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Treatment of relapsed myeloma

Treatment of relapsed myeloma. 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. Factors impacting salvage treatment. Disease:

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Treatment of relapsed myeloma

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  1. Treatment of relapsed myeloma 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

  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 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) When to treat? How to treat? What to use? Mohty et al, Leukemia, 2012

  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 MohtyB, et al. Leukemia. 2012

  4. What to use Depend On What’s been used 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 Chim et al, J HematolOncol, 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 • Improved antitumor activity with consecutive day dosing: D1,2; 8,9;15,16 – q4w • No neurotoxicity in animals Moreau et al, SemHematol, 2012

  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 Moreau et al, Sem Hematol, 2012

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

  13. Pomalidomide in Myeloma C MM cells IL-6 TNF IL-1 B A Bone Marrow Stromal Cells ICAM-1 Bone Marrow Vessels NFAT IL-2 IFN  PKC IL-2 NK Cells NK-T Cells VEGF bFGF PI3K CD28 CD8+ T Cells Dendritic Cells D E 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 Hideshima et al. Blood 96: 2943, 2000 Davies et al. Blood 98: 210, 2001 Gupta et al. Leukemia 15: 1950, 2001

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

  15. Conclusion of Next Generation Novel Agents Are they non-cross-resistant to current agents? Do they carry non-overlapping toxicities? • Carfilzomibvsbortezomib: • Yes. Little neuropathy • No. same thrombocytopenia • Pomvs Len: • No: same myelotoxicity • Pomvs 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

  16. Plethora Of Trials For Rel/Ref MM Rationale Of These Clinical Trials Bortezomib induce Resistance triggers compensatory pathway Antibody/immunotherapy of additional MM targets • 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

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

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

  19. Novel Agents in Phase III Combination Clinical Trials for RRMM

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

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

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

  23. In summary • Are the new agents non-cross resistant to exisiting agents? • partial • Carfilzomibvsbortezomib • Pomalidomidevslenalidomide • Do new agents carry non-overlapping toxicities? • Carfilzomibvsbortezomib: minimal PN • Pomvs Len: same myelotoxicity • 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

  24. Thank You!

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