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Maria Teresa Ambrosini

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1 Maria Teresa Ambrosini
Targeted therapies nella pratica clinica delle neoplasie ematologiche - Mieloma multiplo Dalla terapia ad alte dosi alla talidomide e agli inibitori del proteasoma: una storia terapeutica in evoluzione Roma, 3 febbraio 2006 Slide 1. The aim of research in cancer therapy is targeted therapy (like Glivec or Rituximab). In the management of myeloma we are not, as yet, seeing cures, but in the few last years, we have a acquired new treatment that have enabled steps toward this goal. Cancer is complex, most are the result of multisteps events Redundancy in most signalling patways Multitargeted therapy DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Maria Teresa Ambrosini

2 Criteria for Diagnosis of MM
MM* (all 3 criteria required) Monoclonal plasma cells in the bone marrow 10% and/or presence of a biopsy-proven plasmacytoma Monoclonal protein present in the serum and/or urine† Myeloma-related organ dysfunction (1 or more)†† (C) Calcium elevation in the blood (serum calcium >10.5 mg/L or upper limit of normal) (R) Renal insufficiency (serum creatinine >2 mg/dL) (A) Anemia (hemoglobin <10 g/dL or 2g <normal) (B) Lytic bone lesions or osteoporosis** *Note: These criteria identify Stage IB and Stages II and III A/B myeloma by Durie/Salmon stage. Stage IA becomes smoldering or indolent myeloma; †If no monoclonal protein is detected (nonsecretory disease), then 30% monoclonal bone marrow plasma cells and/or a biopsy-proven plasmacytoma required; ††A variety of other types of end organ dysfunctions can occasionally occur and lead to a need for therapy. Such dysfunction is sufficient to support classification as myeloma if proven to be myeloma related; **If a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) are the sole defining criteria, then 30% plasma cells are required in the bone marrow DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Durie BGM et al. Hematol J. 2003;4:379

3 Melphalan and Prednisone (MP)
Conventional chemotherapy in use for over 40 years Partial Response: 50-60% Complete Response 1% Median Overall Survival 3 years Equivalent mortality and survival between MP and combination chemotherapy Myeloma Trialists' Collaborative Group. J Clin Oncol. 1998;16:3832 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

4 Melphalan dose-response curve
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

5 High dose Melphalan with Autologous Stem Cell Transplantation
Complete Response rate increased from % to % Remission extended from 18 to 30 months Overall survival doubled from 30 to 60 months DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

6 Randomized studies: High Dose Therapy versus Standard Chemotherapy
IFM901 MRC72 100 75 50 25 80 25 50 75 100 20 40 60 Conventional Treatment (mo) Overall Survival (%) P = 0.04 Transplant Transplant Overall Survival (%) Conventional P=0.03 15 30 45 60 Treatment (mo) DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY 1. Attal M et al. N Engl J Med. 1996;335:91 2. Child JA et al. N Engl J Med. 2003;348:1875

7 Single vs Double ASCT For Newly Diagnosed MM Study ASCT n CR (%)
Median EFS (mo) Median OS (mo) Attal et al Single 199 42 25 48 P=NS P=0.03 P=0.01 Double 200 50 30 58 Cavo et al Single 110 21 25 34 No difference P=NS P<0.05 Double 110 24 Fermand et al Single 94 42 No difference No difference Slide 6 Single vs Double ASCT Attalo ha follow up adeguato 7 anni Single vs double auto-transplantation in newly diagnosed MM patients was compared The results of Attal et al suggested that double transplantation improves overall survival of patients with myeloma In contrast with the findings of the Attal group, there was no difference in event-free survival or overall survival in the trial by Fermand et al Attal M et al. N Engl J Med. 2003;349:2495 Fermand JP et al. Blood. 2001;98:815a [abstract 3387] Sonneveld P et al. Blood. 2004;104:271a [abstract 948] P=NS Double 99 37 Sonneveld et al (HOVON 24) Single 148 13 20 55 P=0.002 P=0.02 P=NS Double 155 28 22 50 Attal M et al. N Engl J Med. 2003;349:2495 Cavo M et al. Hematol J 2003;4 abstract P Fermand JP et al. Blood. 2001;98 abstract #3387 Sonneveld P et al. Blood. 2004;104 abstract #948 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

