Rajkumar, S. Vincent

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 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 Background: In previous studies quantitating VEGF receptors we have found no significant differences in expression between plasma cells from normal controls, multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), or smoldering myeloma (SMM). (Kumar S, Blood, May 2004; 10.1182/blood-2003-11-3811 ePub). These studies were done using immunohistochemistry or Western Blotting (on CD138+ plasma cells) and may have been limited by low levels of receptor expression and by heterogeneity of expression. We measured expression of VEGF receptors (VEGFR1, VEGFR2 and VEGFR3) on the surface of plasma cells and in plasma cell subsets using direct and indirect flow cytometric assays to determine if significant differences in VEGF receptor expression existed between MGUS, SMM and MM. Methods: In the indirect flow cytometric assay, 32 bone marrow samples (3 amyloid, 9 MGUS, 12 MM, 8 SMM) were ACK lysed and tested using the FLUOROKINE TM rhVEGF biotin kit (R and D Systems, Minneapolis, MN) according to manufacturer’s instructions. In brief, in one tube (tube 1) cells were incubated with VEGF biotin. In tube 2, VEGF biotin preincubated with a blocking antibody was added to the cells (specificity control), while in a third tube a non-specific biotinylated protein (negative control) was added. After incubation, FITC-avidin, CD38 APC and CD45 Percp was added to each tube. Gates were drawn around the cells of interest and fitc staining was evaluated for the % positive cells. The % of signal blocked was calculated by comparing the fitc intensity (channel number) of the blocked VEGF peak (tube 2) to FITC intensity of tube 1. This system does not determine the identity of the receptor, but indicates the presence of VEGF receptors. In the direct flow cytometric assay, bone marrow from 25 individuals (2 amyloid, 5 MGUS, 7 MM, 7 SMM, and 4 normals) were lysed and blocked with mouse Ig and stained with CD38/CD45. In individual tubes, PE labeled VEGF R1, R2, R3 antibodies (R and D Systems, Minneapolis, MN) or isotype control were added. Plasma cells were identified, divided according to CD45 expression, and analyzed for % and intensity of receptor staining. Results: In the indirect assay, plasma cells in all groups bound VEGF ( 96% positive) at high intensity. There was also no difference in VEGF binding between CD45+ and CD45- plasma cell fractions (93 and 98% respectively).The specificity of VEGF binding (to one of the VEGF specific receptors) was confirmed by a significant drop in peak channel numbers of FITC intensity in the presence of blocking antibody. Specific VEGF binding at a similar intensity was seen in monocytes (95%) and at a lower intensity in lymphocytes (66%) and granulocytes (28%). Staining for VEGFR1, 2, and 3 in plasma cells using the direct assay revealed that except for 2 patients (1 amyloid and 1 SMM) none had >20% cells staining for any of the 3 receptors. The same results were seen in the CD45− fraction as well. In contrast, the CD45+ plasma cell fraction was highly positive for all 3 of the receptors in nearly all cases, with no significant differences between MGUS, SMM, amyloid, or MM. Conclusions: Plasma cells in MM and related disorders have specific VEGF receptors on the cell surface. The expression of VEGFR1, 2, and 3 seems to be primarily restricted to the CD 45+ subset of plasma cells. The finding of specific VEGF binding in CD45− plasma cells seen in the indirect assay may reflect the higher sensitivity of this assay due to the inbuilt amplification process or the presence of additional VEGF receptors such as neuropilin 1.

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 Background: Multiple myeloma (MM) is characterized by accumulation of clonal malignant plasma cells in the bone marrow (BM). CD45 was initially characterized as a leucocyte common antigen and can be found on all hematopoietic cells and is a key regulator of antigen mediated signaling and activation in B and T-lymphocytes. The expression of CD45 appears to be heterogeneous among the plasma cells in MM and this characteristic has been suggested to have biological and prognostic significance. Goals: To study CD45 expression by flow cytometry (FC) on BM plasma cells from patients with different stages of MM, and compared CD45 expression to key clinical and biological characteristics including clinical outcome, labeling index (%S-phase), bone marrow angiogenesis, and bone disease. In addition, the expression profile of various adhesion molecules on CD45+ vs CD45− plasma cells was studied. Results: BM from seventy-five patients seen at the Mayo Clinic during 1995 and diagnosed with newly diagnosed MM (29), relapsed MM (17), smoldering MM (12), and MGUS (17) were studied for CD45 expression.. CD45+ was defined as >20% of gated plasma cells expressing CD45. A mean of 30% of the plasma cells expressed CD45 by flow cytometry (median, 14%; range, 0.1 to 100%). Among the entire cohort of patients, 33 (44%) of the patients were CD45+. Patients with early disease (MGUS and SMM) had a higher percentage of plasma cells expressing CD45 compared with patients with advanced disease (new or relapsed MM) (43% vs. 22%; P = 0.005). Among those with early disease 69% were CD45 positive compared to 28% among those with advanced disease (P = 0.0008). Among the 46 patients with advanced disease, the mean percentage of CD45+ plasma cells was 14% (range, 0.1 – 85) for those with bone lesions compared to 34% (2 – 99) for those with none; P = 0.02. Also, those with high labeling index (>=1%) had a higher percentage of CD45 expressing plasma cells than those with a low labeling index (30% for high LI vs. 15% for low LI; (P = 0.08). Among those with advanced disease, patients with low-grade angiogenesis had a higher percentage of CD45+ plasma cells; 31% vs. 13% (P = 0.03). The median overall survival for the CD45 positive group was 39 mos vs. 18 mos for the CD45 negative group, but the difference was not statistically significant (P=0.1). The expression of CD138 (syndecan-1), CD56 (NCAM) and CD54 (ICAM-1) were higher among the CD45 neg plasma cells. Other adhesion molecules, especially LFA-1, Mac-1, VLA-5, and CD44 were more often expressed on the CD45 + plasma cells. Conclusions: This study demonstrates that CD45 expression is more common in early disease and is lost with disease progression. There are important immunophenotypic and biologic differences in the CD45+ vs CD45− plasma cells that may have implications for the design of immunotherapy for MM.

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.