Gertz, Morie A.

Background: Therapy-related MDS/AML (t-MDS/AML) is a common and devastating complication of treatment with alkylating agents and topoisomerase II inhibitors, often employed with curative intent, in standard or high-doses, in the treatment of hematological malignancies and solid tumors. Allogeneic HSC transplant is considered the standard treatment for t-MDS/AML but its applicability is limited by the unavailability of donors, comorbidities in the recipient and risk of acute and chronic graft-versus-host disease. Patients carrying diseases commonly treated with high-dose chemotherapy and autologous HSC transplant (such as multiple myeloma and non-Hodgkin lymphoma) who latter develop t-MDS/AML occasionally have stored HSC harvested prior to the diagnosis of the secondary malignancy (hereafter called early-stored HSC). The benefit of using early-stored HSC to support myeloablative therapy for the treatment t-MDS/AML is unknown. Methods: Retrospective, single center analysis of patients with t-MDS/AML receiving myeloablative chemotherapy with or without irradiation supported with early-stored HSC. Results: Six patients received early-stored HSC transplant for treatment of t-MDS/AML between 2000 and 2007. Median age at the time of the transplant was 57 years (range 15–71). Three patients had been primarily diagnosed with follicular lymphoma, 2 with multiple myeloma and 1 with Ewing’s sarcoma. One patient had received prior autologous HSC transplantation. Two patients developed AML, 1 patient CMML, 1 patient RCMD, 1 patient RAEB1 and 1 patient RAEB2. Median time from diagnosis of primary malignancy to HSC harvesting was 26 (2–122) months and from harvesting to development of t-MDS/AML 44 (7–79) months. Conditioning regimen was Cy/TBI in three patients, BuCy in 2 patients and Samarium + Melphalan in one patient. Five patients engrafted neutrophils and 4 patients engrafted platelets 10–34 and 13–126 days after transplant respectively. In 3/6 patients there was disappearance of the pre-transplant chromosomic abnormality (2 patients -7 and 1 patient -7 and t(1;7)). Two patients obtained hematologic CR and two patients obtained CR without full recovery of platelets. One patient died of sepsis 230 days after transplant, one died with refractory disease on day 103 after transplant and one patient is alive with recurrence of t-MDS. Three patients are alive and free of disease 7, 73 and 87 months after transplant. Conclusion: Myeloablative conditioning followed by autologous, early-stored HSC transplant can provide prolonged survival to patients with tMDS/AML not suitable to allogeneic SCT.

