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Multiple Myeloma Hartmut Goldschmidt Sektion Multiples Myelom

DGHO - KML 06.09.2009. Multiple Myeloma Hartmut Goldschmidt Sektion Multiples Myelom Medizinische Klinik V, Universität Heidelberg Nationales Centrum für Tumorerkrankungen Heidelberg. Definitions. Multiple Myeloma - Classification. MGUS <3 g M spike AND <10% PC AND. SMM (AMM)

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Multiple Myeloma Hartmut Goldschmidt Sektion Multiples Myelom

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  1. DGHO - KML 06.09.2009 Multiple Myeloma Hartmut Goldschmidt Sektion Multiples Myelom Medizinische Klinik V, Universität Heidelberg Nationales Centrum für Tumorerkrankungen Heidelberg

  2. Definitions Multiple Myeloma - Classification • MGUS • <3 g M spike AND • <10% PC • AND • SMM (AMM) • 3 g M spike OR 10% PC • MM • 10% PC • M spike + • AND • YES • Calcium • Renal Insufficiency • Anemia • Bone disease No Calcium Renal Insufficiency Anemia Bone disease

  3. Multiple Myeloma – ISS-Staging International Staging System for MM * Irrespective of serum albumin level. Greipp PR, et al. J Clin Oncol. 2005;23:3412

  4. Therapy in MM Progress in MM Treatment over 40 Years 1990s Single ASCT From 1980s Myeloablation + BMT 2000s Tandem ASCT? 1970 1980 1990 2000 1984 VAD 1962 Melphalan 1969 Melphalan + Prednisone 1999 Thalidomide 2004 Lenalidomide 2002 Bortezomib 1990s Supportive Care

  5. Upfront Therapy Patient with ‘active disease’ Transplantation No Transplantation High age Multimorbidity Inadequate stem cells Patient’s preference Age up to 60/65/70/75 ‘Normal’ organ function Stem cells Patient’s preference H. Ludwig 2009, Post ASH-Slides

  6. VAD in 2005 - 2009 Cavo et. al., Blood July 2005 Comment: Rajkumar Blood Juli 2005 Matched Case-Control Study 200 pts. 100 pts. VAD ORR 52% 100 pts. Thal.-Dex. ORR 76% ORR= Overall Response Rate (at least PR) It is time to say goodbye to VAD!

  7. ASCT: the Induction Regimen • The goals of the Induction Regimen • Rapid reduction of tumor mass: Dexamethasone based (DEX or VAD) ! • Adequate stem cell collection: No Alkylating (excl. CY) agents ! Q : Could New Drugs improve DEX or VAD ? Attal 2008, ASH Education MM

  8. ASCT and New Drugs: induction Attal 2007, ASH Education MM

  9. Phase 3: PAD vs VAD as induction treatment HOVON 65 MM / GMMG-HD4 study MM Stage II or III, Age 18–65 Randomization 3 x VAD 3 x PAD CAD + GCSF CAD + GCSF MEL 200 + PBSCT MEL 200 + PBSCT Depending on localpolicy for patients PR MEL 200 + PBSCT Allogeneic Tx Depending on local policy for patients PR MEL 200 + PBSCT Bortezomib 1.3 mg/m2 / 2 weeks for 2 years maintenance Thalidomide 50 mg/day for 2 years maintenance Sonneveld et al. ASH 2008 (abstract 653)

  10. Phase 3: PAD vs VAD as induction treatment Response data Sonneveld et al. ASH 2008 (abstract 653)

  11. Phase 3: PAD vs VAD as induction treatment Improvement in CR rate over course of treatment • No difference in hematological toxicities • 80% of patients able to receive 100% of assigned dose during induction Adverse events Sonneveld et al. ASH 2008 (abstract 653)

  12. optional Dex VelCyDex VelCyDex VelCyDex R R R Nil Vel weekly Nil Vel weekly Nil Vel weekly Protocol for newly diagnosed MM < 60 yrs. - DSMM XI IEV 1. HD-Mel200 mg/m² Standard risk High risk HLA identical sibling/MUD 2. HD-Mel 200 mg/m² yes no Allo-SCT 2. HD-Mel 200 mg/m²

  13. Response to VCD treatment with respect tocytogenetic aberrations (n=160) % Best response to VCD treatment (> PR) Knop et al. ASCO 2009

  14. Study Design Primary analysis: post-induction CR+nCR in VAD (A1+A2) vs Vel-Dex (B1+B2) Randomization stratified by β2-microglobulin level (>3mg/L vs ≤3mg/L) and presence of chromosome 13 abnormalities (by FISH analysis) A1 A2 B1 B2 Induction VAD x 4 VAD x 4 Vel-Dex x 4 Vel-Dex x 4 Consolidation DCEP x 2 DCEP x 2 Melphalan 200mg/m2+ ASCT Melphalan 200mg/m2+ ASCT Melphalan 200mg/m2+ ASCT Melphalan 200mg/m2+ ASCT Transplant 1 Second ASCT or RIC allo if <VGPR Harousseau ASH 2008

  15. Progression-Free Survival 2-yr Median Follow-up 100 80 60 40 20 0 Vel-Dex: 71 eventsMedian NR; 2-yr PFS 69% Kaplan-Meier estimate VAD: 101 eventsMedian: 28 months; 2-yr PFS 60% Vel-Dex (B1+B2) VAD (A1+A2) P-value (log-rank) = 0.0115 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Harousseau ASH 2008

  16. Treatment options for patients eligible for transplantation Induction Bortezomib-based: VelDex VTD PAD VCD IMiD-based: Thal/Dex TAD CTD Rd VRD ‘Traditional’ VAD CyDex Stem cell harvest High-dose melphalan Stem cell infusion

