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Should Alkylators be used Upfront in Transplant-Ineligible Patients?
NO!!
Lymphoma-Myeloma
October 2013
Scottsdale, ArizonaScottsdale, Arizona Rochester, MinnesotaRochester, Minnesota Jacksonville, FloridaJacksonville, Florida
Joseph Mikhael, MD, MEd, FRCPC, FACPStaff Hematologist, Mayo Clinic Arizona
Objectives
1. Review the emerging data regarding replacing “MP” as backbone in upfront therapy
2. Provide practical advice as to initiating therapy in older patients with myeloma
3. Unequivocally defeat my friend Antonio in this debate
4. Concede that cyclophosphamide may be an exception to this general rule
Summary Points – Why Melphalan is no longer standard
of initial care in elderly patients
1. Novel agents are equivalent if not superior to MP+novel agent
2. MP+ results in greater short term toxicity
3. As survival is extended in myeloma, using melphalan upfront is not desirable due to marrow toxicity
4. Melphalan can lead to increased second primary malignancies
mSMART 2.0: Classification of Active MM
FISH Del 17p t(14;16) t(14;20)
GEP High risk
signature
All others including: Hyperdiploid t(11;14) t(6;14)
FISH t(4;14)*
Cytogenetic Deletion 13 or hypodiploidy
PCLI >3%
High-Risk 20% Intermediate-Risk 20% Standard-Risk 60%
3 years 4-5 years 8-10 years
Mikhael et al Mayo Clinic Proceedings April 2013
mSMART – Off-StudyTransplant Ineligible
Observation
Intermediate Risk Standard Risk*
MP + weekly Bortezomib or weekly CyBorD
Bortezomib maintenance
Rd
Mikhael et al Mayo Clinic Proceedings April 2013
High Risk
VRd
Argument #1
Novel agents are equivalent if not superior to MP+novel agent
MPT1
N = 129VMP2
N = 337MPR3
N = 153MPR-R4
N = 152VTP5
N = 130
CR 16% 30% 11% 16% 27%
> VGPR 29% Not reported 33% 32% 37%
> PR 69% 71% 68% 77% 81%
PFS 21.8 mo TTP: 24.0 mo 14 mo 31 mo 23 mo
Median follow-up
31.8 mo 36.7 mo 25 mo 25 mo 22 mo
1Palumbo A, et al. Blood. 2008;112:3107-3114; 2Mateos MV, et al. Blood. 2009;114(22). Abstract 3859;
3,4Palumbo A, et al. Blood. 2010;116(21). Abstract 622 and Abstract 566; 5Mateos MV, et al. Blood. 2009;114(22). Abstract 3.
MPT: melphalan, prednisone, thalidomide; VMP: bortezomib, melphalan, prednisone; MPR: melphalan, prednisone, lenalidomide; MPR-R: MPR with maintenance lenalidomide; VTP: bortezomib, thalidomide, prednisone.
Newly Diagnosed, Patients SCT Ineligible
Primary Study SchemaPrimary Study Schema
RANDOMIZATION
445 patients
RDx 4 cycles
Rdx 4 cycles
Less than PR
CR/PR
Thal + Dexx 4 cycles
Patients can go off and proceed to SCT
CR/PR/stable
Rajkumar et al
lenalidomide plus RD versus lenalidomide plus Rd in newly diagnosed MM
BEST RESPONSE: > PR*
RD [n] Rd [n] Odds
Ratio
Fisher's
Exact
Overall 81.3% [214] 70.2% [208] 1.85 p=0.009
< 65 85.4% [103] 66.0% [103] 3.02 p=0.002
> 65 77.5% [111] 74.3% [105] 1.19 p=0.634
> 70 74.6% [71] 73.8% [65] 1.04 p=1.000
> 75 77.8% [36] 70.4% [27] 1.47 p=0.566
*Same observations with VGPR except age > 70 42.3% vs 47.7%
ResultsResultsSecond Interim Analysis RD vs. RdSecond Interim Analysis RD vs. Rd
Rajkumar et al, 2010.