Abstract Massively parallel sequencing analyses have revealed a common mutation within the MYD88 gene (MYD88L265P) occurring at high frequencies in many non-Hodgkin lymphomas (NHL) including the rare lymphoplasmacytic lymphoma, Waldenström’s macroglobulinemia (WM). Using whole exome sequencing, Sanger sequencing and allele-specific PCR, we validate the initial studies and detect the MYD88L265P mutation in the tumor genome of 97% of WM patients analyzed (n=39). MYD88L265P was detected at lower frequencies in other indolent lymphomas including LPL (0%), MALT (4%), nodal MZL (5%) and splenic MZL (8%); all but one MYD88L265P was heterozygous. Due to the high frequency of MYD88 mutation in WM and other NHL, and its known effects on malignant B cell survival, therapeutic targeting of MYD88 signaling pathways may be useful clinically. However, while the effects of MYD88L265P on the activity of IRAK1/4 and NF-κB are have been studied previously, we are lacking a thorough characterization of the role of intermediary signaling proteins such as TRAF6 and TAK1 on the biology of MYD88L265P-expressing B cells. A better understanding of the proteins involved in MYD88L265P signaling may lead to the development of more targeted and effective therapeutic approaches. In an attempt to identify MYD88L265P –specific therapeutic targets we first wanted to characterize the role of intermediary signaling proteins that facilitate the downstream activation of NF-κB. Upon activation of TLRs or IL-1b receptors, MYD88 forms a homodimer and recruits IRAK1/4 and TRAF6 into a complex resulting in association and phosphorylation of TAK1 followed by activation of NF-κB. We monitored the formation of a complex comprised of MYD88, IRAK1, IRAK4 and TRAF6 and immunoprecipitation of either endogenous IRAK4 or IRAK1 revealed constitutive association of IRAK with TRAF6 and MYD88L265P. To assess if the formation of a MYD88L265P/IRAK/TRAF6 complex results in downstream activation of TAK1, constitutive TAK1 phosphorylation was measured and detected in all three cell lines that express MYD88L265P. An association between TAK1 and TRAF6, another measure of TAK1 activation, was also detectable. When a similar analysis of TAK1 was performed in DLBCL cells expressing wild-type MYD88, no phosphorylation of TAK1 was detected, nor was TAK1 associated with TRAF6. IRAK1, IRAK4, TAK1, TRAF6, and MYD88 were expressed at similar levels in all cell lines studied and therefore did not contribute the differences in MYD88 complex formation observed between cell lines. These studies were further confirmed using HEK 293T cells that were transduced with either a vector control plasmid or HA-tagged MYD88WT or MYD88L265P expression plasmids. Together, these studies suggest that MYD88L265P forms a complex with IRAK and TRAF6 resulting in constitutive activation of TAK1 and NF-κB. To confirm the significance of TAK1-mediated MYD88L265P signaling on lymphoma cell growth, the effect of the selective TAK1 inhibitor, (5Z)-7-Oxozeaenol, on cell proliferation was tested. All MYD88L265P-expressing cell lines were sensitive to TAK1 inhibition in a dose-dependent manner (0-10 μM). In contrast, NHL cells expressing MYD88WT were found to be insensitive to TAK1 inhibition. We next tested the impact of the TAK1 inhibitor on a MYD88L265P positive WM patient sample. Similar to what was seen in the WM cell lines, the TAK1 inhibitor inhibited WM cell growth and survival in a dose dependent manner. Additionally, the TAK1 inhibitor significantly reduced the level of IL-10 secreted by each of the cell lines. Together, these data suggest that MYD88L265P drives cell proliferation and cytokine secretion through a TAK1-dependent mechanism. In conclusion, we are the first to validate by NGS in a large patient cohort the high prevalence and specificity of MYD88L265P in WM. Cells harboring the L265P mutation but not wild-type MYD88 exhibit constitutive signaling leading to the hyperactivation of NF-κB. We have established the role of TAK1 as an integral component of MYD88L265P signaling in both WM and DLBCL cell. Our data suggest that targeting TAK1 clinically may be an effective strategy for the treatment of WM and other lymphomas driven by MYD88L265P signaling. Disclosures: Fonseca: millennium: Consultancy; amgen: Consultancy; Binding site: Consultancy; onyx: Consultancy; medtronic: Consultancy; Genzyme: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; lilly: Consultancy; Onyx: Research Funding; cylene: Research Funding.