8 Multiple Myeloma 100 Survival % 50 Median survival = 3-5-years
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

9 Multiple Myeloma SOIL SEED
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

10 Bruno B et al. Lancet Oncology 2003;4:379
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Bruno B et al. Lancet Oncology 2003;4:379

11 Bruno B et al. Lancet Oncology 2003;4:379
DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Bruno B et al. Lancet Oncology 2003;4:379

12 Thalidomide Precise mechanism of action not yet understood
Multiple actions: antiangiogenic effects that provide the rationale for its use in MM immunomodulatory effect apoptotic effect Thalidomide was first shown to be effective as a single agent in patiens with relapsed and refractory disease (Singhal S et al. N Engl J Med. 1999;341:1565) Numerous subsequent studies have confirmed its efficacy with a response rate of 30% alone, 50% when used in combination with dexamethasone and 70% with chemotherapy. Slide XX Thalidomide was first shown to be effective as a single agent in patiens with relapsed and refractory disease (Sighal 1999), Numerous subsequent studies have confirmed its efficacy with a response rate of 30% alone and 60% when used in combination with dexamethasone. This remarkable efficacy has led to the use of thalidomide at earlier stages of the disease and its role as a maintenance or in HD therapy is also being evaluated. DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

13 Thalidomide/dexamethasone combination
Study No CR/nCR CR+PR Toxicity Dimopoulos Ann Oncol 2001 44 (°) na 55% neuropathy, confusion, constipation, sonnolence Palumbo Hematol J 2004 120 (°) na 52% DVT (2), neuropathy( 20), confusion (8), skin rash (4) Rajkumar JCO 2006 103 (*) 4% (CR) 63% DVT (20),neuropathy (7), skin rash (4), deaths (6) Ludwig ASH 2005 22% 52% DVT (5), neuropathy (15), skin rash (7) 60 (*) Cavo Blood 2005 100 (*) 13% 76% DVT (15), constipation (9), infections (4), neuropathy (4), deaths (6) (*) in untreated patients (°) in relapsed patients DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

14 Thalidomide/Dexamethasone vs Dexamethasone in Newly Diagnosed Multiple Myeloma
Phase III Clinical Trial, newly diagnosed MM for whom stem cell transplantation was considerate appropriate Thalidomide 200 mg daily p.o. + Dexamethasone 40 mg p.o. on days 1-4, 9-12, or Dexamethasone alone Every 4 week Dex (n=100) Thal/Dex (n=99) 4 2 Disease progression within first 4 mo, % 1.1 Median time to response, mo 41 (41) 62 (63) Response rate, n (%)* *Best response within 4 courses Endpoint Slide 17. DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Rajkumar SV et al. J Clin Oncol 2006;24:1

15 Deaths within 4 cycles: Thal/Dex, 7%; Dex, 11%
Thalidomide/Dexamethasone vs Dexamethasone: Drug-Related Adverse Events Dex, n (%) (n=102) Thal/Dex, n (%) (n=102) Drug-Related Adverse Event 21 (21) 46 (45) Total 18 (18) 35 (34) Any toxicity ≥ grade 4 4 (4) 7 (7) Neuropathy ≥ grade 3 0 (0) 1 (1) Sinus bradycardia ≥ grade 3 Rash ≥ grade 3 3 (3) 17 (17) DVT ≥ grade 3 Slide 16. Thalidomide/Dexamethasone vs Dexamethasone: Drug-Related Adverse Events More grade 3 and 4 adverse events were reported for patients who were treated with the thalidomide/dexamethasone combination compared with dexamethasone alone In particular, the frequency of deep vein thrombosis (DVT) in the thalidomide/dexamethasone arm was significantly higher compared with the dexamethasone arm (17% vs 3%, P<0.0001) Rajkumar SV et al. Blood. 2004;104(part 1):63a [abstract 205] Deaths within 4 cycles: Thal/Dex, 7%; Dex, 11% DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Rajkumar SV et al. J Clin Oncol 2006;24:1

