Lacy, Martha Q.

Abstract Background: Increasingly thalidomide (Thal) plus dexamethasone (Dex) is being used as initial therapy for multiple myeloma (MM), but there is a need to minimize non-hematologic toxicity with this regimen. CC-5013 (lenalidomide; Revlimid™) is a more potent analog of thalidomide with significantly fewer non-hematologic toxicities that has shown promising results in relapsed refractory myeloma. We report the initial results of the first phase II trial using the combination of CC-5013 plus Dex (Rev/Dex) as initial therapy for newly diagnosed MM. Methods: The trial is designed to accrue 31 eligible patients; 13 patients (pts) (11 male and 2 female) were analyzed in this interim report. Patients were enrolled between February 2004 and July 2004. CC-5013 was given orally at a dose of 25 mg daily on days 1–21 of a 28-day cycle. Dex was given orally at a dose of 40 mg daily on days 1–4, 9–12, 17–20 of each cycle. Patients also received an aspirin once daily as thrombosis prophylaxis. Response was defined as a decrease in serum monoclonal (M) protein by 50% or higher and a decrease in urine M protein by at least 90% or to a level less than 200 mg/24 hours. Responses were assessed on an intent to treat basis. Results: The median age was 61 years (range, 32–78). 8 patients (62%) had Stage III myeloma. 11 of the 13 patients achieved an objective response yielding a response rate of 85% within 1–2 months of therapy. So far 6 patients have experienced grade 3 adverse events. These include one episode each of CD4-count < 200/mm3, anemia, neutropenia, increased liver enzymes, muscle weakness, agitation, hyperglycemia, cardiac arrhythmia, pneumonitis, and colonic perforation (underlying diverticulitis and dexamethasone suspected). No deep vein thrombosis or grade 4 or higher adverse events have been observed so far. Conclusions: Rev/Dex appears active and well tolerated in the treatment of newly diagnosed MM and is a potential alternative to Thal/Dex. However, these results are preliminary and responses are still being evaluated and need to be confirmed in the final analysis of this trial. A large randomized trial using Rev/Dex as initial therapy for MM is expected to be activated by the Eastern Cooperative Oncology Group later this year.

Abstract Abstract 4228 Background Peripheral blood stem cells (PBSC) are the preferred graft type for autologous stem cell transplantation (ASCT) and mobilization is typically done using growth factor (GF) alone or a combination of chemotherapy (CTX) and GF. The success of mobilization is influenced by several factors such as prior therapy, mobilization strategy, underlying disease, among others. Patients (Pts) failing to mobilize successfully often have GF dose increased and if unsuccessful, mobilization is reattempted with chemotherapy + GF or G-CSF (Granulocyte Colony-Stimulating factor) + GM-CSF (Granulocyte–Macrophage Colony-Stimulating factor). More recently, plerixafor, a CXCR4 inhibitor, has been found to enhance G-CSF based collection allowing potential early intervention in poor mobilizers. However, this approach requires valid cut-points for peripheral CD34 counts (pCD34) for cost efficient use. Methods We studied 656 first time, G-CSF based PBSC mobilizers with Non-Hodgkin Lymphoma (562; 86%), or Hodgkin's Disease (94; 14%). Salvage attempts were excluded, as were first attempts using CTX+GCSF, plerixafor or GF combinations. Sensitivity-specificity analysis (Receiver operating characteristic) was used to define ideal cut-points for predefined outcomes. We used a CD34 yield of 2 million/kg as the minimum required collection and 5 million/kg as the ideal collection for the current analysis. Our current practice is to initiate collection at a pCD34 of 10/uL. Results We first determined the best day 1 pCD34 cutoff for being able to collect at least 2 million/kg PBSC to be 9/uL. Among those with ≥9/uL, only 6.6 % failed to collect at least 2 million compared to 55% among the rest (P < 0.001). These numbers were 6.3% and 50% respectively using the traditional cutoff of 10/uL. We then examined how the pCD34 on day 2 predicted collection, among those failing to reach the current threshold of 10/uL. Among this group, a pCD34 on day 2 of 9.1/uL was the best cutoff to predict a collection of 2 million/kg. Among those with >=9.1/uL, only 22% failed to collect at least 2 million compared to 79% among the rest (P < 0.001). Among those with day 1 pCD34 < 10, 49% achieved a count of 9.1/uL on day 2. We then examined what pCD34 on day 1 can best predict a pCD34 ≥ 9.1 on day 2 and found this to be 5.2/uL. Among those with day 1 pCD34 ≥ 5.2/uL, 79% reached day 2 pCD34 ≥ 9.1 compared to 24% among the rest (P < 0.001). We then determined cutoffs based on ideal targets using only those patients achieving pCD34 count > 10/uL by day 2, since these patients would have started collection without any change in the mobilization technique. We used a maximum of 5 collections to achieve the goal as being ideal, taking into account the most commonly used practice of collecting during weekdays. We examined cutoffs for a target of 5 million/kg for one transplant. The