  17. High-doseTherapy in MM Association between Max. Response and OS in Patients with MM Treated with ASCT Adapted from Van de Velde H et al. Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma. Haematologica 2007; 92:1399-1406

  18. PAD Induction, MEL-100, Len/Prednisone Consolidation, and Len Maintenance in Elderly Patients with Newly Diagnosed MM PAD→MEL-100→LP→L L PBSC Mobilization (Cyclophosphamide + G-CSF) MEL-100 ASCT LP PAD 4 cycles 2 cycles 2 cycles 4 cycles PAD = bortezomib + pegylated doxorubicin + dexamethasone; MEL-100 = melphalan100 mg/m2; LP = lenalidomide + prednisone; L= lenalidomide 21-day cycle PAD 1 4 8 11 21 B B B B PLD B = bortezomib 1.3 mg/m2; PLD = pegylated doxorubicin 30 mg/m2; Dex = dexamethasone 40 mg/d *Dex days 1–4, 8–11, 15–18 on cycle 1 Dex* 28-day cycle LP: Consolidation 1 21 28 Lenalidomide 25 mg/d Prednisone 50 mg/every other day 28-day cycle L: Maintenance 1 21 28 Lenalidomide 10 mg/d Palumbo A et al. Blood. 2008;112:65 [abstract 159]; updated results presented at: 50th ASH Annual Meeting; December 6–9, 2008; San Francisco, CA

  19. PAD vs PAD→MEL-100 vs PAD→MEL-100→LP vs PAD→MEL-100→LP→L: Response Rate* 60% 87% 89% 95% % of Patients CR VGPR PR SD PD CR VGPR PR SD PD CR VGPR PR SD PD CR VGPR PR SD PD PAD→MEL-100→LP→L (n=40) PAD→MEL-100 (n=77) PAD 4 Cycles (n=102) PAD→MEL-100→LP (n=56) *Per protocol Palumbo A et al. Blood. 2008;112:65 [abstract 159]; updated results presented at: 50th ASH Annual Meeting; December 6–9, 2008; San Francisco, CA

  20. GMMG-HD5 Randomization8) Inclusion 3 x PAd2) 3 x VCD3) A1 + B1 A2 + B2 1) 1) CAD4) + leukapheresis HDM + TPL5) 2. HDM + TPL5) (if no CR) 2 x R6) A1 B1 A2 B2 Lenalidomide7) for 2 years Lenalidomide7) if no CR Lenalidomide7) for 2 years Lenalidomide7) if no CR 1) Risk assessm. within first 4 weeks; high risk patients may go off protocol with participation in an experimental phase II trial (e.g. allogeneic transplantation) 2) PAd = Bortezomib (PS-341, Velcade) 1,3mg/m² d1,4,8,11; Adriamycin 9mg/m², d1-4; Dexamethasone 20mg, d1-4, d9-12, d17-20 3) VCD = Bortezomib (PS-341, Velcade) 1,3mg/m² d1,4,8,11; Cyclophosphamid 900mg/m², d1, Dexamethasone 40mg, d1-2, d4-5, d8-9, d11-12 4) CAD = Cyclophosphamide 1g/m² d1; Adriamycin 15mg/m², d1-4; Dexamethasone 40mg, d1-4; 5) HDM + TPL = High Dose Melphalan 200mg/m² and autologous stem cell transplantation 6) R = Lenalidomide (Revlimid) 25mg/d, d1-21; 7) Lenalidomide 10mg/d, increase to 15mg/d after 3 months 8) randomization to one of four treatment strategies A1, B1, A2, B2: A1= PAd induction, lenalidomide maintenance for 2 years; B1= PAd induction, lenalidomide maintenance if no CR; A2= VCD induction, lenalidomide maintenance for 2 years; B2 = VCD induction, lenalidomide maintenance if no CR Flowsheet 31.08.09

  21. RAD als Induktion bei Patienten mit neu diagnostiziertem MyelomPhase II - DSMM XII – Studie Professor Einsele * Allo - SCT R - Maint . R - Maint . Treo / Flu Less favourable * Bei Zustimmung des Pat. und HLA- identischem Spender Mel 200 Re- staging CE RAD RAD RAD RAD mg/m ² Very Favourable Mel 200 R - Maint . R - Maint . mg/m ² PBSCT d 29 d 85 d 135 d 1 d 57 d 120 12 Mo 56 – 84 Tage 56 – 112 Tage 28 – 56 Tage

  22. Multiples Myelom Stadium II/III Alter ≤ 55 (60)Jahre Induktionstherapie (freigestellt) CR/ PR / MR or PD, maximal 8 Zyklen Professor Kröger Studieneinschluss Stammzellmobilisierung und Start Spendersuche Melphalan (200 mg/m²) plus autologous PBSCT Spender gefunden (HLA-ident oder MUD (9 oder10/10) 2 Monate nach 1. HDT allogene PBSCT (Mel 140 mg/m²/Flu/ATG) kein Spender gefunden 2 Monate nach 1.HDT 2. autologous PBSCT (Mel 200 mg/m²) Tag 120 nach allogener PBSCT: Thalidomide 100 mg (2 Jahre) Tag 120 nach autologer PBSCT: Thalidomide 100 mg (für 2 Jahre) weitere DLI eskalierend : Tag 180, 250 und 320 mit MRD Messung Bei allen Patienten : zentrale Zytogenetik, MRD- Messung mittels FACS und patientenspez. Primer

  23. Impact of novel agents on outcome – newly diagnosed disease 70 60 50 40 Median overall survival (mos) 30 20 10 1971–1976 1977–1982 1983–1988 1989–1994 1995–2000 2000–2006 Year of Diagnosis Abstract 3594, Kumar et al. Poster session, Monday December 10

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