1. Prof James CS Chim MBChB, MD, PhD, FRCP(London, Edinburgh & Glasgow), FRCPath, FACP, FFSc(RCPA), FHKAM, FHKCP Department of Medicine Queen Mary Hospital University of Hong Kong Treatment of relapsed myeloma

2. Factors impacting salvage treatment Disease: Indolent vs aggressive/extramedullary myeloma To treat OR not to treat Duration of response of last treatment Reinduction or 2 nd 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?

3. 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

4. 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

5. How to treat? Next Generation Novel Agents Proteasome Inhibitor Carfilzomib MLN9708 Marizomib IMiD Pomalidomide

6. Next Generation Novel Agents Proteasome Inhibitor Carfilzomib MLN9708 Marizomib IMiD Pomalidomide

7. Key Features Of Proteasome Inhibitors CharacteristicBortezomibCarfilzomibMLN9708Marizomib Active moietyBoronateEpoxyketoneBoronateβ-lactone Subunits inhibited proteasomeβ5 β5 and β2 ImmunoproteasomeLMP7,β1LMP7?? IC 50, nM Chymotrypsin  Trypsin  Caspase  Binding kinetics Slowly reversibleIrreversibleReversibleIrreversible Half life, minutes110< 3018<10-15 Route of administrationIV OralIV Moreau et al, Sem Hematol, 2012 Improved antitumor activity with consecutive day dosing: D1,2; 8,9;15,16 – q4w No neurotoxicity in animals

8. 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

9. Rapid response

10. Peripheral neuropathy 12 1.0 8

11. Key Features Of Proteasome Inhibitors CharacteristicBortezomibCarfilzomibMLN9708Marizomib Active moietyBoronateEpoxyketoneBoronateβ-lactone Subunits inhibited proteasomeβ5 β5 and β2 ImmunoproteasomeLMP7,β1LMP7?? IC 50, nM Chymotrypsin  Trypsin  Caspase  Binding kinetics Slowly reversibleIrreversibleReversibleIrreversible Half life, minutes110< 3018<10-15 Route of administrationIV OralIV Moreau et al, Sem Hematol, 2012

12. Next Generation Novel Agents Proteasome Inhibitor Carfilzomib MLN9708 Marizomib IMiD Pomalidomide

13. Pomalidomide in Myeloma MM cells Bone Marrow Stromal Cells Dendritic Cells IL-6 TNF  IL-1  A IL-2 IFN  CD8+ T Cells C E Bone Marrow Vessels ICAM-1 VEGF bFGF D B NK Cells NK-T Cells Hideshima et al. Blood 96: 2943, 2000 Davies et al. Blood 98: 210, 2001 Gupta et al. Leukemia 15: 1950, 2001 Mitsiades et al. Blood 99: 4525, 2002 Lentzsch et al Cancer Res 62: 2300, 2002 LeBlanc R et al. Blood 103: 1787, 2004 Hayashi T et al. Brit J Hematol 128: 192, 2005 PKC  NFAT PI3K IL-2 CD28

14. Major Clinical trials of Pomalidomide + LDdex 14 Mayo Clinic (Cohorts 2,3,4) Pom 2mg/4mg-dx Len- and/or bort-resistant MM Significant and rapid response MM002 Pom (4mg/d) + Ldex (N=113) Len-R (68%), Bort-R (65%), double-R (54%) Superior RR and PFS in POM/dex arm IFM 2009-02 Pom 21/dx (N=41) vs Pom 28/dx (N=43) All patients refractory to both len & bortezomib Neutropenia Infection Rare neuropathy & DVT with prophylaxis RR: 34% - 35% PFS: 9m OS: 13.4m POM/dex arm RR: 30% PFS: 3.8m OS: 14.4m Mayo Clinic RR: 26%-32% DOR: 3m-16m OS: 9m-27m

15. 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? 15

16. 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 pathway Antibody/immunotherapy of additional MM targets

17. 17 MM cell CD138 ADCC Antibody-dependent cell- mediated cytotoxicity MM plasma cell NK cell IMiD P13K Akt PKC JAK/STAT3 Raf NF  B IL-6 DKK3 osteoblast osteoclast RANKL Autophagy Ub Aggresome Ub dynein Microtubule Ub Lysosome HDAC6 CD38 cs1 Stromal cell Bortezomib Elotuzumab + lenalidomide Bortezomib + HDAC inhibitor Siltuximab BHQ880 Denosumab Bortezomib + perifosine

18. Synergism Of Concomitant Caspase 8 (Extrsinic) & Caspase 9 (Intrinsic) Activation 18 Velcade Dex IMiD Carfilzomib MLN9708 Marizomib Lenalidomide Pomalidomide VTD VRD CRD vs RD (Aspire) Pom-Vel-Dex Pom-Car-Dex

19. Novel Agents in Phase III Combination Clinical Trials for RRMM AgentagentpatientsStudy armstrial CarfilzomibPI RelapsedCRD vs RDAspire PomalidomideIMiD RRMMPom+dex vs DexNIMBUS SiltuximabIL-6 Ab ElotuzumabCS1 Ab RRMMElo-Rdex vs RdexEloquent-2 PerifosineAKTi relapsedPer-VD vs plac-VD VorinostatHDACi PanobinostatHDACi relapsedPan-VD vs plac-VDPanorama

20. 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) 2 nd ASCT (>2 years from last ASCT) Salvage allo-HSCT EMD, PCL, aggressive V-CMD: restoration of chemosensitivity

21. Restoration of chemosensitivity in relapsed IgA Myeloma After ASCT ABMT Weak MD IgA rise CEOPx3 7-9/06 Vel Dex x 2 10-11/06 MPT 3/07 Vel CMP 6/07 PAD 5/07 Obstructive Jaundice 6/06 Pancreas mass stent MPT 11/06 RT Thal Dex 1-3/07 CT scan Resistant to velcade, CTX, melphalan, dex, thal, epirubicin, (Chim et al, Nat Rev Clin Oncol, 2009) CRx6m nCR

22. Vel+ CMP CEOP x 3 + Vel/Dex2 MPT/RT Thal/Dex restoration of chemosensitivity (Chim et al, Nat Rev Clin Oncol, 2009)

23. When to treat? Indication of treatment Relapse? Pattern of relapse? How to treat? Response to last treatment Retreatment or 2 nd 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 23