best day 1 or day 2 pCD34 predicting a 5 million/kg yield in 5 collections was 17/uL. Among those with day 1or 2 pCD34 ≥ 17/uL, 4% failed to reach 5 million in ≤ 5 days compared to 96% among the rest (P < 0.001). Conclusions This study provides an estimate of optimal pCD34 count thresholds for early identification of patients with lymphoma at high risk of collection failure. It is reasonable to use the first or second day pCD34 count, since a substantial proportion of patients will achieve the threshold value by day 2 and these patients appear to have similar outcome as those reaching the threshold by day 1. Based on the results here, interventions such as addition of plerixafor can be considered if pCD34 count is < 6/uL on day 1 or < 10/uL by day 2, to achieve the minimum collection of 2 million/kg. However, in order to achieve the ideal targets, a higher threshold should be considered and the recommendation based on the current study would be 17/uL for a target of 5 million. Such a target-adapted strategy may be more appropriate. Disclosures: Kumar: Celgene,Genzyme,Millenium,Novartis,Bayer,: Honoraria, Research Funding. Gertz:Genzyme: Research Funding. Micallef:Genzyme: Research Funding.

Abstract Abstract 3854 Poster Board III-790 Background Primary systemic amyloidosis (AL) is an incurable plasma cell disorder. Lenalidomide, especially in conjunction with dexamethasone, has been shown to be active in patients with multiple myeloma. Pomalidomide is a derivative of thalidomide that acts as an immunomodulator. Preliminary data in multiple myeloma demonstrate that this agent is highly active and well tolerated. Methods Eligible patients were accrued into an IRB approved treatment trial with pomalidomide and dexamethasone after signing informed consent. Pomalidomide (2 mg) and dexamethasone (40 mg) were scheduled to be taken orally, the former on a continuous schedule and the latter once weekly. All patients were instructed to take an aspirin daily. Patients were eligible if they had previously treated, biopsy proven, symptomatic AL. Patients were required to have measurable hematologic disease, defined as either a serum M-protein greater than 1 g/dL, a urinary M-protein greater than 200 mg/24-hours, or a serum immunoglobulin free light chain greater than 10 mg/dL. Other eligibility criteria included an ECOG PS>=2, adequate hematologic reserve (ANC>=1000/uL, platelets>=75/uL) and adequate renal function (creatinine <=2.5 mg/dL). They also were required to comply with contraceptive requirements. Patients were excluded if they had uncontrolled infection, another active malignancy, NYHA classification III or IV, a serum troponin T >0.1 ng/mL, >=grade 3 peripheral neuropathy, untreated active thrombosis, or other chemotherapy within 2 weeks of study enrollment. Thirty-four patients are to be enrolled to allow for 2 possible cancels and to provide 90% power to detect a true hematologic response rate of at least 20%. Between 11/24/08-7/28/09, 20 patients have been enrolled. Baseline characteristics and adverse events are available for 17 of the 20 enrolled patients. Results Median age was 63 years (range 52 78), with 60% male. The median time from diagnosis to study entry was 45 months (range 4.5-103). Eighty-two percent had cardiac involvement; 41% renal involvement; 18% peripheral nerve involvement; and 12% autonomic nerve involvement. The cardiac biomarker staging breakdown was: I, 13%; II, 56%; and III, 31%. Patients were heavily treated, with 100% having received prior alkylator (including prior transplant in 9), 44% prior lenalidomide, 31% prior thalidomide, and 37% prior bortezomib. Thirty-three percent of patients had non-hematological adverse events (AEs) >=grade 3 (severe) that were deemed to be at least possibly related to therapy. Thirty-three percent had >=grade 3 hematologic AEs. Neutropenia was most the most common severe hematologic AE; severe thrombocytopenia was observed in only 1 patient, and there was no severe anemia. The most common severe non-hematologic AE was fatigue, which was observed in 3 patients. The only other severe AEs, each of which was observed in one subject each, were pneumonia, weakness, dyspnea, and ascites. As of 8/14/09, 17 patients remain on active therapy. Median time on study is only 3.7 months (range 0.2-8.1). Three patients have discontinued therapy: two progressions; and one death 5 days into treatment, presumably due to cardiac amyloidosis. At the time of this writing response rates could not be calculated given the short follow-up, but hematologic responses have been observed, and details on efficacy will be presented at the meeting. Conclusions Pomalidomide is well tolerated in previously treated AL patients. More information about its activity will be provided at the meeting. Disclosures: Dispenzieri: Celgene: Research Funding. Gertz:Celgene: Honoraria. Kumar:Celgene: Research Funding. Rajkumar:Celgene: Research Funding. Witzig:Novartis: Research Funding. Greipp:Celgene: Research Funding. Fonseca:Celgene: Consultancy. Bergsagel:Celgene: Consultancy. Mikhael:Celgene: Research Funding. Roy:Celgene: Research Funding. Lacy:Celgene: Research Funding.