RD RdCR + PR 79% 68%
1 year OS 87% 96%
Grade 3 or worse AE
52% 35%
RD did not result in superior TTP, PFS, or OS compared to Rd
OS at 1-year was significantly better with Rd than RD, resulting in early closure of the trial
Overall Survival-ITT
Age > 65 yrs
Age > 65
Age > 70Age < 65
Age > 75
Status
RD
N=223 (%)
Rd
N=220 (%)
Total*
N=443Treatment End by Mandatory Crossover
Yes 195 (87.4) 169 (76.8) 364No 28 (12.6) 51 (23.2) 79
Survival Rate by AgeN 12 month
survival probability (95%CI)
24 month
survival
probability
(95%CI)
Age <65
Len-High Dex 104 0.92 (0.87-0.98) 0.86 (0.79-0.93)
Len-Low Dex 108 0.96 (0.93-1.00) 0.92 (0.87-0.97)
Age ≥65
Len-High Dex 119 0.84 (0.78-0.91) 0.72 (0.64-0.81)
Len-Low Dex 114 0.95 (0.91-0.99) 0.85 (0.79-0.92)
650 patients (older than 65 years) randomized from 5 countries
Patients: Symptomatic disease, organ damage, measurable disease
Treatment schedule
RdNine 28-day coursesR: 25 mg, d 1-21d: 40 mga or 20 mgb, d 1,8,15,22
CRPNine 28-day coursesC: 50 mg/daya or 3 times wkb
P: 25 mg, 3 times wkR: 25 mg, d1-21
1°RANDOMIZATION
2°RANDOMIZATION
MAINTENANCE 28-day course until relpaseR: 10 mg/day, days 1-21 P: 25 mg; 3 times wk
MAINTENANCE28-day courses until relapseR: 10 mg/day, days 1-21
MPRNine 28-day coursesM: 0.18 mg/kga or 0.13 mg/kgb, d 1-4P: 1.5 mg/kg, d 1-4R: 10 mg, d1-21
a Pts ≤ 75 yrs; b Pts > 75 yrs; C, cyclophosphamide; R, lenalidomide; M, melphalan; P, prednisone
Rd vs MPR vs CRPRd vs MPR vs CRPProgression Free Survival
Median follow-up 21 months
Rd CPR MPRvs. vs.Rd CPR MPRvs. vs.
0.00
0.25
0.50
0.75
1.00
0 5 10 15 20 25 30 35 40
Larocca A, et al. IMW 2013
months
Pro
port
ion
of p
atie
nts
Rd, lenalidomide-dexamethasone; CPR, cyclophosphamide-prednisone-lenalidomide; MPR, melphalan-prednisone-lenalidomide;
Vsc, subcutaneous bortezomib; C, cyclophosphamide; M, melphalan; P, prednisone
VPNine 35-day coursesVsc: 1.3 mg/sqm, d 1,8,15,22P: 50 mg, 3 times wk
VCPNine 35-day coursesVsc: 1.3 mg/sqm, d 1,8,15,22C: 50 mg, 3 times wkP: 50 mg, 3 times wk
1°RANDOMIZATION
MAINTENANCE 28-day course until relpaseVsc: 1.3 mg/sqm, d 1, 15 P: 25 mg; 3 times wk
150 patients (> 75 years) randomized from 3 countries
Patients: Symptomatic disease, organ damage, measurable disease
Treatment schedule
VMPNine 35-day coursesVsc: 1.3 mg/sqm, d 1,8,15,22M: 2 mg, 3 times wkP: 50 mg, 3 times wk
MAINTENANCE 28-day course until relpaseVsc: 1.3 mg/sqm, d 1, 15 P: 25 mg; 3 times wk
MAINTENANCE 28-day course until relpaseVsc: 1.3 mg/sqm, d 1, 15 P: 25 mg; 3 times wk
Larocca A, et al. Gr. Emat. Milano 2012Larocca A, et al. Gr. Emat. Milano 2012
SubcutaneousVP vs VMP vs VCP
SubcutaneousVP vs VMP vs VCP
Progression Free Survival
Median follow-up 14 months
CVP VMP VPvs. vs.CVP VMP VPvs. vs.
