Martin Gramatzki Division for Stem Cell Transplantation and Immunotherapy, Department of Medicine II, University of Kiel, Kiel, Germany

DGHO 2014, Hamburg Therapie des Patienten

mit rezidiviertem Multiplem Myelom

Behandlungsindikationen

für Patienten mit rezidiviertem MM

• CRAB Kriterien

• Hohe Tumorlast

• Aggressive Proliferation

• Riskofaktoren (Zytogenetik)

• Extramedulläre Manifestation

SC- Mobilization

Cyclo

SC-Collection

Treatment Options in Patients with Multiple Myeloma

Front line

Bortezomib Lenalidomide Thalidomide

Chemo Steroid

SCT

SCT 1

Auto

M E L P H A L A N

SCT 2

Auto

vs.

Allo

M E L P H A L A N

Relapse PI/ Carfilzomib

IMID/ Pomalidomide Bendamustine Panobinostat Elotuzumab

Daratumomab Autologous SCT Allogeneic SCT

Steroid

Consolidation/ Maintenance Lenalidomide Thalidomide

(Frail patients) Continuous Treatment VMP, RD, MPT, VMPT-VT, Thal-Dex

Steroid St id

(Frail( patients)s Continuous Treatment VMP RD MPT VMPT VT Thal Dex

G-CSF

Months

PFS in Trial MM-003 : Pomalidomide (Imnovid®) and Low Dose Dexa

versus High Dose Dexamethason

Median PFS, (Months)

POM plus Low dose Dex (n = 302)

4.0

HiDex (n = 153) 1.9

0 4 M

8 12 16 0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n o

f P

ati

en

ts

Wit

ho

ut

Pro

gre

ssio

n

p < 0.001

(San Miguel et al., Lancet Oncology 2013)

Lenalidomide Treatment and Immunologic Events: Rash

(Taverna et al., Swiss Med Wkly 2012)

Retreatment with Bortezomib in Relapsed Patients with MM is an Option:

Median Duration of Response (DOR)

(Richardson et al., Blood 2014)

RVD in R/R Multiple Myeloma

80%

2nd Autologous SCT as Part of Retreatment in the Relapse Situation of Multiple Myeloma:

Superiority of ASCT

(Cook et al., Lancet Oncology 2014)

ASCT = 19 months Cyclo = 11 months

ASCT = 80.3% Cyclo = 62.9%

- ASCT - Cyclophosphamid

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-κκB 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)

Days

Carfilzomib C C C C

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

D D D D D D D D DDexamethasone

C C C C C C

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

B B

Days

Carfilzomib

Bendamustine

D D D D D D D D DDexamethasone

EMN09 Trial: Carfilzomib, Bendamustine, and Dexamethasone (CBd)

Maintenance

(8 Cycles)

Weekly Carfilzomib and Dexamethasone (Cd) in Relapsed or Refractory MM

(Phase 1 Study: CHAMPION-1)

Grade 3/4 AE %

Increased blood creatinine 7

Dyspnea 7

Hyperglycemia 7

Thrombocytopenia 7

Outcome %

ORR 63

CR 30

VGPR 7

PR 26

Median time to ≥PR, months 1.0

(Berenson et al., ASH 2013)

• 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/m2 C, 2 DLT at 20/88mg/m2

HDAC6

Acytelated α-tubulin

Aggresome- and Proteasome Inhibition

Protein degradation

Apoptosis

Protein degradation

Proteasome Inhibitor

(Bortezomib)�

DAC Inhibitor�

Proteasome No aggresome

formation

roteinradat

Protegrada

Misfolded proteins

Accumulation of misfolded proteins

(K. C. Anderson)

(San Miguel et al., Lancet Oncology 2014)

Phase III Trial PANORAMA 1: Panobinostat and Bortezomib and Dexamethasone R/R MM Patients

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)

0 10 20 30 40 50 60 70 800

250

500

750

1000

1250

1500

1750

2000

2250

2500

2750

Control Isotype Ab & PBS

Elo & PBS

Control Isotype Ab & Velcade

Elo & Velcade

Elo Dose Days

Velcade Dose Days

Study Day

Tu

mo

r V

olu

me (

mm

3)

(van Rhee et al., Mol Cancer Thera 2009; and Facet Biotech)

Bortezomib + Elotuzumab Lenalidomide + Elotuzumab

14 21 28 35 420

100

200

300

400

500

600

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

Study DayTu

mor

vol

ume

(mm

3 )

Elotuzumab Combined with Lenalidomide in R/R Multiple Myeloma

(Phase II- Study 1703)

(Moreau et al., ASCO 2012 / Richardson et al., ASH 2012)

PFS=26.9m PFS=18.6m

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)

0 20 40 60 80 100 120 1400

20

40

60

80

100

control

HM1.24-ETA'

treatment

p<0.02

Day

Per

cen

t su

rviv

al

HM1.24-ETA‘ Inhibits INA-6 Tumor Cells in SCID Mice

HM1.24-ETA‘: 9x15 µg; t= 125 d (Staudinger et al., Blood Cancer J, 2014)

HM1.24-scFv

M protein (serum)

LC (urine)

LC (serum)

5 mg daily

7.5 mg daily

10 mg daily

Everolimus in Advanced MM: Maximal M-Protein Change

(Phase I Study CRAD001C2455)

(Günther et al., 2014)

IL-6

R

IL-6

α-c

hain

β-ch

ain

α

-ch

ain

β-ch

ain

IL6-R

Jak1 Jak2 Tyk2

Ras

GTP

Raf-1

MEK1/2

MAPK

GDP

gp

130

gp

130

Survival Proliferation

mTOR

Inhibition of Signaling Pathways in Myeloma

IL-6

STAT3

STAT3

Small G-

proteins Rapamycin TemsirolimusEverolimus

FTI / GGTI Raf inhibitors

IGF-1R antibody IGF-1R kinase inhibitor

STAT3 antisense /

EGCG

MEK inhibitors

sgp130Fc IL-6

Antibodies/ Immunoconjugates (CD38, CD54, CD56,

CD138, CD317, CD319) JAK inhibitors (Ruxolitinib)

IL-6/IL-6R/gp130 antibodies

PI3K inhibitors (Idelalisib BKM120)

Pim-2

PI3K AKT

Pim-2 Inhibitor (LGH447)

IGF-1

p70S6K

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