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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