Haematologica 2003 - Supplements

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with IMiD (1 µM). Finally, in the presence of cycloheximide (chx) to inhibit de novo protein synthesis, Dex-sensitive MM.1S and Dex-resistant MM.1R cells responded to a similar killing (50- 60%), suggesting that proapoptotic mechanisms induced by SGN- 14 depend on endogenous production of cytotoxic cytokines for induction of cell death. From oligomicroarray analysis, we further identified a 3-5 fold inhibition in anti-apoptotic genes (Mcl-1, Bcl-xL, FLIP) and an increase of apoptosis proteins (Apo2L/TRAIL, p53-regulated apoptosis-inducing protein 1, apoptotic protease activating factor). Taken together, these results further support targeting CD40 in human MM with SGN-14. 388 Therapeutic Potential of Amyloid-Reactive Monoclonal Antibodies in Primary (AL) Amyloidosis Alan Solomon, Deborah T. Weiss, and Jonathan S. Wall Human Immunology and Cancer Program, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920. We have previously reported that certain of our murine (m) antihuman light chain monoclonal antibodies (mAbs) recognized an epitope common to AL and other types of amyloid fibrils (Hrncic R, et al, 2000, Am J Path 157:1239-1246). Based on this evidence, one such antibody, 11-1F4, was administered to mice bearing AL amyloidomas, induced by the subcutaneous injection of human AL extracts. The mAb bound to the amyloid and initiated an Fc-mediated cellular inflammatory response that led to the rapid elimination of the induced tumors. To develop this reagent for clinical use, the 11-1F4 mAb was chimerized and its activity compared to that of the unmodified antibody. The chimeric (c) 11-1F4 mAb was produced in CHOdhfr-stable mammalian cell lines that had been transfected with a supervector DNA encoding the mouse 11-1F4 heavy and light chain variable regions (VH, VL) and human heavy and light chain constant regions (CH, CL). The antibody products were analyzed for their fibril binding activity and ability to effect amyloidolysis in 2 in vivo experimental models. The capability of the c11-1F4 mAb to interact with amyloid was demonstrated in vitro. Administration of this reagent into mice bearing human AL tumors or those with systemic AA deposits resulted in rapid elimination of the amyloid with no evidence of toxicity in the animals. These results have justified the production of GMP-grade c11-1F4 a Phase I/II clinical trial in patients with primary (AL) amyloidosis where the effectiveness of the reagent could be determined. The use of amyloid-reactive antibodies would represent a novel approach in the treatment of individuals with this invariably fatal disorder. 389 Activity of the maytansinoid immunoconjugate BB- 10901 (huN901-DM1) on CD56+ multiple myeloma cells P. Tassone, A. Gozzini, V. S. Goldmacher*, T. Hayashi, L. Catley, T. Hideshima, R. Burger, N. Mitsiades, N. Munshi and K.C. Anderson Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02446. *ImmunoGen, Inc. Cambridge, MA 02139-4239. Immunoconjugates of cytotoxic drugs have the potential to selectively improve the therapeutic anti-cancer efficacy of these drugs. A novel maytansinoid, DM1, was developed, that is very potent and selective when covalently linked to a monoclonal antibody (mAb). The antibody-DM1 conjugate acts as a pro-drug that is activated through binding of its antibody moiety to the target antigen-expressing cells and subsequent internalization of the conjugate by the cells. Antibody-DM1 conjugates that target an antigen present on multiple myeloma (MM) cells could therefore be tested as a novel strategy for anti-myeloma treatment. CD56 (N-CAM) is expressed on malignant plasma cells in a subpopulation of MM patients. Hu-N901 is a humanized mAb that binds to CD56 with high affinity. We therefore evaluated the cytotoxicity and specificity of a conjugate of hu-N901 with DM1, huN901-DM1, on a panel of cell lines, that included three CD56-expressing MM cell lines, OPM1, OPM2 and U266, two CD56-negative MM cell lines, LP-1, MM- AS, and a CD56-negative Waldenstrom’s macroglobulinemia (WS) cell line, WSU-WM. The cytotoxicity of the conjugate was evaluated by the MTT assay. HuN901-DM1 treatment decreased survival of CD56+ cell lines (IC50: 50-200 nM after a 48 h exposure), but did not affect CD56- MM or WS cell lines. In contrast, the cytotoxicity of non-conjugated DM1 was equally detected (following a 24 h exposure) in both CD56+ and CD56- cells (5-200 nM). The exposure of cells to the non-conjugated mAb huN901 (6-60 nM, up to 96 h exposure) did not produce any cytotoxic effects. We also examined the cytotoxicity of nonconjugated mAb, huN901-DM1 and DM1 for CD56+ and CD56- cell lines in the presence of bone marrow stromal cells (BMSC). Non-conjugated mAb did not induce any detectable cytotoxicity while huN901-DM1 showed specific activity against CD56+ cells, but not against BMSC. DM1 induced toxicity in all cells including BMSC. To further evaluate the specific activity of huN901-DM1 in a co-culture setting, we evaluated the activity of the immunoconjugate against CD56+ and CD56- cells. By flow cytometry, we detected that huN901-DM1 selectively depleted CD56+ cells. Moreover, induction of apoptosis was detected by Annexin-V in CD56+ cells exposed to huN901-DM1 after 24 h. In vivo efficacy of huN901-DM1 is presently under investigation in hu-SCID MM mice. In conclusion, our data suggest that huN901-DM1 may have therapeutic potential in the treatment of MM. 390 Inhibitors of the mevalonate pathway as potential therapeutic agents in multiple myeloma. Cindy Baulch-Brown and Andrew Spencer Myeloma Research Group, Alfred Hospital, Melbourne, Australia Clinical studies have suggested that in addition to preventing osteoclast-mediated osteolytic bone disease, bisphosphonates (BPs) may induce a reduction of the tumour burden and prolong the survival