Abstract Introduction: High dose melphalan followed by stem cell transplantation (HDM-SCT) is currently the most effective therapy for primary systemic (AL) amyloidosis. Recent data showed a 40% complete hematologic response rate and median survival of 4.6 years with HDM-SCT can be obtained. Despite its advantages, treatment mortality can be excessive in high-risk patients. Previously, extensive cardiac, hepatic or renal involvement had been identified as risk factors for poor outcome. We observed that patients who had more than 2% weight gain during mobilization also had a poorer survival after HDM-SCT. This study was undertaken to further examine the outcome of these patients. Patients: Consecutive patients who underwent HDM-SCT for AL between 7/97 and 6/04 were retrospectively studied. Weight (kg) was measured just prior to mobilization, at its peak during mobilization and collection, and just prior to conditioning. Baseline characteristics were extracted from medical records along with left ventricular ejection fraction (LVEF), septal thickness, glomerular filtration rate (GFR), proteinuria, alkaline phosphatase, and the number of visceral organ involved with AL. Mobilization was achieved by cyclophosphamide (C) with granulocyte colony growth factor (GCSF), C with granulocyte-macrophage colony stimulating factor (GMCSF), GCSF alone and GMCSF alone or in combination with GCSF. Patients were conditioned with melphalan in doses of 100mg, 140mg or 200mg per m2 or 140 mg/m2 in combination with total body irradiation. Hematologic response was determined by A 50% reduction in measurable monoclonal protein levels or complete eradication by immunofixation if too small to quantify. Results: During the time period, 128 patients underwent HDM-SCT for AL. One patient was excluded because no weight was recorded during mobilization and 1 refused consent. Weight gain of 2% or greater was noted in 51.6% (65) of the patients. Mortality at 1 year was significantly higher in patients with > 2% weight gain (32.3%) compared to those without (9.8%) (OR = 4.37, 95% CI 1.71 to 12.77, p = 0.004). Univariate analysis identified septal thickness, GFR, alkaline phosphatase, organ involvement and weight gain as risk factors of mortality at 1 year. Using the logistic model, only septal thickness (p =0.04), GFR (p = 0.009) and weight gain (p = 0.009) remained independent predictors of first year mortality in the multivariate analysis. No association was found between weight gain and mobilization regimen. Analysis of patient who survived the first 100 days posttransplant showed no correlation between weight gain and hematologic response. Finally, weight reduction to baseline prior to conditioning did not improve first year survival for those who gained > 2% during conditioning. Conclusion: Our study found weight gain of 2% or more was associated with significantly higher first year mortality after HDM-SCT. The effect of weight gain was independent of both cardiac and renal involvement with AL. Fluid retention was not directly responsible for the higher mortality, as weight reduction to baseline failed to improve the outcome of these patients. Weight gain during mobilization appears to be a novel pretransplant risk factor that predicts the outcome of HDM-SCT based on response to mobilization.