0.00
0.25
0.50
0.75
1.00
0 5 10 15 20 25
months
Pro
port
ion
of p
atie
nts
CVP, cyclophosphamide-bortezomib-prednisone; VMP, bortezomib-melphalan-prednisone; VP, bortezomib-prednisone; VD, bortezomib-dexamethasone;
Conclusion #1
• MP is not necessary
• Lenalidomide-dexamethasone and bortezomib-dexamethasone are effective and viable options
Argument #2
MP+ results in greater short term toxicity
Discontinuation reduces dose-intensityDiscontinuation reduces dose-intensity
3-drug 2-drug
Discontinuation %
65 - 75 years 17 10
> 75 years 34 16
Cumulative dose intensity %
65 - 75 years 88 97
> 75 years 56 97
3-drug 2-drug
Discontinuation %
65 - 75 years 17 10
> 75 years 34 16
Cumulative dose intensity %
65 - 75 years 88 97
> 75 years 56 97
Palumbo A, et al. EHA 2011;96:0514
Melphalan-prednisone-lenalidomide: MPR-R vs MPR vs MP
Melphalan-prednisone-lenalidomide: MPR-R vs MPR vs MP
R1:1:1
N = 459
•Newly diagnosed•Transplant-ineligible MM•Stratified by
– age (65–75 vs> 75 years)
– disease stage (ISS I/II vs III)
MPR-R (n = 152)M: 0.18 mg/kg, days 1–4P: 2 mg/kg, days 1–4R: 10 mg/day p.o., days 1–21
MPR (n = 153)M: 0.18 mg/kg, days 1–4P: 2 mg/kg, days 1–4R: 10 mg/day p.o., days 1–21
MP (n = 154)M: 0.18 mg/kg, days 1–4P: 2 mg/kg, days 1–4PBO: days 1–21
Dis
eas
e pr
ogre
ssio
n
Lena
lidom
ide
25 m
g/da
y ±
Dex
Double-blind treatment Open-label
Cycles (28-day) 1–9 Cycles 10+
Maintenance
Lenalidomide10 mg/day; days 1–21
Placebo
Placebo
* All patients received thromboprophylaxis during induction; thromboprophylaxis could be continued during maintenance at physician’s discretion.
Palumbo A, et al. N Engl J Med. 2012;366:1759-69.
MPR-R, melphalan-prednisone-lenalidomide followed by lenalidomide maintenance; MPR, melphalan-prednisone-lenalidomide; MP, melphalan-prednisone; PBO, placebo
MPR-R: landmark PFS analysis by ageMPR-R: landmark PFS analysis by age
Palumbo A, et al. Haematologica. 2011;S238:[abstract 514; presented at EHA 2011].
> 75 years of age
INDUCTION MAINTENANCE
Disc. for AEs
%
*Dose intensity - % Disc. for AEs
%
*Dose intensity - %
Len Mel Pred Len
28 76 85 89 17 87
INDUCTION MAINTENANCE
Disc. for AEs
%
*Dose intensity - % Disc. for AEs
%
*Dose intensity - %
Len Mel Pred Len
28 76 85 89 17 87
INDUCTION MAINTENANCE
Disc. for AEs
%
*Dose intensity - % Disc. for AEs
%
*Dose intensity - %
Len Mel Pred Len
12 88 91 94 8 92
INDUCTION MAINTENANCE
Disc. for AEs
%
*Dose intensity - % Disc. for AEs
%
*Dose intensity - %
Len Mel Pred Len
12 88 91 94 8 92
65-75 years of age
* Median relative dose
* Median relative dose
100 5 15 20 250
25
50
75
100
100 5 15 20 25100 5 15 20 250
25
50
75
100
0
25
50
75
100
HR 0.297p = 0.030
MPR-R
MPR
Lenalidomide continuous therapyMPR Lenalidomide continuous therapyMPR
Time (months)Cycle 10
HR 0.349p < 0.001
MPR-R
MPR
Time (months)Cycle 10
0 5 10 15 20 25 300
25
50
75
100
0 5 10 15 20 25 300 5 10 15 20 25 300
25
50
75
100
0
25
50
75
100
Lenalidomide continuous therapyMPR Lenalidomide continuous therapyMPR
New treatment algorithm for elderly MM
PATIENT STATUS ASSESSMENT
- Age
- ADL
- IADL
- Charlson co-morbidity score
FIT UNFIT FRAIL
Age <80 yr
ADL 6
IADL 8
Charlson 0
Fit >80 yr
