Haematologica 2003 - Supplements

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Pathophysiology of myeloma bone disease and management of skeletal complications MULTIPLE MYELOMA PATHOPHYSIOLOGY AND DISEASE OVERVIEW Robert Vescio, MD The great majority of patients with multiple myeloma develop pain and complications related to the destruction of bone at sites of disease. It is often the presentation of bone pain and fatigue that brings patients with multiple myeloma to medical attention. It has been estimated that 80% of patients with multiple myeloma will have lytic lesions present on radiographic skeletal survey. These lesions predominate in areas of particularly high concentrations of tumor cells within the bone marrow. However, even patients without discernible lytic lesions on radiographic assessment, often are noted to have significant osteoporosis on bone densitometry. These patients often have a more diffuse infiltration of tumor throughout their marrow and can present with features mistakenly attributed to complications of severe osteoporosis such as kyphosis of the spine due to vertebral fractures. Unfortunately, even patients who respond to chemotherapy may have progression of skeletal disease and once a lytic bone lesion develops, recalcification and radiographic improvement are rare. Pathologic fractures within the spine are particularly problematic and can lead to chronic pain since these lesions rarely fully heal without surgical intervention. To appreciate the impact this bone destruction can induce without treatment, one can look at the results of the first trial demonstrating a benefit for the use of bisphosphonates in this disease. In this 370 patient trial, patients with multiple myeloma were randomized to receive monthly pamidronate or placebo. Within 9 months, 30% of patients receiving placebo infusions developed a fracture and 22% of similarly randomized patients required radiation treatment for symptoms of bone pain or impending fracture. Even more catastrophic was the 3% of patients receiving placebo who developed spinal cord compression. In this trial, patients with relapsed disease randomized to receive pamidronate had a seven month improvement in median survival as well. The explanations for this survival advantage vary. Certainly, some survival advantage may be attributable to the reduced pain, reduction in need for radiation and surgical procedures and the consequent complications when bisphosphonates were used. However, recent evidence suggests that these bisphosphonates may directly or indirectly impair tumor growth. Initially, Mundy and colleagues identified a number of proteins known as OAFs, (osteoclastic activating factors), which were thought to be the proteins responsible for enhanced bone loss in myeloma patients.(1) These factors including lymphotoxin (tumor necrosis factor (TNF) β), and interleukin-1 (IL-1) β were identified in the supernatants from cultures from myeloma cells lines and fresh myeloma bone marrow in these early studies. However, more recent studies have suggested that other factors are more important in the high rate of bone turnover in multiple myeloma. The role of lymphotoxin in myeloma bone disease has been downplayed by more recent studies failing to find significant differences in the amount of this cytokine in supernatants derived from myeloma patients compared to controls.(2) In addition, antibodies to lymphotoxin do not reduce the bone resorbing activity of fresh bone arrow plasma from myeloma patients.(3) Another tumor necrosis factor, TNF, is found at higher levels in supernatants from these patient’s bone marrow cultures, and is capable of stimulating osteoclast formation. Its effects are mediated by stimulation of the proteolytic breakdown of IκB that leads to the release of NF-κB. This enhancer translocates into the nucleus where it induces transcription of specific genes, some of which are involved in enhancing bone resorption. The importance of NF-κB in bone resorption is supported by studies showing that NF-κB knockout mice show osteopetrotic bones.(4) It is likely that the proteosome inhibitor PS-341 (Velcade) which inhibits NF-κB and is highly active in multiple myeloma may also be a potent osteoclast inhibitor. The pathophysiology of osteoclast development has more recently been elucidated. Osteoclasts develop from monocytes which have been exposed to either M-CSF or VEGF. This process is insufficient for complete osteoclastic development, however. These immature osteoclasts only mature into active bone resorbing after direct contact with osteoblasts, stromal cells or by exposure to the ligand for the receptor for activation of NFκB (RANK) called RANKL. The identification of RANK expressed on the surface of osteoclasts and RANKL on osteoblasts and stromal cells explains how this interaction leads to osteoclast development. TNF itself is capable of stimulating osteoblasts to