Dispenzieri, Angela

Abstract Abstract 2868 Introduction: Improvement in renal parameters is fundamental for the assessment of organ response to treatment in immunoglobulin light chain amyloidosis (AL). Renal response, defined as a >50% reduction in proteinuria with <25% decrease in renal function, is associated with superior overall survival (OS); however, a systematic study of the interplay of proteinuria, creatinine, and free light chain has not been performed. The intent of this study is to better understand the components of the renal response criteria. Methods: Patients who underwent autologous stem cell transplantation from 1995 to 2010 were eligible for this retrospective analysis if they had > 1 year of follow-up and a baseline 24 hour urine protein > 1 g/d. Those who were dialysis dependent or died before 1 year were excluded as not evaluable for renal response. Results: Of the 435 patients screened, 152 met criteria. On univariate analysis, >50% proteinuria reduction (p < 0.001), serum free light chain (sFLC) reduction by >50% (p = 0.002), <25% increase in serum creatinine (Scr) (p = 0.0003), and a 50% proteinuria reduction within 15 months of treatment (p = 0.04) were associated with better OS. Multivariate analysis using a proportional hazard model showed that sFLC reduction by >50% (0.006), <25% increase in serum creatinine (Scr) (p = 0.0005) and >50% proteinuria reduction (p = 0.0006) were independently associated with OS. In addition, OS was significantly better among patients achieving >85% reduction in proteinuria than those with < 85% but >50%, p = 0.03 (Figure 1). Patients with >75% reduction in sFLC were more likely to achieve >50% proteinuria reduction (p = 0.009). Most importantly, among those with > 25% increase in Scr, only those patients who had <85% proteinuria reduction had a worse OS (Figure 2a, p = 0.006). There was no difference in OS among those with >85% proteinuria reduction and a rise in Scr of > 25% (Figure 2b, p = 0.77). Conclusion: Renal response is an excellent prognostic marker in patients with AL. This is the first study to show the depth of renal response correlates with OS. Patients who had the highest levels of proteinuria reduction (> 85%) had a significantly better OS than those with >50% but <85%. We also found that the negative impact of >25% decrease in renal function was only pertinent in those who did not have >85% reduction in proteinuria. These findings should help better refine the definition of renal response criteria in AL patients. Disclosures: Leung: Binding Site: Honoraria.

Abstract Abstract 3101 The POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) syndrome is a rare paraneoplastic disorder secondary to a clonal plasma cell process. The most experience with successful outcomes in POEMS with disseminated disease has been with high dose chemotherapy followed by autologous stem cell transplantation (ASCT). However, the risk of relapse of POEMS following an ASCT or the outcome of the patients who relapse is not known. We therefore performed a retrospective review of POEMS patients who underwent ASCT at our center and subsequently relapsed or progressed. Over the past 12 years, 58 patients with POEMS underwent autologous stem cell transplantation at the Mayo Clinic, Rochester between Mar 18, 1999 and Jun 22, 2011. With a median follow up of 40 months (1–147 months), 12 patients have relapsed. The median time to relapse was 41 months. The 1, 2, and 5 year PFS rates were 98%, 94%, and 75%, respectively (Figure 1), and the 1, 2, and 5 year OS rates were 98%, 98%, and 94%. Of the 12 patients with documented relapse, 7 had baseline PET/CT scans all of which had FDG avid lesions. By 1 year, the FDG avidity had not resolved in 4 of these patients who then went on to either develop additional lesions or increasing SUV of existing lesions. Of the 12 patients with documented relapse, 8 had baseline VEGF measurements, and all but 1 had normalization by 1 year. The first sign of relapse was a clinical deterioration in 2, a rising M-protein in 3, and a rising plasma VEGF level in 5 patients. All of these patients had new or worsening of existing lesions on PET/CT scan (n= 9) or x-ray imaging (n= 3). The