Presentation is loading. Please wait.

Presentation is loading. Please wait.

MIELOMA MULTIPLO tumore delle plasmacellule producono immunoglobuline vivono nelle ossa DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI.

Similar presentations


Presentation on theme: "MIELOMA MULTIPLO tumore delle plasmacellule producono immunoglobuline vivono nelle ossa DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI."— Presentation transcript:

1 MIELOMA MULTIPLO tumore delle plasmacellule producono immunoglobuline vivono nelle ossa DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

2 Multiple myeloma uncontrolled proliferation of Ig secreting plasma cells –most commonly IgG (57%), IgA (21%) or light chain only (18%) twice as common in men as women and in blacks as whites 1% of all cancers –2% in african americans incurable median survival 3 years few therapeutic advances since the introduction of melphalan (Bergsagel, 1962)

3 Myeloma bone pathology

4 Multiple Myeloma (MM) B-cell neoplasia, characterized by the expansion of plasma cells producing an abnormal monoclonal immunoglobulin 21,500 new cases yearly in Europe Median age at diagnosis: 65 years incurable disease

5 MM – Impact for Patients Consequences of MM include: Painful osteolytic bone lesions Bone marrow infiltration, causing anemia, fatigue, and immunodeficiency, with an increased risk of serious infections The abnormal proteins may cause renal dysfunction or kidney failure

6 Bruno B, Rotta M, and Boccadoro M, Lancet Oncology 2004

7 IL-1 OAF IL-6 MIELOMA MULTIPLO hepatocyte CRP OSTEOCLAST DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA S. GIOVANNI BATTISTA TORINO, ITALY

8 MIELOMA MULTIPLO malattia dell'anziano 5/ /pazienti/anno 350 pazienti/anno in Piemonte età media alla diagnosi 70 anni DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

9 Serum protein electrophoresis (SPEP) albumin Elevated total protein suggests hypergammaglobulinemia Total protein= Albumin + Globulins

10 Serum protein electrophoresis (SPEP) albumin Elevated total protein suggests hypergammaglobulinemia Total protein= Albumin + Globulins Quantitative immunoglobulins measures amount of IgM, IgG and IgA in myeloma, typically see reciprocal depression of uninvolved Igs

11 Serum protein electrophoresis (SPEP) albumin Immunoeletrophoresis

12 Serum protein electrophoresis (SPEP) albumin Immunoeletrophoresis SP Immunofixation

13 Serum protein electrophoresis (SPEP) SP Immunofixation IgG57% IgA21% IgD1% IgM or IgEalmost never Light chain only 18%

14 Serum protein electrophoresis (SPEP) SP Immunofixation IgG57% IgA21% IgD1% IgM or IgEalmost never Light chain only 18% M-spike stands for Monoclonal, not IgM

15 Serum protein electrophoresis (SPEP) SP Immunofixation IgG57% IgA21% IgD1% IgM or IgEalmost never Light chain only 18% M-spike stands for Monoclonal, not IgM IgM, IgG and IgA are all gamma-globulins

16 Serum protein electrophoresis (SPEP) SP Immunofixation IgG57% IgA21% IgD1% IgM or IgEalmost never Light chain only 18% M-spike stands for Monoclonal, not IgM Light chains (Bence-Jones proteins) are not detected in the serum, because of their low molecular weight, they are secreted in the urine IgM, IgG and IgA are all gamma-globulins

17 Table 1 Multiple myeloma* Diagnostic criteria 1 Monoclonal plasma cells in the bone marrow 10% and/or presence of a biopsy-proven plasmacytoma 2 Monoclonal protein present in the serum and/or urinea 3 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 >2mg/dl) [A] Anemia (hemoglobin o10 g/dl or 2 gonormal) [B] Lytic bone lesions or osteoporosisc

