Haematologica 2003 - Supplements

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37.5%. Patients who do not achieve a 25% reduction in monoclonal protein at 6 weeks are unlikely to respond later on. 32.5% of patients needed to interrupt therapy with thalidomide early or late because of severe adverse events. 314 Long Term Treatment with low dose of Thalidomide in Refractory Multiple Myeloma: Preliminary Results A Alegre(1), JJ Gil-Fernández(2), C. Martínez-Chamorro(2), A. Escudero(3), A. Granda (1), B.Aguado(1), S.Osorio(1), S. Nistal(1), R. Córdoba (1), JM Fernández-Rañada(1) Hospital Universitario de la Princesa(1). Clínica Ruber (2)(Madrid), (Madrid) Spain Introduction. Thalidomide has been shown to be active in relapsed and refractory patients with multiple myeloma and its current role as a first line agent in the induction treatment is currently being investigated. The role and clinical results of thalidomide as maintenance treatment at low dose for prolonging response is not known. The potential toxic effects of this drug has limited its use as long term, however there is a rational for its use in this setting: As the number of treatment lines increases in MM patients, including intensification schemes, the response phase becomes progressively shorter suggesting development of multidrugs resistance (MDR). Thalidomide could maintain the response or plateau phase acting at different pathogenic levels. We present the preliminary experience of a preliminary group of patients that received thalidomide in a log term period. Patients and treatment: Eigth patients with MM that had received oral Thalidomide as rescue for relapse after autologous hematopoietic transplantation and that showed favourable response were intended to keep on treatment with thalidomide at low dose to prolong response. The initial treatment included oral Thalimodide® 100 mg (Grunnenthal, Germany): 200 mg/d, escalating doses every 14 d, according tolerance until a maximum daily dose of 800 mg. Median dose received was 400 mg/d. In 4 patients thalidomide were used alone. Rest of the patients received this drug associated to Dexamethasone ( 20 mg x 4 every 21-28 d). 2-3 weeks after observing the maximum response thalidomide was reduced and maintained for long term at low dose 50-100 mg/d continuously or on alternate weeks, according tolerance, until relapse or progression. Neurological examinations and study of thyroid hormones levels were periodically performed. Results. Three patients progressed after 6-9 months on treatment and five patients were evaluable for “long term” follow up wit at least 10 months of treatment. One patient maintain CR, two cases objective response and two patients presents stable disease.(Anecdotically one patient (3) on dialysis recovered from renal failure after 24 months on treatment). Median duration of treatment was 12 months (12-30). Somnolence, cutaneous rash and peripheral mild neuropathy that improved alternating the low dose were the main secondary effects. Comments and Conclussions. Long term treatment with low dose of thalidomide presents an acceptable tolerance The stable and long duration of responses, observed in this group of patients, suggest a possible role of this drug as maintenance treatment. This role of thalidomide at low dose in the long term, prolonging the response phase of multiple myeloma, needs to be studied in randomized trials 315 EFFICACITY OF THALIDOMIDE ALONE IN 25 RELAPSED OR REFRACTORY MULTIPLE MYELOMA PATIENTS. Desmaris R., Hulin C., Guibaud I., Bologna S., Witz F., Lederlin P. Hématologie, CHU Nancy-Brabois, 54511 Vandoeuvre, France. Thalidomide, is an active agent in the treatment of relapsed or refractory myeloma. In this retrospective study, responses and time of reponses were observed with thalidomide alone. Dexamethasone was added in a second time if necessary. Our study population comprised 25 patients (median age 60 years) who received directly thalidomide alone for relapsed or refractory myeloma between january 2000 and january 2002. Responses were defined according to M-component reduction in serum or in urines at 21st and 90th median days. Median time from myeloma diagnosis to onset of thalidomide therapy was 26 months (range 9-76 months). Patients had either prior conventional therapy alone (n=8) or intensive treatment with a single or a tandem transplantation (n=17). All the patients had received 2 or more previous treatments before thalidomide had been instituted. Thalidomide usually began in oral dose of 100 to 200 mg every evening, increased at weakly intervals when tolerable. At the reference date, the median follow up from the start of thalidomide treatment was 17,5 months. All responses occured with dose ranging from 100 to 400 mg. No complete responses were observed. At the 21st median day, 9 patients (36%) achieved Partial Response (PR) : 2 PR>50% and 7 PR>25%. At the 90th median day, a dexamethasone addition was necessary for 6 of them. PR were recorded in 14 patients (56%) : 6 PR>50% and 8 PR>25%. Major adverse effects included somnolence and sedation (43%), peripheral neuropathy (38%), dizziness (31%) and constipation (24%). We observed a good response after only 21 days of treatment, which is increased after 3 months. However efficacity of thalidomide is short (median time 7 months) and an association is frequently required to maintain or increase response. 