determinant of clinical outcome. Cardiac amyloidosis is a restrictive infiltrative cardiomyopathy in which, despite declines in stroke volume that accompany disease progression, the ejection fraction (EF) often remains preserved even in advanced stages of the disease. King et al. proposed a novel index of myocardial function, the myocardial contraction fraction (MCF), defined as the ratio of stroke volume (SV) to myocardial volume (MV). MCF is a measure of myocardial shortening, which differentiated myocardial performance in patients with similar degrees of hypertrophy and in a recent small cohort of AL amyloidosis patients appeared superior to left ventricular ejection fraction (EF) in predicting overall survival (OS). It was our goal to assess the prognostic role of MCF in a large cohort of patients with AL amyloidosis in the context of other prognostic variables. Methods: Patients seen between 4/1/1999 and 2/1/2015 were eligible for this retrospective study if they had an ECHO at the Mayo Clinic, Rochester, MN within 30 days of their AL amyloidosis diagnosis with measurements of left ventricular chamber size and wall thickness needed to calculate MCF, EF, and the presence or absence of pericardial effusion. To capture the full cohort, modeling was done first excluding Mayo (2012) staging and global averaged left ventricular longitudinal peak systolic strain (LV strain) since limited numbers of patients had these studies, 342 and 294, respectively. Thresholds of continuous variables were chosen based on receiver operator curves targeting death at 1-year. Cox proportional hazards analysis was used to identify factors that were prognostic for OS. Statistical analyses were done using JMP 9.0 (SAS, Cary, NC). Results: Among the 722 patients satisfying entry criteria,median age was 64 years (range 32-94) and 66% were male. The best cutoff for MCF was 21% (sensitivity: 74%, specificity: 60%; AUC=0.699) and distinguished two groups with different OS (median 53 vs. 9 months, P<0.0001; Figure). On univariate analysis the baseline ECHO variables predicting OS were interventricular septum thickness (IVS) >12 mm (RR 1.8, P=0.0002), EF <60% (RR 1.7), MCF ≤21% (RR 2.1), and presence of pericardial effusion (RR 2.0), all with P<0.0001. On multivariate MCF ≤21% (RR 1.6, P <0.0001), EF <60% (RR 1.4, P=0.0007) and the presence of pericardial effusion (RR 1.3, P=0.002) were independent predictors of OS. Additional modeling was done with the subset of 342 patients who were assessable for Mayo (2012) staging, (i.e. measurements of immunoglobulin free light chain, NT-proBNP, and troponin T). On univariate analysis, patients with a Mayo (2012) stage ≥ 3 had a RR 2.1, p<0.0001. On multivariate, only MCF ≤21% (RR 1.5, P =0.01), Mayo (2012) stage ≥ 3 (RR 1.5, P=0.01) and EF<60% (RR 1.7, P=0.0006) were independent prognostic determinants. Finally, we addressed LV-strain among the 294 patients in whom the study was performed. There was a significant correlation between MCF and LV strain (rho =-0.86, P<0.0001). On univariate, LV-strain less negative than -13 generated a RR of 2.3, p<0.0001. In contrast to the model containing MCF, on LV-strain multivariate, EF was no longer significant, but LV-strain less negative than -13 (RR 2.0, P=0.008) and Mayo (2012) stage ≥ 3 (RR 2.0, P=0.008) predicted independently OS. Conclusions: MCF ≤21% identified a subgroup of patients with a high mortality risk, and it was independent of the Mayo (2012) staging but highly correlated with LV strain. An advantage of MCF, which is a novel volumetric measurement of the left ventricular chamber, is that, unlike LV-strain, MCF is simple to calculate from routine ECHO measures. Figure 1. Overall survival of 722 patients according to MCF<21%. Figure 1. Overall survival of 722 patients according to MCF<21%. Disclosures Kumar: AbbVie: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Skyline, Noxxon: Honoraria; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Sanofi: Research Funding; Millenium/Takeda: Research Funding; Onyx: Research Funding.