of MM patients. Evidence from in vitro studies by a number of groups indicates that nitrogen-containing BPs such as Zometa interfere with osteoclast recruitment, differentiation and action, and induce apoptotic cell death of these cells by disrupting the mevalonate pathway. A large body of evidence indicates that the mevalonate pathway plays an important role in cell growth and survival. Mevalonate is synthesized intracellularly from 3’hydroxy-3methylglutaryl coenzyme A (HMGCoA) in a process catalysed by HMGCoA reductase, the rate-limiting enzyme in this pathway. Mevalonate metabolism yields a series of isoprenoid compounds that are incorporated into cholesterol, isopentenyl adenine, prenylated proteins and other end products essential for cell growth. Data generated in our laboratory has demonstrated that inhibitors of the mevalonate pathway vary in their ability to inhibit cellular proliferation and/or induce cell death in myeloma cell lines. We found that the HMGCoA reductase inhibitor fluvastatin inhibits proliferation of a number of myeloma cell lines of different clinical origin more effectively than the farnesyl transferase inhibitor SCH66336 or Zometa, S261
which acts to prevent the synthesis of geranyl diphosphate, a precursor of FPP and GPP, from mevalonate. After 3 days culture, fluvastatin concentrations as low as 2.5microM significantly inhibited proliferation of all cell lines except RPMI-8226 (p
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Focussed Symposia Arsenic trioxide
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assess whether such a program will
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The overall response rate was noted
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Figure 5A Table 1: VEL + THAL for R
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naturally occurring OPG. Present tr
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0.505). Finally, the multiple event
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CLINICOPATHOLOGICAL DEFINITION OF W
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Plenary Sessions 1. Development of
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clonotypic IgH VDJ signature confir
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can be considered as two entities,
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immunofluorescence staining for DKK
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P2.3 DEVELOPMENT OF A MULTIPLE MYEL
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P2.5 MOLECULAR CYTOGENETICS OF MYEL
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clear that the biggest challenge fo
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esponse and have demonstrated that
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variable region of the idiotypic im
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4. From MGUS to symptomatic MM Fig.
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(MRI); some have claimed that level
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P4.5 CYTOKINES IN MGUS: THERAPEUTIC
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preventing phosphorylation of p70S6
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transducing component of the interl
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survive initial drug exposure and a
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quiescent counterpart, the human um
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transcriptional activity of NF-êB;
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manifestations and anomalous protei
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P7.4 ROLE OF SERUM FREE LIGHT CHAIN
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P7.6 IMMUNOPHENOTYPIC INVESTIGATION
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presumably through the circulation,
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9. Chemotherapy, maintenance treatm
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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
Page 219 and 220: patients(pts) aged ≥60 yrs. We co
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Page 223 and 224: their leukocytes and platelets. No
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Page 229 and 230: 296 PERIPHERAL BLOOD STEM CELL TRAN
Page 231 and 232: References Effect of dose-intensive
Page 233 and 234: with cyclosporine A and methotrexat
Page 235 and 236: 11.Role of novel therapies targetin
Page 237 and 238: 312 Thalidomide as Rescue of Relaps
Page 239 and 240: patients, light chain in 1 patients
Page 241 and 242: platelets of 207 (76-402), B2M of 3
Page 243 and 244: 325 Low Dose Thalidomide plus Dexam
Page 245 and 246: in 5 pts (11%), M protein decreased
Page 247 and 248: time from diagnosis was 3.7 years a
Page 249 and 250: 339 Thalidomide, Clarithromycin and
Page 251 and 252: 344 COMBINATION OF THALIDOMIDE, DEX
Page 253 and 254: experienced early death during the
Page 255 and 256: untreated patients with high tumor
Page 257 and 258: 357 Thalidomide protects endothelia
Page 259 and 260: 362 EOSINOPHILIA IS A VERY COMMON F
Page 261 and 262: 11.5 CC 4047, PS 341 and arsenic tr
Page 263 and 264: without chromosome 13. Mean IC50 fo
Page 265 and 266: myeloma patients. Phase I data indi
Page 267 and 268: 11.6 Other drugs 380 EFFECT OF STI5
Page 269: significant inhibition of cell prol
Page 273 and 274: of B and its metabolites, however,
Page 275 and 276: and 10 months after start of therap
Page 277 and 278: terminal kinase (JNK) pathway which
Page 279 and 280: lymphocytes was tested by Ellispot.
Page 281 and 282: 411 Dendritic Cell-Based Idiotype V
Page 283 and 284: Author Index Abe M 74 160 Abelman W
Page 285 and 286: 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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