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
Multiple Myeloma Pathophysiology 4 Dysregulation of cyclins, oncogenes, and tumor suppressors1 Cytogenetic changes and/or mutations1 DC Failure of immune surveillance2-3 MM tumor cells Immunosuppression2 ICAM-1 Cytokines and growth factors2 Stromal cell support, TNF- production4-5 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.
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, 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 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 VD, VTD, PAD, TT3, VCD, VRD IMID-based TD, TAD, CTD VTD, TT3, Rd, VRD Fit Elderly and Frail Specific complication Low dose Px MPT, Bort, MP, Dex, Rd, CTDa, CyPred Yes No Stem Cell Harvest High-dose Melphalan Stem cell infusion Renal – bort-based VTE/PE – bort-based Poor risk cytogenetics: bort-or len-based PN – len-based Bort-based VMP ≥VGPR IMID-based MPT, CTDa, Rd, MPR Yes No No Treatment Consolidation Thal, VTD, Len? 2nd 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
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
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 IMWG Consensus Recommendations on Risk Assessment
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 GEM2000 & GEM2005: Impact on survival of achieving an immunophenotypic response after HDT/ASCT independent of induction regimen
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
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 Possibility of Cure?
Bz Bz Bz Bz Dex Dex Dex Dex Dex Dex Dex Dex 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 1 2 4 5 8 9 11 12 14 21 Lenalidomide daily 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 • 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 % Patients 29 37 CR nCR VGPR 11 PR 20 27 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 RVD x 3 Cy (3g/m2) Mobilization Goal: 5x106 cells/kg) Cy (3g/m2) Mobilization Goal: 5x106 cells/kg) Stem Cell Collection Mel (200 mg/m2) + ASCT Consolidation RVD x 2 RVD x 2 Lenalidomide 18 Mo Maintenance 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 13q by metaphase, t(4:14), t(14;16), del 17p, 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 CD34+ 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.