myeloma 2013-what we know-what we don’t know and what we don’t know we don’t know. sergio a....
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Myeloma 2013-What we know-What we don’t know and what we don’t know we
don’t know.
Sergio A. Giralt, MDChief, Adult Bone Marrow Transplant Service
Division of Hematologic OncologyDepartment of Medicine
Memorial Sloan-Kettering Cancer CenterNew York, New York
Disclosures
• Grant Support– Celgene– Millenium– Onyx
• Honoraria– Celgene– Millenium– Onyx– Novartis– Sanofi/Genzyme
• Most important I am a transplanter
Initial PresentationInitial Presentation
• 45-year-old woman • Presents with proteinuria. • Normal Physical• Laboratory findings
– Hemoglobin 11 gm/dl normal iron stores– Total proteinuria 5.82 g/day– Bence Jones protein (BJP) 3.6 g/day– Hypogammaglobulinemia– Albumin 3.9 g/dL – β2-microglobulin 4.7 mg/L– Creatinine 1.7 mg/dl – No paraprotein peak but kappa light chain 120000 with lambda light
chain at 0.01– Kappa/lambda ratio=12000000
• Bone marrow biopsy – Cellularity 80% with 25% plasma cells– Cytogenetics 46, XX, inversion 9 (p11;q13)
• FISH no abnormalities• Skeletal survey: extensive lytic bone disease with healing fractures
of left 7th and the 8th ribs• MRI of the spine: diffuse hyper-intense homogenous signal on STIR
sequence• MRI of the pelvis: diffuse marrow infiltrative changes due to
myeloma• Comorbidities: Diabetic on metformin, no history of coronary artery
disease or other comorbidities
Multiple Myeloma: AnalysisMultiple Myeloma: Analysis
3 decades
Myeloma
M0 M1 M2 M3 M4 M5 M6 M7
Hyperdiploidy
t(6:14)SC Pre Pro Early Mid SHM ICS PC
t(14;16)
t(4:14)
t(11;14)
Images courtesy of Raphael Fonseca, MD.
Multiple Myeloma Treatment LinesMultiple Myeloma Treatment Linesaa
Induction Consolidation
Front-line treatment
Maintenance
Maintenance
Rescue
Relapsed
IMID:Thal-LenProteosome Inhibitor: Bor-Car
Steroids: Dex-PredAlkylator: Cyclo-Mel
Anthracycline: LipoDnr-Adr
SCT
ObservationIMID:Thal-Len
Proteosome Inh-BorSteroids:Dex-Pred
IMID:Thal-Len-PomProteosome Inh:Bor-Car
Steroids: Dex-PredAlkylators:Mel-Cy-Benda
Investigational
aTransplant eligible patients.Bor/Dex = bortezomib, dexamethasone; Bor/Dex/Dox = bortezomib, dexamethasone, doxorubicin; Bor/Thal/Dex = bortezomib, thalidomide, dexamethasone; Len/Dex = lenalidomide, dexamethasone; SCT = stem-cell transplant;
Thal/pred = thalidomide, prednsione; Bor/Liposomal/Dox = bortezomib, liposomal doxorubicin.NCCN, 2009.
IS THERE AN OPTIMAL INDUCTION REGIMEN?