ADL 5
IADL 6-7
Charlson 1
Unfit >80 yr
ADL ≤4
IADL ≤5
Charlson ≥2
Full-dose regimensDose level 0
Reduced-dose regimensDose level -1
Reduced-dose Palliative approach
Dose level -2
PATIENT STATUS ASSESSMENT
- Age
- ADL
- IADL
- Charlson co-morbidity score
FIT UNFIT FRAIL
Age <80 yr
ADL 6
IADL 8
Charlson 0
Fit >80 yr
ADL 5
IADL 6-7
Charlson 1
Unfit >80 yr
ADL ≤4
IADL ≤5
Charlson ≥2
Full-dose regimensDose level 0
Reduced-dose regimensDose level -1
Reduced-dose Palliative approach
Dose level -2
Go-go moderate-go slow-go
ADL, Activity of Daily Living; IADL, Instrumental Activity of Daily Living; ASCT, autologous stem cell transplantation
PATIENT STATUS ASSESSMENT
- Age > 80 years
- ADL, , Activity of Daily Living
- IADL, Instrumental Activity of Daily Living
- Charlson co-morbidity score
PATIENT STATUS ASSESSMENT
- Age > 80 years
- ADL, , Activity of Daily Living
- IADL, Instrumental Activity of Daily Living
- Charlson co-morbidity score
Rd Lenalidomide Dex; Vd Bortezomib Dex ; CCd Carfilzomib Cyclophosphamide Dex
MPVdMPVdMPRdMPRdlower frequency of SAE
better outcome in frail patients
• lower doses• 2 drug combination• 2 drugs 3 drugs or higher doses
CCdCCd
ConclusionConclusion
Conclusion #2
• 3 drug regimens that include melphalan are more toxic (and not necessarily more effective)
• Dose reduction is critical in the elderly
Argument #3
As survival is extended in myeloma, using melphalan upfront is not desirable due to marrow toxicity
CP1315995-1
Multiple Myeloma 1971-2006n=2,981
0.0
0.2
0.4
0.6
0.8
1.0
0 20 40 60 80 100 120 140
Pro
port
ion
surv
ivin
gP
ropo
rtio
n su
rviv
ing
Time from diagnosis (months)Time from diagnosis (months)
Kumar et al: Blood 111:2516, 2008Kumar et al: Blood 111:2516, 2008
Diagnosis after 1996Diagnosis after 1996
Diagnosis during/before 1996Diagnosis during/before 1996
P<0.001P<0.001
Survival, med44.8 moSurvival, med44.8 mo
Survival, med29.9 moSurvival, med29.9 mo
Multiple MyelomaMayo Patients
2001-2005
2006-2010
47%
66%P < 0.0001
S. Kumar, 2012
Argument #4
Melphalan can lead to increased second primary malignancies
Solid SPMs
Cumulative incidence (95% CI)
Lenalidomide onlyLenalidomide + cyclophosphamideLenalidomide + melphalan
Melphalan only
36 months 60 months
0.3 (0.0-0.07) 1.3 (0.0-2.7)0.3 (0.0-0.09) -1.8 (1.0-2.6) 3.9 (2.3-5.5)
0.4 (0.0-0.09) 1.4 (0.0-3.6)
Cumulative incidence (95% CI)
Lenalidomide only
Lenalidomide + cyclophosphamideLenalidomide + melphalan
Melphalan only
36 months 60 months
2.2 (0.7-3.7) 2.6 (0.9-4.3)
3.5 (0.0-8.3) -2.7 (1.8-3.7) 4.4 (2.9-5.8)
2.9 (1.4-4.4) 3.4 (1.6-5.2)
Cumulative incidence of SPMsDifferent lenalidomide combinations
Months
Hematologic SPMs
Months
0 20 40 60
Melphalan only
Lenalidomide only
Lenalidomide + cyclophosphamide
Lenalidomide + melphalan
Melphalan only
Lenalidomide only
Lenalidomide + cyclophosphamide
Lenalidomide + melphalan
HR 3.8 (95% CI 2.11-6.86), p<0.001
0
0.05
0.10
0.04
0.03
0.02
0.01
0.09
0.08
0.07
0.06
0
0.05
0.10
0.04
0.03
0.02
0.01
0.09
0.08
0.07
0.06
0 20 40 60 80
HR 1.09 (95% CI 0.73-1.63), p=0.67
0
0.05
0.10
0.04
0.03
0.02
0.01
0.09
0.08
0.07
0.06
0
0.05
0.10
0.04
0.03
0.02
0.01
0.09
0.08
0.07
0.06
Melphalan only