Abstract Abstract 534 Background: Light chain (AL) amyloidosis is characterized by deposition of amyloid derived from immunoglobulin light chains in various organs. Cardiac involvement can lead to a variety of manifestations including congestive heart failure (CHF), conduction disturbances, and arrhythmias, including sudden death. Patients (pts) with cardiac involvement, especially in the presence of CHF, have a poor prognosis. Autologous peripheral blood stem cell transplantation (SCT) is increasingly being used for AL and has been associated with high rates of hematologic and organ responses. However, cardiac involvement due to AL is also associated with higher rates of complications following SCT; and those with advanced cardiac involvement are rarely considered for SCT. As such, our study does not represent the full spectrum of pts with cardiac involvement due to AL, but only those who are considered transplant eligible. Patients and methods: Of the 382 pts with AL who underwent SCT at our institution between May 1996 and September 2008, 194 had documented cardiac involvement. Six pts who underwent heart transplantation were excluded; and188 (49%) pts were considered for this study. Groups were compared using Fisher's exact test or t-test, and survival was calculated using Kaplan Meier method. Survival curves were compared using log rank test. Results: The median (range) age of pts at the time of SCT was 57.3 years (31-71); 122 (64%) were males. The median (range) duration from AL diagnosis to SCT was 3.6 mos (1-75). The estimated median follow up for the entire cohort was 44 mos (95% CI; 38-54) and 39 mos (95% CI; 32-51) from AL diagnosis and SCT, respectively. The estimated median overall survival (OS) for the cohort was 77 mos (95% CI; 38-86) and 69 mos (95% CI; 33-80) from AL diagnosis and SCT, respectively, and 107 (57%) pts were alive at the time of analysis. One, 2 or 3 organs were involved in 32 (17%), 106 (57%) and 50 (26%) pts, respectively. At the time of SCT, the median (range) septal thickness was 14 mm (9-25), and the median (range) EF was 63% (28-84). The cTnT/NT-ProBNP stage was availabel for 100 pts (6, 51 and 43 pts in stages 1, 2 and 3, respectively). Melphalan 200/m2 (85 pts) or Mel/TBI (10 pts) was used for conditioning in 51% pts, whereas the other half had reduced doses of melphalan (100-160 mg/m2). Thirty-one (16.5%) pts had died within 100 days of SCT. A hematologic response was obtained in 129 (69%) pts. A decrease in septal thickness was seen in 88 (47%) pts, with the median (range) decrease being 2mm (1-8). An increase in EF was seen in 85 (45%) pts and the median (range) increase was 6% (1-29). A conventional cardiac response (septal decrease > 2 mm or EF increase '20%) was seen in 62 (33%) pts. A decrease in NT-ProBNP was seen in 31 pts (90 with availabel values). The impact of hematologic or organ response on the OS from SCT was assessed only for those surviving beyond 100 days (landmark analysis). The median OS for those with a hematologic response (149 evaluable) was not reached (NR) compared with 22 mos for those with no response (P < 0.001) (fig B). The median OS for those with a conventional cardiac response was NR compared with 69 mos for those with no response (p=0.003) (fig A). The median OS for those with any decrease in NT-ProBNP was NR compared with 26 mos for those without any decrease (P<0.001). The best cutoff for NT-ProBNP decrease to predict pts being alive at 2 years was 55%, with all such pts alive at the time of analysis. A baseline troponin of <0.02 ng/ml or NT-ProBNP <5000 pg/ml best predicted the possibility of being alive at 1-year post SCT. Transient worsening of echocardiogram as well as cardiac biomarkers were seen in some pts who eventually improved. Eighty-one pts (43%) have died after SCT due to cardiac (37 pts) and non-cardiac (27 pts) causes; while the cause of death was not known in others. Conclusion: SCT is an effective approach in pts with cardiac involvement due to AL, with hematologic and cardiac responses seen in over two-thirds and one-thirds of the pts, respectively. Improved survival is associated with hematologic and organ responses. Cardiac biomarker improvement may be used as a measure of organ improvement and correlates with outcome. This finding will need to be confirmed in a larger group of pts, as well as with other therapies for AL. Disclosures: Lacy: Celgene: Research Funding.