What we know…
Protocol GIMEMA 26866138-MMY-3006Protocol GIMEMA 26866138-MMY-3006VTD vs TD incorporated into double ASCT for MMVTD vs TD incorporated into double ASCT for MM
RANDOMIZATION
INDUCTION• VEL-THAL-DEX
TRANSPLANTATION• MEL 200• MEL 200
CONSOLIDATION• VEL-THAL-DEX
MAINTENANCE• DEX
INDUCTION• THAL-DEX
PBSC COLLECTION• CTX
CONSOLIDATION• THAL-DEX
RESPONSE TO PRIMARY THERAPYRESPONSE TO PRIMARY THERAPY
% of patients% of patients
RESPONSERESPONSEVTDVTD
(n=129)(n=129)
TDTD(n=127)(n=127) P valueP value
CR+nCRCR+nCR 3636 99 <0.001<0.001
VGPRVGPR 6060 2727 <0.001<0.001
< PR< PR 77 2020 0.0030.003
ProgressionProgression 00 5.55.5 0.0080.008
EBMT criteria (with added nCR and VGPR categories)
RESPONSE (CR+nCR) TO PRIMARY THERAPY RESPONSE (CR+nCR) TO PRIMARY THERAPY ACCORDING TO GENETIC ABNORMALITIESACCORDING TO GENETIC ABNORMALITIES
27
32
43
47
0
10
20
30
40
50
60
%
13 t(4;14)
P=0.06 P=0.1
43
47
4
8
0
10
20
30
40
50
60
%
13 pos t(4;14) pos
P<0.001 P=0.002
neg pos neg pos
VTD VTD vs TD
VTD VTD
TD
GIMEMA: Results
• Secondary endpoints– PFS
– OS• 96% (VTD) vs 91% (TD); P = .2
• Primary endpoint: CR + nCR (VTD vs TD as induction therapy)
Cavo M, et al. ASH 2008. Abstract 158.
Response, %VTD
(n = 226)TD (n = 234)
P Value
CR + nCR 32 12 < .001
≥ VGPR 62 29 < .001
≥ PR 94 79 < .001
Progression 0 4.7 .001
Modified EBMT and Uniform Criteria (nCR and VGPR categories) 0.0
0.2
0.4
0.6
0.8
1.0
0 5 10 15 20 25 30
Mos
2-yr rates
P = .009
VTD (n = 226): 90%TD (n = 234): 80%
Meta-analysis
Phase II Study of Len, Bortezomib, and Dex (RVD) in Newly Diagnosed MM (Richardson et al)
• Pts• 35 enrolled in phase II; median age 59 (22-86) yrs; • ISS Stage II/III 54%/11%
• Dose • Lenalidomide 25 mg/d, d 1-14 in 21 day cycle• Bortezomib 1.3 mg/m2 d 1, 4, 8, 11• Dexamethasone 20 mg day of and after bortezomib• Aspirin and antiviral prophylaxis
• Safety• Grade > 3 PN in 1 pt only, VTE in 2 pts, no rx related mortality
Response n = 35 evaluable
CR/nCR 52%
< VGPR 74%
ORR (≥PR) 100%
• Results• At 19 mos of follow-up, TTP, PFS, At 19 mos of follow-up, TTP, PFS, and OS have not been reachedand OS have not been reached• Median stem cell collection in 15/35 Median stem cell collection in 15/35 patients: 4.4 x 106 CD34+ cells/kgpatients: 4.4 x 106 CD34+ cells/kg
Newly Diagnosed MM
Kaplan-Meier analyses of treatment outcomes.
Kumar S et al. Blood 2012;119:4375-4382
©2012 by American Society of Hematology
Stem Cell CollectionStem Cell Collection
• After 4 cycles of RVD she achieves a VGPR with kappa light chains reduced to 10 and lambda light chains recovered to 0.1.
• Her marrow reveals 4% kappa restricted plasma cells.
• MRI demonstrates significant resolution of infiltrative images.
• She agrees to proceed to stem-cell collection and transplantation.
OPTIMAL MOBILIZATION STRATEGYOPTIMAL MOBILIZATION STRATEGY
What we know…
Effect of Lenalidomide Duration of Therapy on Stem Cell Collection
Effect of Lenalidomide Duration of Therapy on Stem Cell Collection
Paripati H. Leukemia. 2008;22:12821284.