increase the expression of RANKL. We have recently noted that malignant plasma cells from myeloma patients also express RANKL and can replace exogenous sRANKL as a promotor for complete osteoclast development. This may further explain how multiple myeloma cells promote local bone resorption. In fact, a vicious circle of osteoclast stimulation and subsequent myeloma cell proliferation is likely to exist in the bone marrow of patients with multiple myeloma. IL-6, which is mainly produced by nonmalignant cells in the bone marrow of myeloma patients, is a cytokine capable of stimulating growth and preventing apoptosis of the malignant cells in myeloma patients. Stromal cells, osteoclasts and osteoblasts are all major sources of IL-6 in the bone marrow microenvironment. Recent studies show that malignant cells from myeloma patients increase IL-6 production by osteoblasts both by direct cell-to-cell contact and release of soluble factors. Since some studies report that malignant cells from myeloma patients produce IL-1 and TNF and both of these cytokines stimulate IL-6 production by osteoblasts,(5, 6) either or both may be the soluble factor(s) involved in myeloma cell-induced release of IL-6 by osteoclasts. Thus, these studies suggest the role of bone cells not only in bone-related changes in these patients but also in the promotion of growth and prevention of apoptosis of the tumor cells themselves as mediated by IL-6. Importantly, a soluble decoy receptor called osteoprotegerin (OPG) was discovered that binds RANKL and prevents the binding of the ligand to RANK. The importance of this natural inhibitor of bone resorption was shown in experiments using knockout mice whereby OPG deficient animals suffered from profound osteoporosis. It appears that the balance between soluble OPG and RANKL may significantly determine the degree of bone resorption in the local bone marrow microenvironment. Clinical trials using synthetic OPG analogues or blocking antibodies to RANKL have been initiated and show early promise in clinical trials. The first trial using AMGN-0007 showed that obtainable levels of this synthetic OPG analogue could suppress bone resorption markers to a similar degree as pamidronate.(7) The drug was also well tolerated. Unfortunately, one patient developed an antibody to the agent which led to temporary bone turnover greater than baseline by presumably interfering with S8
naturally occurring OPG. Present trials are focusing on RANK-Fc which also blocks the RANK-RANKL interaction. Recently, macrophage inflammatory protein-1α (MIP-1α) has been identified as an important factor involved in myeloma bone disease.(8) Levels of this cytokine are elevated in the bone marrow of these patients. This chemokine is capable of inducing osteoclast formation in vitro, and antibodies to this protein block the induction of osteoclast formation by fresh bone marrow plasma from myeloma patients. In addition, this chemokine attracts and activates monocytes, and is a potent inhibitor of early hematopoiesis. As noted earlier, VEGF is another cytokine important in promoting osteoclast development. It is now clear that VEGF is produced by malignant plasma cells, and the receptors that bind this factor are expressed on bone marrow stromal cells.(9) In fact, recent results show that VEGF increases IL-6 production by bone marrow stromal cells from myeloma patients. This may indirectly lead to enhanced bone loss in these individuals. It is hoped that a combination of these newer agents and bisphosphonates may further reduce the devastating effects that myeloma has on bone. While further osteoclastic inhibition should improve the quality of life that multiple myeloma patients have, it may also promote improved survival by disrupting this vicious cycle of myeloma cell mediated growth by the bone marrow microenvironment. 1 Mundy, G.R., et al., Evidence for the secretion of an osteoclast stimulating factor in myeloma. N Engl J Med, 1974. 291: 1041-6. 2 Choi, S.J., et al., Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma. Blood, 2000. 96: 671-5. 3 Kawano, M., et al., Interleukin-1 beta rather than lymphotoxin as the major bone resorbing activity in multiple myeloma. Blood 1989. 73: 1646-9. 4 Iotsova, V., et al., Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2 [see comments]. Nat Med, 1997. 3: 1285-9. 5 Ishimi, Y., et al., IL-6 is produced by osteoblasts and induces bone resorption. J. Immunol, 1990. 145: 3297-303. 6 Linkhart, T.A., et al., Interleukin-6 messenger RNA expression and interleukin-6 protein secretion in cells isolated from normal bone: regulation by interleukin-1. J Bone Miner Res 1991. 6: 1285-94. 7 Body, J-J. et al., A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer <strong>2003</strong>. 97 (Suppl 3): 887-92. 8 Oyajobi, B.O. and Mundy, G.R. Receptor activator of NF-κB ligand, macrophage inflammatory protein-1a, and the proteosome. Cancer <strong>2003</strong>. 