Haematologica 2003 - Supplements

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evidence for the presence of CD4+ and CD8+ subsets.Br J Haematol. 1997 Feb;96(2):338-45. 6. Trojan et al. Immunoglobulin framework-derived peptides function as cytotoxic T-cell epitopes commonly expressed in B- cell malignancies. Nature Medicine 2000; 6(6): 667-72. 7. Sze et al. Multiple myeloma idiotypic peptide-cytotoxic T cell interaction constitutes a minimal anti-tumour response. Blood 2001;98: 652a. 8. Brown et al. Detection of anti-idiotypic T cells in patients with myeloma using immunodominant peptide tetramers. Blood 2002;100: 807a. 9. Brown et al. Dendritic cells from patients with myeloma are numerically normal but functionally defective as they fail to upregulate CD80(B7-1) expression after huCD40LT stimulation due to inhibition by TGF∃ and IL-10. Blood 2001;98: 2992- 2998. 10. Ruffini et al. Recent advances in multiple myeloma immunotherapy. Biomedicine & Pharmacotherapy 2002; 56(3): 129-132. P3.3 PLASMA CELL/MICROENVIRONMENT INTERACTIONS IN MULTIPLE MYELOMA: A PARADIGM AND A CHALLENGE F. Caligaris-Cappio Università Vita Salute San Raffaele, Milano, Italy Multple Myeloma (MM) is a paradigmatic example to illustrate the concept that host-tumor interactions contribute to cancer cell proliferation, survival and progression and to show the mutual importance of the "seed" and the "soil". BM microenvironmental stromal cells play an essential role in the growth of plasma cell tumors both in mice and in humans. They are well equipped with a large series of adhesion molecules and extracellular matrix (ECM) proteins that mediate homotypic and heterotypic interactions and provide anchorage sites to cells selectively exposed to locally released growth factors. MM BM stromal cells also produce cytokines, like IL-6, that play a crucial role in the evolution of the disease. In turn MM malignant plasma cells produce a number of of angiogenetic factors and of cytokines able to influence the microenvironment. Finally, the whole BM environment in MM is organized to favour the bone lysis outlining, though in a perverted way, the dynamic relationhips between immune system and bone. Contrasting to the distribution of normal PC, MM PC localize uniquely within the BM and are widespread troughout the BM from the early stages of the disease. These notions have suggested that human MM may be disseminated by a pool of circulating clonal cells that need to reach the proper microenvironment (i.e. the BM) in order to fully exploit their potentiality. Even if we accept that the clonal founder cells of MM and monoclonal gammopathy of undetermined significance (MGUS) have had an experience within peripheral lymphoid organs, it is evident that their progenies have a predilection for the BM microenvironment which supports their extended survival. Other chronic B-cell malignancies like Follicular Lymphoma (FL) and Chronic Lymphocytic Leukemia (CLL) have a similar general outline with clonal founder cells originating in the periphery and a striking propensity to invade the BM. However, the pattern of BM invasion reveals significant differences between FL and CLL on one side and MM on the other side. No follicular dendritic cells (FDC) are observed in MM BM and CD4 + T cells are sparse if at all present. The most prominent aspect of MM BM microenvironment is the impressive amount of BM-derived endogenous stromal cells which are highly activated. The overall picture of BM microenvironment is essentially identical in MGUS with a major difference: MGUS BM stromal cells are definitely less active. The stromal cells growing in vitro from MGUS BM are rare, do not support the growth of autologous B cells and produce very low amounts of IL-6 in the culture supernatants. Taken together, a number of observations suggest that MM plasma cells are able to “instruct” the local components of BM environment to help the expansion of the malignant clone. Despite the fact that the clonal founder cell of MM must have been involved in a T cell-dependent antigenic response, the evolution of MM malignant clone appears to be T-cell independent but strongly dependent on the BM stromal cell stimulating and nourishing activity, thereby explaining why MM is confined within the BM. It may be asked why several environmental cells, that normally would be quiescent, above all in a certain age range, are instead activated in the BM of MM. As normal BM stromal cells produce IL-6 after activation by inflammatory cytokines like IL-1, it is not unreasonable to consider the activated state of stromal cells in MM as a direct consequence of the influence of accessory cell-activating cytokines produced by the expanding monoclonal B cell population. In MGUS patients, the clonal population is below the theshold size that may produce enough cytokines to initiate the activation of BM stromal cells. Once the threshold size is reached, BM stromal cells become activated and trigger a selfperpetuating mechanism of mutual help and recruitment between malignant plasmacells and BM stromal cells that favours the progressive expansion of the B cell clone. In conclusion, it is not unreasonable to postulate that the acquisition of the capacity to activate endogenous stromal cells is the real turning point in the natural history of MGUS. It likely gives a decisive impulse to the malignant clone growth and marks the progression of MGUS into overt MM. MM PC have also an extended life span due to defective apoptosis. Both external stimuli and intrinsic genetic defects of the neoplastic cell may concur to influence the ability of MM PC to avoid apoptosis. In the initial phases of the disease, when the malignant clone growth is highly dependent upon the supportive role of the BM stromal microenvironment, the stroma itself may be involved in the production of anti-apoptotic factors. Dissecting the multiple molecular mechanisms that underlie these interactions may spawn new treatment approaches. P3.4 TUMOR CELL TARGET STRUCTURES AND T-CELL FUNCTIONS IN MYELOMA Håkan Mellstedt Departments of Oncology and Hematology, CancerCenter Karolinska, Karolinska Hospital, SE-171 76 Stockholm, Sweden The myeloma clone consists of plasma cells and pre-plasma cells. Within the tumor clone, cells are expressing MHC class I as well as class II molecules. A hallmark of the myeloma clone is the idiotypic immunoglobulin, of which complete molecules are expressed on the surface of pre-plasma cells. As the idiotypic protein is also present in the cytosol peptides of the idiotypic protein should be presented in the groove of MHC class I and class II molecules. Peptide sequences of the idiotype presented by HLA molecules might be targets for T cells. Using bioinformatics and analyzing the presence of naturally occurring T cells against idiotype derived peptides, we could identify T cell epitopes of the S28
variable region of the idiotypic immunoglobulin heavy chain in multiple myeloma. A large number of HLA (class I and II) peptides were identified in five studied patients. The frequency of predicted epitopes was dependent on the data base used: 245 in BIMAS and 601 in SYFPEITHI. Most of the peptides displayed a binding half-life or score in the low to intermediate affinity range. The majority of the predicted peptides were complementarity determining regions (CDR) rather than framework regions (FR) derived (52 – 60% vs. 40 - 48%). Most of the predicted peptides were confined to the CDR2-FR3- CDR3 “geographical” region of the IgVH region (70%). Significantly fewer peptides were found within the flanking (FR1-CDR1-FR2 and FR4) regions (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 and 8: Figure 5A Table 1: VEL + THAL for R
Page 9 and 10: naturally occurring OPG. Present tr
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: esponse and have demonstrated that
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,
Page 57 and 58: 9. Chemotherapy, maintenance treatm
Page 59 and 60: stratified according to their antim
Page 61 and 62: explore higher doses of zoledronic
Page 63 and 64: initial therapy. However, the role
Page 65 and 66: P10.2.2 SINGLE VERSUS TANDEM HIGH D
Page 67 and 68: With a median follow-up of 38 month
Page 69 and 70: cells could be harvested following
Page 71 and 72: 11. What is the role of allogeneic
Page 73 and 74: found that 75% of patients who were
Page 75 and 76: patients with responsive disease 3
Page 77 and 78: 9. Giralt S, Estey E, Albitar M, et
Page 79 and 80: 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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