Dispenzieri, Angela

Abstract Abstract 4867 Introduction Both multiple myeloma (MM) and (AL) amyloidosis are clonal plasma cell proliferative disorders. While AL rarely “progresses” to MM, probably due to the shorter survival of AL patients, patients with MM have been reported to develop overt AL at a higher frequency. We conducted this study to identify and describe the clinical features, diagnosis, treatment patterns and response, and outcome among patients diagnosed with AL following an initial diagnosis of MM. Patients and Methods Of the 354 patients identified from a prospectively maintained database who carried a diagnosis of both MM and AL during the interval between January 1990 and December 2008, 44 patients had a histologic diagnosis of AL, at least 6 months after the diagnosis of MM. The organ involvement and treatment response (organ and hematologic) for AL as well as MM response to treatment were assessed according to conventional criteria. Results The median age at diagnosis of MM and AL was 63 years (range, 42-82) and 68 years (range, 45-86), respectively; 27 (61%) were males. The median time to AL diagnosis after MM diagnosis was 41 months (range, 7.6-134). The estimated median follow up from diagnosis of MM and AL is 15.5 years and 10 years, respectively and 39 (89%) patients have died. The median overall survival (OS) from diagnosis of MM and AL was 68.6 months and 9.1 months, respectively. At the time of AL diagnosis, 33 (75%) patients had developed typical features suggestive of AL [heart failure (12), paresthesias (11), nephrotic range proteinuria (9), elevated alkaline phosphatase and hepatomegaly (2), fatigue (7), weight loss (5), macroglossia (4) and periorbital ecchymoses (1)]; while others developed atypical features (3) (7%) or had an incidental finding of AL (8) (18%) [autopsy (2), unexplained cytopenia (2), mild proteinuria (1) and no symptoms (3)]. Cumulatively, amyloid deposits were revealed by biopsy of: bone marrow (23) (52%), subcutaneous abdominal fat (17) (39%), organ (10) (23%) and carpal tunnel tissue (6) (14%). Organ involvement, treatment response and hematologic status of MM at AL diagnosis were assessed for the evaluable patients. None, 1 and >1 organ involvement occurred in 5 (11%), 28 (64%) and 9 (20%) patients, respectively at AL diagnosis or follow up; while AL as the cause of neuropathy was questionable in 2. The organs involved were: heart (14, including 8 with >1 organ involvement), nerves (11), kidney (10), soft tissue (6), lung (5), GI (1) and liver (1). The hematologic status of MM at AL diagnosis included SD (22), progression (10), PR (3), VGPR (3) and not evaluable (6). The subsequent hematologic and organ response did not differ significantly among those who had a treatment change or started (20) (45%) compared with those who did not have a treatment change (20) (45%) at AL diagnosis [excluding those lost to follow up (2) or diagnosed at autopsy (2)]; although more patients (8/10) who had biochemically progressive MM belonged to the former group. The best hematologic response to treatment(s) after AL diagnosis (28) (64%) was: SD (17), PR (3), VGPR (6), CR (1), and progression (1); and not evaluable in others. The organ response (excluding patients with carpal tunnel surgery) to treatment(s) (18) (41%) was: progression (11), stable (4) and organ improvement (3). More patients with an improved (2/3) and stable (1/4) organ response had hematologic PR or better than those with progression (0/11) of organ disease. Five (11%) patients were alive at last follow up; and had either isolated kidney (3) and soft tissue (macroglossia) (1) or no organ involvement (1). All patients with an organ improvement, and 2/5 patients alive, had received PBSCT after AL diagnosis. Fewer patients with >1 organ involvement (1/9) underwent PBSCT compared with those without organ involvement (2/5); and achieved (0) PR versus (3) VGPR (to any treatment), respectively. Only 1/8 patient with an incidental discovery of AL developed symptomatic (cardiac) AL after 108 months of MM diagnosis and died; the remaining are either alive (1) or died from MM and its complications (3), infection (1), or were diagnosed at autopsy (2). Conclusion The recognition of AL (especially cardiac and multiorgan involvement) is critical in MM patients in order to determine prognosis and influence treatment. A high index of suspicion is required for the prompt recognition of AL to ensure timely institution of therapy with a goal of achieving hematologic and organ response. Disclosures No relevant conflicts of interest to declare.