symptoms of clinical relapse included pain at the site of the lytic lesion and generalized pain with swelling. Of the patients who relapsed, 5 were treated with radiation therapy, 4 received lenalidomide or thalidomide, 2 had alkylator based therapy and 1 had bortezomib based therapy. One patient was treated with surgical resection of his hepatic plasmacytoma and 2 patients have been observed without needing definitive treatment as of yet. One patient also received anti-VEGF treatment with bevacizumab unsuccessfully after failing cyclophosphamide therapy. In this large cohort of POEMS patients treated with high dose chemotherapy and autologous stem cell transplantation in a single center, a relapse rate of 21% was noted. Not every patient who relapsed has been deemed to need further treatment, and most patients could be salvaged with chemotherapy or radiation. Only one patient died from relapsed POEMS following stem cell transplantation. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Obesity is increasing in prevalence worldwide and has potential implications on chemotherapy dosing and selection of patients for therapy. Auto HCT improves outcomes for patients with MM, but optimal chemotherapy dosing for obese patients is poorly defined. Methods: We identified 1087 patients reported to the CIBMTR between 1995 and 2003 who underwent auto HCT for MM as part of initial therapy, defined as within 18 months of diagnosis, and received high-dose melphalan conditioning, with or without total body irradiation (TBI). We categorized patients by body mass index (BMI) as normal (18.5– 24.9), overweight (25–29.9), obese (30–34.9), or severely obese (≥35). Underweight patients (BMI <18.5, N=9) were excluded from analysis. We analyzed overall survival (OS) and progression-free survival (PFS) from date of transplant, using Kaplan-Meier curves and the log-rank test for univariate analyses and using Cox proportional hazards models for multivariate analyses. Results: Cases were reported from 114 centers in 10 countries. There were 292 patients of normal weight (27%); 472 were overweight (43%), 198 were obese (18%), and 125 severely obese (11%). Median follow-up of survivors was 63, 61, 60 and 59 months, respectively. Significant baseline differences among BMI groups indicate that obese patients selected for transplant were younger (median age 58, 58, 56, and 55 years, respectively, p=0.005) and had less severe disease at diagnosis, with lower bone marrow plasmacytosis and less frequent renal failure, hypercalcemia, and severe anemia. Obese patients received higher total melphalan doses but lower doses per square meter of body surface area (calculated based on actual body weight). Univariate analyses show no significant effect of BMI category on either OS or PFS. However, among patients who received TBI as part of conditioning, multivariable analyses show a significant effect of BMI on PFS (p-value for interaction 0.006). In this subgroup, a higher BMI was associated with longer PFS (p=0.006, Figure 1). Among patients who received melphalan alone, no effect of BMI was apparent (Figure 2). The difference in PFS for patients receiving melphalan/TBI was due to a decreased risk of relapse among obese patients. Pairwise comparisons of conditioning regimen (TBI vs. no TBI) within BMI categories showed significant reduction in risk of treatment failure for obese (HR=0.54, p=0.04) and severely obese (HR=0.32, p=0.001) patients who received TBI. No differences in OS were apparent in multivariate analyses. Relative risks (RR) for PFS from a multivariable model adjusting for possible confounders are shown below: TBI No TBI n RR (95% CI) P n RR (95% CI) P Normal 44 1.00 Poverall=0.006 248 1.00 Poverall=0.18 Overweight 62 0.92 (0.60–1.40) 0.69 405 0.90 (0.75–1.08) 0.24 Obese 21 0.49 (0.27–0.90) 0.021 177 0.85 (0.68–1.07) 0.16 Severely obese 22 0.39 (0.20–0.76) 0.005 100 1.12 (0.86–1.45) 0.42 Conclusion: Obesity, when measured by BMI, has no statistically significant effect on OS among patients with myeloma receiving high-dose melphalan. Among patients receiving melphalan with TBI, a higher BMI is associated with improved PFS. The reason for the restriction of this effect to TBI-containing conditioning regimens requires further investigation. The current common strategy of reducing melphalan doses (i.e. calculating based on ideal or adjusted body weight) does not appear to impair outcomes for obese patients. Obesity should not exclude patients from consideration of autologous transplantation. Figure Figure