Abstract Abstract 2253 Background: Lenalidomide based combinations are among the most common initial therapies for myeloma. Previous studies have suggested that lenalidomide therapy can result in suboptimal stem cell collection in patients eligible to undergo autologous stem cell transplantation, especially older patients after prolonged exposure to the drug. Many salvage approaches are used when attempting repeat stem cell collection in this patient group. Patients and Methods: Two hundred twenty four patients who underwent stem cell collection following lenalidomide-dexamethasone induction from July 2004 and December 2009 were included in the current analysis. Data pertaining to the duration of lenalidomide therapy, stem cell mobilization regimen, and the collection yields were collected from the medical records. Results: The median age at mobilization was 60.6 years (range; 29, 76) and 136 (60%) were male. There were a total of 245 collection attempts from among 224 patients, 21 (9.8%) patients attempting to remobilize after failing to collect the desired numbers of stem cells at the first attempt. We first analyzed the results of the initial collection attempt. The median duration of lenalidomide therapy prior to stem cell collection was 4 months (range; 1, 26). The mobilization strategies were GCSF (Granulocyte Colony Stimulating Factor) alone in 151 (67%) patients, cyclophosphamide (CTX) followed by GCSF in 29 (13%) patients, and GCSF plus AMD3100 in 44 (20%) patients. Among those receiving AMD3100, it was added either due to peripheral blood CD34 cell count not reaching the threshold for initiation of harvest or for poor first day CD34 cells collection in 34 patients and given in a planned fashion in 10 patients. Overall 15 patients (7%) failed to reach the peripheral CD34 cell counts required to initiate apheresis, and among those starting apheresis 6 patients failed to collect at least 2 million CD34 cells/kg; a cumulative failure rate of 9%. Another 18 (8%) patients failed to collect at least 4 million CD34 cells /kg. The CD34 cells yield on day 1, the total yield, number of collections, the average daily yield and the percentage of the targeted cells collected for each mobilization strategy including failure rates are detailed in the table. Twenty-one patients reattempted stem cell mobilization; including 14 that failed a first attempt and 7 did who not achieve the intended goal even though they collected more than 2 million CD34 cells/kg. The mobilization regimens were GCSF alone, CTX + GCSF, GCSF + GM-CSF (Granulocyte Macrophage Colony Stimulating Factor) and GCSF + AMD in 5, 8, 3, and 4 patients respectively. All patients collected at least 2 million CD34 cells /kg and 14 patients (70%) collected more than 4 million CD34 cells /kg. The median CD34 cells collected with the second attempt was 5.4 million/kg (rang; 2, 19.5) bringing the median total collection for these 21 patients to 9.6 million/kg (2.6-19.6). Overall, of the 224 patients studied, all but the 6 patients who failed initially and did not attempt a second collection collected at least 2 million CD34 cells /kg and 197 (88%) collected at least 4 million CD34 cells/kg. Conclusion: While the overall failure rate of stem cell collection in patients receiving initial therapy with lenalidomide is 10%, a risk adapted approach of adding AMD3100 appear to decrease the risk of failure. However, majority of patients failing a stem cell harvest attempt can be salvaged with a second collection allowing these patients to proceed to a stem cell transplant if desired. Disclosures: Gertz: Celgene: Honoraria; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Research Funding. Lacy: Celgene: Research Funding. Dispenzieri: Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Micallef: Genzyme: Membership on an entity's Board of Directors or advisory committees. Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