16 Thalidomide Chemotherapy combinations
DVT (4), neutropenia (6), thrombocytopenia (6), constipation (4), neuropathy (2) 64% 10% T-VAD (*) Vcr + Adria + Dex + THAL 39 Zervas Ann Oncol 2004 Death (4), DVT (17), infection (11), neuropathy(31) 76% 28% MPT (*) M + P + THAL 129 Palumbo ASH 2005 53% CR+PR 32% na CR/nCR Toxicity Regimen No Study Infections (6), Neuropathy (2), constipation (7) CTD (°) Cy + Dex + THAL 22 Garcia-Sanz Hemat J 2002 Schutt Eur J Haematol 2005 31 T-VED (*) Vcr + Epir + Dex +THAL 19% 80% DVT (8), neutropenia (10), infection (7), neuropathy (20) Offidani Haematologica 2006 50 DVd-T (°) Vcr+AdriaLipo + Dex + THAL DVT (6),neutropenia (8), constipation (1), neuropathy (1) DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY (*) in untreated patients (°) in relapsed patients

17 Thalidomide With Melphalan and Prednisone in Elderly Patients With MM
Phase III Randomized Controlled Trial MPT Arm (Median age 72) Melphalan, 4 mg/m2 (7 days/mo) Prednisone, 40 mg/m2 (7 days/mo) Thalidomide, 100 mg/d (continuously)* (n=129) Newly diagnosed MM patients, aged >65 yr (n=255 as of 3/05)   6 courses MP Arm (Median age 72) Melphalan, 4 mg/m2 (7 days/mo) Prednisone, 40 mg/m2 (7 days/mo) (n=126) Thalidomide With Melphalan and Prednisone in Elderly Patients With MM In this phase III randomized controlled trial, 255 patients with newly diagnosed MM, who were over the age of 65 years, were randomized to receive treatment with either thalidomide, oral melphalan, and prednisone or oral melphalan and prednisone. Median age for both arms was 72 years Palumbo A et al. Blood. 2005;106:230a [abstract 779] *Thalidomide dose reduced to 50% if grade 2 toxicity. Follow-up ≥6 mos. Palumbo A et al. Blood. 2005;106: abstract #779 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

18 MPT in Elderly Patients With MM: Response
MPT, % (n=129) MP, % (n=126) P value CR + nCR 28 7 <0.001 CR 16 2 nCR 12 5 PR 60 45 ORR 76 47 <0.001 Median EFS, mo 29.2 13.6 <0.001 MPT in Elderly Patients With MM: Response Addition of thalidomide to oral melphalan and prednisone was associated with significantly greater response rates in these newly diagnosed, elderly MM patients; the overall response rate (CR + nCR + PR) was 76% vs 47% for MPT and MP, respectively A significant improvement in event-free survival was seen in the MPT arm compared with the MP arm Significant differences in overall survival were seen after 9 mo Other effects of MPT included improvements in performance status, skeletal pain, anemia, and the need for transfusion Palumbo A et al. Blood. 2005;106:230a [abstract 779] OS at 36 mo 80 64 NS PR (>50%), nCR (IF+), CR (IF-) DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Palumbo A et al. Blood. 2005;106: abstract#779