Abstract Abstract 615 Background: Trials comparing efficacy of standard melphalan prednisone (MP) therapy with MP plus thalidomide (T) in the transplant ineligible, elderly patients with multiple myeloma have provided conflicting evidence. While there is greater agreement with regard to superior response rates (RR) with the addition of T to MP in elderly patients, the impact on progression free survival (PFS) and overall survival (OS) is less clear with some trials showing an improvement in PFS and/or OS with MPT and others demonstrating no difference in outcomes. We performed a systematic review to integrate the existing outcome data related to the efficacy of MP vs. MPT using a meta-analytic approach. Methods: A comprehensive search of electronic database through July 31st, 2009 was performed for publications, abstracts and presentations to identify randomized controlled trials (RCTs) comparing MP with MPT. A meta-analysis was performed by pooling results on clinical endpoints of RR, PFS and OS reported in all the identified RCTs under a random effects model. We did not have access to individual patient data from these trials. Results: Overall, five prospective RCTs (3 published articles and 2 abstracts) comparing MP with MPT regimen and comprising a total of 1571 patients were identified. For the endpoints of OS and PFS, data were extractable only from 4 RCTs (abstract by Gulbrandsen et al. was excluded). The Bregg and Egger funnel plot for OS demonstrated a symmetric distribution (P = 0.6) indicating no significant publication bias. The test of heterogeneity among all RCTs was statistically significant in the estimate of RR (tau2=0.21; chi2=16.33; p=0.003 (df=4); I2 = 75.5%), but not significant for the estimates of PFS (tau2=0.01; chi2=4.61; p=0.2 (df=3); I2 = 34.9%), and OS (tau2=0.02; chi2=5.53; p=0.14 (df=3); I2 = 45.8%). As expected, the pooled odds ratio of responding to treatment with MP versus MPT was 0.307 (P&lt;0.001) indicating that MP was worse than MPT in achieving at least a partial response. The pooled hazard ratios (HR) for PFS and OS were 1.59 (p&lt;0.001) and 1.34 (p=0.006), respectively (see table for forest plots) in favor of MPT. Conclusion: Our meta-analysis implies that in previously untreated, transplant ineligible elderly patients with multiple myeloma, the addition of thalidomide to melphalan-prednisone demonstrates improved RR, PFS and OS compared with the use of melphalan-prednisone alone. Although the results from a comprehensive individual patient data pooled analysis would give a more precise estimate, our analysis suggests that MPT is superior to MP in terms of response and survival. Disclosures: Dispenzieri: Celgene: Research Funding. Gertz:Celgene: Honoraria. Kumar:celgene, genzyme, millennium, novartis, bayer: Research Funding; genzyme: Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 3853 Poster Board III-789 Background Light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by progressive multiorgan deposition of amyloid fibrils derived from immunoglobulin light chains. Treatment strategies for AL have typically targeted the clonal plasma cell and have paralleled that for myeloma, with recent clinical trials evaluating the role of novel agents such as immune modulatory drugs (IMiDs). Lenalidomide has activity in patients with AL, and given the synergy seen with alkylating agents, we designed a phase 2 clinical trial of cyclophosphamide added to lenalidomide and dexamethasone. Methods Patients (Pts) with newly diagnosed or previously treated AL, with adequate hematological and organ function, were enrolled between December 2007 and November 2008. Treatment consisted of 28-day cycles with Lenalidomide at 15 mg daily (days 1-21), oral cyclophosphamide 300 mg (days 1, 8, 15) and dexamethasone 40 mg weekly. All patients received aspirin for thromboprophylaxis. Hematological and organ responses were assessed using conventional response criteria. Results Thirty-five pts, 11 (31%) previously treated, with a median age of 64 yrs (range 44-82) were enrolled. Median time from diagnosis to trial enrollment was 1.6 mos (range; 0.1- 129) and 23 (66%) were alive at the time of analysis with a median follow up of 8.7 mos (range; 1.5-17.6). Three or more organs were involved in 10 (28%) pts with cardiac and renal involvement present in 22 (63%) and 27 (77%) respectively. Fifteen pts (44%) had advanced stage III disease by the troponin/ NT-ProBNP staging system. Seven (20%) pts had previous stem cell transplant, one pt had thalidomide and others had melphalan, dexamethasone or a combination of the two. The median duration on study was 6.5 months and the median number of cycles administered was 6, with 27 (77%) patients completing at least 3 cycles of therapy. Thirteen patients still remain on study, with the most common reason for study discontinuation being toxicity (10 pts, 45%). There were 15 (43%) and 24 (69%) episodes