Abstract Abstract 806FN2 POEMS syndrome is defined by the presence of peripheral neuropathy (P), monoclonal plasma cell disorder (M), organomegaly (O), endocrinopathy (E) and skin changes (S). The majority of patients have sclerotic bone lesions, although the underlying mechanisms are still unclear. Increased circulating vascular endothelial growth factor (VEGF) is another feature of the disease. However, there is almost no information on the role of other angiogenic molecules in POEMS biology. The aim of the study was to evaluate bone metabolism and angiogenic cytokines in POEMS and compare the results with multiple myeloma (MM) and osteosclerotic patients of other etiology. We retrospectively studied 61 POEMS patients (40M/21F, median age 52 years) who were diagnosed between 1996 and 2010 and were treated and followed in Mayo Clinic Rochester (MN, USA), Hôpital Saint-Louis, Paris (France) and in Alexandra Hospital, Athens (Greece). We evaluated the following indices of bone remodeling and angiogenesis in all patients at diagnosis and in 22 of them one month after front-line treatment: i) osteoclast regulators [sRANKL and osteoprotegerin (OPG)]; ii) osteoblast inhibitor dickkopf-1 (Dkk-1); iii) bone resorption marker CTX; iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin]; and v) angiogenic cytokines [VEGF, angiogenin (ang), angiopoietin (angp)-1 and -2]. These molecules were also measured in 60 newly diagnosed, untreated MM patients (34M/26F, median age: 54 years) and 44 healthy controls. Bone markers were also evaluated in 24 patients with HbS/beta-thalassemia (10M/14F, median age: 43 years) who presented with osteosclerosis, defined as osteosclerotic bone lesions in plain radiography and high T-score of lumbar spine DXA (median: +3.6, range: +2 to +7.9). All POEMS patients presented with P and M, while 90% had E, 83% had S, 61% had O and 32% had papilloedema. One or more documented sclerotic bone lesions in plain X-rays were observed in 78% of patients (diffuse lesions in 44%), while 43% of patients had also an osteolytic component. Seven patients had Castleman disease. At diagnosis, compared to controls, POEMS patients had increased levels of bALP (mean ± SD: 48.3 ± 22.9 IU/L vs. 21.6 ± 8.2 IU/L; p<0.001), CTX (0.97 ± 0.94 ng/ml vs. 0.33 ± 0.24 ng/ml; p<0.001), Dkk-1 (p<0.001), sRANKL (p<0.001) and sRANKL/OPG ratio (p<0.001). Patients with diffuse osteosclerosis had increased levels of Dkk-1 compared to others (p = 0.05), suggesting a balance effect to increased formation activity. Patients with POEMS had increased levels of bALP and decreased levels of CTX compared to MM patients (p<0.001 and p = 0.03, respectively), while they had increased levels of CTX and sRANKL/OPG ratio compared to HbS/beta-thal patients (p = 0.001 for both comparisons). There were no other differences regarding bone markers among studied groups. Regarding angiogenic cytokines, at diagnosis, POEMS patients had elevated VEGF (1232 ± 565 pg/ml vs. 195 ± 211 pg/ml; p<0.001), ang (266 ± 82 ng/ml vs. 190 ± 45; p<0.001) and angp-2 (3.5 ± 2.2 ng/ml vs. 1.2 ± 0.6 ng/ml; p<0.001) and decreased angp-1 (p =0.05) and angp-1/angp-2 ratio (reflects increased angiogenic capacity; 9.1 ± 8.8 vs. 44.8 ± 76.1; p<0.001) compared to normal controls. We found no strong correlations between the levels of VEGF, ang and angps. When compared to MM patients, POEMS patients had increased circulating VEGF (p = 0.001) without any difference regarding the other angiogenic cytokines. Response to therapy was accompanied by a dramatic reduction of VEGF only (551 ± 541 pg/ml compared to baseline 1800 ± 1510 pg/ml; p = 0.003). Receiver-operating characteristic (ROC) curve analysis showed that high levels of angiopoietin-2 (≥ 2.3 ng/ml) and high bALP (≥ 38 IU/l) each have a 95% specificity for patients with POEMS syndrome. These results suggest that patients with POEMS syndrome have high bone turnover with increased bone formation as compared to healthy subjects, to MM patients, who have reduced bone formation, and to osteosclerotic HbS/beta-thal patients, who have diminished bone resorption. Importantly, our analysis supports the use of angp-2, bALP along with VEGF as minor criteria for the diagnosis of POEMS. Successful treatment reduced VEGF, which seems to be a suitable marker for the follow-up of POEMS patients. Furthermore the imbalance of angp-1/angp-2 pathway may indicate possible targets for the development of novel agents against POEMS. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2945 Background: We have previously reported on a Phase II trial using IL-1Ra and dexamethasone, in patients with SMM/IMM, showing that IL-1Ra targets the myeloma proliferative component which parallels a decrease in the C-reactive protein, a surrogate for IL-6 production. (Mayo Clinic Proceedings 84 :114 (Feb. 2009)). In early stage myeloma, IL-6 is a central myeloma growth factor and we have shown that abnormal production of IL-1 β in the myeloma microenvironment stimulates the generation of paracrine IL-6. These patients are the individuals most likely to benefit from anti-cytokine therapy in an attempt to delay/prevent the development of active myeloma. We now present updated results of this study including survival data. Methods: Patients that had ≥ 10% bone marrow plasma cells and/or an IgG or IgA M-spike ≥ 3 g/dL and did not require immediate chemotherapy were eligible. All patients received 100 mg of Anakinra (IL-1Ra) SQ qd for 6 months. Patients with evidence of reduction in M-protein levels continued receiving IL-1Ra alone. Patients with stable disease at 6 months or those with a rising M-protein before 6 months received low dose dexamethasone (20 mg qweek) in addition; the dose was adjusted based on response/toxicity. Results: Data were available on 47 patients based on intent to treat, and pts were classified as smoldering (72%) vs. indolent (28%). All SMM patients were in Group 1 or 2 and thirty-eight patients (81%) had greater than 20% bone marrow plasma cells. All 47 patients received IL-1Ra initially and 25/47 subsequently received IL-1Ra/Dex. Seven patients had a decrease in the plasma cell labeling index (PCLI) on IL-1Ra alone which paralleled a decrease in the high sensitivity C-reactive protein (CRP) in all cases. Three patients achieved a minor response to IL-1Ra alone and 9 patients achieved a PR/MR after addition of dexamethasone. For the group of 47 patients, the median progression-free survival was 45 months and the median overall survival has not been reached. When patients were grouped into whether they exhibited a reduction in the C-reactive protein from baseline after 6 months of therapy, the median PFS for patients without (21 patients) or with (26 patients) a greater than one-third reduction in baseline CRP was 1 year vs more than 8 years (p<.01). Similarly, the median OS for patients without or with a reduction in baseline CRP was 7.9 years vs. median not reached (p=.02; see Figure). Toxicity included injection site reactions during the first month of therapy in 86% of patients. Grade 3–4 adverse events consisted mainly of asymptomatic neutropenia (17% of patients) and infection (18% of patients). Patients that progressed to active MM have been treated with standard therapies including lenalidomide, bortezomib, transplant, and novel therapies. In contrast, seven of the 26 patients with a CRP decrease continue with stable disease and minimal toxicity on IL-1Ra alone or in combination with standard agents. Conclusion: The above results suggest that agents such as IL-1Ra that specifically inhibit paracrine IL-6 production are effective at targeting the proliferative myeloma component and warrant further investigation in combination with standard myeloma therapies. Combination therapy that effectively targets both the proliferative and the IL-1 producing myeloma components may be useful in patients with active myeloma that have an elevated growth rate at diagnosis. Disclosures: Lust: Mayo Clinic: Patents & Royalties. Off Label Use: IL-1Ra use in smoldering myeloma. Donovan:Mayo Clinic: Patents & Royalties.