97 (Suppl 3): 813-7. 9 Dankbar, B., et al., Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma. Blood 2000. 95: 2630-6. CLINICAL OUTCOME OF VERTEBRAL AUGMENTATION FOR MYELOMATOUS OSTEOLYTIC COLLAPSE Isador Lieberman MD, Mohamed Hussein MD, Mary Kay Reinhardt RN. Departments of Orthopaedics and Hematology Oncology, The Cleveland Clinic Foundation Purpose: To assess the clinical outcome of methylmethacrylate vertebral augmentation in a prospective group of patients debilitated by myelomatous osteolytic vertebral collapse. Method: A consecutive prospective series of patients who presented with painful progressive osteolytic vertebral body collapse secondary to multiple myeloma in the absence of neurological symptoms or signs were treated with percutaneous vertebral body reduction and cavity creation using an inflatable bone tamp followed by methylmethacrylate augmentation to the vertebral body defect. Symptomatic levels were identified by correlating the clinical data with MRI findings. Peri-operative variables and complications or issues were recorded and analyzed. Pre-operative and post-operative x-rays and CT scans were compared to calculate vertebral body morphology and the rate of cement leak. Outcome data was obtained by comparing pre-operative and latest post-operative Oswestry Disability Index (ODI), Visual Analogue Pain (VAS) and SF-36 Generic Health Questionnaire (SF-36) outcome scores. Results: A total of two hundred & sixty-four vertebral bodies in sixty-three consecutive patients presented for treatment between April 1999 and September 2002. Fifty-two patients had multiple myeloma, 11 presented with other lytic metastases. The mean duration of symptoms was 12 months. In this group there were no peri-operative complications associated with the technique or tools. Asymptomatic cement leaks were noted in less than 5% of the vertebral bodies treated. The patients reported statistically significant improvement in SF-36 scores for Bodily Pain: 28.33 to 47.56, (p=0.0003) and Physical Function: 24.48 to 47.17, (p
Page 1 and 2: Focussed Symposia Arsenic trioxide
Page 3 and 4: assess whether such a program will
Page 5 and 6: The overall response rate was noted
Page 7: Figure 5A Table 1: VEL + THAL for R
Page 11 and 12: 0.505). Finally, the multiple event
Page 13 and 14: CLINICOPATHOLOGICAL DEFINITION OF W
Page 15 and 16: Plenary Sessions 1. Development of
Page 17 and 18: clonotypic IgH VDJ signature confir
Page 19 and 20: can be considered as two entities,
Page 21 and 22: immunofluorescence staining for DKK
Page 23 and 24: P2.3 DEVELOPMENT OF A MULTIPLE MYEL
Page 25 and 26: P2.5 MOLECULAR CYTOGENETICS OF MYEL
Page 27 and 28: clear that the biggest challenge fo
Page 29 and 30: esponse and have demonstrated that
Page 31 and 32: variable region of the idiotypic im
Page 33 and 34: 4. From MGUS to symptomatic MM Fig.
Page 35 and 36: (MRI); some have claimed that level
Page 37 and 38: P4.5 CYTOKINES IN MGUS: THERAPEUTIC
Page 39 and 40: preventing phosphorylation of p70S6
Page 41 and 42: transducing component of the interl
Page 43 and 44: survive initial drug exposure and a
Page 45 and 46: quiescent counterpart, the human um
Page 47 and 48: transcriptional activity of NF-êB;
Page 49 and 50: manifestations and anomalous protei
Page 51 and 52: P7.4 ROLE OF SERUM FREE LIGHT CHAIN
Page 53 and 54: P7.6 IMMUNOPHENOTYPIC INVESTIGATION
Page 55 and 56: presumably through the circulation,
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stratified according to their antim
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explore higher doses of zoledronic
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initial therapy. However, the role
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P10.2.2 SINGLE VERSUS TANDEM HIGH D
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With a median follow-up of 38 month
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cells could be harvested following
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11. What is the role of allogeneic
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found that 75% of patients who were
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patients with responsive disease 3
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9. Giralt S, Estey E, Albitar M, et
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Badros A, Barlogie B, Siegel E, et
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Figure 3b. Event-free Survival 4-Ye
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improve patient outcome in MM. Impo
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myeloma and in 40% of previously un
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degrade OPG in the same way as myel
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P12.2.5 MONOCLONAL ANTIBODY THERAPY
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myeloma. Blood 2001; 98:210-216. 6.