18 Myeloma - clinical features bone pain - often with loss of height constitutional - weakness, fatigue and weight loss anemia - responds to erythropoeitin renal disease -renal tubular dysfunction susceptibility to infections - neutropenia, hypogammaglobulinemia) hypercalcemia - myeloma cells secrete osteoclast activating factors hyperviscosity - 2 % with myeloma, 50 % with macroglobulinemia neurologic dysfunction - spinal cord or nerve root compression

19 Myeloma staging system cells x 10 /m 12 2 Median Survival (months) Stage INo anemia>60<0.6 No hypercalcemia no more than one bony lesion low M protein Stage IIin between I and III Stage III Anemia23>1.2 hypercalcemia advanced lytic bone disease high M protein

20 Principles of treatment no evidence that early treatment prolongs survival wait for symptoms, or evidence of disease progression to start treatment supportive measures are critically important –drink 3l of fluids daily –treat infections promptly –prophylactic bisphosphonates reduce skeletal cmplications –anemia responds to erythropoeitin

21 Causes of death in multiple myeloma Progressive myeloma45% Sepsis25% Renal failure10% Other (old age)20%

22 Treatment course Asymptomatic MGUS Stable MM YearsMonthsDays

23 Treatment course Asymptomatic MGUS Stable MM Symptomatic YearsMonthsDays Treatments M protein

24 Treatment course Asymptomatic MGUS Stable MM SymptomaticAcute Pancytopenia Plasma cell leukemia YearsMonthsDays Treatments M protein

25 MIELOMA MULTIPLO trattato con blande chemioterapie parzialmente chemiosensibile il tumore si riduce ma dopo breve intervallo riprende a crescere DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

26 MIELOMA MULTIPLO chemioterapia Melphalan e Prednisone (MP) (Alexanian, 1969) DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

27 MIELOMA MULTIPLO mesi sopravvivenza DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

28 MULTIPLE MYELOMA DOSE RESPONSE Melphalan dose-response curve DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

29 MIELOMA MULTIPLO relazione dose-risposta ALTA-DOSE = + risposte complete + lunga sopravvivenza DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

30 RIDUZIONE DELLA TOSSICITA' DELLE TERAPIE AD ALTE DOSI FATTORI DI CRESCITA CELLULE STAMINALI PERIFERICHE tossicità comparabile alla terapia convenzionale possibilità di trattare pazienti anziani alte percentuali di risposte complete

31 A PROSPECTIVE, RANDOMIZED TRIAL OF AUTOLOGOUS BONE MARROW TRANSPLANTATION AND CHEMOTHERAPY IN MULTIPLE MYELOMA Sopravvivenza a 5 anni 52% trapianto 12% convenzionale Attal, et al., NEJM, 1996

32 EFS TOT MEL100 MP Months % of patients p<0.001 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

33 OS TOT Months % of patients MEL100 MP p<0.005 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

34 MULTIPLE MYELOMA DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALYAGE AGE AT DIAGNOSIS DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

35 MULTIPLE MYELOMA DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY AGE AGE AT DIAGNOSIS HIGH-DOSE CONVENTIONAL

36 survival % years 100 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY MALATTIA INCURABILE

37 Relapsed Disease Transient Response to Therapy Survival 1- 3 years Multiple myeloma Diagnosis Survival 3-5 yrs Relapsed and Refractory Resistant to all therapy Universally fatal Survival 6-9 months Unmet Medical Need DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

38 Bruno B, Rotta M, and Boccadoro M, Lancet Oncology 2004 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

39 Advancing Treatment Options in MM Melphalan From 1990s Myeloablation + ASCT 1999 First report thalidomide 1962 Prednisone + melphalan Thalidomide Pharmion licence Aus/NZ 2003 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY VELCADE ® US licence 2003 VELCADE ® EU positive opinion 2004

40 scenario MULTIPLE MYELOMA + DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

41 Thalidomide Originally developed in 1950s as a treatment for insomnia and morning sickness in pregnancy Thalidomide is an immunomodulatory agent –Precise mechanism of action not yet understood –Multiple actions, including anti-angiogenic effects Anti-angiogenic effects of thalidomide provide the rationale for its use in MM Angiogenesis in bone marrow supports growth and development of MM cells DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