of Grade 3 or 4 hematologic and non-hematologic adverse events respectively. The most common non-hematologic toxicities seen were fatigue, edema, constipation and rash. Six patients died while on study due to sepsis (1), multiorgan failure (1), arrhythmia (1), or heart failure (3). The overall hematologic response rate was 60% (21 pts; CR (2), VGPR (10) and PR (9)); 79% for stage I and II pts and 40% for stage III patients. Among those patients receiving at least four cycles, the response rate was 20/23 (87%); 2CR, 10 VGPR and 8 PR. At least one organ response was documented in 8 (24%) patients. The median overall survival (OS) for all enrolled patients is 16.1 mos (95% CI; 10.8-NR). The median OS was not reached for stage I and stage II patients, and was 7 mos (95% CI; 4.6 - 16.1) for stage III pts. The median time to hematologic progression was 16.1 mos and to hematologic or organ progression was 6.7 mos (95% CI; 6.3, 16.1). The median OS among those with a hematologic response was 16.1 mos, and not reached among the group with a VGPR or better. Among the 31 patients with measurable FLC, those (n=24) with a ≥50% decrease in the difference between light chains had superior OS compared to the rest (16.1 mos vs. 4.3 mos). The six patients who died on study all had cardiac involvement and significantly higher NT-ProBNP/ BNP compared to the rest. Conclusion The combination of cyclophosphamide, lenalidomide and dexamethasone has significant activity in patients with light chain amyloidosis. Toxicity is manageable with dose reductions, but patients with advanced cardiac involvement are at a higher risk for toxicity and early discontinuation of therapy. Future trials with this combination should compare this regimen with other treatment approaches in selected patients, as well as pursue a dose-adapted strategy in those with advanced cardiac involvement. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Celgene: Research Funding.

Abstract Abstract 4953 Introduction Primary systemic (AL) amyloidosis occurs as a result of the production a monoclonal protein by a clonal plasma cell or B-cell proliferative disorder. Reduction or complete eradication of the underlying clonal cell disorder is essential for an organ response. Melphalan/ dexamethasone or high dose chemotherapy with autologous hematopoietic stem transplant is currently considered the standard of care. Bortezomib a proteosome inhibitor is effective in reducing or eradication clonal plasma cells and has been shown to produce high complete hematologic response (CHR) rates in multiple myeloma. We therefore hypothesized that Bortezomib will produce a high CHR rate and hence a higher organ response in patients with AL. Material and Methods Our amyloidosis data base which is prospectively collected was searched for patients with primary amyloidosis (AL) who were treated with Bortezomib containing regimen during their disease course. We identified 20 patients. We then assessed clinical features, hematologic and organ response based on the amyloidosis consensus working group criteria. We also evaluated overall survival and time to next therapy. Results We identified 20 patients who received a Bortezomib containing regimen. The median age at diagnosis was 57 yr (range 43 - 79). There were 12 (60%) males. All patients had clonal plasma cell disorder except one patient with lymphoplasmacytic lymphoma. Median bone marrow plasma cell involvement was 10%. The amyloid protein was Lambda light chain in 12 patients and Kappa in 6 patients. Data was missing in 2 patients. The median serum m-spike was 0.5g/dL (range 0 to 3.5). The median number of organs involved was 1 (range 1 – 4). Nine patients had 2 or more organs involved. The specific organs involved were Kidney (13), Cardiac (12), Nerve (5) and liver (2). Median number of prior regimen was 1(range 0 to 3). Seven patients had received no prior therapy. The remaining 13 patients had received various treatments including oral Melphalan/dexamethasone (9), Lenalidomide/dexamethasone (3), Thalidomide/dexamethasone (1) and one patient who received R-CHOP for underlying lymphoplasmacytic lymphoma. Four patients had received a prior autologous stem cell transplant. The median time form diagnosis to Bortezomib treatment was 5 months. The Bortezomib regimen was mainly Bortezomib/dexamethasone (17patients), Bortezomib/Thalidomide/dexamethasone (1), Bortezomib/cyclophosphamide/dexamethasone (1). The Bortezomib was given mainly in the standard dosing 1.3mg/m2 days 1, 4, 8, and 11. Treatment was well tolerated. Hematologic response was seen in 17 patients including CHR (11), VGPR (3), PR (1), and MR (2). Thus resulting in a better than PR response of 75%. Three patients had no response. The median number of cycles to best hematologic response was 4 (range 1 – 9). The median total number of cycles administered was 4 (range 1 – 10). Organ response was seen in 10 patients (50%). These