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Abstract Background: Monoclonal gammopathy of undetermined significance (MGUS) affects 3% of persons age 50 yrs or greater. Reliable predictors of progression of MGUS to myeloma or related malignancy are needed. We hypothesized that the presence of monoclonal unbound (free) kappa or lambda immunoglobulin light chains in MGUS, as detected by an abnormal serum kappa/lambda free light chain (FLC) ratio would indicate clonal evolution in the neoplastic plasma cell and increase risk of progression to malignancy. Methods: Patients (pts) from Southeastern Minnesota with MGUS seen at the Mayo Clinic from Jan 1, 1960 through Dec 31, 1994 who had baseline serum samples collected and stored at the time MGUS was first recognized were studied. Free kappa and lambda chains were measured using the serum FLC assay (FREELITETM, The Binding Site Ltd). Results: Of 1384 pts with MGUS during the defined time period, baseline serum samples obtained within 30 days of diagnosis of MGUS were available in 1148 pts. At a median follow-up of 15 yrs, malignant progression has occurred in 87 (7.6%) pts: myeloma (53 pts), IgM lymphoma (17), primary amyloidosis (6), macroglobulinemia (6), chronic lymphocytic leukemia (3) and plasmacytoma (2). An abnormal kappa/lamda FLC ratio (kappa/lambda ratio <0.26 or >1.65) indicating presence of monoclonal FLC was detected in 379 (33%) pts. In a Cox proportional hazards model, the risk of progression in pts with an abnormal kappa/lamda FLC ratio was significantly higher (hazard ratio 3.5, 95% CI 2.3–5.5; p<0.001) compared to pts with a normal ratio. After adjusting for the size of the serum monoclonal (M) protein by multivariate analysis, the hazard ratio was only slightly reduced to 2.8, p<0.001. The risk of progression to myeloma or related malignancy at 10 years was 17% with an abnormal kappa/lambda FLC ratio versus 5% with a normal ratio; corresponding rates at 20 years were 35%, and 13%, respectively. MGUS pts with both an abnormal serum FLC ratio and high serum M protein had a risk of progression at 20 years of 46% (high-risk), versus 26% with one of two risk factors (intermediate-risk) and 7% with no risk factors (low-risk) (Table). The true life-time (28 year) risk of myeloma or related malignancy in the low-risk group was only 5.3% when other competing causes of death were taken into account. Conclusions: Presence of monoclonal FLC in the serum as detected by an abnormal kappa/lamda FLC ratio is a major independent risk factor for progression of MGUS to myeloma or a related malignancy. The new risk-stratification identifies a low-risk subset with a remarkably small life-time risk of progression, a finding of significant importance for the management of MGUS. Risk-stratification of MGUS using the size of the serum M spike and free light chain ratio Risk Group No. of patients Hazard ratio Absolute risk of progression at 20 years Low-risk (Serum M protein <1.5 gm/dL and normal FLC ratio [0.26–1.65]) 606 1 7% Intermediate-risk (Either risk factor present) 373 3.5 26% High-risk (Serum M protein >/=1.5 gm/dL and abnormal FLC ratio [<0.26 or >1.65]) 169 6.8 46%

AbstractRecent observations have underscored the biologic relevance of intratumoral angiogenesis and its potential impact on prognosis. Increased bone marrow angiogenesis has been demonstrated in a variety of hematologic disorders, including multiple myeloma. The extent and prognostic significance of bone marrow angiogenesis in 114 patients with myelofibrosis with myeloid metaplasia (MMM) was investigated. A control group of 44 patients without bone marrow disease, 15 patients with polycythemia vera, and 17 patients with essential thrombocythemia was also studied. Bone marrow microvessel density was assessed by a semiquantitative method, visual microvessel grading, and 2 separate quantitative methods, visual count and computerized image analysis. Angiogenesis estimation by all 3 methods was highly comparable. On visual microvessel grading, a grade 3 or 4 increase in bone marrow angiogenesis was demonstrated in 70% of patients with MMM, 33% of patients with polycythemia vera, 12% of patients with essential thrombocythemia, and 0% of normal controls. In a multivariate analysis, increased angiogenesis in MMM correlated significantly with increased spleen size and was found to be a significant and independent risk factor for overall survival. Increases in marrow angiogenesis correlated with hypercellularity and megakaryocyte clumping. In contrast, these 2 features were inversely proportional to reticulin fibrosis, whereas increases in marrow angiogenesis were independent of reticulin fibrosis. These preliminary findings suggest that neo-angiogenesis is an integral component of the bone marrow stromal reaction in MMM and may provide useful prognostic information and a rationale for the therapeutic investigation of anti-angiogenic agents.