42 Antitumor activity of thalidomide in refractory multiple myeloma. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B. N Engl J Med 1999 Nov 18;341(21): Myeloma and Lymphoma Program, South Carolina Cancer Center, University of South Carolina, Columbia, USA. BACKGROUND: Patients with myeloma who relapse after high-dose chemotherapy have few therapeutic options. Since increased bone marrow vascularity imparts a poor prognosis in myeloma, we evaluated the efficacy of thalidomide, which has antiangiogenic properties, in patients with refractory disease. METHODS: Eighty-four previously treated patients with refractory myeloma (76 with a relapse after high-dose chemotherapy) received oral thalidomide as a single agent for a median of 80 days (range, 2 to 465). The starting dose was 200 mg daily, and the dose was increased by 200 mg every two weeks until it reached 800 mg per day. Response was assessed on the basis of a reduction of the myeloma protein in serum or Bence Jones protein in urine that lasted for at least six weeks. RESULTS: The serum or urine levels of paraprotein were reduced by at least 90 percent in eight patients (two had a complete remission), at least 75 percent in six patients, at least 50 percent in seven patients, and at least 25 percent in six patients, for a total rate of response of 32 percent. Reductions in the paraprotein levels were apparent within two months in 78 percent of the patients with a response and were associated with decreased numbers of plasma cells in bone marrow and increased hemoglobin levels. The microvascular density of bone marrow did not change significantly in patients with a response. At least one third of the patients had mild or moderate constipation, weakness or fatigue, or somnolence. More severe adverse effects were infrequent (occurring in less than 10 percent of patients), and hematologic effects were rare. As of the most recent follow-up, 36 patients had died (30 with no response and 6 with a response). After 12 months of follow-up, Kaplan-Meier estimates of the mean (+/-SE) rates of event-free survival and overall survival for all patients were 22+/-5 percent and 58+/-5 percent, respectively. CONCLUSIONS: Thalidomide is active against advanced myeloma. It can induce marked and durable responses in some patients with multiple myeloma, including those who relapse after high-dose chemotherapy

43

44 Bruno B, Rotta M, and Boccadoro M, Lancet Oncology 2004, in Press DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

45 Thalidomide: mechanism of action ?? Human myeloma Human liver Thal Human myeloma ~ reduced unchanged Yaccoby et Al, Blood, 2002 Thal metabolism required for its anti-myeloma efficacy DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

46 MELPHALAN, PREDNISONE + THALIDOMIDE (MPT) versus MELPHALAN PREDNISONE (MP) GRUPPO ITALIANO PER LO STUDIO DEL MIELOMA MULTIPLO INTERIM ANALYSIS PROSPECTIVE RANDOMIZED TRIAL NEWLY DIAGNOSED PATIENTS, AGE > 65 YEARS NEWLY DIAGNOSED PATIENTS, AGE > 65 YEARS DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

47 ADVERSE EVENTS Hematologic (%) Constipation (%) Neurologic (%) Cardiac (%) Cutaneous (%) Infection (%) Thromboemb.(%) Early death (%) WHO (grade) MPT MP DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

48 RESPONSE TO THERAPY Dept. Hematology, University of Torino 27.7% 5.4% 33.8% 15.6% 13.3% 28% 77.1% 46.7% % of Response

49 EVENT-FREE SURVIVAL (median follow up 13.6 months) Months Proportion p<0.001 MPT MP DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

50 RESPONSE TO THERAPY % CR MP Thal MP + Thal 27.7% DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY 5%3-5%

51 Revlimid (lenalidomide) (CC-5013) Actimid (CC-4047) Thalomid ® (thalidomide)

52 Bruno B, Rotta M, and Boccadoro M, Lancet Oncology 2004, in Press The Proteasome: A Target for Novel Therapies DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