CD
34+
Co
un
t (C
ells
µl-1
)
5
10
15
20
25
30
35
0
1
2
3
4
5
6
7
8
9C
D34
+ C
ou
nt
(in
Mil
lio
ns)
0 0
0.5
2
1.5
4
2.5
6
3.5
8
4.5
Day
s
05
101520253035
404550
Per
cen
tag
e
Mean Peripheral BloodCD34+ Count
Total CD34+ Cellscollected
(Mean x 106 cells Kg-1)
Mean number ofdays of collection
Percentage of patientswho failed
first collection
Lenalidomide Therapy Other Induction Therapies
n=16
n=40 n=40
n=40n=18
n=18
P value = 0.0002 P value=0.0025 P value = 0.07 P value = 0.0011
Overcoming the Negative Effects of Lenalidomide on Stem Cell Mobilization
Utilizing Plerixafor
Overcoming the Negative Effects of Lenalidomide on Stem Cell Mobilization
Utilizing Plerixafor
• Plerixafor + G-CSF– N = 60 patients with myeloma frontline
mobilization: 20 patients & CUP: 40 pts– Median CD34 collected 5.6 x 106 CD34/kg– 87% collected ≥ 2 x 106 CD34/kg– 63% collected ≥ 5 x 106 CD34/kg– Up front pts: 100% (≥ 2) & 95% (≥ 5)– CUP pts: 80% (≥ 2) & 48% (≥ 5)
Micallef I, et al. Haematologica. 2009;94(suppl 2):0718; Tarantolo S, et al. Biol Blood Marrow Transplant. 2009;15(2 suppl 2):91.
What we don’t knowWhat we don’t know
• Is VRD superior to VTD or CyBorD?• Should the goal be ‘X” number of cycles and
proceed to SCT or should patients continue induction until best response?
• Is “response adapted” therapy appropriate?• Is there a role for carfilzomib based induction?• Should anybody be chemomobilized in the era of
plerixafor?
Stem Cell TransplantationStem Cell Transplantation
• She collects 10 million CD34 cells per kg over 3 days and is ready to be admitted for high dose melphalan and autologous stem cell transplantation.
• She asks what is it going to be like and does she really need a SCT?
ROLE OF SCT IN THE ERA OF IMIDS AND PROTEOSOME INHIBITION
ROLE OF SCT IN THE ERA OF IMIDS AND PROTEOSOME INHIBITION
What we don’t know…
Figure 2
Source: Biology of Blood and Marrow Transplantation 2007; 13:183-196 (DOI:10.1016/j.bbmt.2006.09.010 )
Copyright © 2007 American Society for Blood and Marrow Transplantation Terms and Conditions
BENEFIT OF AUTOGRAFTING FOR MYELOMAKoreth et all BBMT
Early-vs-Late SCT Study?
m
A
A
mm
A
A
AA
Risk profile
Optimalinductionregimen
Maintenance
COLLECT HD THERAPY + SCT
HARVEST AND HOLDSCT UPON RELAPSE
IFM/DFCI 2009 StudyNewly Diagnosed MM Pts (SCT candidates)
VRD x 3
VRD x 2
VRD x 5
Lenalidomide 12 mos
Melphalan 200mg/m2* +
ASCT
Induction
Consolidation
Maintenance
CY (3g/m2) MOBILIZATIONGoal: 5 x106 cells/kg
VRD x 3
CY (3g/m2)MOBILIZATIONGoal: 5 x106 cells/kg
Randomize, stratification ISS & FISH
Collection
Lenalidomide 12 mosSCT at relapse
MEL 200 mg/m2 if <65 yrs, ≥65 yrs 140mg/m2
http://www.clinicaltrials.gov/ct2/show/NCT01208662?term=nct01208662&rank=1
Melphalan/Prednisone/Lenalidomide (MPR) vs MEL200/ASCT Following
Lenalidomide/Dexamethasone (Ld) Induction
Primary end point: PFS
RANDOMIZE
Lenalidomide: 25 mg, days 1–21Low-dose Dex:40 mg, days 1, 8,15, 22 q 28 days ×4
Consolidationn=402
<65 years RANDOMIZE
Nomaintenance
Maintenancelenalidomide: 10 mg/d, Days 1–21q 28 days until relapse
Palumbo A et al. Blood. 2009;114:Abstract 350.