Abstract Abstract 4184 Introduction: FACT-MM was developed with the aim to create a disease-specific, patient-reported outcomes (PRO) measure as part of the FACT measurement system to assess multiple myeloma (MM)-related symptoms. Literature review identified 52 MM specific symptoms and concerns. 13 MM expert clinicians rated these 52 items on relevance to health-related quality of life (HRQL) for MM patients and added 11 items for comprehensive PRO assessment in MM. These 63 candidate items were rated by 13 MM patients recruited through the International Myeloma Foundation website. Disease-related symptoms and concerns were described and provided by patients through free-text comments. Information from both the MM expert clinician and MM patient surveys including free-text items was analyzed and 14 highest ranked items were selected for the FACT-MM. The FACT-MM subscale (score 0–56), the FACT-G physical and functional well-being subscales (score 0–28), and the FACT-Neurotoxicity (FACT-Ntx) subscale (score 0–44) was administered to 48 E1A05 participants to assess disease and treatment-related symptoms of patients with newly diagnosed MM receiving 8 cycles of VRd versus Vd. Methods: In this study, the first three of seven sequential assessments were evaluated: baseline, cycle 5 and end of treatment (after cycle 8 or early diconstinuation). Instruments were scored as per the FACT scoring guidelines. Descriptive statistics were provided for each timepoint and changes in scores from baseline. The Wilcoxon rank sum test was used to assess differences in scores by ISS stage and ECOG PS. Pearson correlation coefficients were obtained between the scores. Cronbach's alpha was used to evaluate internal consistency of the FACT-MM. Results: At baseline and end of treatment, 46 and 41 patients, respectively, completed assessments. The FACT-MM demonstrated good to very good internal consistency (Cronbach alpha 0.79 – 0.89). The FACT-MM subscale was significantly correlated with the FACT physical and functional well-being subscales at baseline (r = 0.72), cycle 5 (r = 0.64; r = 0.49) and end of treatment (r = 0.72; r = 0.66). All scores declined modestly by cycle 5 and end of treatment from baseline. While sample size was limited, there appeared association with ECOG PS with higher scores for patients with PS 0 status. Conclusions: The 14-item FACT-MM scale is feasible for use to measure myeloma-related symptoms and has demonstrated acceptable psychometric properties based on findings from E1A05, an ECOG myeloma trial. Disclosures: Cella: Novartis: Research Funding. Fonseca:Consulting:Genzyme, Medtronic, BMS, Amgen, Otsuka, Celgene, Intellikine, Lilly Research Support: Cylene, Onyz, Celgene: Consultancy, Research Funding.