Abstract Abstract 3095 Background: Although HDM is the standard conditioning for pts with MM undergoing ASCT, it is not sufficient for cure. In an effort to improve upon this standard, we added escalating doses of Y-90 Zevalin (a murine IgG1 kappa monoclonal antibody Ibritumomab conjugated to Y-90) to HDM in a standard 3+3 phase I trial design. Y-90 is a beta-emitting radioisotope with a path length of 5 mm allowing it to target CD20+ cells and bystander cells within 5 mm. Methods: Eligibility included being a candidate for ASCT. Consenting patients (pts) received: day -22, rituximab 250 mg/m2 with In2B8 for scanning; day -14, rituximab 250 mg/m2 with escalating doses of Y90-Zevalin; day -2 and -1, melphalan 100 mg/m2/day; day 0, at least 2 × 10(6) CD34/kg stem cells; and GM-CSF until ANC engraftment. The 6 dose levels (DL) were (in Gy): 10; 12; 14; 16; 18; and 20. Dose limiting toxicity (DLT) was defined as: sustained pulmonary or liver toxicity (grade3; 96 hours duration or VOD that does not resove by day 30); delayed engraftment (ANC < 500 at day 21 or platelet transfusion dependence at day 35); and non-hematologic grade (gr) 4 toxicity excluding gastrointestinal or constitutional. Responses were according to IMWG criteria. Accrual was between May 2005 and June 2011. Data was frozen as of August 2, 2011. Results: Thirty pts have been accrued: DL1, 3; DL2, 3; DL3, 3; DL4, 6, DL5, 6; DL6, 6. The median age of patients was 59 (range 32, 73), and 70% were male. 60% had ASCT as primary therapy. The other patients were transplanted in chemosensitive relapse (n=3), chemoresistant relapse (n=7), and untested relapse (n=2). Median time from diagnosis to protocol therapy was 10.4 months (range 3.5, 94.3). Five pts had prior radiation therapy, and 11 had prior ASCT. Maximum tolerated dose (MTD) of Zevalin with fixed dose melphalan 200 mg/m2 was DL 5 (18 Gy) which amounted to 168 mCi (124, 182) administered. No DLTs were observed at DL 1, 2, 3, or 5. There was 1 DLT at DL 4, comprising hepatic failure (gr 5) CMV viremia (gr 3), and delayed engraftment, in a 73 yo patient with chemoresistant relapsed disease, and 2 DLTs at DL 6. These DL 6 DLTs included: 1) fatal bowel necrosis (day 12 post ASCT) in a 67 yo patient with relapsed refractory MM and history of CAD, ischemic colitis, DM; and 2) fatal biopsy proven venoocclusive disease (gr 5), which began day 91 post ASCT in a 62 yo patient with primary refractory MM, peri-mobilization S. aureus bacteremia with septic embolic, and line associated venous thrombosis. Overall, gr 3 or higher AEs were observed in 100% of pts. Non-heme gr 4 AEs were seen in: DL1, 1; DL2, 2; DL3, 0; DL4, 1; DL5, 0; DL6, 4. Median time to ANC >=500 and plts>=50 was 11 (range 8, 17) and 15 days (range 11, 89). Confirmed response rates from immediately pre-protocol to best confirmed response were: CR, 5; VGPR, 5; continued VGPR, 4, and continued PR, 7. If one includes best confirmed response from baseline for those patients using transplant as primary consolidation, 4 PRs are upstaged to VGPRs. Median follow-up for all pts is 24.5 months (0.8, 64.8), and 10 pts have died. The median PFS