Lenalidomide only
Lenalidomide + cyclophosphamide
Lenalidomide + melphalan
Melphalan only
Lenalidomide only
Lenalidomide + cyclophosphamide
Lenalidomide + melphalan
Incidence rate per 100 per yearDifferent lenalidomide combinations
Hematologic SPMs
0 0,5 1 1,5 2
Melphalan only
Hematologic SPMs
0 0,5 1 1,5 2
Melphalan only
Lenalidomide + melphalanLenalidomide + melphalan
Lenalidomide + cyclophosphamideLenalidomide + cyclophosphamide
Lenalidomide onlyLenalidomide only
Lenalidomide + melphalanLenalidomide + melphalan
Lenalidomide + cyclophosphamideLenalidomide + cyclophosphamide
Lenalidomide onlyLenalidomide only
Solid SPMs
0 0,5 1 1,5 2
Melphalan only
Incidence Rate per 100 per year
Solid SPMs
0 0,5 1 1,5 2
Melphalan only
Incidence Rate per 100 per year
Cumulative incidence (95% CI) 36 months 60 months
Oral melphalan 2.8 (1.3-4.3) 7.2 (3.0-11.4)
IV melphalan (ASCT) 1 (0.1-1.8) 2 (0.5-3.5)
Cumulative incidence (95% CI) 36 months 60 months
Oral melphalan 2.8 (1.3-4.3) 7.2 (3.0-11.4)
IV melphalan (ASCT) 1 (0.1-1.8) 2 (0.5-3.5)
Cumulative incidence of hematologic SPMsOral versus high-dose intravenous melphalan
Len, lenalidomide; Mel, melphalan; IV, intravenous; ASCT, autologous stem cell transplantation
0 20 40 60 80
0
0.05
0.10
0.15
Months
Cu
mu
lativ
e In
cide
nce
Len + oral melphalan
Len + IV melphalan (ASCT)
HR: Oral Mel vs IV Mel 3.3 (1.46-7.46), p=0.004
Melphalan only
Lenalidomide only
0 20 40 60 80
0
0.05
0.10
0.15
Months
Cu
mu
lativ
e In
cide
nce
Len + oral melphalan
Len + IV melphalan (ASCT)
HR: Oral Mel vs IV Mel 3.3 (1.46-7.46), p=0.004
Melphalan only
Lenalidomide only
Incidence rate per 100 per yearOral versus high-dose intravenous melphalan
Solid SPMs
0 0,5 1 1,5 2
Melphalan only
Lenalidomide + IV melphalan (ASCT)
Lenalidomide + oral melphalan
Lenalidomide only
0 0,5 1 1,5 2
Melphalan only
Lenalidomide + IV melphalan (ASCT)
Lenalidomide + oral melphalan
Lenalidomide only
Incidence Rate per 100 per year
Hematologic SPMs
0 0,5 1 1,5 2
Melphalan only
Lenalidomide + IV melphalan (ASCT)
Lenalidomide + oral melphalan
Lenalidomide only
Melphalan only
Lenalidomide + IV melphalan (ASCT)
Lenalidomide + oral melphalan
Lenalidomide only
The “NEW” CyBorD• All three drugs given weekly
• Cyclophosphamide 300mg/m2 PO• Bortezomib 1.5 mg/m2 IV or SQ• Dexamethasone 40mg PO
• We consider one cycle a 4 week course
• No “week off”
• Less neuropathy, more convenience, equal efficacy
• Always give viral prophylaxis
Comment – I see CyBorD as a slight modification to VMP
Summary Points – Why Melphalan is no longer standard
of initial care in elderly patients
1. Novel agents are equivalent if not superior to MP+novel agent
2. MP+ results in greater short term toxicity
3. As survival is extended in myeloma, using melphalan upfront is not desirable due to marrow toxicity
4. Melphalan can lead to increased second primary malignancies
Quote – ASCO 2013 – Dr. Antonio Palumbo
“Gli Americani avevano ragione: non dobbiamo usare melphalan come terapia iniziale nei pazienti anziani”
“The Americans were right – we should not use melphalan upfront in elderly patients”
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