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Best Upfront Treatment for MM: The Road toward a Cure
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Transcript of Best Upfront Treatment for MM: The Road toward a Cure
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 MMNatural Course of MM
Progress in the Treatment of Progress in the Treatment of MM in the Past 40 YearsMM in the Past 40 Years
4
Multiple Myeloma Pathophysiology
DC
Cytogenetic changes and/or mutations1
Dysregulation of cyclins, oncogenes, and tumor suppressors1
Failure of immune surveillance2-3
Immunosuppression2
Cytokines and growth factors2
Stromal cell support, TNF- production4-5
MM tumor cells
These events lead to uncontrolled tumor cell growthDC, dendritic cell; MM, multiple myeloma;
NK, natural killer; NKT, natural killer T cell; TNF, tumor necrosis factor.
ICAM-1
Interaction of MM Cells and BM Interaction of MM Cells and BM MicroenvironmentMicroenvironment
Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC. Nat Rev Cancer 2007;7(8):585-98.
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 Mechanisms of Novel Therapy in MMTherapy in MM
Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC. Nat Rev Cancer 2007;7(8):585-98.
Frontline TreatmentFrontline 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
Yes No
No Treatment Consolidation
Thal, VTD, Len?
2nd SCT Consolidation
Thal, other combos?
No
Fit or Frail
Elderly and Frail
Low dose Px
MPT, Bort, MP,
Dex, Rd, CTDa, CyPred
Fit
Specific complication
Yes No
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.
Changing the Treatment Landscape of Changing the Treatment Landscape of MM by Novel AgentsMM by Novel Agents
Bortezomib, lenalidomide/ dex, thalidomide/ dex, Bortezomib, lenalidomide/ dex, thalidomide/ dex, bortezomib/ liposomal doxorubicin, bortezomib/ bortezomib/ liposomal doxorubicin, bortezomib/ MP, bortezomib/ dexMP, bortezomib/ dex
Targeting MM in the BM microenvironment to Targeting MM in the BM microenvironment to overcome conventional drug resistance in vitro overcome conventional drug resistance in vitro and in vivoand in vivo
Effective in relapsed/refractory MMEffective in relapsed/refractory MM
Effective as induction/first-line therapyEffective as induction/first-line therapy
Emerging role of transplant/maintenanceEmerging role of transplant/maintenance
Treatment Goal in MM PatientsTreatment Goal in MM Patients
Appropriate balance between treatment Appropriate balance between treatment efficacy, toxicity and costsefficacy, toxicity and costs
PatientsPatients GoalGoalFit elderly patients (65-80 yr)Fit elderly patients (65-80 yr)
Young patients with severe co-Young patients with severe co-morbiditiesmorbidities
Prolong survivalProlong survival
Ensure QoLEnsure QoL
Very elderly patients (>80-85 yr)Very elderly patients (>80-85 yr) Ensure QoLEnsure QoL
Avoid unnecessary costly Avoid unnecessary costly treatmentstreatments
Young patients (<65 yr)Young patients (<65 yr) Investigate therapeutic schemes Investigate therapeutic schemes with curative intentwith curative intent
CureCure VS VS ControlControl
CureCure as treatment goal as treatment goal– Therapeutic Therapeutic aim to achieve CRaim to achieve CR– Use intensive upfront therapy to maximize the chance of Use intensive upfront therapy to maximize the chance of
achieving CR achieving CR longer PFS, TTP longer PFS, TTP– ““CR correlates with prolonged OS ?”CR correlates with prolonged OS ?”
Disease controlDisease control as treatment goal as treatment goal– Therapeutic Therapeutic aim to prolong OSaim to prolong OS– Use less intensive, sequential approach to balance efficacy Use less intensive, sequential approach to balance efficacy
with quality of lifewith quality of life– Leave reserve for later salvage therapyLeave reserve for later salvage therapy– Not all studies support correlation between CR and OSNot all studies support correlation between CR and OS
Actions to Achieve CureActions to Achieve Cure
To eradicate the tumor clone (stem cells)To eradicate the tumor clone (stem cells)– To achieve and maintain the best possible To achieve and maintain the best possible
responseresponse
A small number of residual tumor cells A small number of residual tumor cells may persist under control of immune may persist under control of immune system for long timesystem for long time– Avoid over-treatmentAvoid over-treatment
IMWG Consensus Recommendations IMWG Consensus Recommendations on Risk Assessmenton Risk Assessment
High riskHigh risk
High ISS stageHigh ISS stage
Chromosomal aberrations Chromosomal aberrations by FISHby FISH– del 17pdel 17p– t(4;14)t(4;14)– t(14;16)t(14;16)
Metaphase cytogenetic Metaphase cytogenetic del 13 or 13q-del 13 or 13q-
Other factorsOther factors
LDHLDH
IgA subtypeIgA subtype
Extramedullary diseaseExtramedullary disease
Renal impairmentRenal impairment
High serum free light High serum free light chainchain
Plasmablastic featurePlasmablastic feature
PC leukemiaPC leukemia
Aim of Induction TherapyAim of Induction Therapy
Prevent and reverse end-organ Prevent and reverse end-organ dysfunctiondysfunction
Minimize toxicity associated with induction Minimize toxicity associated with induction regimenregimen
Induce deep responseInduce deep response
Current Induction RegimensCurrent Induction Regimens
Two-drugTwo-drug– Bortezomib-dexamethasoneBortezomib-dexamethasone– Lenalidomide-dex or thalidomide-dexLenalidomide-dex or thalidomide-dex
Three-drugThree-drug– Thalidomide, bortezomib, dexThalidomide, bortezomib, dex– Lenalidomide, bortezomib, dexLenalidomide, bortezomib, dex– Cyclophosphamide, bortezomib, dexCyclophosphamide, bortezomib, dex– Bortezomib, doxorubicin, dexBortezomib, doxorubicin, dex
Four-drugFour-drug– Cyclophosphamide, lenalidomide, bortezomib, dexCyclophosphamide, lenalidomide, bortezomib, dex– Cyclophosphamide, bortezomib, thalidomide, dexCyclophosphamide, bortezomib, thalidomide, dex– Lenalidomide, bortezomib, liposomal doxorubicin, dexLenalidomide, bortezomib, liposomal doxorubicin, dex
Impact of CR in the ASCT Impact of CR in the ASCT SettingSetting
In the ASCT setting, there is a large body of evidence In the ASCT setting, there is a large body of evidence showing an association between optimal response showing an association between optimal response (CR/VGPR) and long-term outcome (PFS and OS)(CR/VGPR) and long-term outcome (PFS and OS)
10 prospective trials (2991 patients): all showed a 10 prospective trials (2991 patients): all showed a positive correlation (statistically significant in 8). Similar positive correlation (statistically significant in 8). Similar findings in 5/8 retrospective trials findings in 5/8 retrospective trials (Van de Velde. (Van de Velde. Haematologica 2007;92:1399.)Haematologica 2007;92:1399.)
Significant correlation between maximal response and Significant correlation between maximal response and outcome prospective studies (<0.00001) & retrospective outcome prospective studies (<0.00001) & retrospective studies (<0.00001)studies (<0.00001)
MRD evaluation by PCR (Qualitative & Semi-MRD evaluation by PCR (Qualitative & Semi-Q) in MM patients: Prognostic ValueQ) in MM patients: Prognostic Value
Distinction between Myelomatous & Distinction between Myelomatous & Normal Plasma CellsNormal Plasma Cells
GEM2000 & GEM2005: Impact on survival GEM2000 & GEM2005: Impact on survival of achieving an immunophenotypic of achieving an immunophenotypic
response after HDT/ASCT independent of response after HDT/ASCT independent of induction regimeninduction regimen
Prognostic Relevance of Durable CRPrognostic Relevance of Durable CR
Maintenance Therapy in MMMaintenance 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 MaintenanceTTP with and Without Lenalidomide Maintenance
CALGB 100104, ASH 2010 update.
Median follow-up of 28 monthsCALGB 100104, follow up to 04/17/2011
23 deaths in the lenalidomide arm and 39 deaths in the placebo arm p value=0.018Placebo patients who had PD were not eligible to cross over to lenalidomide on study
Possibility of Cure?Possibility of Cure?
Selection of Selection of appropriate patientsappropriate patients– Young without Young without
comorbiditycomorbidity
No adverse No adverse cytogenetics riskscytogenetics risks
Combinations of Combinations of novel agents during novel agents during inductioninduction
Integration of ASCT Integration of ASCT after induction?after induction?
Achieving more depth Achieving more depth of CR of CR Immunophenotypic Immunophenotypic CRCR– ConsolidationConsolidation– Maintenance therapy Maintenance therapy
with novel agentswith novel agents
Phase I/II Trial of RVD in Newly Phase I/II Trial of RVD in Newly Diagnosed MMDiagnosed MM
N = 66N = 66 Phase I up to 8 3-wk cycles at 5 dose levels, phase II dose: 25-mg/1.3 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 dexamethasonemg/m2 lenalidomide/bortezomib + 20-mg dexamethasone After 4 cycles, patients with PR could proceed to ASCTAfter 4 cycles, patients with PR could proceed to ASCT After 8 cycles, responding patients could receive maintenance 3-wk After 8 cycles, responding patients could receive maintenance 3-wk
cycles of lenalidomide (D1-14); weekly bortezomib at doses tolerated 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, at end of cycle 8 (days 1, 8); plus 10-mg dexamethasone (Days 1, 2, 8, 9)8, 9)
D 1 2 4 5 8 9 11 12 14 21
Bz
Dex Dex
Bz
Dex Dex
Bz
Dex Dex
Bz
Dex Dex
Lenalidomide daily
Richardson PG, et al. Blood 2010;116.
RVD in Newly Diagnosed Myeloma - OutcomeRVD in Newly Diagnosed Myeloma - Outcome
Median follow-up 27.3 monthsMedian follow-up 27.3 monthsMedian PFS and OS not Median PFS and OS not reachedreached– Estimated 24-month PFS: 68% Estimated 24-month PFS: 68%
(95% CI: 55-78%)(95% CI: 55-78%)– Estimated 24-month OS: 95% Estimated 24-month OS: 95%
(95% CI: 86-98%)(95% CI: 86-98%)
At 1-yr, 53 patients had not At 1-yr, 53 patients had not progressed (26 with ASCT, 27 progressed (26 with ASCT, 27 without ASCT)without ASCT)– No significant difference in PFS No significant difference in PFS
between those with ASCT and between those with ASCT and those withoutthose 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
Approach to TherapyApproach to Therapy
Patients with early transplant Patients with early transplant better betterPatients with delayed transplant until Patients with delayed transplant until relapserelapse
IFM/DFCI Study: Newly Diagnosed MMIFM/DFCI Study: Newly Diagnosed MM
RVD x 3
Cy (3g/m2)
Mobilization
Goal: 5x106 cells/kg)
Mel (200 mg/m2) +
ASCT
RVD x 2
Lenalidomide 18 Mo
RVD x 3
Cy (3g/m2)
Mobilization
Goal: 5x106 cells/kg)
RVD x 2
Lenalidomide 18 Mo
SCT at relapse
Randomize
Induction
Stem Cell Collection
Consolidation
Maintenance
RVD Induction Followed by ASCT: Retrospective RVD Induction Followed by ASCT: Retrospective Analysis of DFCI’s ExperienceAnalysis of DFCI’s Experience
MethodsMethods– MM patients treated at DFCI Jan, 2005 – Dec, 2010 MM patients treated at DFCI Jan, 2005 – Dec, 2010
(n 481)(n 481)– At least two cycles of RVD induction followed by At least two cycles of RVD induction followed by
ASCTASCT
Patient characteristicsPatient characteristics– 81 patients81 patients– Median 5 cycles of inductionMedian 5 cycles of induction– ISS stage II/III: 32%/ 12%ISS stage II/III: 32%/ 12%– 33% of patients with high-risk cytogenetics including 33% of patients with high-risk cytogenetics including
del 13q by metaphase, t(4:14), t(14;16), del 17p, del 13q by metaphase, t(4:14), t(14;16), del 17p, complex karyotypecomplex karyotype
Luskin, M et al. ASH 2011
ASCT Following RVD Induction: ASCT Following RVD Induction: DFCI ExperienceDFCI Experience
Response to inductionResponse to induction– PR or better 96%PR or better 96%– VGPR 26%VGPR 26%– CR 44%CR 44%– 50% of those with CR have no clonal marrow plasma cells by 50% of those with CR have no clonal marrow plasma cells by
IHCIHC
Post ASCT responsePost ASCT response– 33% with improvement in overall response33% with improvement in overall response
Stem cell collectionStem cell collection– Median CD34+ stem cell yield: 9.6 x 10Median CD34+ stem cell yield: 9.6 x 1066/kg/kg– Plerixafor used in one patientPlerixafor used in one patient
ToxicityToxicity– 50% with any grade of peripheral neuropathy50% with any grade of peripheral neuropathy– VTE in 2 patientsVTE 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.