Abstract Abstract 1965 Background: Pomalidomide is an immunomodulatory compound to be used for heavily pre-treated patients with relapse and refractory multiple myeloma and has shown considerable efficacy in recent clinical trials. It is not clear how patients may respond to other therapies, once the disease becomes refractory to pomalidomide. We examined this question among a cohort of patients receiving pomalidomide therapy in phase 2 clinical trials. Methods: Patients enrolled in an ongoing phase 2 clinical trial of pomalidomide (2-4 mg daily) along with dexamethasone (40 mg weekly), in relapsed myeloma, form the study population. Several cohorts of patients (>= 3 prior therapies not specified, lenalidomide refractory, and lenalidomide and bortezomib refractory patients were enrolled sequentially in this trial (Lacy, M.Q., et al., J Clin Oncol, 2009. 27(30): p.5008–14). Only those patients who have gone off study for disease progression were included in the current analysis. Details of subsequent therapies and survival data were obtained from the medical records. Results: Forty-seven patients from among 142 patients enrolled on the clinical trial between November, 2007 and April, 2010 were included in the study. The median (range) duration of pomalidomide therapy was 4 (0.6-16) months. 15 (32%) patients were lenalidomide refractory and 11 (23%) were refractory to both lenalidomide and bortezomib at the time of study entry. The best confirmed response to pomalidomide was MR (Minimal Response) or better in 23 patients (52%). Various regimens were employed following relapse on pomalidomide. The response to the first regimen following relapse in the 34 patients where salvage therapy was initiated is as shown in Table 1. Overall, 81 regimens were employed across 34 patients; median (range) number of regimens per patients was 1 (0-8). The response rates to the different regimens were as shown in the Table 1. The median overall survival (OS) from the time of progression on pomalidomide was 14.7 months (95% CI; 4, NR). The OS was similar between those patients who had a response to pomalidomide (MR or better) and those who did not. However the OS was shorter for patients who were refractory to lenalidomide and bortezomib (2.1 months) compared to those who were lenalidomide refractory only (6.5 months), and the non-refractory group (NR), P=0.06. Conclusions: This study confirms poor outcome of the patients relapsing after all available therapies. It also gives interesting insights into the activity of different regimens among patients who have relapsed after pomalidomide. The findings once again highlight the incurable nature of the disease and warrant further investigation to develop newer effective treatment regimens for this group of patients who presently do not have effective therapeutic options especially in the relapsed setting. Regimens: ASCT: Autologous Stem Cell Transplantation, Bz: Bortezomib, Mel=Melphalan, Dex: Dexamethasone, CRD: Cyclophosphamide, Revlimid (Lenalidomide), Dexamethasone, CTX; Cyclophosphamide, Len; Lenalidomide, Sor: Sorafenib, VDT-PACE: Velcade (Bortezomib), Dexamethasone, Thalidomide, Cisplatin, Adriamycin, Cyclophosphamide, Etoposide. Response: SD; Stable Disease; Prog; Progression MR: Minimal Response; PR: Partial Response. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Mikhael:Celgene: Research Funding; Onyx: Research Funding; Novartis: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.

Abstract Background Induction with novel agents, including proteasome inhibitors and immunomodulators, prior to autologous stem cell transplantation (ASCT) is the standard of care frontline treatment of transplant-eligible patients with multiple myeloma (MM). Common novel agent-based induction regimens include three drug combinations with a backbone of bortezomib (V), thalidomide (T) and/or lenalidomide (R). There is limited information on the comparative efficacy of novel regimens used as part of initial therapy prior to an ASCT in terms of overall survival (OS). To address this question, we retrospectively analyzed 1096 consecutive patients undergoing ASCT for MM at Mayo Clinic. Methods Study patients included those who underwent first transplant within 12 months of diagnosis, did not receive more than one induction regimen, did not relapse prior to transplant and did not receive treatment for smoldering MM in the past. Baseline characteristics, response rates and survival data were extracted from an electronic medical record and statistical analysis was done using JMP 10.0.0 (SAS Institute Inc.). Choice of induction regimen was almost exclusively made by the referring physician. Results Median age at diagnosis was 60.3 years (Interquartile range 53.9-65.9). ISS staging at diagnosis was available for 49.7% of patients, of which, 34.2%, 39.3% and 26.5% of patients had ISS stage 1, 2 and 3 disease, respectively. Estimated median follow up was 65.6 months (95% CI 58.3-73.3). Baseline characteristics of patients by initial treatment have been summarized in table 1. Major subgroups by induction therapy included patients receiving Cy-Bor-d (n=193, 17.6%), Vd (n=64, 5.83%), Rd (n=253, 23.1%), VRd (n=126, 34.6%), Td (n=157, 14.3%) and VAD or dexamethasone alone as the non-novel agent