53 TNF R TNF IkB p65 p50 IkB p65 p50 P P P Ub IkB p65 p50 P P P p65 IkB P P P Ub Protein kinases NFkB -IkB complex IkB P P P Ub Degradation of IkB by 26S proteasome

54 TNF R TNF IkB p65 p50 IkB p65 p50 P P P Ub IkB p65 p50 P P P p65 IkB P P P Ub IkB P P P Ub NFkB binding site Protein kinases NFkB -IkB complex p65 p50 NFkB Nuclear translocation NFkB Induced protein s Block of programmed cell death Increase in Cytokine production Increase in adhesion molecules Degradation of IkB by 26S proteasome PS 341

55 TNF R TNF IkB p65 p50 IkB p65 p50 P P P Ub IkB p65 p50 P P P p65 IkB P P P Ub NFkB binding site Protein kinases NFkB -IkB complex p65 p50 NFkB Nuclear translocation NFkB Induced protein s Block of programmed cell death Increase in Cytokine production Increase in adhesion molecules Degradation of IkB by 26S proteasome PS 341

56 TNF R TNF IkB p65 p50 IkB p65 p50 P P P Ub IkB p65 p50 P P P p65 IkB P P P Ub NFkB binding site Protein kinases NFkB -IkB complex NFkB Nuclear translocation NFkB Induced protein s Block of programmed cell death Increase in Cytokine production Increase in adhesion molecules Degradation of IkB by 26S proteasome PS 341 p50 p65 IkB P P P Ub p50 p65 IkB P P P Ub

57 TNF R TNF IkB p65 p50 IkB p65 p50 P P P Ub IkB p65 p50 P P P p65 IkB P P P Ub Protein kinases NFkB -IkB complex NFkB Induced protein s Block of programmed cell death Increase in Cytokine production Increase in adhesion molecules Degradation of IkB by 26S proteasome PS 341 p50 p65 IkB P P P Ub p50 p65 IkB P P P Ub NFkB Nuclear translocation

58 TNF R TNF IkB p65 p50 IkB p65 p50 P P P Ub IkB p65 p50 P P P p65 IkB P P P Ub Protein kinases NFkB -IkB complex NFkB Induced protein s Block of programmed cell death Increase in Cytokine production Increase in adhesion molecules Degradation of IkB by 26S proteasome PS 341 p50 p65 IkB P P P Ub p50 p65 IkB P P P Ub Antimyeloma effect NFkB Nuclear translocation

59 SUMMIT (025): A Phase II Study of VELCADE (bortezomib) for Injection in Patients With Relapsed and Refractory Multiple Myeloma Paul G. Richardson, 1 Bart Barlogie, 2 James Berenson, 3 Seema Singhal, 4 Ann Traynor, 4 Sundar Jagannath, 5 David Irwin, 6 Vincent Rajkumar, 7 Gordan Srkalovic, 8 Melissa Alsina, 9 Raymond Alexanian, 10 David Siegel, 11 Robert Orlowski, 12 David Kuter, 13 Steven Limentani, 14 Dixie Esseltine, 15 Gretchen Richards, 15 Michael Kauffman, 15 Julian Adams, 15 David P. Schenkein, 15 and Kenneth C. Anderson 1 1 Dana-Farber Cancer Institute, 2 University of Arkansas, 3 Cedars-Sinai Medical Center, 4 Northwestern University Medical Center, 5 St Vincents Comprehensive Cancer Center, 6 Alta Bates Cancer Center, 7 Mayo Clinic, 8 Cleveland Clinic Foundation, 9 H. Lee Moffitt Cancer Center, 10 M.D. Anderson Cancer Center, 11 Carol G. Simon Cancer Center, 12 University of North Carolina at Chapel Hill, 3 Massachusetts General Hospital, 14 Charlotte Medical Clinic, 15 Millennium Pharmaceuticals, Inc

60 Median number of lines of prior therapy = 6 (range 2-15) 92% of patients received at least 3 of the drug therapies listed here (excluding stem cell transplant) 91% of patients were refractory to the last prior therapy SUMMIT – Prior Therapy 99.5% 92% 64% 81% 83%

