1. Best Upfront Treatment for MM: The Road toward a Cure Archrob Khuhapinant M.D., Ph.D. Board of Internal Medicine Board of Hematology Board of Clincial Pathology Division of Hematology, Department of Medicine Faculty of Medicine, Siriraj Hospital, Mahidol University Thailand 31 August, 2012

2. Natural Course of MM

3. Progress in the Treatment of MM in the Past 40 Years

4. 4 Multiple Myeloma Pathophysiology DC Cytogenetic changes and/or mutations 1 Dysregulation of cyclins, oncogenes, and tumor suppressors 1 Failure of immune surveillance 2-3 Immunosuppression 2 Cytokines and growth factors 2 Stromal cell support, TNF-  production 4-5 MM tumor cells These events lead to uncontrolled tumor cell growth DC, dendritic cell; MM, multiple myeloma; NK, natural killer; NKT, natural killer T cell; TNF, tumor necrosis factor. ICAM-1

5. Interaction of MM Cells and BM Microenvironment Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC. Nat Rev Cancer 2007;7(8):585-98.

6. Targeting MM cell IGF-1 inhibitor, CD40 Ab, elotuzumab,HSP 90 inhibitors, plitidepsin, everolimus, temsirolimus (mTORi) Targeting MM cell and BM milieu Bortezomib, carfilzomib, NP1052, MLN9708, thalidomide, lenalidomide, pomalidomide, HDACi, vorinostat, panobinostat, romidepsin, perifosine Targeting BM milieu IKK inhibitors, defibrotide, plerixafor, p38MAPK inhibitors, IL6 Ab Mechanisms of Novel Therapy in MM Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC. Nat Rev Cancer 2007;7(8):585-98.

7. Frontline Treatment Yes Candidate for ASCT Induction Bortezomib-based VD, VTD, PAD, TT3, VCD, VRD IMID-based TD, TAD, CTD VTD, TT3, Rd, VRD Stem Cell Harvest High-dose Melphalan Stem cell infusion ≥VGPR YesNo No TreatmentConsolidation Thal, VTD, Len? 2 nd SCTConsolidation Thal, other combos? No Fit or Frail Elderly and Frail Low dose Px MPT, Bort, MP, Dex, Rd, CTDa, CyPred Fit Specific complication YesNo Renal – bort-based VTE/PE – bort-based Poor risk cytogenetics: bort-or len-based PN – len-based Bort-based VMP IMID-based MPT, CTDa, Rd, MPR Ludwig H, et al. Oncologist 2011;16:388-403.

8. Changing the Treatment Landscape of MM by Novel Agents Bortezomib, lenalidomide/ dex, thalidomide/ dex, bortezomib/ liposomal doxorubicin, bortezomib/ MP, bortezomib/ dex Targeting MM in the BM microenvironment to overcome conventional drug resistance in vitro and in vivo Effective in relapsed/refractory MM Effective as induction/first-line therapy Emerging role of transplant/maintenance

9. Treatment Goal in MM Patients Appropriate balance between treatment efficacy, toxicity and costs PatientsGoal Fit elderly patients (65-80 yr) Young patients with severe co- morbidities Prolong survival Ensure QoL Very elderly patients (>80-85 yr) Ensure QoL Avoid unnecessary costly treatments Young patients (<65 yr) Investigate therapeutic schemes with curative intent

10. Cure VS Control Cure as treatment goal –Therapeutic aim to achieve CR –Use intensive upfront therapy to maximize the chance of achieving CR  longer PFS, TTP –“CR correlates with prolonged OS ?” Disease control as treatment goal –Therapeutic aim to prolong OS –Use less intensive, sequential approach to balance efficacy with quality of life –Leave reserve for later salvage therapy –Not all studies support correlation between CR and OS

11. Actions to Achieve Cure To eradicate the tumor clone (stem cells) –To achieve and maintain the best possible response A small number of residual tumor cells may persist under control of immune system for long time –Avoid over-treatment

12. IMWG Consensus Recommendations on Risk Assessment High risk High ISS stage Chromosomal aberrations by FISH –del 17p –t(4;14) –t(14;16) Metaphase cytogenetic del 13 or 13q- Other factors LDH IgA subtype Extramedullary disease Renal impairment High serum free light chain Plasmablastic feature PC leukemia

13. Aim of Induction Therapy Prevent and reverse end-organ dysfunction Minimize toxicity associated with induction regimen Induce deep response

14. Current Induction Regimens Two-drug –Bortezomib-dexamethasone –Lenalidomide-dex or thalidomide-dex Three-drug –Thalidomide, bortezomib, dex –Lenalidomide, bortezomib, dex –Cyclophosphamide, bortezomib, dex –Bortezomib, doxorubicin, dex Four-drug –Cyclophosphamide, lenalidomide, bortezomib, dex –Cyclophosphamide, bortezomib, thalidomide, dex –Lenalidomide, bortezomib, liposomal doxorubicin, dex