MPR (n=202)Melphalan: 0.18 mg/kg/d, days 1–4Prednisone: 2 mg/kg/d, days 1–4 Lenalidomide: 10 mg/d, days 1–21q 28 days ×6
Tandem MEL200 ASCT
stem cells mobilized with cyclophosphamide + G-CSF
Median follow-up 26 months
Progression Free Survival
HR 0.506
P = 0.0002
MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2; PFS, progression free survival; HR, hazard ratio; mos, months
0.00
0.25
0.50
0.75
1.00
0 5 10 15 20 25 30 35 40 45
2-years PFS
MPR
MEL200
54%
73%
Median PFS
Not reached
25.26 mos
Pat
ien
ts (
%)
Months
49.4% Reduced Risk of Progression
MPR MEL200 P value
CR 20% 25% P=0.55
PFS @ 24 months 54% 73% P=0.0002
OS @ 24 months 87% 90% P=0.19
Less G3-4 hematologic toxicity in MPR arm (P<0.001)
Less mucositis and infections in MPR arm (P<0.001)
No difference in term of early deaths
Significantly longer PFS after ASCT (P<0.001)
Longer follow up is needed to assess OS
Conclusions
MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2; CR, complete response; PFS, progression-free survival; OS, overall survival; ASCT, autologus stem cell transplantation
eastern cooperative oncology groupeastern cooperative oncology group
E4A03: Landmark Analysis at Median Follow-up of 36 mo
Rajkumar SV et al. The Lancet Oncology, Volume 11, Issue 1, Pages 29 - 37, January 2010
431 patients alive at 4 cycles
Off therapy at 4 cycles
n=183
Primary therapy beyond 4 cycles
n=248
no transplantN=93
(median age 68)
Transplant n=90
(median age 57)
Ldn=140
(median age 66)
LDn=108
(median age 65)
eastern cooperative oncology groupeastern cooperative oncology group
Outcomes in pts Age <65
Progression Free Survival Overall Survival
What we don’t knowWhat we don’t know
• Should everybody be collected upfront?– How much?
• Who should undergo upfront SCT?– All patients?– Only those with suboptimal response?
What is suboptimal?– PR– VGPR– Near CR
– Who is truly transplant ineligible?– What about low risk patients in CR?
• What role does risk stratification play in deciding therapies?
FUNCTIONAL ASSESSMENT
32
Aging Heterogeneity
Community Dwelling, Typical
Institutionalized, FrailAges 84,81
Community Dwelling, Healthy
Age 82
Community Dwelling, FrailAges 19, 82, 23
Xz12_56.ppt
Transplant-related Mortality after Autologous Transplant-related Mortality after Autologous Hematopoietic Cell Transplantation for Hematopoietic Cell Transplantation for
Malignant Diseases by HCT-CI, 2007-2009Malignant Diseases by HCT-CI, 2007-2009
100
0
20
40
60
80
90
10
30
50
70
0
100
20
40
60
80
90
10
30
50
70
Incid
en
ce,
%
Years
0 15 305 252010
HCT-CI=1-2 (n=2,813)
HCT-CI=0 (n=5,185)
HCT-CI3 (n=2,388)
p<0.001
100-Day Mortality by HCT-CI After Autologous 100-Day Mortality by HCT-CI After Autologous Hematopoietic Cell Transplantation Hematopoietic Cell Transplantation
According to Performance Score and Disease According to Performance Score and Disease IndicationIndication
10
0 d
ay m
ort
ality
,%
P<0.001 P<0.001
Rate of SCT in US according to AgeRate of SCT in US according to AgeCosta et al ASH 2012Costa et al ASH 2012
<50 years 50-64 years ≥ 65 years
Figure 1
0
1
2
3
4
5
6
Baseline Conditioning Regimen
Day of Transplant
Nadir of WBC Hospital Discharge
30 days post BMT
Mea
n of
5 M
ost S
ever
e S
ympt
oms
Time
Symptom Severity by CD34 Positive Cells Infused
4 - 6x10^6 CD34 Cells/Kg
10 - 15x10^6 CD34 Cells/Kg
Randomized Phase II LD/HD CD34Randomized Phase II LD/HD CD34
In my humble opinionIn my humble opinion
• High dose melphalan is one of the most active agents in myeloma today– 30-40% CR– 24 months median remission duration without maintenance– Name another agent with similar single agent activity– It is also cost-effective
• With stem cell support it can be given safely to older patients with comorbidities.