316 THALIDOMIDE ALONE OR WITH DESAMETHASONE IN THE MANAGEMENT OF MULTIPLE MYELOMA: OUR EXPERIENCE. Montero I, Puertas A, Martino ML, Vaquero A, CampoT, Parody R, Rodriguez Fdez;JM. Division of Haematology. University Hospital "Virgen del Rocío". Seville (Spain) INTRODUCTION: Multiple myeloma (MM) remains an incurable malignance, as a results of innate drug resistance present at diagnosis. Thalidomide(THAL) is a novel antimyeloma agent because of its multiple, including antiangiogenic, antitumor mechanisms. This drug, alone or with dexamethasone, was given in several trials in patients with refractory or relapsed MM after stem cell transplantation or conventional chemotherapy, as well as a response maintenance therapy. PURPOSE: To evaluate the activity of thalidomide as a drug included in a new protocol for patients diagnosed of MM. PATIENTS AND METHODS: The study included a group of 13 consecutive patients diagnosed of multiple myeloma and treated with THAL alone or in combination with dexamethasone in a dose-scalating schedule as a part of a novel total MM therapeutic protocol, between January 2000 and December 2002. The median age was 56 years (range, 31-71 years); of them 8 were males and 5 females. M-component isotype was IgG in 9 patients, IgA in 2 S229
patients, light chain in 1 patients and 1 patient was diagnosed of non-secretor myeloma. At the onset of THAL, 2 (15%) patients were in complete remission (CR), 3 patients (23%) in partial response (PR) and 8 patients (62%) were refractory to treatment. Four patients had mass tumoral previously. Response was assessed by monoclonal protein quantitation in serum or urine, bone marrow plasma cells percentage and mass tumoral disappearance. Parameters as hemoglobin level, neutrophils and platelets ciphers before and after THAL, side effect were evaluated. RESULTS: CR was seen in 4 patients(37%), PR was achieved in 5 patients(45%) and 2 patients (18%) were refractory to treatment. Comparing to the state of disease at the onset of THAL, 44% of obteined response should be attributable to this drug. Two deaths were registered before evaluation (in one patient infection was the cause and in the other was progression of MM). Two responding patients (18%) had relapsed after evaluation in a extramedullar mode and died due to myeloma progression; both of them had tumoral mass previously to THAL treatment. Median of following up was 11 months (range 4-22). Although side effects with THAL were frequent (69%), they were nearly always mild and reversible beeing of grade 1 or 2 degrees (fatigue, sedation, numbness, unsteadiness). Only one patient required cessation of THAL due to intolerance. Concerning blood count, lower neutrophils ciphers had been observed after THAL treatment although no significative difference was observed(median of group before THAL was 2.6 x 109/L vs 2,2 x109/L after THAL). CONCLUSIONS: In our experience THAL alone or with dexamethasone is a good alternative as salvage therapy in patients with refractory myeloma without severe side effects. In patients with high tumoral burden this treatment should be completed with others therapy strategies. 317 Combination therapy with thalidomide plus oral melphalan compared with Thalidomide alone for advanced multiple myeloma M. Offidani, M. Marconi, L. Corvatta A. Olivieri, §M. Catarini, #A. Mele °M. Brunori, *M. Candela, L. Malerba, D. Capelli, M. Montanari, S. Rupoli, , P. Leoni Clinica di Ematologia and*Clinica Medica, University of Ancona, Italy#Division of Hematology S. Salvatore Hospital, Pesaro, Italy§Division of Medicine, Macerata Hospital, Italy°Division of Medicine, Fano Hospital, Italy To date, few therapeutic options are available for patients with relapsed MM, especially when the relapse occurs after stem cell transplantation. In this context, several trials demonstrated that thalidomide alone or in combination with dexamethasone produce response rates of about 30% and 50%, respectively. We report our experience using a combination of thalidomide and oral melphalan compared with thalidomide alone in a casecontrol study including patients with advanced MM. From May 2000 to July 2002, 27 patients were treated with thalidomide plus oral melphalan (TM group) and 23 patients with thalidomide alone (T group). Patients were not excluded because of either poor performance status or cardiopulmonary, renal and liver disfunctions. The initial dose of thalidomide was planned to be 100 mg p.o. daily at bedtime, escalated weekly by 100 mg increments until a maximum dose of 600 mg daily continuously until side effects or disease progression were documented. Melphalan was administered intermittently at a dose of 0.20 mg/kg/d orally for four days every 28 days for almost one course after greatest response or until severe