Dalla terapia ad alte dosi alla talidomide e agli inibitori del proteasoma: una storia terapeutica in evoluzione

1. Dalla terapia ad alte dosi alla talidomide e agli inibitori del proteasoma: una storia terapeutica in evoluzione Maria Teresa Ambrosini 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 therapySlide 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

2. Criteria for Diagnosis of MM

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

5. High dose Melphalan with Autologous Stem Cell Transplantation Complete Response rate increased from 1 - 3% to 30 - 50% Remission extended from 18 to 30 months Overall survival doubled from 30 to 60 months

6. Randomized studies: High Dose Therapy versus Standard Chemotherapy

7. Single vs Double ASCT 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] 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]

8. Multiple Myeloma

9. Multiple Myeloma

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.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.

13. Thalidomide/dexamethasone combination

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, 17-20 or Dexamethasone alone Every 4 week Slide 17. Slide 17.

15. Thalidomide/Dexamethasone vs Dexamethasone: Drug-Related Adverse Events 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] 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]

16. Thalidomide Chemotherapy combinations

17. Thalidomide With Melphalan and Prednisone in Elderly Patients With MM 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 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]

18. MPT in Elderly Patients With MM: Response 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]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]

19. Thromboembolism in MPT-Treated Elderly Patients Reduced With Prophylaxis 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]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]

20. MP vs MP-Thal and MP vs Mel100 in Newly Diagnosed MM Patients Aged 65�75 Years Slide 102. MP vs MP-Thal and MP vs Mel100 in Newly Diagnosed MM Patients Aged 65�75 Years: IFM 99-06 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] Slide 102. MP vs MP-Thal and MP vs Mel100 in Newly Diagnosed MM Patients Aged 65�75 Years: IFM 99-06 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]

21. Maintenance With Thalidomide after ASCT 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]  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]

22. 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

23. Phase III Trial of Lenalidomide/Dex in Relapsed or Refractory MM 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 Blad� 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: http://ir.celgene.com/phoenix.zhtml?c=111960&p=irol-newsArticle&ID=709974&highlight= Dimopoulous M et al. Blood. 2005;106:6a [abstract 6]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 Blad� 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: http://ir.celgene.com/phoenix.zhtml?c=111960&p=irol-newsArticle&ID=709974&highlight= Dimopoulous M et al. Blood. 2005;106:6a [abstract 6]

24. Phase III Trial of Lenalidomide/Dex in Relapsed or Refractory MM

25. Bortezomib

26. APEX : Treatment plan Slide XX Velcade PS-341 � 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 therapySlide XX Velcade PS-341 � 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

27. APEX: Outcome

28. APEX: response rates (CR, PR)

29. APEX: Treatment-emergent = grade 3 AEs reported by = 5% of patients 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%). 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%).

30. 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

31. PAD combination therapy (bortezomib (PS-341), Adriamycin and Dexamethasone) for untreated MM

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 100-200 mg each evening Dexamethasone 20 mg/m2 days 1-4, 9-12, 17-20 q 28 days 28- day treatment cycle, 2 cycles Institutional experience of 36 patients 92% Response rate (CR+PR) PBSC easily collected

33. A phase I/II study of Bortezomib plus Melphalan and Prednisone (V-MP) in Elderly Untreated MM patients

34. V-MP: Response Rates (N=53)

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

39. Combinations therapies in Multiple Myeloma Bortezomib + Thalidomide +/- cytotoxic drugs

40. Take home message