Post on 13-Jan-2016
Prof James CS ChimMBChB, MD, PhD, FRCP(London, Edinburgh & Glasgow), FRCPath, FACP, FFSc(RCPA), FHKAM, FHKCP
Department of MedicineQueen Mary Hospital
University of Hong Kong
Treatment of relapsed myeloma
Factors impacting salvage treatment • Disease:
• Indolent vs aggressive/extramedullary myeloma
• To treat OR not to treat
• Duration of response of last treatment
• Reinduction or 2nd ASCT
• Patient: performance status, organ failure (renal failure, bone marrow failure), co-morbid illness
• Prior treatment:
• resistant disease (bort-, thal-, len-: double- or triple-resistant)
• residual toxicities (peripheral neuropathy, marrow failure)
Mohty et al, Leukemia, 2012
When to treat?
How to treat?
What to use?
When to treat?Patterns of Relapse
• Is it a relapse?• Oligoclonal reconstitution (Chim et al, 2010; Chim et al, 2012)
• What is the type/pattern of relapse?• Symptomatic
• CRAB• Infection • New bone lesions on imaging• EMD at relapse: circulating PC, plasmacytoma, CNS, pleural effusion
• Biochemical : • SPE-ve SPE+ve (WMD)• Slowly progressive increase of M-protein• Rapid rise of M-protein
Chim et al, Ann Hematol, 2010 Mohty B, et al. Leukemia. 2012
Transplant-eligible:• Ind > ASCT >maintenance
• Bortezomib-based • Mostly triplet
• VTD, PAD, VD
• VRD
• Standard for FISH t(4;14)
Transplant-ineligible:
• Ind > maintenance
• MPT, MPV• CTD
• Vcd
What to use Depend On What’s been used
Chim et al, J Hematol Oncol, 2012
How to treat?Next Generation Novel Agents
• Proteasome Inhibitor
• Carfilzomib
• MLN9708
• Marizomib
• IMiD
• Pomalidomide
Next Generation Novel Agents
• Proteasome Inhibitor
• Carfilzomib
• MLN9708
• Marizomib
• IMiD
• Pomalidomide
Key Features Of Proteasome Inhibitors
Characteristic Bortezomib Carfilzomib MLN9708 Marizomib
Active moiety Boronate Epoxyketone Boronate β-lactone
Subunits inhibited
proteasome β5 β5 β5 β5 and β2
Immunoproteasome LMP7,β1 LMP7 ? ?IC50 , nM
Chymotrypsin
Trypsin
Caspase
Binding kineticsSlowly
reversible Irreversible Reversible Irreversible
Half life, minutes 110 < 30 18 <10-15
Route of administration IV IV Oral IV
Moreau et al, Sem Hematol, 2012
• Improved antitumor activity with consecutive day dosing: D1,2; 8,9;15,16 – q4w
• No neurotoxicity in animals
Single Agent Carfilzomib In RRMM With Progressive Disease
• N=266
• Schedule: 20mg/m2 cycle 1, then 27mg/m2 up to 12 cycles
• On days 1,2; 8,9; 15,16; q4w
• 2-10 min infusion
• 80% double-refractory to both lenalidomide & bortezomib
• All progressive diseases at recruitment
• Unfavorable cytogenetics in 28%
Siegel et al, Blood 2012
Rapid response
Peripheral neuropathy 12 1.0 8
Key Features Of Proteasome Inhibitors
Characteristic Bortezomib Carfilzomib MLN9708 Marizomib
Active moiety Boronate Epoxyketone Boronate β-lactone
Subunits inhibited
proteasome β5 β5 β5 β5 and β2
Immunoproteasome LMP7,β1 LMP7 ? ?IC50 , nM
Chymotrypsin
Trypsin
Caspase
Binding kineticsSlowly
reversible Irreversible Reversible Irreversible
Half life, minutes 110 < 30 18 <10-15
Route of administration IV IV Oral IV
Moreau et al, Sem Hematol, 2012
Next Generation Novel Agents
• Proteasome Inhibitor
• Carfilzomib
• MLN9708
• Marizomib
• IMiD
• Pomalidomide
Pomalidomide in Myeloma
MM cells
Bone Marrow Stromal Cells
Dendritic
Cells
IL-6
TNFIL-1A
IL-2
IFN
CD8+ T Cells
C
E
Bone Marrow Vessels
ICAM-1
VEGFbFGF
D
B
NK CellsNK-T Cells
Hideshima et al. Blood 96: 2943, 2000Davies et al. Blood 98: 210, 2001Gupta et al. Leukemia 15: 1950, 2001
Mitsiades et al. Blood 99: 4525, 2002Lentzsch et al Cancer Res 62: 2300, 2002 LeBlanc R et al. Blood 103: 1787, 2004Hayashi T et al. Brit J Hematol 128: 192, 2005
PKCNFAT
PI3K
IL-2
CD28
Major Clinical trials of Pomalidomide + LDdex
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Mayo Clinic (Cohorts 2,3,4)Pom 2mg/4mg-dx
Len- and/or bort-resistant MMSignificant and rapid response
MM002Pom (4mg/d) + Ldex (N=113)
Len-R (68%), Bort-R (65%), double-R (54%)Superior RR and PFS in POM/dex arm
IFM 2009-02Pom 21/dx (N=41) vs Pom 28/dx (N=43)
All patients refractory to both len & bortezomib
NeutropeniaInfection
Rare neuropathy&
DVT with prophylaxis
RR: 34% - 35%PFS: 9m
OS: 13.4m
POM/dex armRR: 30%
PFS: 3.8mOS: 14.4m
Mayo ClinicRR: 26%-32%DOR: 3m-16mOS: 9m-27m
• Carfilzomib vs bortezomib:
• Yes. Little neuropathy
• No. same thrombocytopenia
• Pom vs Len:
• No: same myelotoxicity
• Pom vs thalidomide:
• Yes. Little neuropathy
• Induce moderate response in bortezomib- or lenalidomide-resistant cases
• POM (30%) in len-ref
• CAR (15%) in bort-ref
• Hence partially non-cross-resistant to lenalidomide or bortezomib
• Rapid response (TTR: <2m)
• Response durable in responsive patients
Conclusion of Next Generation Novel Agents
Are they non-cross-resistant to current agents?Do they carry non-overlapping toxicities?