Abstract Background: Folate receptor (FR) is a recently recognized tumor marker that is being investigated for targeted delivery of drugs, imaging of cancer cells, and tumor immunotherapy. The small size of the molecule, simple conjugation chemistry and lack of immunogenicity make folate an ideal candidate for targeted delivery to tumors bearing the FR (Lu Y, Low PS. Folate-mediated delivery of macromolecular anticancer therapeutic agents. Adv Drug Deliv Rev. 2002 Sep 13;54(5):675–93). FR is overexpressed in 90% of ovarian cancers and in other human tumors including endometrial, colorectal, breast, and neuroendocrine carcinomas, it is negatively or only weakly expressed in most normal tissues including some myeloid cells. In view of the above we wished to learn if overexpression of FR by marrow plasma cells (PC) might differentiate MM from MGUS and SMM. Methods: We obtained marrow biopsy sections from 20 patients each with MM, MGUS, or SMM, and 11 normals and stained them by immunohistochemistry using a FR-beta antibody. Expression was graded 0 (negative), 1 (equivocal), 2 (positive) or 3 (strong positive) based on immunohistochemical staining of marrow PC. We recorded the percent PC, percent positive PC, and the staining of other cell types including myeloid, erythroid, lymphocytes, macrophages, megakaryocytes and control tissues. Results: PC of patients with MM positively expressed FR compared to MGUS, SMM and normal PC (p<0.0001) (Figure 1 and 2). Of interest, 6 of 20 SMM patients showed positive expression. Maturing myeloid cells were also positive, acting as internal positive controls. Macrophages were often positive; some endothelial cells were positive; early erythroid precursors were rarely positive; megakaryocytes, maturing erythroid precursors and lymphocytes did not express FR. The chromosomal location of the FOLR gene cluster is 11q13. Gene expression arrays of purified PC failed to show evidence of overexpression of FOLR1, FOLR2, or FOLR3. We are currently performing Western blots to examine levels of protein product of purified PC. Conclusion: Immunohistochemistal studies show differential expression of FR in MM PC compared to absent or equivocal expression in MGUS and normal PC and variable expression in SMM. The data suggest that FR may be used as a diagnostic tumor marker and has implications for development of folate-based tumor imaging, drug delivery, and immunotherapy. Figure Figure Figure Figure

Abstract Background: Multiple myeloma (MM) is a heterogeneous disease with very divergent outcomes that are dictated in a large part by specific cytogenetic abnormalities, as well as other prognostic factors such as the proliferative rate of marrow plasma cells. Prognostic systems incorporating these factors have shown clinical utility in identifying high-risk patients, and are increasingly being utilized for treatment decision-making. However, the prognostic relevance of these factors may change with the application of novel therapies. The objective of this study was to determine the impact of risk-stratification (incorporating plasma cell metaphase cytogenetics, interphase fluorescent in-situ hybridization (FISH) and the slide-based plasma cell labeling index (PCLI)) in a cohort of patients with newly diagnosed MM treated initially with lenalidomide + dexamethasone (Rev-Dex). Methods: From March 2004 to November 2007, 100 consecutive patients treated with Rev (25mg/day) on days 1 through 21 of a 4-week cycle in combination with dexamethasone as initial therapy for newly diagnosed myeloma, were identified. High-risk MM was defined as presence of any one or more of the following: hypodiploidy, monoallelic loss of chromosome 13 or its long arm (by metaphase cytogenetics only), deletion of p53 (locus 17p13) or PCLI ≥ 3% or immunoglobulin heavy chain (IgH) translocations, t(4;14) (p16.3;q32) or t(14;16)(q32;q23) on FISH. PFS and OS survival estimates were created using the Kaplan Meier method, and compared by log-rank tests. Results: The median estimated follow-up of the entire cohort (N=100) was 36 months. The median PFS was 31 months; the median OS has not been reached. The 2- and 3-year OS estimates were 93% and 83%, respectively. 