Therapie des Patienten mit rezidiviertem Multiplem Myelom

Transcription

1 DGHO 2014, Hamburg Therapie des Patienten mit rezidiviertem Multiplem Myelom Martin Gramatzki Division for Stem Cell Transplantation and Immunotherapy, Department of Medicine II, University of Kiel, Kiel, Germany

2 Behandlungsindikationen für Patienten mit rezidiviertem MM CRAB Kriterien Hohe Tumorlast Aggressive Proliferation Riskofaktoren (Zytogenetik) Extramedulläre Manifestation

3 Treatment Options in Patients with Multiple Myeloma Front line Bortezomib Lenalidomide Thalidomide Chemo Steroid SC- Mobilization Cyclo G-CSF SCT 1 Auto M E L P H A L A N SC-Collection SCT SCT 2 Auto vs. Allo M E L P H A L A N Consolidation/ Maintenance Lenalidomide Thalidomide Relapse PI/ Carfilzomib IMID/ Pomalidomide Bendamustine Panobinostat Elotuzumab Daratumomab Autologous SCT Allogeneic SCT Steroid (Frail patients) Continuous Treatment VMP, RD, MPT, VMPT-VT, VT Thal-Dex

4 PFS in Trial MM-003 : Pomalidomide (Imnovid ) and Low Dose Dexa versus High Dose Dexamethason Proportion of Patients Without Progression Median PFS, (Months) POM plus Low dose Dex 4.0 (n = 302) HiDex (n = 153) 1.9 p < Months (San Miguel et al., Lancet Oncology 2013)

5 Lenalidomide Treatment and Immunologic Events: Rash

6 Retreatment with Bortezomib in Relapsed Patients with MM is an Option: Median Duration of Response (DOR) (Taverna et al., Swiss Med Wkly 2012)

7 RVD in R/R Multiple Myeloma 80% (Richardson et al., Blood 2014)

8 2 nd Autologous SCT as Part of Retreatment in the Relapse Situation of Multiple Myeloma: Superiority of ASCT - ASCT - Cyclophosphamid ASCT = 19 months Cyclo = 11 months ASCT = 80.3% Cyclo = 62.9% (Cook et al., Lancet Oncology 2014)

9 Mucositis Grade 4 Low-power Laser (Heltschl, Schlüsslberg, Austria)

10 Meta- analysis of Low- power Laser Light to Prevent Grade 3 / 4 Mucositis (Oberoi et al., PLoS ONE 2014)

11 Allogenic SCT for Plasma Cell Diseases: The Kiel Experience in Relapsed Disease (Years 2004 to 2013)

12 Bortezomib Inhibits NF-κB and the Degradation of DRiPs (Meister et al., Cancer Res, 67:1783, 2007)

13 Bendamustine, Velcade and Dex (BVD) in RR Multiple Myeloma (Offidani et al., Blood Cancer J, 2013)

14 EMN09 Trial: Carfilzomib, Bendamustine, and Dexamethasone (CBd) Days Carfilzomib Bendamustine C C C C C C B B (8 Cycles) D D D D D D D D Dexamethasone Maintenance Days Carfilzomib C C C C D D D D D D D D Dexamethasone

15 Weekly Carfilzomib and Dexamethasone (Cd) in Relapsed or Refractory MM (Phase 1 Study: CHAMPION-1) Patients n = 27, median age: 64 years, 1 prior therapy Carfilzomib, 30 minutes, days 1, 8, and 15 Dexamethasone 40 mg days 1, 8, 15 and 22 Carfilzomib MTD = 20/70 mg/m 2 C, 2 DLT at 20/88mg/m 2 Outcome % ORR 63 CR 30 VGPR 7 PR 26 Median time to PR, months 1.0 Grade 3/4 AE % Increased blood creatinine 7 Dyspnea 7 Hyperglycemia 7 Thrombocytopenia 7 (Berenson et al., ASH 2013)

