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MULTIPLE MYELOMA

MULTIPLE MYELOMA. MULTIPLE MYELOMA. Median age at diagnosis, 65 years MM accounts for 1 - 2 % of all malignant diseases. MULTIPLE MYELOMA Monoclonal Gammopathies. M.Waldenström (2%). Solitary Plasmacytoma (2%). Others (5%). Smoldering Myeloma (3%). MGUS (55%).

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MULTIPLE MYELOMA

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  1. MULTIPLE MYELOMA

  2. MULTIPLE MYELOMA • Median age at diagnosis, 65 years • MM accounts for 1 - 2 % of all • malignant diseases

  3. MULTIPLE MYELOMA Monoclonal Gammopathies M.Waldenström (2%) Solitary Plasmacytoma (2%) Others (5%) Smoldering Myeloma (3%) MGUS (55%) Lymphoprolif. Diseases (3%) Amyloidosis AL (12%) Multiple Myeloma (18%) n= 882 Adapted from Kyle RA, 1997

  4. MULTIPLE MYELOMA Diagnostic criteria for MGUS • Monoclonal Immunoglobulin (<3 g/dl) • No anaemia, hypercalcaemia or renal insufficiency • No osteolytic lesions • Bone marrow infiltration with <10% plasma cells • (no plasmablasts)

  5. Progression to MM(17%) NHL(5%) or Amyloidosis(3%) 26% Paraprotein > 3g/dl 10% Alive with MGUS 12% Death unrelated to MGUS MULTIPLE MYELOMA Long-term Follow-up of Patients with MGUS Probability after 24-38 Years MGUS 52% Conclusion: The risk of progression of MGUS to MM (or a related disorder) is about 1% per year. Kyle RA et al., NEJM 2002

  6. MULTIPLE MYELOMA Indications for therapy • M-protein in serum and/or urine • Hemoglobin • Calcium or creatinine • Lytic bone lesions • Extramedullary plasmacytoma

  7. MULTIPLE MYELOMA Primary Treatment > age 65 < age 65 Standard-dose chemotherapy High-dose therapy (high-dose melphalan, followed by autotransplantation) (melphalan/prednisone or combination chemotherapy)

  8. MULTIPLE MYELOMA STANDARD-DOSE CHEMOTHERAPY IN MULTIPLE MYELOMA Single (MP) vs. combination chemotherapy (CCT) n=6,633 (27 trials) Therapy Response (%) MP 53 P<.00001 CCT 60 No difference in survival No subsets with benefit Myeloma Trialists, JCO 1998

  9. MULTIPLE MYELOMA TREATMENT Interferon-alpha Therapy Relapse-free survival Overall survival at 5 years (%) at 5 years (%) IFN 23 31 No IFN 16 28 P=.00001 P=.008 Meta-analysis of 20 trials (n = 4000) Myeloma Trialists, Br J Haematol 1998

  10. STANDARD-DOSE THERAPY IN MM Second-line treatment Duration of remission / plateau-phase > 6 months Retreatment with initial therapy < 6 months VAD ID, VRID VMCP / VBAP DCEP Thalidomide Thal / Dexa

  11. MULTIPLE MYELOMA

  12. STANDARD versus HIGH-DOSE THERAPY IN MM Study Therapy %CR OS(months) P Attal (1996) VMCP/VBAP 5 44 MEL140+TBI 22 57 <.001 Barlogie (1997)1 Conventional NA 48 MEL200x2 40 62+ .01 Palumbo (1999)1,2 MP 5 48 MEL100x2/3 47 56+ <.01 Lenhoff (2000)1 Standard dose NA 44 MEL 200 34 60+ .001 Child (2001) ABCM 14 42 MEL200 53 52 <.05 1 Pair-mate analysis 2 Patients at >60 years of age

  13. PROGNOSTIC FACTORS FOR SURVIVAL AFTER HIGH-DOSE THERAPY P RR No -13/13q- 0.4 < .0001 B2M < 2.5 mg/l 0.6 < .0001 < 12 months prior SDT 0.7 .0001 CRP < 4.0 mg/l 0.7 < .0002 Sensitive disease (SDT) 0.7 .0002 Days to 2ndHDT 0.4 .001 Any 2nd HDT 0.02 < .0001 Non-IgA isotype 0.7 .002 "Arkansas 1000 " Desikan et al., Blood 2000

  14. MULTIPLE MYELOMA SINGLE versus DOUBLE AUTOTRANSPLANTATION IFM 94 (Attal et al.) MEL140(+TBI) MEL140x2(+TBI) CR 34% 35% NS Median EFS 31 months 37 months .03 EFS at 6 years 19% 28% Median OS 50 months 58 months .02 OS at 6 years 26% 46% Interim analysis, January 2002

  15. CHROMOSOME 13q14 (FISH) AND SURVIVAL IN MM Study Therapy1 13q14 n OS(months) P Perez-Simon (1998) SDT normal 32 60 deleted 16 14 .001 Zojer (2000) SDT normal 51 60+ deleted 46 24 <.005 Fonseca (2002) SDT normal 149 51 deleted 176 35 .02 Worel (2001) HDT normal 17 72+ deleted 11 24 .012 Facon (2001) HDT normal 68 65 deleted 42 26 .0001 1SDT, standard-dose chemotherapy; HDT, high-dose therapy (MEL + autologous PBSCS)

  16. PROGNOSTIC MODEL IN MM Chromosome 13q14 (FISH) and 2M FEATURESMEDIAN SURVIVAL Standard-dose chemotherapy: No del13q and B2M < 4 mg/l Del13q or B2M > 4 mg/l Del13q and B2M > 4 mg/l Königsberg (JCO 2000) 102 months 46 months 11 months High-dose chemotherapy: No del13q and B2M < 2.5 mg/l Del13q or B2M > 2.5 mg/l Del13q and B2M > 2.5 mg/l > 111 months 47 months 25 months Facon (Blood 2001)

  17. THALIDOMIDE IN ADVANCED AND REFRACTORY MM • 169 patients (76% with prior high-dose therapy). • Thalidomide at a dose of 200-800 mg daily. • Objective responses (25% tumor regression) in • 37% of patients, with near-complete or complete • remissions in 14%. • Two-year event-free and overall survival rates were • 20% and 48%, respectively. Barlogie et al., Blood 98: 492, 2001

  18. TREATMENT OF MULTIPLE MYELOMA SUMMARY • High-dose chemotherapy is superior to standard-dose chemotherapy in MM (improved CR rate, prolonged event-free and overall survival). • The current standard of high-dose therapy is melphalan 200 mg/m2 followed by autologous peripheral blood stem cell support, with some evidence suggesting a beneficial role of tandem transplantation. • Cytogenetics has emerged as an important prognostic factor in MM, and deletion of chromosome 13q14 is a major independent parameter predicting for short survival of patients with MM. • Since patients with del13q14 do poorly with current treatment approaches, they should be considered for enrollment in clinical trials evaluating novel agents and treatment strategies.

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