19 Thromboembolism in MPT-Treated Elderly Patients Reduced With Prophylaxis
More DVT with MPT than with MP (P=0.003) DVT prophylaxis: enoxaparin, 0.4 mL/day for 4 months 0.0 1.5 Arterial occlusion 4.6 Pulmonary thromboembolism 3.0 18.4 DVT With Prophylaxis (n=64) No Prophylaxis (n=65) Adverse Event Incidence, % Slide 100. Thromboembolism in MPT-Treated Elderly Patients Reduced With Prophylaxis Treatment of these patients with MPT was associated with more adverse events compared with MP, particularly deep vein thromboses (DVT; P=0.003) and neurotoxicities (P<0.001) Thromboembolism in MPT-treated patients was reduced with prophylactic use of enoxaparin, 0.4 mL/day for 4 months Palumbo A et al. Blood. 2004;104(part 1):63a [abstract 207] DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Palumbo A et al. Blood. 2005;106:abstract #779

20 MP vs MP-Thal and MP vs Mel100 in Newly Diagnosed MM Patients Aged 65–75 Years
IFM Trial Response to Treatment* MP 12 courses Random MP + THAL 12 courses 2 VAD  CTX 3g/mq  MEL100  MEL 100 Response MP (n=191) MP-Thal (n=124) MEL100 (n=121) PFS 17,1 27,6 19 OS 30,3 > 55 38,6 Slide 102. MP vs MP-Thal and MP vs Mel100 in Newly Diagnosed MM Patients Aged 65–75 Years: IFM Trial Response to Treatment Response data are available from the planned second interim analysis (July 4, 2004); median follow-up time = 28 months Total patients analyzed = 340 (350 for toxicity); MP = 153; MP-Thal = 95; MEL100 = 92 MP-Thal and MEL100 response rates are similar Overall survival data do not support stopping patient recruitment in any arm A third interim analysis is planned Facon T et al. Blood. 2004;104(part 1):63a [abstract 206] 3nd planned interim analysis 5/2005; median follow-up time = 32.2 months Facon T et al. Blood. 2005;106 abstract#780 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

21 Maintenance With Thalidomide after ASCT
ASCT (MEL140  MEL200) as front line therapy Month 3 after 2 ASCT, if no progression Random No maintenance Pamidronate, 90 mg/mo Pamidronate, 90 mg/mo Thalidomide, 100 mg/day Endpoint No maintenance Pam Thal/Pam P Value Patients, n 197 195 201 4-yr EFS, % 39 37 50 0.001 4-yr OS, % 86 78 ns Slide 109. Maintenance With Thalidomide After ASCT for MM In the management of aggressive myeloma, almost all patients ultimately relapse after high-dose therapy supported with ASCT The Intergroupe Francophone du Myelome (IFM) is conducting a study to evaluate the effect of thalidomide maintenance treatment on the duration of response after high-dose therapy and ASCT Attal M et al. Blood. 2004;104(part 1):155a [abstract 535] DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Attal M et al. Blood. 2005;106 abstract #1148

22 Thalidomide Analog; REVLIMID™ (CC5013)
CC5013 is more potent and less toxic than the parent compound Induces apoptosis in MM cells Decreases binding of MM cells to bone marrow stromal cells Inhibits cytokine production (IL-6, VEGF, TNF-alfa) Blocks angiogenesis DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