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 POEMS syndrome is defined by the presence of peripheral neuropathy (P), monoclonal plasma cell disorder (M), organomegaly (O), endocrinopathy (E), and skin changes (S). Virtually all patients will have sclerotic bone lesions, although the mechanisms of their development have not been clarified to-date. Increased plasma level of VEGF is another characteristic of the disease. However, there is very little information for the role of other angiogenic molecules in POEMS pathogenesis. The aim of this 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. Seven patients with POEMS at diagnosis (6M/1F; median age: 49 years) were evaluated. A series of bone remodeling indices were measured: i) bone resorption markers [C- and N- telopeptide of type-I collagen (CTX and NTX), TRACP-5b], ii) bone formation markers [bone-alkaline phosphatase, osteocalcin (OC), and C-terminal propeptide of type-I collagen (CICP)], and iii) osteoclast regulators [soluble RANKL, osteoprotegerin (OPG), MIP-1α, and TNF-α]. Furthermore, the following angiogenic cytokines were measured in the plasma of POEMS patients: VEGF, VEGF-A, angiogenin, angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and bFGF. All above molecules were also measured in 25 newly diagnosed, untreated MM patients (14M/11F, median age: 64 years) and 20 healthy controls. Bone markers were also evaluated in 24 patients with HbS/beta-thalassemia (10M/14F, median age: 43 years) who presented with osteosclerosis, i.e. osteosclerotic bone lesions in plain radiography and a median T-score of lumbar spine Bone Mineral Density of +3.6 (range: +2 to +7.9). All POEMS patients had P, O, E, S, edema and thombocytosis; 6 had E and 2 Castleman’s disease. Six patients had sclerotic bone lesions, while 4 had also a lytic component in their bone lesions. POEMS patients had increased levels of sRANKL (p=0.003), OPG (p=0.008), TNF-α (p=0.001), NTX (p<0.001), CTX (p=0.001) and CICP (p=0.001) compared with controls. Interestingly, NTX levels were even higher in POEMS than in MM patients (p<0.01). NTX and CTX were elevated in POEMS compared with osteosclerotic HbS/β-thal patients (p<0.01), who had reduced bone resorption compared with controls. POEMS patients had increased levels of OC and CICP compared with MM (p=0.02 and p=0.003, respectively), and increased levels of OC compared with osteosclerotic HbS/β-thal patients (p<0.01). In terms of angiogenic cytokines, POEMS patients had increased levels of all studied cytokines compared with controls (p<0.01). All POEMS patients had at least 1.8-fold higher value of VEGF-A (the major angiogenic component of VEGF) compared with the higher value observed in controls. Furthermore, VEGF (p=0.03), VEGF-A (p<0.001), angiogenin (p<0.001), and bFGF (p=0.01) were higher in POEMS than in MM. The ratio of Ang-1/Ang-2 was very low in POEMS compared with both controls and MM. These results suggest that POEMS patients have increased bone turnover in contrast to MM patients who have reduced bone formation and osteosclerotic HbS/β-thal patients who have diminished bone resorption. Furthermore the imbalance of Ang-1/Ang-2 pathway and the increased levels of angiogenic cytokines, even compared with MM, may indicate possible targets for the development of novel agents against POEMS.

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 532 Primary Plasma cell leukemia (PCL) is a rare plasma cell disorder characterized by an aggressive clinical course. The efficacy of autologous and allogeneic HCT in PCL is uncertain due to the small number of patients that have been reported in the literature. To determine the potential for long-term disease control using HCT in PCL, we performed a retrospective review of 160 patients with primary PCL who received autologous (n=107), allogeneic (n=52) or syngeneic (n=1) HCT and were reported to the CIBMTR between 1995 and 2006. Kaplan–Meier analysis was used for overall survival (OS) and progression free survival (PFS). Cumulative incidence estimates of non-relapse mortality (NRM), relapse, acute and chronic GVHD were calculated. Median age at the time of autologous HCT was 57 years (range, 32-74 years) and allogeneic HCT was 48 years (range, 24-62 years). Median time from initial treatment to autologous HCT was 7 months and allogeneic HCT was 6 months. At the time of transplant, in the autologous HCT group, 19% patients were in complete remission, 56% in partial remission and 1% had relapsed/progressive disease; in the allogeneic HCT group, 17% were in complete remission, 46% in partial remission and 10% had relapsed/progressive disease. In the allogeneic HCT group, 83% of the patients received myeloablative conditioning regimens and 17% received nonmyeloablative/reduced-intensity conditioning. The rate of acute GVHD was 35% (95% confidence interval [CI], 22%-49%) and the rate of chronic GVHD at 3 years was 27% (95% CI, 13%-40%). After a median follow-up of 38 months, 20 of the 52 patients (38%) are alive in the allogeneic HCT group and 68 of the 107 pts (64%) are alive in the autologous HCT group (Figure 1). Progressive disease accounted for 38% of the deaths in the allogeneic HCT group and 86% of the deaths in the autologous HCT group. The outcomes are summarized in table 1. The remarkable overall survival of patients after autologous HCT in this analysis is noteworthy and indicates that autologous HCT is a safe and acceptable treatment option for patients with primary PCL. Although relapse rates are lower, allogeneic HCT carries a much higher risk of NRM and should be considered primarily in the context of a clinical trial. Disclosures: Lonial: Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding.