for pts proceeding to early and delayed ASCT was 30.4 months (95%CI 4.1-NR) and 10.3 months (95%CI 2.8–21.7), respectively. The median OS for pts proceeding to early and delayed ASCT was not attained and 11.4 months (95%CI 2.8-NA), respectively. Conclusions: For patients with multiple myeloma, the MTD of Zevalin with fixed high-dose melphalan is 18 Gy. The combination of a VGPR plus continued VGPR rate of 60%, a median PFS of 13.1 months, and a 73% 1 year OS rate make this a regimen worthy of further study. Disclosures: Kumar: Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract Multiple Myeloma (MM) is the most common indication for autologous hematopoietic stem cell transplantation (auto HCT). However, little information is available regarding the outcome of patients (pts) with the rarer immunoglobulin subtypes IgD and IgM, which represent 2% and 0.5%, respectively, of all MM cases. In addition, IgD MM has been reported previously to have a poorer prognosis, at least after conventional therapy. The CIBMTR conducted a retrospective analysis of MM pts transplanted between 1995–2005 to describe the characteristics and results of auto HCT in IgD (n=36) and IgM (n=11) among 3578 MM patients with auto HCT during this period. Median follow-up of survivors was 41 (range 2–130) months for pts with IgD and 58 (range 5–101) months for those with IgM MM. Among pts with IgD subtype, median age was 52 years (yrs), 67% were male, 36% had a creatinine >2 mg/L, 61% had Durie-Salmon stage III disease at diagnosis and 33% had Kappa Serum Light chain; the corresponding values for IgM pts were 58 yrs, 36%, 73% and 55% respectively. Prior to auto HCT, 75% of IgD pts were chemosensitive and 25% had received >2 lines of chemotherapy, while all IgM pts were chemosensitive and none had received more than 2 lines of prior therapy. Median time from diagnosis to auto HCT was 9 months in both subtypes. The most common conditioning regimen was singleagent melphalan, and all but 1 pt with IgD disease were grafted with blood stem cells. The small sample size precluded multivariate analysis for potential prognostic factors for outcome. Below table summarizes the post-auto HCT results in these pts contrasted with a reference pool of IgG and IgA MM receiving auto HCT in the same time period. Outcomes, probability (95% CI) IgD IgM IgG/IgA (n=36) (n=11) (n=1475) 100-day mortality, % 0 9 ( 0 – 32) 7 (5 – 8) Non MM deaths, % @ 1 yr 0 9 (0 – 32) 5 (4 – 7) @ 3 yrs 3 (0 – 13) 21 (2 – 51) 16 (14 – 18) Relapse/ Progression, % @ 1 yr 21 (9 – 37) 20 (2 – 49) 18 (16 – 20) @ 3 yrs 59 (41 – 76) 32 (8 – 64) 36 (34 – 39) Progression-free survival, % @ 1 yr 79 (63 – 91) 71 (41 – 93) 77 (74 – 79) @ 3 yrs 38 (21 – 56) 47 (17 – 78) 47 (44 – 50) Overall survival, % @ 1 yr 87 (74 – 97) 91 (68 – 100) 79 (77 – 85) @ 3 yrs 69 (51 – 84) 68 (36 – 93) 53 (50 – 57) No striking differences are apparent in the post auto HCT outcomes of patients with IgD and IgM MM. These results are also consistent with published outcomes of pts with IgD/ IgM MM (Wechaleker et al Ann Hematol. 2005 Feb; 84(2):115–7; Maisner et al Bone Marrow Transplant. 2008 Jan; 41(1):51–4).