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MHC molecules, in effectively prese
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mice demonstrate that class II-spec
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detected in 293 and NIH3T3 cells. S
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hypothesis that (1) CCND1 and FGFR3
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patient samples. In addition, the p
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016 NEUTRAL ENDOPEPTIDASE (CD10) KN
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2. Genetic heterogeneity in MM: imp
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evidence from two t(11;14) cases wh
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immunoglobulin heavy chain (IgH) lo
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034 Instability of Pericentromeric
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clusters were found, the first was
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MGUS but most likely not crucial fo
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Objective: To compare the impact on
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4 patients had MMSET/IgH but did no
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and clonal PC from MGUS, MM and PCL
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059 VEGF receptor expresion in Mult
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two HLA-A2+ myeloma patients with C
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molecules expressed on the surface
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Recognition of these antigens appea
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Diagnosis requires a single area of
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081 Incidence of solid tumors in co
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Growth Factor (VEGF), Hepatocyte Gr
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PC-AI levels of MGUS and SMM patien
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093 The predominant pathway of tran
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was associated with I.V. line, whil
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103 Vascular amyloidosis induces se
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5. Signal transduction pathways and
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integrin in IGF-1-triggered MM cell
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118 IL-6- Induced Phosphorylation o
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123 THE IGF/IGF-1R SYSTEM IS A MAJO
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human myeloma cell line (HMCL) to a
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ligation or dexamethasone (Georgii-
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6. Role of microenvironment 6.1 Cel
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141 Human myeloma cells adhere to f
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145 STUDY OF BONE MARROW ANGIOGENES
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patients, the growth of primary mye
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tibia (con=49.1±0.7mg/cm2 vs 5T2=4
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157 The Nitrogen-Containing Bisphos
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7. New prognostic criteria for clas
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atio of >3. This system has subdivi
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Patient 1 (IgG/κ);IgG - 16.5 days,
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176 Pro-inflammatory and angiogenic
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180 Clinical study on the bone lesi
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7.2 Imaging studies 185 99mTc-MIBI
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189 Factors Predicting Occult Spina
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vivo detected resonances was invest
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Support Unit (CTSU) with flexibilit
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(β2m) & C reactive protein (CRP).
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plasmids carrying the clonotypic in
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newly diagnosed multiple myeloma as
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216 Transgenic expression of Myc an
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221 Prolonged survival in the 5T2MM
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9. Chemotherapy, maintenance, treat
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229 EFFECTIVENESS OF STANDARD CHEMO
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234 Melphalan and Dexamethasone- Is
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Methods. We investigated the VECD p
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9.2 Renal complications. 243 MERIT
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cost of SRE-related care was $10,24
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those with Hb >13 g/dL. Analysis of
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sustained response, lasting from 52
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proportion of bone abnormality. IgD
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disease. The lack of response to in
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yielding a median of 3x106/kg CD34
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patients(pts) aged ≥60 yrs. We co
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PBSC mobilizing regimen utilizing C
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their leukocytes and platelets. No
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25 Gy to marrow. The tracer dose wa
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non-CR after the first transplant a
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296 PERIPHERAL BLOOD STEM CELL TRAN
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References Effect of dose-intensive
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with cyclosporine A and methotrexat
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11.Role of novel therapies targetin
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312 Thalidomide as Rescue of Relaps
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patients, light chain in 1 patients
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platelets of 207 (76-402), B2M of 3
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325 Low Dose Thalidomide plus Dexam
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in 5 pts (11%), M protein decreased
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time from diagnosis was 3.7 years a
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339 Thalidomide, Clarithromycin and
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344 COMBINATION OF THALIDOMIDE, DEX
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experienced early death during the
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untreated patients with high tumor
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357 Thalidomide protects endothelia
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362 EOSINOPHILIA IS A VERY COMMON F
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11.5 CC 4047, PS 341 and arsenic tr
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without chromosome 13. Mean IC50 fo
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myeloma patients. Phase I data indi
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11.6 Other drugs 380 EFFECT OF STI5
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significant inhibition of cell prol
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which acts to prevent the synthesis
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of B and its metabolites, however,
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and 10 months after start of therap
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terminal kinase (JNK) pathway which
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lymphocytes was tested by Ellispot.
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411 Dendritic Cell-Based Idiotype V
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Author Index Abe M 74 160 Abelman W
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De La Serna J 291 De Laurenzi A P11
Page 287 and 288:
Hull DR 338 Hullen C P10.2.1 Humes
Page 289 and 290:
Morra E 249 280 359 Morris CM 226 M
Page 291 and 292:
Siegel D 70 115 250 Sierra J 304 30
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