Abstract Abstract 4876 Background Recent studies have found obesity to be associated with a 1.5- to 2-fold elevated risk of developing multiple myeloma. This is of particular interest given that elevated levels of the pro-inflammatory cytokine interleukin (IL)-6 have been found in obese persons, and, at the same time, IL-6 has well-known proliferative and anti-apoptotic effects on monoclonal plasma-cells. Also insulin-like growth factors (IGFs) have been proposed to play a role since obesity often causes insulin resistance, which in turn modulates the bioavailability of IGF-1 Similar to IL-6, prior studies have found IGF-1 to have both growth and survival effects on monoclonal plasma-cells. Based on these facts, we have speculated that obesity might increase the risk of the multiple myeloma precursor monoclonal gammopathy of undetermined significance (MGUS), or, alternatively, that obesity may increase the risk for transformation from MGUS to multiple myeloma. We conducted the first large screening study designed to assess the association between obesity and MGUS among almost 2,000 African-American and Caucasian women. Methods We included 1000 African-American and 996 Caucasian women (age 40-79, median 48 years) from the Southern Community Cohort Study to assess MGUS risk in relation to obesity. Per our sampling strategy, about 50% of the participants were obese. Medical record-abstracted weight and height (measured on the day of study enrollment) and self-reported values had very high concordance (Pearson correlation >0.95). Serum samples from all subjects were analyzed by electrophoresis performed on agarose gel; samples with a discrete or localized band were subjected to immunofixation. Using logistic regression models, we estimated odds ratios (ORs) as measures of risk. Results Among all study participants, 39 (3.9%) African-Americans and 21 (2.1%) Caucasians were found to have MGUS, yielding a 1.9-fold (95%CI 1.1-2.3; p=0.021) higher risk of MGUS among African-Americans (vs. Caucasians). On multivariate analysis, we found obesity (OR=1.8, 95%CI 1.03-3.1; p=0.039), African-American race (OR=1.8, 95%CI 1.04-3.1; p=0.037), and increasing age (quartiles: ≥55 vs. <43 years) (OR=2.5, 95%CI 1.1-5.7; p=0.028) to be independently associated with an excess risk of MGUS. Another interesting finding was that the distribution of the monoclonal immunoglobulin isotype usage among African-American and Caucasian women was significantly different (p=0.007). Their respective rates were: IgG in 79.5% and 71.3 %; IgA in 7.7% and 0%; IgM in 7.7% and 19%; biclonal in 5.1% and 4.7%; and triclonal in 0% and 4.7%. The distribution of serum light-chain types between the two races was also significantly different (P=0.003, chi-square test): kappa in 53.8% and 47.6%; lambda in 43.6% and 42.8%; biclonal 2.6% and 4.7%; and triclonal in 0% and 4.7%. Conclusions Our finding that MGUS is twice as common among obese (vs. non-obese) women, and independent of race, supports the hypothesis that obesity is etiologically linked to myelomagenesis and may have public health impact. The observed 2-fold excess of MGUS among African-Americans (vs. Caucasians) of similar socio-economic status, coupled with other recent studies supports a role for susceptibility genes as the cause for racial disparity in the prevalence of MGUS. Disclosures No relevant conflicts of interest to declare.

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.