were mainly partial responses was seen primarily in patients with renal amyloidosis. Median time to next treatment was 7.5 months (95% CI: 4-9). Seven patients have received further therapy after their Bortezomib treatment. Three patients received consolidation treatment with Autologous PBSCT although they had all achieved VGPR or CHR. The other four received salvage chemotherapy for disease progression or lack or response, BMT (1), FCR (1), Pomalidomde/dexamethasone (1) and Melphalan/dexamethasone (1). Median follow up of all patients from diagnosis is 12 months (range 2 – 64). The median survival from diagnosis is estimated at 44.7 months (95% CI; 29.1 – 64.8). Median follow up from Bortezomib treatment is 5 months and median survival from Bortezomib treatment has not been reached. Conclusion Bortezomib produced high hematologic response in this population of patients. Organs response was seen in 50% of patients. The durability of these responses is not known, because of the short follow up time. This study suggests that Bortezomib containing regimen may be beneficial in amyloidosis patients. A larger prospective study, looking at single agent Bortezomib or in combination with alkylator agents compared to standard melphalan/dexamethasone or autologous stem cell transplant is needed to help define the role of Bortezomib in primary amyloidosis. Disclosures Lacy: celgene: Research Funding. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 4954 Background Multiple Myeloma (MM) remains incurable with current approaches and newer therapies targeting the abnormal disease biology need to be developed. The malignant plasma cell is highly dependent on the marrow microenvironment, which promotes tumor cell proliferation as well as survival. There is increased bone marrow vascular density in patients with MM and the degree of neo-angiogenesis appear to be prognostic in this disease. Studies have also shown that vascular endothelial growth factor (VEGF) is intricately involved in the interaction between the marrow microenvironment and the myeloma cell. These findings suggested that the VEGF pathway may be a valuable target for therapeutic approach in this disease. Patients and Methods We designed a phase 2 trial of Sunitinib in patients with relapsed multiple myeloma who had received less than three prior therapies. Sunitinib malate (SU11248; Sutent) is a novel, multi-targeted, small molecule inhibitor of the receptor tyrosine kinases (RTKs), including vascular endothelial growth factor receptor-1 (VEGFR-1), -2, and -3, and platelet-derived growth factor receptor (PDGFR) -α and -β. The treatment consisted of Sunitinib 37.5 mg given daily in a continuous fashion in six-week cycles. Toxicities were graded according to CTCAE response version 3.0 and responses were assessed according to the International Myeloma Working Group consensus criteria. Response rate of single agent Sunitinib was the primary endpoint of the study. Results 13 patients were accrued between July of 2007 and April 2009 before the study was closed. The median age of the study population was 61 years (range, 53 - 84), and included nine females (69%). The median time from diagnosis to registration was 39.2 months (range, 4.5 - 88) and 10 patients had received previous stem cell transplant. Previous therapy included lenalidomide in 7 patients, thalidomide in 5 patients and bortezomib in 2 patients. All 13 patients were alive at last follow up with a median follow-up of 11.2 months (range, 1.3 -21.2). All patients have gone off study, disease progression being the most common cause (9 patients), followed by adverse events (3 pts) and alternate treatment in the remaining patient. A hematological grade 3 or higher adverse event was documented in 6 patients and a grade 3 or higher non-hematological adverse event was seen in 8 patients. A grade 3 or higher neutropenia was observed in 5 pts and thrombocytopenia in 2 pts. Fatigue was common and was seen in 11 pts. The median number of cycles administered was one (range, 1-5) and the total number of cycles across 13 patients was 22. Treatment delays or interruptions were seen in five and six patients respectively. The most common reason for treatment delays was hematologic adverse events. No responses (PR or better) were seen, and stable disease was seen in eight of the 13 patients as the best response. The median time to progression was 2.9 months. Conclusions Single agent Sunitinib has no clinically relevant efficacy in this group of patients with relapsed myeloma with one or two previous therapies. Hematological toxicity was higher than anticipated. Whereas these results indicate that VEGFR TK inhibitors are not active in previously treated myeloma, it does not preclude the possibility that VEGF targeting strategies may enhance the efficacy of other therapies. Disclosures Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Celgene: Research Funding.