23 Phase III Trial of Lenalidomide/Dex in Relapsed or Refractory MM
International MM-010 (51 Centers Europe/Australia/Israel): Dimopoulos (351 patients) Lenalidomide 25 mg d 1–21 Placebo d 22–28 Dex 40 mg, d 1–4, 9–12, 17–20 Inclusion criteria ≤3 prior therapies No Dex resistance Normal liver/renal function CONTINUE UNTIL PD  4 COURSES Placebo d 1–28 Dex 40 mg, d 1–4, 9–12, 17–20 Same, except Dex d 1–4 Two Phase III Trials of Lenalidomide/Dex in Relapsed or Refractory MM Phase I trials showed the MTD of lenalidomide to be 25 mg/day. Phase II trials showed that an interrupted 25-mg daily dose maintained response with ameliorated myelosuppression, forming the basis for the dosing used in these phase II trials Patients in arm 1 were given lenalidomide on days 1–21 (placebo on days 22–28) and high-dose dexamethasone ([HDD] 40 mg) in the typical pulsed fashion on days 1–4, 9–12, and 17–20. Patients in arm 2 were given placebo on days 1–28 and HDD on days 1–4, 9–12, and 17–20. Treatment was continued for 4 cycles and thereafter with HDD on days 1–4 only until disease progression Primary endpoint was time to progression (by Bladé criteria). Secondary endpoints were overall survival (OS), response rate (RR), safety (toxicity), 1st skeletal-related event, decreased performance status (PS) Patients were additionally stratified according to 2M (≤2.5 mg/dL vs >2.5 mg/dL), prior transplant (0 vs >1) and prior MM treatment regimens (<1 vs >1) Inclusion criteria: refractory or relapsing MM, ≤3 previous regimens Exclusion criteria: resistance to >200 mg Dex over 1 month, liver enzymes <3  normal, creatinine <2 mg/dL Weber D. Presented at: ASCO Annual Meeting; May 13–17, 2005; Orlando, FL. Available at: Dimopoulous M et al. Blood. 2005;106:6a [abstract 6] Primary endpoint: TTP (by Bladé criteria) Secondary endpoints: OS, RR, safety, 1st skeletal-related event, PS DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Dimopoulous M et al. Blood. 2005;106 abstract #6

24 Phase III Trial of Lenalidomide/Dex in Relapsed or Refractory MM
Endpoint Lenalidomide/ Dex Placebo/Dex P value Time To Progression 13 mo 5 ,1 mo < Overall Response Rate 58% 22% <0.001 An independent commettee closed the study: Revlimid superior to Dex DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Dimopoulous M et al. Blood. 2005;106 abstract #6

25 The Proteasome: A Target for Novel Therapies
Bortezomib The Proteasome: A Target for Novel Therapies DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Bruno B et al. Lancet Oncology 2004

26 APEX : Treatment plan Bortezomib Dexamethasone Randomization Induction
8 cycles 4 cycles 1.3 mg/m2 IV push Days 1, 4, 8, 11 Q3W cycle 40 mg po Days 1–4, 9–12, 17–20 Q5W cycle Maintenance 3 cycles Slide XX Velcade PS-341 è il primo inibitore del proteasoma ad essere testato in clinical trial Fase II: SUMMIT; CREST Bortezomib proteasome inhibitor Richardson et al compared bortezomib with high dose dexamethasone in patients with relapsed MM, who had received one to three prior therapy 5 cycles 1.3 mg/m2 IV push Days 1, 8, 15, 22 Q5W cycle 40 mg po Days 1–4 Q4W cycle 273 treatment days 280 treatment days DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Richardson et al. N Engl J Med 2005;352:2487

27 Time to progression (n = 669)
APEX: Outcome 1-year survival (n = 669) Time to progression (n = 669) Endpoint Bortezomib Dexamethasone Time To Progression 6,2 mo 3,5 mo Overall 1yr 80% 66% DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Richardson et al. N Engl J Med 2005;352:2487

28 APEX: response rates (CR, PR)
Median time to response (TTR) 43 days in both arms Duration of response Bortezomib 8.0 months Dexamethasone 5.6 months Median follow-up ~8.3 months 100 90 80 P<.0001 70 60 Response (%) 50 38% 40 30 25% PR 18% <1% nCR 20 7% nCR 16% PR <1% CR 10 6% CR Bortezomib Dexamethasone DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Richardson et al. N Engl J Med 2005;352:2487

29 APEX: Treatment-emergent ≥ grade 3 AEs reported by ≥ 5% of patients
Bortezomib (n = 331) Dexamethasone (n = 332) Patients % 10 20 30 40 50 Hyperglycemia Pneumonia Dyspnea Fatigue Diarrhea Peripheral neuropathy Among the 331 patients in the VELCADE group, the only  Grade 3 adverse events occurring at an incidence > 10% were thrombocytopenia (97 patients; 29%) and neutropenia (48 patients; 15%). The only  Grade 3 adverse event that occurred at an incidence > 10% among the 332 dexamethasone-treated patients was anemia NOS (35 patients; 11%). Anemia Neutropenia Thrombocytopenia DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Richardson et al. N Engl J Med 2005;352:2487