Abstract Abstract 2887 Introduction: Cardiac involvement is the major cause of death in patients with immunoglobulin light chain amyloidosis (AL). Detection of cardiac involvement and risk stratification has been facilitated by cardiac biomarkers like troponin T (cTnT) and N-terminal brain natriuretic peptide (NT-proBNP). A novel high sensitivity cTnT (hs-cTnT) assay has been developed, and we evaluated its diagnostic use with three questions in mind: 1) How do the cTnT and hs-cTnT perform in the AL amyloid staging system? 2) Does higher sensitivity add significant additional value in terms of prognosticating outcomes for patients with AL amyloidosis? 3) Can the current AL amyloidosis staging system be further improved upon? Methods: Stored serum samples (-20°C) from 224 pts with AL were analyzed for concentrations of hsTnT, TnT, and NT-proBNP on the E170 Modular analyzer (Roche Diagnostics, Penzberg, Germany). 99th percentile reference limits were <0.014 and <0.010 mcg/L for hsTnT and TnT, respectively. Results: Median values for hsTnT, TnT, and NT-proBNP were 38 ng/L (range 0–075.4), 0.017 mcg/L (<0.0–0.904), and 1230 ng/L (0–32, 226), respectively. The correlation coefficient between hsTnT and TnT was 0.972. Those classified by echocardiographic parameters as having (n=143) or not having (n=81) cardiac involvement had TnT concentrations of 0.04 and 0.01 mcg/L and hsTnT levels of 52.2 and 15.6 ng/L, respectively. The direct numeric result from the hs-cTnT result CANNOT merely be substituted for a cTnT result in the Mayo AL staging system since 14% of patients would be misclassified. The performance of the receiver operation curve derived hs-cTnT cut-point of 54 ng/L is a slight improvement over the direct substitution of 35 ng/L if replacement of one assay for another is required. An alternate staging option using hs-cTnT alone—using the two thresholds14 ng/L and 54 ng/L (figure)—performs as well as either the original Mayo AL staging system or a derivative system incorporating hs-cTnT with respective relative risks of death (95%CI) of 3.6 (2.3, 5.7), 3.8 (2.5, 5.9), and 3.3 (2.2, .50). On multivariate analysis, our newly described alternate 3 level, hs-cTnT alone staging system is independent of other factors including period of diagnosis, type of therapy, and NT-proBNP value, the last of which dropped out of the model. Alternate models using NT-proBNP and cTnT were explored, but none performed better than the original staging system or the new hs-cTnT system. Conclusion: The direct numeric result from the hs-cTnT result cannot merely be substituted for a cTnT result in the Mayo amyloid staging system. Consideration could be made for AL staging systems using hs-cTnT alone and relegating the NT-proBNP for measuring cardiac response. Disclosures: Jaffe: Roche: Consultancy.

Abstract 5079 Introduction: IgD monoclonal proteins are rare. They are not seen as a MGUS and are present in 1% to 2% of patients with myeloma. In light chain amyloidosis (AL), IgD monoclonal proteins are rare. When an IgD protein is found, amyloidosis is often omitted from the differential diagnosis. An IgD protein in amyloidosis has been reported in single cases but never as a patient series. We report IgD AL in 53. Patients & Methods: Clinical and demographic data for patients were retrieved from the patient records. Factors of interest were compared between patients who did and did not have an IgD protein. Results: Among 3,955 patients with AL amyloidosis seen, 53 patients (1.3%) had a serum IgD monoclonal protein. (Table 1) A serum monoclonal protein peak was visible on SPE in only 14, and only 5 had an M spike greater than 1 g/dL. On immunofixation of the serum, the IgD light chain was k in 11, λ in 35, and uncertain in 6; 1 patient had a biclonal D λ and G k protein. A urine monoclonal protein was detected in 43 of 51 patients; urinary immunofixation detected a λ light chain in 33 and a k light chain in 10. Biopsy of tissues showed amyloid deposits in the bone marrow in 47% and in the fat aspirate in 73%. Six patients (age 47–63 years) underwent autologous SCT. Four had renal & two had cardiac AL. All 6 had hematologic PR, 4 CR, and 4 had organ response. One patient had relapse of disease and is now on dialysis, and another had relapse and is alive with salvage chemotherapy. One patient had disease relapse and died of progressive GI amyloidosis at 22 months. The other 5 are alive at a median of 68 months (range, 7.5–83.5 months). We compared the 53 patients with IgD amyloidosis with 144 patients with non-IgD amyloidosis. (Table 2) Findings that were significantly different between groups included a lower frequency of renal amyloidosis (P=.005) and a lower prevalence of cardiac amyloidosis (P=.047). There was a higher serum albumin level (P=.04) related to the lower level of proteinuria. No difference in survival was seen between the groups. (Figure). Variables that might affect survival—liver size, performance status, septal thickness, serum creatinine level, and β2-microglobulin level—were not different between groups. Conclusions: IgD AL patients have a lower frequency of renal involvement and possibly also of cardiac involvement. The overall survival of these patients does not appear to be different from that of patients who have AL associated with another monoclonal protein. IgD monoclonal proteins are so closely linked to the diagnosis of multiple myeloma in the mind of a clinician that the possibility of amyloidosis may be overlooked. Disclosures: No relevant conflicts of interest to declare.

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 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 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.