comparator group (n=229, 20.9%). Median overall survival (OS) was significantly different between novel agent-based and conventional regimens (Log-rank test; p=0.0029), which were 102.7 months (95% CI, 95.2-112.2) and 78.8 months (95% CI, 67.8-92.6) respectively. Median OS with each regimen is shown in table 1. Among novel agent-based regimens, there was no significant difference in median OS, except Td, which was inferior to Rd (HR 1.62; 95% CI 1.17-2.24). Conclusion We cannot demonstrate with overall survival as an endpoint that the doublets of Vd and Rd are inferior to VRd or Cy-bor-d. There were insufficient patients treated with VTd to be included. Our study shows that the choice of novel induction regimen prior to ASCT does not affect survival (with the exception of Td being inferior to Rd), reflecting the wide array of effective salvage options. However, further prospective randomized clinical trials comparing these regimens are required to validate these findings. Table 1. Baseline characteristics and overall survival. Baseline characteristics and survival Cy-Bor-d (n=193) Vd (n=64) Rd (n=253) VRd (n=126) Td (n=157) VAD or Dex (n=229) p-value Median age 61.9 62.15 60.8 60.8 59.3 58.5 0.0041 Sex (percent males) 56.48 57.81 56.92 61.91 57.96 59.82 0.9271 ISS at diagnosis 1:24.82% 2:40.69% 3:34.48% 1:29.73% 2:24.32% 3:45.94% 1:40% 2:43.78% 3:16.22% 1:41.76% 2:34.06% 3:24.18% 1:28% 2:36% 3:36% 1:20% 2:60% 3:20% 0.0005 Median follow-up (95% CI) 20.3 (17.1-22.7) 49.5 (44.7-55.7) 59 (54.5-67) 26.9 (22.8-30.7) 126.7 (120.2-132.9) 143.4 (132.5-152.6) <0.0001 Median OS Not reached (Estimated 5 year OS rate 75%) 97.2 months (95% CI, 66.6-NR) 112 months (95% CI, 97.4-124.3) Not reached (Estimated 5-year OS rate 77%) 81.1 months (95% CI, 59.1-99.1) 78.8 months (95% CI, 67.8-92.6) 0.0019 Figure 1. Figure 1. Disclosures Kumar: Onyx: Consultancy, Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Celgene: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Gertz:Smith Kline: Honoraria; Novartis: Honoraria; Onyx: Honoraria; millenium: Consultancy, Honoraria; Celgene: Honoraria.

Abstract Dexamethasone is a powerful anti-inflammatory, immunosuppressive agent widely used in the treatment of MM with pleiotropic effects on both the tumor, and host immune cells. We report on a completely novel approach to immune modulation using an agent with almost directly opposite effects to glucocorticoids on innate immune cells. LCL161 is an IAP antagonist targeting the cellular inhibitor of apoptosis proteins cIAP1 and -2 (cIAP1/2) that in a phase I study in solid tumors was well tolerated with a cytokine release syndrome as the dose limiting toxicity. We previously reported that loss of cIAP1/2 in MM cells results in the stabilization of NIK and activation of the non-canonical NFkB pathway, a pathway we found frequently activated by a promiscuous array of mutations in multiple myeloma (MM). As expected, we found that LCL161 has no direct anti-tumor activity against MM cells in vitro and ex vivo. However, the non-canonical NFkB pathway is also a key activator of the innate immune response. Remarkably, we found that in vivo LCL161 has dramatic, apoptosis-independent activity associated with marked phagocytosisagainst MM that develops spontaneously in an immunocompetent genetically engineered mouse model of MM (Vk*MYC). Cyclophosphamide (Cy), which has been shown to induce an acute secretory activating phenotype in tumor-associated macrophages, markedly potentiated the anti-tumor effects of LCL161. We show that phagocytes (depleted by liposomal clodronate), but not adaptive immune cells, are required for the anti-tumor effect. Consistently we show that LCL161 activates dendritic cells and macrophages in vitro, and in vivo, and upregulates production of inflammatory cytokines. A phase 2 clinical trial of LCL161 was conducted in 24 patients with relapsed MM previously exposed to both IMiDs and PIs, but less than 5 prior lines of therapy. Patients received LCL161 1200mg po weekly, with Cy 500mg po weekly added for progressive disease or lack of response. Single agent LCL161 was well-tolerated, with grade 3 or 4 non-hematologic toxicity in four patients, and following the addition of cyclophosphamide in 9 patients. No patients responded to single agent LCL161, and the best response was stable disease in 6/24. In 21 patients, Cy was added after a median of 2 cycles, in whom the best response was stable disease or better in 18/21 (p<0.001 compared to LCL161 alone), and a PR or better (including 1 VGPR and 1 CR) in 5/21 (p<0.001 compared to LCL161 alone). Six months