30 Bortezomib+Dexamethasone
Bortezomib alone and in combination with Dexamethasone for untreated MM Treatment Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 of 21-day cycle Dexamethasone 40 mg P.O. on days 1, 2, 4, 5, 8, 9, 11, 12 added if <PR after 2 cycles or <CR after 4 cycles N= 32 Bortezomib Bortezomib+Dexamethasone CR 3% 6% nCR 9% 19% PR 28% 63% DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Jagannath et al. Br J of Haematology 2005;129:776

31 PAD combination therapy (bortezomib (PS-341), Adriamycin and Dexamethasone) for untreated MM
Treatment Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 of 21-day cycle Dexamethasone 40 mg on days 1-4, 8-11, during cycle 1, days 1-4 cycles 2-4 Doxorubicine 0 - 4,5 – 9 mg/mq on days 1-4 95% ORR 33% PR VGPR 5% nCR 24% CR Response Rate: DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Oakervee et al. Br J of Haematology 2005;129:755

32 VTD (VELCADE®, Thalidomide, Dexamethasone) as Primary Therapy for Newly-Diagnosed MM
Treatment: Bortezomib 1.0 to 1.9 mg/m2 days 1, 4, 8, 11 q 28 days Thalidomide mg each evening Dexamethasone 20 mg/m2 days 1-4, 9-12, q 28 days 28- day treatment cycle, 2 cycles Institutional experience of 36 patients 92% Response rate (CR+PR) PBSC easily collected DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Wang et al. Blood 2005;106 Abstract#784

33 A phase I/II study of Bortezomib plus Melphalan and Prednisone (V-MP) in Elderly Untreated MM patients Treatment V-MP 9 courses Four 6-week courses Melphalan p.o. 9 mg/m2 on days 1-4, Prednisone p.o. 60 mg mg/m2 on days 1-4 VELCADE i.v 1,3 mg/m2 days 1, 4, 8, 11, 22, 25, 29, and 32 Five 5-week courses VELCADE i.v 1,3 mg/m2 days 1, 8, 22, and 29 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Mateos et al. Blood 2005;106 Abstract#786

34 V-MP: Response Rates (N=53)
After 1st cycle Best response (median 3 cycles) 72% 85% 0% CR IF- CR IF+ PR MR SD 28% 11% 45% 3% 13 % 70% 64% 70% 60% 60% 50% 50% 40% 40% 30% 30% 20% 20% 10% 6% 2% 10% 0% CR IF- CR IF+ PR DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Mateos et al. Blood 2005;106 Abstract#786

35 V-MP: Conclusions High Response Rate Manageable toxicities:
Neutropenia and thrombocytopenia were the only Gr3 events Basis for VISTA Phase III trial (n=680): VMP vs MP DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

36 Bortezomib + Melphalan + Prednisone + Thalidomide
HOW TO IMPROVE VMP ? V-MPT Bortezomib + Melphalan + Prednisone + Thalidomide DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

37 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

38 Protocol GIMEMA-MM-03-05 A PHASE III, MULTI-CENTER, RANDOMIZED OPEN LABEL STUDY OF VELCADE, MELPHALAN, PREDNISONE AND THALIDOMIDE (V-MPT) Versus VELCADE, MELPHALAN, PREDNISONE (V-MP) IN ELDERLY UNTREATED MULTIPLE MYELOMA PATIENTS DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

39 Combinations therapies in Multiple Myeloma
Bortezomib + Thalidomide +/- cytotoxic drugs induction relapse M-COMPONENT High-dose remission DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

40 Combinations increase response rate
Take home message + New Drugs Combinations increase response rate Frontline therapy DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