15. Impact of CR in the ASCT Setting In the ASCT setting, there is a large body of evidence showing an association between optimal response (CR/VGPR) and long-term outcome (PFS and OS) 10 prospective trials (2991 patients): all showed a positive correlation (statistically significant in 8). Similar findings in 5/8 retrospective trials (Van de Velde. Haematologica 2007;92:1399.) Significant correlation between maximal response and outcome prospective studies (<0.00001) & retrospective studies (<0.00001)

19. MRD evaluation by PCR (Qualitative & Semi-Q) in MM patients: Prognostic Value

20. Distinction between Myelomatous & Normal Plasma Cells GEM2000 & GEM2005: Impact on survival of achieving an immunophenotypic response after HDT/ASCT independent of induction regimen

21. Prognostic Relevance of Durable CR

22. Maintenance Therapy in MM Ludwig H, et al. IMWG consensus on maintenance therapy in multiple myeloma. Blood 2012;119:3003-15.

23. TTP with and Without Lenalidomide Maintenance CALGB 100104, ASH 2010 update.

24. Median follow-up of 28 months CALGB 100104, follow up to 04/17/2011 23 deaths in the lenalidomide arm and 39 deaths in the placebo arm p value=0.018 Placebo patients who had PD were not eligible to cross over to lenalidomide on study

25. Possibility of Cure? Selection of appropriate patients –Young without comorbidity No adverse cytogenetics risks Combinations of novel agents during induction Integration of ASCT after induction? Achieving more depth of CR  Immunophenotypic CR –Consolidation –Maintenance therapy with novel agents

26. Phase I/II Trial of RVD in Newly Diagnosed MM  N = 66  Phase I up to 8 3-wk cycles at 5 dose levels, phase II dose: 25- mg/1.3 mg/m2 lenalidomide/bortezomib + 20-mg dexamethasone  After 4 cycles, patients with PR could proceed to ASCT  After 8 cycles, responding patients could receive maintenance 3-wk cycles of lenalidomide (D1-14); weekly bortezomib at doses tolerated at end of cycle 8 (days 1, 8); plus 10-mg dexamethasone (Days 1, 2, 8, 9) D 12458911121421 Bz Dex Bz Dex Bz Dex Bz Dex Lenalidomide daily Richardson PG, et al. Blood 2010;116.

27. RVD in Newly Diagnosed Myeloma - Outcome Median follow-up 27.3 months Median PFS and OS not reached –Estimated 24-month PFS: 68% (95% CI: 55-78%) –Estimated 24-month OS: 95% (95% CI: 86-98%) At 1-yr, 53 patients had not progressed (26 with ASCT, 27 without ASCT) –No significant difference in PFS between those with ASCT and those without 33 27 11 29 26 17 20 37 CR nCR VGPR PR % Patients All patients (N 66) Patients in Phase II only (N 35) Best Responses

28. Approach to Therapy Patients with early transplant  better Patients with delayed transplant until relapse

29. IFM/DFCI Study: Newly Diagnosed MM RVD x 3 Cy (3g/m 2 ) Mobilization Goal: 5x10 6 cells/kg) Mel (200 mg/m 2 ) + ASCT RVD x 2 Lenalidomide 18 Mo RVD x 3 Cy (3g/m 2 ) Mobilization Goal: 5x10 6 cells/kg) RVD x 2 Lenalidomide 18 Mo SCT at relapse Randomize Induction Stem Cell Collection Consolidation Maintenance

30. RVD Induction Followed by ASCT: Retrospective Analysis of DFCI’s Experience Methods –MM patients treated at DFCI Jan, 2005 – Dec, 2010 (n 481) –At least two cycles of RVD induction followed by ASCT Patient characteristics –81 patients –Median 5 cycles of induction –ISS stage II/III: 32%/ 12% –33% of patients with high-risk cytogenetics including del 13q by metaphase, t(4:14), t(14;16), del 17p, complex karyotype Luskin, M et al. ASH 2011

31. ASCT Following RVD Induction: DFCI Experience Response to induction –PR or better 96% –VGPR 26% –CR 44% –50% of those with CR have no clonal marrow plasma cells by IHC Post ASCT response –33% with improvement in overall response Stem cell collection –Median CD34+ stem cell yield: 9.6 x 10 6 /kg –Plerixafor used in one patient Toxicity –50% with any grade of peripheral neuropathy –VTE in 2 patients

34. Jakubowiak AJ, et al. A phase 1/ 2 study of carfilzomib combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 2012;120(9):1801-9.