following the initiation of Cy, 35% of patients remain event-free. Two patients had stable disease for more than nine months after stopping treatment. One, relapsing after VDT-PACE, HDM200, RVd x 3 years with t(11;14) and del17p, received only three months of LCL161, the last month in combination with Cy. He then achieved a PR, reconstitution of his uninvolved IgG to normal levels for the first time in more than 3 years and still has not progressed one year after stopping therapy. Similar changes in serum and bone marrow inflammatory cytokines and gene expression were observed in patients following treatment with LCL161 to those observed in the mice. We conclude that LCL161 is able to modulate the tumor microenvironment to exert long-term disease control in combination with Cy, and deserves further study in combination with agents that more directly depend on phagocytic cell activity (e.g., monoclonal antibodies, inhibitors of "Don't eat me" signals). Disclosures Bergsagel: Novartis: Research Funding; Constellation Pharmaceuticals: Research Funding; Incyte: Consultancy; Jannsen: Consultancy; Mundipharma: Consultancy. Off Label Use: Use of LCL161 to treat multiple myeloma. Kumar:Celgene: Research Funding; Millenium/Takeda: Research Funding; Onyx: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria. Stewart:Oncospire Genomics: Research Funding.

Abstract Abstract 1878 Poster Board I-900 Autologous stem cell transplant as a platform for multiple myeloma treatment is the standard of care for patients who can safely withstand the procedure. Before novel agents were introduced, one-third to one-half of patients did not achieve partial response at transplant. Previously published medical literature has showed that in this past era, absence of initial response to induction therapy had no impact on progression-free survival and overall survival after high-dose therapy. Lack of response to initial induction did not preclude a good response after stem cell transplant. With the introduction of novel agents—immunomodulatory drugs and proteasome inhibitors—response rates with initial therapy are now between 70% and 100%. This retrospective study analyzes progression-free survival and overall survival in patients who do not have a partial response after induction therapy with a regimen that contains a novel agent. Unlike patients in reports published previously—before novel agents—patients who do not achieve partial remission have a significantly shorter overall survival from transplant (74.0 vs 43.5 months) and a shorter progression-free survival (22.6 vs 13.1 months; P<.001). Absence of a response to induction therapy with a novel agent predicts a poorer outcome after high-dose therapy.{abstabft}.b CR+VGPR for plateau, P<.001 compared with other 3 categories. Failure to respond to novel-agent induction leads to shorter posttransplant progression-free survival (PFS). Failure to respond to novel-agent induction leads to shorter posttransplant overall survivalDisclosures: Gertz: celgene: Honoraria; millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Kumar: celgene: Honoraria; millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Lacy: celgene: Honoraria; millenium: Honoraria.TableMultivariable Analysis of Posttransplant Progression-Free SurvivalVariableP ValuePlateau vs relapsed-refractory.003Albumin.86Sex.94b2-Microglobulin.89Bone marrow plasma cells.18Age.75Abnormal cytogenetics.002CTX mobilization.51Labeling index.002

Abstract Abstract 1228 Poster Board I-250 Background It is generally believed that a ‘deeper’ response in multiple myeloma is associated with an improved outcome, including time to progression (TTP) as well as overall survival. Before the advent of novel agents such as IMiDs or bortezomib, complete responses (CR) were rare in the absence of stem cell transplantation (ASCT). In that era, the depth of response achieved before ASCT tended to be dwarfed by the impact of the conditioning used for stem cell transplant. Hence, the time to progression in patients achieving CR before ASCT was not different from those who achieved CR after ASCT. With novel agents, CR rates are higher and again raises the question of whether patients who achieve CR before ASCT benefit from consolidation with ASCT. The purpose of this analysis was to determine whether CR achieved before ASCT still benefit when consolidated with ASCT Methods After approval from the Institutional Review Board at Mayo Clinic Rochester, the transplant dysproteinemia database was searched for all patients treated with novel agents and patients who achieved CR before