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• Membrane
• CD138 (BT062)
• CD38 (Daratuzumab)
• CS1 (Elotuzumab)
• Micro-environment
• Bone targets
• DKK1 (BHQ880)
• RANKL (Denuszumab)
• Signaling
• IL-6 (Siltuximab)
• Upregulate HSP90
• V+HSP90i
• Upregulate AKT
• V+perifosine
• Activate aggresome pathway
• V+HDAC inhibitors
• Non-specific:
• Vorinostat; Panobinostat
• Inhibit DNA repair
• V+doxorubicin
Plethora Of Trials For Rel/Ref MM Rationale Of These Clinical Trials
Bortezomib induce Resistance
triggers compensatory pathwayAntibody/immunotherapy of additional MM targets
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MM cell
CD138
ADCCAntibody-dependent cell-mediated cytotoxicity
MM
plasma
cell
NK cell
IMiD
P13K
Akt
PKC
JAK/STAT3
Raf
NFB
IL-6
DKK3osteoblast
osteoclast
RA
NK
L
Autophagy
UbUb
Ub Ub
Ub
Aggresome
UbUb
dynein
Microtubule
Ub Ub
Ub
Lysosome
HDAC6
HDAC6
HDAC6
CD38 cs1
Stromal cell
Bortezomib
Elotuzumab + lenalidomide
Bortezomib + HDAC inhibitor
Siltuximab
BHQ880
Denosumab
Bortezomib + perifosine
Synergism Of Concomitant Caspase 8 (Extrsinic) & Caspase 9 (Intrinsic) Activation
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Velcade
DexIMiD
CarfilzomibMLN9708Marizomib
LenalidomidePomalidomide
VTDVRD
CRD vs RD (Aspire)Pom-Vel-DexPom-Car-Dex
Novel Agents in Phase III Combination Clinical Trials for RRMM
Agent agent patients Study arms trial
Carfilzomib PI Relapsed CRD vs RD Aspire
Pomalidomide IMiD RRMM Pom+dex vs Dex NIMBUS
Siltuximab IL-6 Ab
Elotuzumab CS1 Ab RRMM Elo-Rdex vs Rdex Eloquent-2
Perifosine AKTi relapsed Per-VD vs plac-VD
Vorinostat HDACi
Panobinostat HDACi relapsed Pan-VD vs plac-VD Panorama
Asia: Less Access To Novel Agent
• In addition to the commercially a/v agents
• need alternative approaches
• In those with Prolonged DOR from last treatment:
• Retreatment (durable response for >6m)
• 2nd ASCT (>2 years from last ASCT)
• Salvage allo-HSCT
• EMD, PCL, aggressive
• V-CMD: restoration of chemosensitivity
Restoration of chemosensitivityin relapsed IgA Myeloma After ASCT
0
500
1000
1500
2000
2500
3000
Sep-05 Dec-05 Mar-06 Jul-06 Oct-06 Jan-07 Apr-07 Aug-07
ABMT
Weak MD
IgA rise
CEOPx37-9/06
VelDex x 2
10-11/06
MPT3/07
VelCMP6/07
PAD5/07
ObstructiveJaundice
6/06Pancreas mass
stent
MPT11/06
RT ThalDex
1-3/07
CT scan
Resistant to velcade,
CTX, melphalan, dex, thal, epirubicin,
(Chim et al, Nat Rev Clin Oncol, 2009)
CRx6m
nCR
Vel+CMP
CEOP x 3 + Vel/Dex2
MPT/RT
Thal/Dexrestoration of
chemosensitivity
(Chim et al, Nat Rev Clin Oncol, 2009)
• When to treat?
• Indication of treatment
• Relapse?
• Pattern of relapse?
• How to treat?
• Response to last treatment
• Retreatment or 2nd ASCT
• Availability of novel agents
• Carfilzomib/pomalidomide
• Availability of Clinical trials
• Anti-CS1, V+HSP90i, V+perifosine, V+HDACi
• Are the new agents non-cross resistant to exisiting agents?
• partial
• Carfilzomib vs bortezomib
• Pomalidomide vs lenalidomide
• Do new agents carry non-overlapping toxicities?
• Carfilzomib vs bortezomib: minimal PN
• Pom vs Len: same myelotoxicity
IN SUMMARY
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