• Thus not planning for it’s use upfront is similar to telling a patient I am never going to use bortezomib or lenalidomide during your disease course because “I don’t like it” or I don’t believe in it”.
• Whether early or late, once twice or more times it remains an active agent that can be extremely effective in all stages of the patients disease journey.
POST SCT THERAPIESPOST SCT THERAPIES
Tales of Two Cases
Case 1• 55-year-old female presents
with asymptomatic anemia of 10 gm/dL and total serum protein 10 gm/L
• Workup reveals– 30% plasma cells– Cytogenetic diploid– IgA kappa peak of 3.2– β2M of 3.0
• Receives 4 cycles of Bz/Thal/Dex
• Followed by Auto SCT on day 60 documented stringent CR
Case 2• 55-year-old female presents
with asymptomatic anemia of 10 gm/dL and total serum protein 10 gm/L
• Workup reveals– 30% plasma cells– Cytogenetic t(4;14)– IgA kappa peak of 3.2– β2M of 3.0
• Receives 4 cycles of Bz/Thal/Dex
• Followed by Auto SCT on day 60 documented paraprotein peak of 0.4 g/dL
Both have a 10/10 sibling donor available.
Multiple Myelomameeting
eligibility criteria
High-dose melphalan (200 mg/m2) + autologous PBSC transplant
60 to 120 days
No eligible HLA-matched sibling donor
Non-myeloablative conditioningTBI 200 cGY
allogeneic PBSC transplant
High-dose melphalan (200 mg/m2) + autologous PBSC transplant
ObservationThalidomide
Dexamethasone x12 months.
Biologic assignment*
Eligible HLA-matched sibling donor
Randomization†
PRIMARY ENDPOINT : 3yr Progression Free Survival
BMT CTN 0102 Study SchemaBMT CTN 0102 Study Schema
HLA typing of all patients with siblings*Biologic assignment
occurred when HLA-typing results were available after enrollment.
† Randomization occurred once patients were assigned to auto-auto
1st Autologous Transplant
N=710
No Sibling DonorAuto-Auto
N=484
Sibling DonorAuto-Allo
N=226
High RiskN=48
Standard Risk
N=189
Standard Risk
N=436
High RiskN=37
Main groups compared
Monitoring DiseaseCR Definition Does Matter With Regards to Depth of
Remission
Rate of molecular CR with HDT is 5%
At diagnosis
Partial response – 50% reduction in M protein
Near complete remission – immunofixation positive only
Complete remission – immunofixation negative
Nonquantitative ASO-PCR
Quantitative ASO-PCRflow cytometryMRD
1 × 104
1 × 106
1 × 108
1 × 1012N
um
ber
of
Mye
lom
aC
ells
Summary
• High dose melphalan with autologous stem cell support remains the standard of care for consolidation therapy for patients with chemosensitive disease
• Current therapy with high dose melphalan followed by maintenance therapy results in more than 70% major responses and median remission durations of around 3.5-4 years.
• Moving forward minimizing toxicities, developing more effective conditioning regimens and better risk stratification will allow us to provide each patient with the best chance of a long life with myeloma control, good quality of life with the least treatment burden
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