16% patients were deemed high-risk by at least one of the 3 tests (cytogenetics, FISH or PCLI). Response rates (PR or better) were 81% versus 89% in the high-risk and standard risk groups, respectively, P=NS; corresponding values for CR plus VGPR rates were 38% and 45% respectively. The median PFS was 18.5 months in high-risk patients compared to 37 months in the standard-risk patients (n=84), P<0.001(Figure). Corresponding values for TTP were 18.5 months and 36.5 months, respectively, P=<0.001. OS was not statistically significant between the two groups; 92% 2-year OS was noted in both the groups. Overall, 95 patients had at least one of the 3 tests to determine risk, while 55 patients could be adequately stratified based on the availability of all the 3 tests, or at least one test result that led to their inclusion in the high-risk category. The significant difference in PFS persisted even when the analysis was restricted to the 55 patients classified using this stringent criterion; 18.5 months vs. 36.5 months in the high-risk and standard- risk groups respectively; P<0.001. In a separate analysis, patients who underwent SCT before the disease progression were censored on the date of SCT to negate its effect, and PFS was still inferior in the high-risk group (p=0.002). Conclusion: The TTP and PFS of high-risk MM patients are inferior to that of the standard-risk patients treated with Rev-Dex, indicating that the current genetic and proliferation-based risk-stratification model remains prognostic with novel therapy. However, the TTP, PFS, and OS obtained in high-risk patients treated with Rev-Dex in this study is comparable to overall results in all myeloma patients reported in recent phase III trials. In addition, no significant impact of high-risk features on OS is apparent so far. Longer follow-up is needed to determine the impact of risk stratification on the OS of patients treated with Rev-Dex. Figure Figure

Abstract Background: Though STI-571 (Gleevec™) was designed to specifically inhibit the bcr-abl gene product, it inhibits other receptor tyrosine kinases at physiologically attainable concentrations, including c-kit (steel factor receptor, stem cell factor receptor, SCF-R or CD 117). Studies have shown that about one-third of patients with multiple myeloma or monoclonal gammopathy of undetermined significance have plasma cells that display reactivity for c-kit. Others have shown that several myeloma cell lines and fresh myeloma bone marrow cells proliferate in response to stem cell factor. mRNA transcripts for c-kit ligand and, more commonly, its receptor have been detected in myeloma cell lines RPMI 8226, JJN3, U266 B1, NCI-H929, ARH77 and HS-Sultan by RT-PCR. Methods: Patients were eligible for study if they presented with relapsed or refractory myeloma, an ECOG performance score < 3, ability to sign informed consent, serum creatinine <3.5 mg/dL, direct bilirubin <2 mg/dL, alkaline phosphatase <750 U/L, absolute neutrophil count > .5 x 10(9)/L and platelet count > 50 x 10(9)/L. Patients were treated with Gleevec™ 400 mg po qd. The purpose of the study was to assess the response rate of the drug Gleevec™ in patients with relapsed multiple myeloma. Secondary objectives included assessment of the tolerability of the regimen in this cohort of patients and to correlation between disease response and c-kit positivity (CD117) by flow cytometry. Results: Overall, 23 patients were enrolled between 12/01 and 11/02, of which 16 were male and 12 had a prior PBSCT. Median age was 63 years (range: 49 – 82), and the baseline performance scores were 0 (8 patients), 1 (10), and 2 (4). Median time from MM diagnosis to enrollment was 57 months (range: 11 – 133). Patients were high risk with a median PCLI of 1.3 (range: 0 – 23%) and a median beta-2 microglobulin of 4.6 (range: 1.4 – 10.1). Eleven of 21 tested patients had positive CD117 (≥20%) staining of their bone marrow plasma cells by flow cytometry. None were PDGF positive. The treatment was well tolerated. After treatment with Gleevec™, there were only 3 non-hematologic grade 3 or 4 toxicities, and they occurred in 1 patient: he developed a capillary leak type syndrome, ascites, and dyspnea as part of his terminal phase of myeloma which included evolution into plasma cell leukemia. Grade 3 myelosuppression was observed in a minority of patients: thrombocytopenia (3), neutropenia (1), and anemia (3). There were no responses, and no patients are currently receiving treatment. Patients ended treatment due to progressive disease (18 patients), death on study (3), adverse reactions (1), and other reasons (1). The median duration of treatment was 48 days (range: 12 to 349). Of the 7 patients who remained on study for more than 60 days, CD117 status was as follows: positive (4); negative (3); not ascertained (1). As of August 2004, 12 patients have died. Conclusions: Though forty-eight percent of the enrolled myeloma patients were CD117 positive, providing a putative target for the Gleevec™, no responses were seen in this high risk population of relapsed patients. Further study will be necessary to determine the significance of the observed stabilization of disease in 36% of the CD117 positive patients.

