Transcript File

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
mutations1
Dysregulation of
cyclins, oncogenes, and
tumor suppressors1
DC
Failure of
immune
surveillance2-3
Immunosuppression2
MM tumor cells
ICAM-1
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.
Cytokines
and growth
factors2
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
Fit
Bortezomib-based
IMID-based
VD, VTD, PAD,
TD, TAD, CTD
TT3, VCD, VRD
VTD, TT3, Rd, VRD
Specific complication
Yes
No
Stem Cell Harvest
Low dose Px
MPT, Bort, MP,
Dex, Rd, CTDa, CyPred
High-dose Melphalan
Stem cell infusion
≥VGPR
Yes
Elderly and Frail
Renal – bort-based
VTE/PE – bort-based
Bort-based
Poor risk cytogenetics:
VMP
bort-or len-based
No
PN – len-based
IMID-based
MPT, CTDa,
Rd, MPR
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
Patients
Goal
Fit elderly patients (65-80 yr)
Young patients with severe comorbidities
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
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 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
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
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
D1 2
4
5
8
9
11
12
Bz
Bz
Bz
Bz
Dex Dex
Dex Dex
Dex Dex
Dex Dex
14
21
Lenalidomide daily


N = 66
Phase I up to 8 3-wk cycles at 5 dose levels, phase II dose: 25mg/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)
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
nCR
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 (3g/m2)
Mobilization
RVD x 3
Cy (3g/m2)
Stem Cell Collection
Goal: 5x106 cells/kg)
Mobilization
Goal: 5x106 cells/kg)
Mel (200 mg/m2) +
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 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.