41 GIMEMA: Italian Myeloma Network
1. ALESSANDRIA Levis, Baraldi 2. ANCONA Leoni, Offidani 3. AOSTA Di Vito 4. ASCOLI PICENO Galieni, Bigazzi 5. ASTI Scassa, Campa 6. AVELLINO Cantore, Volpe 7. AVIANO Tirelli, Rupolo 8. BARI Dammacco, Lauta 9. BARI Liso 10. BERGAMO Barbui, Galli 11. BIELLA Tonso 12. BOLOGNA Cavo, Tosi 13. BOLZANO Pescosta 14. BRA Vanni, Stefani 15. BRESCIA Rossi, Crippa 16. CAGLIARI Angelucci, Carubelli 17. CAGLIARI Mantovani 18. CAMPOBASSO Storti 19. CANDIOLO Aglietta, Capaldi 20. CATANIA Giustolisi,Di Raimondo 21. CATANZARO Piro 22. CATTOLICA Pasquini 23. CESENA Guardigni 24. CHIOGGIA Battista 25. CIRIE' Freilone, Beggiatto 26. COSENZA Morabito 27. CREMONA Passalacqua, Morandi 28. CREMONA Morandi 29. CUNEO Gallamini, Grasso 30. FIRENZE Bosi/Nozzoli 31. FOGGIA Ferrandina 32. FOGGIA Monaco 33. FORLI’ Amadori, Gentilini 34. GALLARATE Ciambelli 35. GENOVA Gobbi, Canepa 36. GENOVA Carella 37. LATINA Zapone 38. LECCE Pavone 39. MATERA Ciancio 40. MESSINA Brugiatelli, Mamone 41. MESSINA Musolino 42. MILANO Corradini, Montefusco 43. MILANO Morra 44. MILANO Bregni 45. MODENA Narni 46. MONTEFIASC. Montanaro, Niscola 49. MONZA Pogliani, Rossini 50. NAPOLI Rotoli,Catalano 51. NAPOLI Ferrara 52. NOCERA INF. D’Arco, Califano 53. NOVARA Gaidano, Rossi 54. NUORO Latte, Palmas 55. ORBASSANO Saglio, Guglielmelli 56. PADOVA Semenzato, Zambello 57. PALERMO Mirto, Cangialosi 58. PARMA Rizzoli, Giuliani 59. PAVIA Lazzarino, Corso 60. PERUGIA Liberati, Nunzi 61. PESARO Visani, Leopardi 62. PESCARA Fioritoni, Spadano 63. PIACENZA Cavanna, Lazzaro 64. PINEROLO Griso 65. PISA Petrini/Benedetti 66. POTENZA Ricciuti, Vertone 67. RAVENNA Zaccaria, Molinari 68. REGGIO CAL. Nobile, Callea 69. REGGIO EMILIA Gugliotta,Masini 70. RIMINI Pasquini, Fattori 71. ROMA Annino, Bongarzoni 72. ROMA Andriani 73. ROMA 1 Foà, Petrucci 74. ROMA Cattolica Leone, De Stefano 75. ROMA R.Elena Petti, Pisani 76. ROMA S. Camillo Majolino, De Rosa 77. ROMA T. Vergata Amadori, Caravita, i 78. ROZZANO Santoro, Nozza 79. S. G. ROTONDO Musto, Merla 80. SASSARI Longinotti, Dore 81. SIENA Lauria, Gozzetti 82. TARANTO Mazza, Casulli 83. TORINO 1 Boccadoro, Palumbo 84. TORINO 2 Gallo, Pregno 85. TORINO MAURIZ. Poccardi, Gottardi 86. TORINO S. VITO Marinone, Ficara 87. TREVISO Foscolo, Gherlinzoni 88. TRIESTE De Sabbata 89. UDINE Fanin, Patriarca 90. VARESE Pinotti 91. VENEZIA Chisesi 92. VERBANIA Montanara, Luraschi 93. VERONA Pizzolo, Meneghini 94. VICENZA Rodeghiero, Elice


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