Abstract In individuals with the plasma cell malignancy multiple myeloma, there is evidence that bone formation rates are reduced and that increased ostoeclastic bone resorption is associated with impaired osteoblast function. We investigated the osteogenic differentiation capacity of myeloma bone marrow mesenchymal progenitor cells (MPCs). We also examined the expression levels and activity of Runx2, the transcription factor required for osteogenesis. Bone marrow MPCs were cultured in osteogenic induction medium and assessed for bone alkaline phosphatase (bALP) expression (Sigma kit), induction of osteoblast specific genes like osteocalcin (RT-PCR) and mineralization by von Kossa staining. Immunoblot analysis and electrophoretic mobility shift assays (EMSA) were used to determine Runx2 expression and DNA-binding activity respectively. RT-PCR was used to sequence Runx2 and detect any mutations or deletions present within its domains. Transactivation ability of Runx2 was measured by its ability to activate osteocalcin promoter in transient transfection assays. Myeloma -derived MPCs showed reduced levels of bALP and osteocalcin transcript and a lower degree of mineralization, in osteogenic induction medium, as compared to that of the healthy donors. Immunoblot analysis and EMSA indicated equivalent Runx2 expression and DNA-binding capacity, respectively, in both healthy donor and myeloma-derived MPCs. Sequence analysis of Runx2 indentified a splice variant of Runx2 lacking exon 8 (Runx2D8) in myeloma patients with reduced transactivation ability. Co-transfection of the splice variant led to reduced transcriptional activity of the full-length Runx2. The reduced transactivation ability of spliced Runx2, as well as its suppressive action on the transactivation function of full-length Runx2, likely contributes to the defective osteogenesis clinically observed in myeloma pateints.

Abstract Background: Previous studies quantitating VEGF in plasma cells from multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), and smoldering myeloma (SMM) have found no significant difference in expression between the groups. These studies have been done using immunohistochemistry, quantitative RT-PCR, and Western Blots using material from isolated CD138+ plasma cells. These studies may have been limited by specificity of reagents, low numbers of plasma cells, or heterogeneity within the plasma cell population. Asosingh et al have shown that 5T2MM murine myeloma cells show greater VEGF expression in the CD45- compared to the CD45+ plasma cell compartment (Asosingh K, Blood2004;103:3131–7). Quantitative flow cytometric methods allow for the quantitation of antigen expression with high sensitivity and allow discrimination among cell subsets. Flow studies have suggested that myeloma patients have both CD45+ and CD45 - plasma cell subsets and that each compartment may contain phenotypic and functionally different types of clonal plasma cells. This two part study evaluated bone marrow plasma cells for intracellular and surface levels of VEGF in MM, MGUS, SMM, amyloid, and normal controls. Methods: Cytoplasmic VEGF expression (cVEGF) was measured on lysed and permeabilized (FACSTM Permeabilizing Solution, BD Biosciences, San Jose, CA) whole bone marrow samples using anti-VEGF PE (R and D Systems, Minneapolis, MN). With each run, QuantumTM Simply Cellular Beads (Bangs Laboratories, Fishers, IN) were stained with the same VEGF antibody to create a standard curve for calculation of MESF/ABC (antibody binding capacity) values. A median VEGF MESF value was calculated for the plasma cells, lymphocytes, and granulocytes from each patient sample. Surface expression of VEGF (sVEGF) was determined using CD138 FITC/ VEGF PE/ CD45 Percp/ CD38 APC staining on ACK lysed whole bone marrow cells. sVEGF expression was determined on the plasma cell population as a whole and on the individual CD45 fractions. Median expression and proportion of cases with plasma cells expressing >20% sVEGF were calculated. Cytoplasmic kappa and lambda staining was also done to determine clonality. Results: cVEGF MESF differences within the plasma cell populations were greater than in the other cell types. The MESF was higher in MM (n=14 patients, median MESF 247,866) compared to MGUS/SMM (n=14, median MESF 89,794) and amyloid (n=5, median MESF 134,429)(p=0.038). The lymphocytes and granulocytes in each group had similar MESF values, but the median MESF was lower than in the plasma cells (median 41,485 for lymphocytes, and 24,227 for granulocytes). sVEGF was expressed by less than 20% of plasma cells in all groups studied. Similar results were also seen in the CD45- plasma cell fraction. In the CD45+ plasma cell fraction, all groups showed varying levels of positive expression: MM (n=15 patients; median, 52% cells positive), normal controls (n=4; 51%), MGUS/SMM (n=11; 34%). Conclusions: cVEGF expression was significantly higher in MM compared to SMM/MGUS in this study. On the other hand, sVEGF expression was confined to the CD45+ plasma cell compartment in all groups studied, with a trend to higher % positive cells in the MM group compared to MGUS. We are working on studying levels of secreted VEGF in various human plasma cell subsets, both alone and in conjunction with stromal cell contact.

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.