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
Behandlungsindikationen für Patienten mit rezidiviertem MM CRAB Kriterien Hohe Tumorlast Aggressive Proliferation Riskofaktoren (Zytogenetik) Extramedulläre Manifestation
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
PFS in Trial MM-003 : Pomalidomide (Imnovid ) and Low Dose Dexa versus High Dose Dexamethason Proportion of Patients Without Progression 1.0 0.8 0.6 0.4 0.2 Median PFS, (Months) POM plus Low dose Dex 4.0 (n = 302) HiDex (n = 153) 1.9 p < 0.001 0 0 4 8 12 16 Months (San Miguel et al., Lancet Oncology 2013)
Lenalidomide Treatment and Immunologic Events: Rash
Retreatment with Bortezomib in Relapsed Patients with MM is an Option: Median Duration of Response (DOR) (Taverna et al., Swiss Med Wkly 2012)
RVD in R/R Multiple Myeloma 80% (Richardson et al., Blood 2014)
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)
Mucositis Grade 4 Low-power Laser (Heltschl, Schlüsslberg, Austria)
Meta- analysis of Low- power Laser Light to Prevent Grade 3 / 4 Mucositis (Oberoi et al., PLoS ONE 2014)
Allogenic SCT for Plasma Cell Diseases: The Kiel Experience in Relapsed Disease (Years 2004 to 2013)
Bortezomib Inhibits NF-κB and the Degradation of DRiPs (Meister et al., Cancer Res, 67:1783, 2007)
Bendamustine, Velcade and Dex (BVD) in RR Multiple Myeloma (Offidani et al., Blood Cancer J, 2013)
EMN09 Trial: Carfilzomib, Bendamustine, and Dexamethasone (CBd) Days 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Carfilzomib Bendamustine C C C C C C B B (8 Cycles) D D D D D D D D Dexamethasone Maintenance Days 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Carfilzomib C C C C D D D D D D D D Dexamethasone
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)
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)
Phase III Trial PANORAMA 1: Panobinostat and Bortezomib and Dexamethasone R/R MM Patients (San Miguel et al., Lancet Oncology 2014)
Phase III PANORAMA 1 Trial: Panobinostat plus Bortezomib and Dex in Relapsed or Refractory MM Patients
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 ) 2500 2250 2000 1750 1500 1250 1000 750 500 250 0 0 10 20 30 40 50 60 70 80 Study Day Control Isotype Ab & PBS Elo & PBS Control Isotype Ab & Velcade Elo & Velcade Elo Dose Days Velcade Dose Days Tumor volume (mm 3 ) 600 500 400 300 200 100 0 14 21 28 35 42 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)
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)
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)
HM1.24-ETA Inhibits INA-6 HM1.24-scFv Tumor Cells in SCID Mice 100 HM1.24-ETA' Percent survival 80 60 40 20 treatment control p<0.02 0 0 20 40 60 80 100 120 140 Day HM1.24-ETA : 9x15 µg; t= 125 d (Staudinger et al., Blood Cancer J, 2014)
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)
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
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