Abstract Abstract 3884 Poster Board III-820 Background and Objective Thalidomide/dexamethasone (thal/dex) combination has shown high activity in newly diagnosed multiple myeloma (MM) (Rajkumar SV. at al, J Clin Oncol 2006;24:431-436). In newly diagnosed patients, lenalidomide/dexamethasone (len/dex) has demonstrated superiority compared with high-dose dexamethasone alone (Zonder JA et al, Blood 2007;110:77). Although both thal/dex and len/dex are active in newly diagnosed MM, no randomized trial has been reported comparing these two regimens, and unfortunately none are ongoing or planned. We compared the efficacy and the toxicity of thal/dex and len/dex as primary therapy in 411 newly diagnosed MM patients treated at the Mayo Clinic. Patients and methods 411 consecutive patients seen at Mayo Clinic between 2001 and 2008, who received induction with thal/dex (n=183) or len/dex (n=288) were retrospectively studied. Thalidomide was given at a dose ranging from 100 mg/day to 400 mg/day continuously; the lenalidomide dose was 25 mg/day, days 1-21 on a 28-day cycle. All patients received dexamethasone, either at high-dose (40 mg orally on days 1-4, 9-12, and 17-20) or at low-dose (40 mg orally day 1, 8, 15, 22); each cycle was repeated every 4 weeks. In addition, a case-matched subgroup analysis that adjusted for age, gender and transplantation status was performed among patients who received high-dose dexamethasone comparing the thal/dex (n=72) and len/dex (n=72) groups. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method and all comparisons were determined by the log-rank test and by the Cox proportional hazards model. Results On intention-to-treat analysis, of 411 patients, 80.3% versus 61.2% patients, respectively in the len/dex group and in the thal/dex group (p < 0.001), achieved at least a partial response. A significant difference between the 2 groups was found in terms of both very good partial response or better (34.2% vs 12.0%, p < 0.001) and complete response rate (13.6% vs 3.3%, p < 0.001). Duration of therapy was significantly longer in len/dex patients as compared to thal/dex patients: 36.7% vs 12.6% of patients who did not stop treatment to receive SCT were still receiving therapy at 1 year (p < 0.001).Time-to-progression was significantly better in the len/dex group than in patients receiving thal/dex (median 27.4 vs 17.2 months, HR 0.64; 95% CI 0.44-0.93; p = 0.019). Similarly, progression-free-survival was significantly higher in len/dex patients (median 26.7 vs 17.1 months, HR 0.69; 95% CI 0.48-0.98; p = 0.036). This translated into an increase in overall survival (OS) (median not reached for len/dex group compared to 57.2 months in thal/dex patients, HR 0.60; 95% CI 0.40-0.92; p = 0.018). Survival advantages were evident in patients presenting with International Staging System Stage (ISS) I/II (HR 0.57; 95% CI 0.32-1.00; p = 0.052) at diagnosis but not in patients with ISS stage III in subgroup analysis. There was a trend toward better OS in len/dex group compared to thal/dex group both for patients who underwent transplant and for patients who did not. A similar rate of patients experienced at least one grade 3 or higher adverse event (57.5% vs 54.6% in len/dex and thal/dex groups, respectively, p = 0.568). However, the toxicity profile was different in the two groups: major grade 3-4 toxicities of len/dex were hematological, in particular neutropenia (14% with len/dex vs 0.6% with thal/dex, p<0.001) while the most common toxicities in thal/dex were venous thromboembolism (15.3% vs 9.2%, p = 0.058) and peripheral neuropathy (10.4% vs 0.9%, p < 0.001). The data on efficacy and safety shown above were also confirmed in the subgroup case-matched analysis which included only high-dose dexamethasone patients. Conclusions This cohort study shows the superiority of len/dex in terms of response rates and survival, compared to thal/dex. The toxicity profile of the 2 regimens is different and len/dex treatment, although more active, was not associated with increased toxicity (grade 3-4 AEs). These data need to be carefully evaluated and randomized prospective phase III studies are necessary to confirm these results and determine the optimal initial therapy for MM. Disclosures: Off Label Use: research drugs in combination to standard care. Lacy:celgene: Research Funding. Gertz:celgene: Honoraria; genzyme: Honoraria; millenium: Honoraria; amgen: Honoraria. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; Novartis: Research Funding; Genzyme: Research Funding. Dispenzieri:celgene: Research Funding. Bergsagel:amgen: Membership on an entity's Board of Directors or advisory committees; genetech: Membership on an entity's Board of Directors or advisory committees; merck: Research Funding; celgene: Membership on an entity's Board of Directors or advisory committees. Witzig:celgene: Research Funding. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Greipp:celgene: Research Funding.