or after ASCT were identified. In addition, we identified patients with IMiDs induction therapy and achieved CR but did not proceed with ASCT. Relevant demographic, clinical and laboratory characteristics were determined at the time of ASCT. Comparisons between groups were performed with non-parametric tests. Overall survival and TTP were determined from the time of ASCT using the Kaplan-Meier method. Results A total of 354 patients who underwent ASCT within a year from diagnosis of multiple myeloma were identified. Of these, 24 achieved CR before proceeding to ASCT while another 100 patients achieved CR after ASCT. There were no differences between the two cohorts with respect to age (58 vs 57.5 yr, p=0.14), gender, number of treatment regimens (1 vs 1, p=0.83), time to ASCT (6.5 vs 6.3 months, p=0.80), b2M (2.41 vs 2.26, p=0.58) and ISS (p=0.23). Patients who achieved CR before ASCT had a lower plasma cell burden (1.0 vs 5.0%, p<0.0001) and lower labeling index (0 vs 0, p=0.0007). Aneuploidy was present in none of the patients with CR before transplant compared to 10% in patients who achieved CR after ASCT (p=0.11). The median TTP for patients with CR before ASCT has not been reached (71% at 70 months) compared to 30 months for patients who achieved CR after ASCT (p=0.07). After a median follow up of 70 months, 21 of 24 patients (88%) with CR before transplant are alive compared to 76 of 100 patients with CR after ASCT (p=0.44). In contrast, for patients who achieved CR with IMiDs but did not proceed with ASCT, 55% have not progressed at 51 months and 71.7% are alive at 51 months (Gay et al ASH, 2009). Conclusion Our results suggest that patients who achieve CR before ASCT benefit from high-dose therapy and experience prolonged TTP without the need for maintenance therapy. ASCT after achieving CR can result in a deeper response with improvement in disease free and overall survival. Disclosures Lacy: celgene: Research Funding. Gertz:celgene: Honoraria; genzyme: Honoraria; millenium: Honoraria; amgen: Honoraria.

Abstract Background: Thrombotic microangiopathy (TMA) is a hematologic syndrome associated with endothelial injury, microvascular thrombosis, and hemolytic anemia resulting in end organ damage. TMA is rarely associated with multiple myeloma (MM) and is usually reported in the setting of allogeneic hematopoietic stem cell transplants (AHSCT), with associated graft versus host disease and calcineurin inhibitor use. We present 11 cases of TMA in MM patients not associated with AHSCT. Methods: Cases were collected from multiple centers in patients with confirmed diagnosis of MM. TMA was diagnosed by the presence of thrombocytopenia and evidence of microangiopathic hemolytic anemia. Results: Eleven patients with MM were identified to have developed TMA during the course of their disease. Two patients presented with TMA at the time of MM diagnosis. A third had been off treatment for over a year prior to presenting with a TMA which correlated with a significant increase in her free light chains. The other cases occurred during active treatment. All remaining patients received proteasome inhibitors, with three patients on bortezomib-based regimens and five patients on carfilzomib. One patient on a bortezomib-based regimen had been stable prior to developing a TMA in the setting of sepsis. In the remaining patients, the TMA developed rapidly after initiating the proteasome inhibitor. In all cases, the TMA improved after drug withdrawal. One patient was later rechallenged with bortezomib and again developed TMA. Discussion: A review of the literature reveals only nine cases of TMA with MM. Of these, 4 patients had TMA as the initial presentation of MM, and 5 patients were on treatment, most often bortezomib-based regimens. Our series patients match those in the literature closely and demonstrate that TMAs can occur in MM outside of the context of AHSCT. In roughly one third of patients, TMAs were the initial presentation of MM and improved with treatment of the MM. In others, the use of proteasome inhibitors appears to be associated with development of TMA. In these cases, the temporal correlation, resolution of TMA after medication withdrawal, and the instance of recurrence of TMA with rechallenge of bortezomib, support a causal relationship between the medication and the TMA. Thus, a high clinical suspicion for TMA must exist for patients on proteasome inhibitors who develop worsening anemia and thrombocytopenia. Medication should be withdrawn if TMA is diagnosed. Disclosures Vij: Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy.