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.