toxicity. No patients received antithrombotic prophylaxis. Prognostic features such as 2-microglobulin, hemoglobin level, prior regimens, prior high-dose therapy and disease history did not significantly differ between the two groups of patients while age was significantly lower in the TM group (69 vs 74 years; p = 0.042) and median follow-up was significantly longer in the TM group (13 vs 10 months; p = 0.022). Rate of paraprotein decrease ≥ 50% was significantly higher in the TM group compared with T group (63% vs 26% p = 0.009). Remarkably, ≥ 75% paraprotein decrease was obtained in 4 patients (15%; ¾ true CR) of TM patients compared with only 1 (4%; no true CR) of T group. The median time to remission was significantly shorter in the TM group (4 weeks vs 7 weeks; p= 0.0312). Multivariate analysis selected only TM therapy (p = 0.008) as factor associated with better response. After a median follow-up of 13 months (range 6- 32), 18 patients (36%) had disease progression and 11 (22%) died. Eight patients died of disease progression, and 1 patient died for pulmonary embolism, infection and hearth failure, respectively. PFS was significantly longer in TM group compared with T group (median NR vs 13 months; 61% vs 45% at 2 years; p= 0.0356) whereas OS did not most likely because of a median follow-up significantly shorter in the T group. In the multivariate analysis only response ≥ 50% was associated with higher PFS at two years (66% vs 42%; p= 0.0464) and only Hb ≥ 10.5 mg/dl significantly affected longer OS (76% vs 49% at 2 years; p= 0.0449). Fourteen patients (28%) stopped and 24 (48%) reduced thalidomide because of side effects. In the TM group, 4 patients (15%) delayed the administration of melphalan because of hematologic toxicity. The main side effects attributable to thalidomide were constipation (72%), somnolence (38%), asthenia (24%) and sensory peripheral neuropathy (44%). This latter adverse event was cause of thalidomide withdrawal in 7 patients (14%). Central nervous system adverse effects (dizziness, numbness, headache) were found in 8 patients (16%) although severe toxicity was rare. No differences were found between the two groups with respect to the above side effects while rate of deep venous thrombosis (11% vs 4%; p = 0.614) and grade 3 (WHO) leukopenia (30% vs 13%; p= 0.073) were higher in the TM group. This study suggests that oral melphalan added to thalidomide improves response rate and PFS in advanced poor prognosis multiple myeloma without increasing severe toxicity. Consequently, combination of thalidomide plus oral melphalan should be further investigated in the context of controlled studies. 318 Thalidomide in Relapsed/Refractory Multiple Myeloma: Experience of a Single Center G. Esteves, J. Raposo, C. Martins, C. Lopes, J. Lacerda, J. Alves Carmo, J. M. Forjaz Lacerda Haematology-Day’s Hospital, Hospital de Santa Maria, Lisboa, Portugal Background: Thalidomide (THAL) has significant activity both as a single agent and in combination with other therapies in patients with de novo and advanced multiple myeloma. We presented our results treating advanced disease with THAL alone or in combination. Methods: We treated patients with relapsed/refractory myeloma using dose-escalated THAL up to maximum dose of 800 mg/day. THAL was given orally for 2 weeks at 200 mg/d, increasing of 200 mg/day each 2 weeks if tolerated. In those patients with no S230
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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
Page 187 and 188: (β2m) & C reactive protein (CRP).
Page 189 and 190: plasmids carrying the clonotypic in
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Page 193 and 194: 216 Transgenic expression of Myc an
Page 195 and 196: 221 Prolonged survival in the 5T2MM
Page 197 and 198: 9. Chemotherapy, maintenance, treat
Page 199 and 200: 229 EFFECTIVENESS OF STANDARD CHEMO
Page 201 and 202: 234 Melphalan and Dexamethasone- Is
Page 203 and 204: Methods. We investigated the VECD p
Page 205 and 206: 9.2 Renal complications. 243 MERIT
Page 207 and 208: cost of SRE-related care was $10,24
Page 209 and 210: those with Hb >13 g/dL. Analysis of
Page 211 and 212: sustained response, lasting from 52
Page 213 and 214: proportion of bone abnormality. IgD
Page 215 and 216: disease. The lack of response to in
Page 217 and 218: yielding a median of 3x106/kg CD34
Page 219 and 220: patients(pts) aged ≥60 yrs. We co
Page 221 and 222: PBSC mobilizing regimen utilizing C
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: 312 Thalidomide as Rescue of Relaps
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 and 270: significant inhibition of cell prol
Page 271 and 272: which acts to prevent the synthesis
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
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Morra E 249 280 359 Morris CM 226 M
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Siegel D 70 115 250 Sierra J 304 30
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Haematologica 2003 - Supplements

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