61 SUMMIT – Response Rates with VELCADE ® Alone 35% response rate 10% CR (IF+ and IF-) 28% CR+PR 59% of patients SD or better Mean duration of response 12 months 35% + - CR IF- CR IF+ PRMRSD Prior treatment had no significant effect on response rate DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

62 Treatment plan – APEX 273 treatment days 280 treatment days 1.3 mg/m 2 IV push Days 1, 4, 8, 11 Q3W cycle 8 cycles 1.3 mg/m 2 IV push Days 1, 8, 15, 22 Q5W cycle 4 cycles 3 cycles 5 cycles 40 mg po Days 1–4, 9–12, 17–20 Q5W cycle 40 mg po Days 1–4 Q4W cycle Randomization Bortezomib Dexamethasone Induction Maintenance Richardson et al. NEJM 2005

63 APEX: Time to Progression (n=669) 78% improvement in median TTP with bortezomib Median TTP: Bortezomib 6.2 months vs dexamethasone 3.5 months Richardson et al. NEJM 2005

64 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 <1% nCR 25% PR 16% PR 7% nCR 6% CR Bortezomib Dexamethasone Response (%) 38% 18% P< <1% CR Richardson et al. NEJM 2005

65 APEX: 1-year survival (n=669) 41% decreased risk of death with bortezomib 80% 66% Richardson et al. NEJM 2005

66 APEX: Overall survival (n=669) Median duration of follow-up 8.3 months Richardson et al. NEJM 2005

67 Conclusion Phase III APEX: Bortezomib demonstrated superior efficacy to high- dose dexamethasone in relapsed MM –Significant TTP benefit (P<.0001) –Response rate advantage (P<.0001) –Superior 1-year survival (P=.0005, HR=.53) –Superior overall survival (P=.0013, HR=.57) Richardson et al. NEJM 2005

68 Most common adverse events from Phase I, SUMMIT, CREST and APEX trials Adverse eventPhase I 1 SUMMIT 2 CREST 3 APEX 4 (%)(%)(%) (%) Thrombocytopenia Fatigue Nausea Diarrhea Constipation Vomiting3027NR 35 Peripheral neuropathy NR = not recorded 1 Orlowski et al. J Clin Oncol 2 Richardson et al. N Engl J Med 2003;348:2609; 1 Orlowski et al. J Clin Oncol 2002;20:4420; 2 Richardson et al. N Engl J Med 2003;348:2609; 3 Jagannath et al. Br J Hematol 2004;127:165; 4 Richardson et al. ASH 2004 (abstract 336.5) Toxicities were predictable and manageable

69 Combinations therapies in Multiple Myeloma Bortezomib + Thalidomide +/- cytotoxic drugs M-COMPONENT induction High dose relapse remission

70 Dana Farber Richardson Phase II VELCADE alone in 1st line tx CHU de Nantes Harousseau Phase II VELCADE + high-dose dexamthasone 1st line, pre-transplant LocationPIStudy ECOG/CTEPDispenzieri Phase II VELCADE in high risk myeloma, 1st line U. Maryland Badros Phase I/II VELCADE + DT-PACE, 1st line CALGBOrlowski Phase II VELCADE + Doxil U. Arkansas Barlogie Phase II VELCADE + Total Therapy III in high risk myeloma 1st line Salick Group Jagannath Phase II VELCADE monotx Dex after 2 cycles for less than optimal response Multiple Myeloma Studies in Development: Front Line

71 AUTOLOGOUS FIRST STEP Thalidomide Proteasome inhibitors MULTIPLE MYELOMA Mini allo DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

72 Thalidomide Proteasome inhibitors MULTIPLE MYELOMA DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY ChemoLanilomide

73


Download ppt "MIELOMA MULTIPLO tumore delle plasmacellule producono immunoglobuline vivono nelle ossa DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI."

Similar presentations


Ads by Google