Best Upfront Treatment for MM The Road toward

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

Natural Course of MM

Progress in the Treatment of MM in the Past 40 Years

4 Multiple Myeloma Pathophysiology Cytogenetic changes and/or mutations 1 Dysregulation of cyclins, oncogenes, and tumor suppressors 1 DC Failure of immune surveillance 2 -3 Immunosuppression 2 MM tumor cells ICAM-1 Stromal cell support, TNF- production 4 -5 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. Cytokines and growth factors 2

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.

Mechanisms of Novel Therapy in MM Targeting MM cell IGF-1 inhibitor, CD 40 Ab, elotuzumab, HSP 90 inhibitors, plitidepsin, everolimus, temsirolimus (m. TORi) Targeting MM cell and BM milieu Bortezomib, carfilzomib, NP 1052, MLN 9708, thalidomide, lenalidomide, pomalidomide, HDACi, vorinostat, panobinostat, romidepsin, perifosine Targeting BM milieu IKK inhibitors, defibrotide, plerixafor, p 38 MAPK inhibitors, IL 6 Ab Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC. Nat Rev Cancer 2007; 7(8): 585 -98.

Frontline Treatment Candidate for ASCT Yes No Induction Fit or Frail Bortezomib-based IMID-based VD, VTD, PAD, TD, TAD, CTD TT 3, VCD, VRD VTD, TT 3, Rd, VRD Fit Specific complication Yes No Stem Cell Harvest High-dose Melphalan Stem cell infusion Yes Renal – bort-based No Low dose Px MPT, Bort, MP, Dex, Rd, CTDa, Cy. Pred VTE/PE – bort-based Bort-based Poor risk cytogenetics: VMP bort-or len-based ≥VGPR Elderly and Frail PN – len-based IMID-based MPT, CTDa, Rd, MPR No Treatment Consolidation Thal, VTD, Len? 2 nd SCT Consolidation Thal, other combos? Ludwig H, et al. Oncologist 2011; 16: 388 -403.

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

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

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

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

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

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

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

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)

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

Distinction between Myelomatous & Normal Plasma Cells GEM 2000 & GEM 2005: Impact on survival of achieving an immunophenotypic response after HDT/ASCT independent of induction regimen

Prognostic Relevance of Durable CR

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

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

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 CALGB 100104, follow up to 04/17/2011 Median follow-up of 28 months

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

Phase I/II Trial of RVD in Newly Diagnosed MM D 1 2 Bz Dex 4 5 8 Bz 9 Bz Dex Dex 11 12 14 21 Bz Dex Lenalidomide daily § N = 66 § Phase I up to 8 3 -wk cycles at 5 dose levels, phase II dose: 25 - mg/1. 3 mg/m 2 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 (D 1 -14); weekly bortezomib at doses tolerated at end of cycle 8 (days 1, 8); plus 10 -mg dexamethasone (Days 1, 2, 8, 9) Richardson PG, et al. Blood 2010; 116.

RVD in Newly Diagnosed Myeloma - Outcome Median follow-up 27. 3 months Median PFS and OS not reached % Patients CR – Estimated 24 -month PFS: 68% (95% CI: 55 -78%) – Estimated 24 -month OS: 95% (95% CI: 86 -98%) 29 At 1 -yr, 53 patients had not progressed (26 with ASCT, 27 without ASCT) 27 – No significant difference in PFS between those with ASCT and those without 37 n. CR VGPR 11 PR 20 17 33 26 All patients (N 66) Patients in Phase II only (N 35) Best Responses

Approach to Therapy Patients with early transplant better Patients with delayed transplant until relapse

IFM/DFCI Study: Newly Diagnosed MM Randomize RVD x 3 Induction Cy (3 g/m 2) Mobilization RVD x 3 Cy (3 g/m 2) Stem Cell Collection Goal: 5 x 106 cells/kg) Mobilization Goal: 5 x 106 cells/kg) Mel (200 mg/m 2) + ASCT Consolidation RVD x 2 Maintenance Lenalidomide 18 Mo RVD x 2 Lenalidomide 18 Mo SCT at relapse

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 13 q by metaphase, t(4: 14), t(14; 16), del 17 p, complex karyotype Luskin, M et al. ASH 2011

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 CD 34+ stem cell yield: 9. 6 x 106/kg – Plerixafor used in one patient Toxicity – 50% with any grade of peripheral neuropathy – VTE in 2 patients

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.