Abstract Abstract 2950 Background: The median age of patients diagnosed with MM is approximately 70 years, and it is a relatively uncommon disease in the younger population. Both conventional chemotherapy and stem cell transplantation (SCT) have favorably impacted the overall survival (OS) of young MM patients. The median survival of patients < 40 years of age, diagnosed prior to 1993 was reportedly 54 months at our institution. However, the impact of novel agents in this patient population is not well known. We studied the outcome of young patients presenting to our institution over the last decade. Methods: Records of 1538 patients presenting between 01/99 to12/08 were reviewed. The demographics, features and therapeutic interventions in patients up to 45 years of age at diagnosis were analyzed using descriptive statistics. The survival outcome of this group was compared with the remainder of the cohort using the Kaplan-Meier method. Results: One-hundred (6.5%) out of 1538 newly diagnosed MM patients were ≤ 45 years of age at diagnosis. The median follow-up of this group of young patients was 86 months. The disease and patient characteristics are outlined in table 1. A median of 5 regimens (range 1–14) was administered, and 85% patients had received high-dose therapy. 15 patients underwent allogeneic SCT after at least one prior autologous SCT. Novel agents were used both in the front-line and relapsed setting (lenalidomide 60%, thalidomide 56%, pomalidomide 9% and bortezomib 49%), and 45% of initial regimens were novel agent based. The 5 and 7-year OS from diagnosis was 69% and 59%, respectively and the median OS was 93 months. In contrast, the median OS of patients >45 years diagnosed during this period was 53 months (P=0.001, figure 1). Conclusion: A marked improvement in OS of young patients with MM diagnosed in the novel agent era is noted in comparison to the historical control of similar age group. In addition, the age associated survival benefit in the younger patient population prevails in the era of novel therapies. Disclosures: Gertz: Celgene: Honoraria. Lacy:Celgene: Research Funding. Dispenzieri:Binding site: Honoraria; Celgene: Research Funding. Kyle:Millennium: Consultancy; Binding Site: Honoraria. Kumar:Millennium Pharmaceuticals, Inc.: Research Funding; Celgene: Consultancy, Research Funding; Genzyme: Research Funding; Novartis: Research Funding; Merck: Consultancy, Honoraria.

Abstract Abstract 2992 Background: Patients with myeloma receiving initial therapy with lenalidomide-based regimens can have difficulty collecting adequate stem cells for an autologous transplant. Stem cell collection in these patients can be significantly enhanced by addition of the CXCR-4 antagonist plerixafor to the mobilization regimen. Plerixafor is typically given subcutaneously (SQ), with collection approximately 11 hours after injection to obtain maximum yield. Intravenous administration can potentially allow more rapid and predictable mobilization compared to the SQ route. We designed this trial to prospectively assess the efficacy of intravenous plerixafor administration in patients undergoing lenalidomide therapy. Patients and methods: Patients who were receiving initial therapy with a lenalidomide-based regimen and were undergoing stem cell collection within 12 months of their myeloma diagnosis were enrolled. Patients received GCSF at 10 μg/kg/day for 4 days followed by addition of plerixafor at 0.24 mg/kg/dose starting on day 5. Plerixafor was administered intravenously early morning (6–7 am) followed by apheresis beginning 4–5 hours later. Plerixafor was administered for a maximum of 4 days; but patients could continue apheresis beyond the 4th day at treating physician discretion. The aims of the study were to determine the proportion of patients reaching a stem cell yield of at least 3 million CD34 cells/kg by second day of apheresis, the safety and tolerability of intravenously administered plerixafor, and the overall rate of failure to mobilize (defined as less than 2.5 million CD34 cells/kg in 4 collections). Results: Thirty-seven patients were accrued between December 2009 – April 2011, and 36 were eligible for analysis. The median age was 61 years (range; 28–73); 61% were male. The median time from start of initial therapy to enrollment was 4.6 months (range; 2.6 to 11.1) and the median cycles of lenalidomide were 4 (range; 3–11). Thirty-four (94%) of the patients achieved at least 3 million CD34 cells/kg within 2 days of apheresis. The median CD34 cells/kg after 1 day of collection was 3.9 million (range; 0.7 to 9.2) and after two days of collection was 7.02 million (range: 1.1–16.5). Two patients failed the mobilization (<2.5 million CD34 cells/kg). There were no grade 3 or 4 non-hematological adverse events and one patient experienced grade 4 thrombocytopenia. The most common grade 1 or 2 adverse events seen were gastrointestinal, namely nausea, diarrhea and abdominal pain or bloating. Grade 1 dizziness was reported in 8 patients. Overall, the infusion was well tolerated. Conclusion: Intravenously administered plerixafor is an effective strategy for mobilization in this patient group with low rate of failure to mobilize. It is well tolerated with toxicity comparable to the SQ administration. It also offers flexibility in patient scheduling with a convenient schedule for early morning infusion followed by apheresis later in the day. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Genzyme: Research Funding; Novartis: Research Funding. Off Label Use: Use of the investigational agent MLN9708 for the treatment of previously untreated multiple myeloma. Lacy:Celgene: Research Funding.