16 Aggresome- and Proteasome Inhibition DAC Inhibitor Acytelated α-tubulin Misfolded proteins Proteasome Inhibitor (Bortezomib) HDAC6 No aggresome formation Proteasome Protein degradation Accumulation of misfolded proteins Protein degradation Apoptosis (K. C. Anderson)

17 Phase III Trial PANORAMA 1: Panobinostat and Bortezomib and Dexamethasone R/R MM Patients (San Miguel et al., Lancet Oncology 2014)

18 Phase III PANORAMA 1 Trial: Panobinostat plus Bortezomib and Dex in Relapsed or Refractory MM Patients

19 In Preclinical Xenograft Models Bortezomib as well as Lenalidomide are Synergistic to Elotuzumab (Anti-CS1/CD319) Bortezomib + Elotuzumab Lenalidomide + Elotuzumab 2750 Tumor Volume (mm 3 ) Study Day Control Isotype Ab & PBS Elo & PBS Control Isotype Ab & Velcade Elo & Velcade Elo Dose Days Velcade Dose Days Tumor volume (mm 3 ) Study Day cigg1 (1 mg/kg) + DMSO Elotuzumab (1 mg/kg) + DMSO Len 50 mg/kg + cigg (1 mg/kg) Len 50 mg/kg + Elo (1mg/kg) lenalidomide dosing elotuzumab or cigg dosing (van Rhee et al., Mol Cancer Thera 2009; and Facet Biotech)

20 Elotuzumab Combined with Lenalidomide in R/R Multiple Myeloma (Phase II- Study 1703) PFS=26.9m PFS=18.6m (Moreau et al., ASCO 2012 / Richardson et al., ASH 2012)

21 Therapy with CD38- Antibody Daratumumab in R/R MM: Best Change in M-Protein S = Serum U = Urine F = Free light chains (Lokhorst, Plesner et al., ASCO 2014)

22 HM1.24-ETA Inhibits INA-6 HM1.24-scFv Tumor Cells in SCID Mice 100 HM1.24-ETA' Percent survival treatment control p< Day HM1.24-ETA : 9x15 µg; t= 125 d (Staudinger et al., Blood Cancer J, 2014)

23 Everolimus in Advanced MM: Maximal M-Protein Change (Phase I Study CRAD001C2455) M protein (serum) LC (urine) LC (serum) 5 mg daily 7.5 mg daily 10 mg daily (Günther et al., 2014)

24 Inhibition of Signaling Pathways in Myeloma sgp130fc JAK inhibitors (Ruxolitinib) STAT3 antisense / EGCG IL-6 IL-6R Jak1 Jak2 Tyk2 gp130 IL-6 IL-6 IL6-R STAT3 STAT3 gp130 IL-6/IL-6R/gp130 antibodies Antibodies/ Immunoconjugates (CD38, CD54, CD56, CD138, CD317, CD319) PI3K PI3K inhibitors (Idelalisib BKM120) AKT IGF-1 α-chain β-chain mtor β-chain α-chain GDP FTI / GGTI Ras GTP Rapamycin Temsirolimus Everolimus IGF-1R antibody IGF-1R kinase inhibitor p70s6k Raf inhibitors Raf-1 MEK1/2 MAPK Small G- proteins MEK inhibitors Pim-2 Inhibitor (LGH447) Pim-2 Survival Proliferation

25 Behandlungsoptionen für Patienten mit rezidiviertem Multiplen Myelom (Ältere) Novel drugs: nicht eingesetzte (Ältere) Novel drugs: wieder eingesetzte Pomalidomid bei Lenalidomid Vorbehandelten Kombination von PI und IMiD Erneute ASCT Allogene SCT Chemotherapie, speziell Bendamustin Bendamustin in Kombination Neuer PI Carfilzomib HDAC-Inhibitor Panobinostat in Kombination mit PI (Klinische Studie mit) - Antikörper / Immunkonjugat - Signaltransduktionshemmer