Abstract Background Acquired factor X (FX) deficiency is associated with immunoglobulin light chain (AL) amyloidosis and may be accompanied by hemorrhage. There are limited data on the effects of autologous stem cell transplant (ASCT) on FX deficiency. We reviewed hemorrhagic complications and the effect of high dose melphalan (HDM) and ASCT on FX levels in AL amyloidosis patients with FX deficiency. Methods We conducted a retrospective chart review of patients with AL amyloid with FX levels below 60%, not on chronic anti-coagulation who underwent HDM/ASCT at the Mayo Clinic, Rochester, MN between 1995 and 2011. Results Forty-one of 358 patients (11%) met our study criteria. Median pre-ASCT FX was 45% (range: 2%, 59%). The most common bleeding complication was central line associated n=15 (37%) followed by gastrointestinal n=10 (24%) and genitourinary n=9 (22%). The most frequent and severe bleeding complications occurred in patients with FX levels less than 10%. Four patients required emergent splenectomy owing to splenic rupture; one of these patients died from hemorrhagic shock. Periprocedural prophylaxis included activated recombinant Factor VII (rFVIIa) infusions, fresh frozen plasma (FFP) infusions and platelet transfusions. rFVIIa was efficacious in controlling bleeding during splenectomy (n=5) and, in conjunction with arterial embolization, for retroperitoneal bleed (n=1). Elective splenectomy for FX deficiency (n=1) resulted in only transient improvement in FX level. No relationship between the degree of pre-ASCT FX deficiency and other laboratory values (alkaline phosphatase, AST, total bilirubin, serum albumin, total serum protein, serum creatinine, total urine protein, beta2 microglobulin, troponin T) was found. Post-ASCT FX levels were determined in seventeen patients. In four of these patients, post-ASCT FX levels were determined in the acute/subacute phase of ASCT before steady state FX levels could be achieved; the median change in FX for these patients was -6.5% (range: -19%, 3%). In the remaining thirteen patients, who were between 99 and 1920 days from ASCT, FX improved by median 26% (range: -15%, 92%). Overall post-ASCT FX increased in twelve of thirteen (92%) patients. The improvement in FX correlated with improvement in the degree of proteinuria (p = 0.04) and showed a trend towards significant correlation with improvement in serum alkaline phosphatase (p = 0.06). Conclusions Hemorrhagic complications are most frequent and severe for FX levels below 10%. rFVIIa infusions, FFP and platelets were effective prophylactic agents. In the single patient who underwent elective splenectomy, a transient improvement in FX level was seen. Splenectomy was otherwise reserved for patients with splenic rupture/hematoma. Post-ASCT FX levels increased in twelve (92.3%) of the remaining thirteen patients; five of the patients (38.5%) were no longer FX deficient after ASCT. The degree of improvement in FX levels was correlated with improvement in markers of renal or hepatic involvement by amyloid. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.