Which regimens are best Suzanne Lentzsch MD PhD Columbia University New York Disclosures for Suzanne Lentzsch MD PhD Honoraria Scientific Advisory Board Speakers Bureau No relevant conflicts of interest to declare ID: 431965
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Slide1
Update on transplant-ineligible patients: Which regimens are best?
Suzanne Lentzsch MD, PhDColumbia University, New YorkSlide2
Disclosures for Suzanne Lentzsch, MD, PhD
HonorariaScientific Advisory BoardSpeakers BureauNo relevant conflicts of interest to declare
Major Stockholder
Consultant
No relevant conflicts of interest to declare
Employee
Celgene
Research Support/P.I.
No relevant conflicts of interest to declare
Amgen, Bristol-Myers Squibb,
Celgene
, Janssen,
Millenium
, Onyx
No relevant conflicts of interest to declare
No relevant conflicts of interest to declareSlide3
Treatment Decision in Older Patients
PatientsADLIADLComorbiditiesHospitalizationMedicationsSocial SupportMultiple Myeloma CytogeneticsStage
Tumor burden
Optimal Chemo
Supportive
meds
Goals of Care (CR
vs
Disease Control?)
Expectations
Understanding
Life ExpectancySlide4
Treatment Decision in Transplant I
neligible Patients Frailty ???Melphalan based regimens ???Doublets ???Triplets ???Maintenance ??? Slide5
Frailty score
VariableHR (CI 95%)
P
SCORE
AGE
Age <75 years
1
-
0
Age 75-80 years
1.37 (0.93-2.03)
0.114
1
Age >80 years
2.75 (1.81-4.18)
<0.001
2
CHARLSON INDEX
Charlson
<
1
1
-
0
Charlson
>
2
1.6 (1.07-2.39)
0.021
1
ADL SCORE
ADL >4
1
-
0
ADL
<
4
1.76 (1.14-2.71)
0.01
1
IADL SCORE
IADL >5
1
-
0
IADL
<51.53 (1.03-2.27)0.0361
ADDITIVE TOTAL SCOREPATIENT STATUS0FIT1UNFIT>2FRAIL
Slide courtesy of Palumbo, ASH 2013Slide6
Patients (%)
Overall
Survival
Multivariate Analysis
Lower
risk
Death
FIT
ISS
1-2
FISH
neg
Fit vs. Unfit vs.
Frail
Fit
defined as: score=0 Unfit defined as: score=1 Frail defined as: score
>
2
1-yr OS
Fit
96%
Unfit
93%
Frail
78%
Unfit
vs
Fit
Frail
vs
Fit
ISS 3 vs ISS 1-2
HR vs SR
Fish
ECOG 2-3 vs 0-1
1.24
(0.74,
2.08)
3.11
(1.97,
4.90)
1.77
(1.23,
2.54)1.83 (1.26, 2.63)1.19 (0.81, 1.76)Higher risk DeathFRAIL ISS 3FISH pos
Unfit vs Fit, HR=1.61 p=0.042Frail vs Fit, HR=3.57 p<0.001Slide courtesy of Palumbo, ASH 2013Slide7
Slide courtesy of Palumbo, ASH 2013Slide8
PATIENT STATUS ASSESSMENT
Age (score 0 – 1 – 2) Charlson (score 0 – 1)
ADL (score 0 – 1) IADL (score 0 – 1)
FIT
UNFIT
FRAIL
Additive total score = 0
Additive total score = 1
Additive total score
≥ 2
GO-GO
MODERATE-GO
SLOW-GO
Full-dose
Reduced-dose
Further reduced dose
Dose level 0
Dose level -1
Dose level -2
Lenalidomide
25 mg/d
15 mg/d
10 mg/d
Bortezomib
1.3 mg/m
2
/wk
1.0 mg/m
2
/wk
1.3 mg/m
2
/2wk
Dexamethasone
40 mg/wk
20 mg/wk
10 mg/wk
Cyclophosphamide
300 mg/m
2
d 1,8,15
50 mg/d
50 mg/
qod
T
reatment
algorithm for elderly MM
Slide courtesy of Palumbo, ASH 2013Slide9
Unanswered Question for Transplant Ineligible Patients
Frailty-Adjust Treatment IntensityMelphalan ???Doublets ???Triplets ???Maintenance ??? Slide10
MP better
MPT betterProgression-free survivalMPT betterMP betterOverall survival
NOTE: weights are from random effects analysis
Overall
(I-squared = 61.7%,
p = 0.023)
FR < 75
NMSG
HOVON
Italy
Fr
≥ 75
Turkey
Study
0.67 (0.55– 0.80)
0.50 (0.39– 0.65)
0.89 (0.70–1.13)
0.79 (0.62–1.00)
0.62 (0.48–0.80)
0.61 (0.46–0.82)
0.59 (0.35–0.99)
HR (95% CI)
HR (95% CI)
1
0.5
0.75
1.5
NOTE: weights are from random effects analysis
Overall
(I-squared = 60.6%,
p = 0.026)
NMSG
Study
Italy
FR < 75
HOVON
Fr
≥ 75
Turkey
0.82 (0.66–1.02)
1.12 (0.85–1.47)
HR (95% CI)
1.04 (0.75–1.44)
0.61 (0.45– 0.81)
0.75 (0.57–1.00)0.68 (0.48– 0.96)0.87 (0.46–1.67)HR (95% CI)
10.50.75
1.5
Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials
Fayers
P M et al. Blood 2011;118:1239-1247Slide11
MPT
MPmOS39.3
m
32.7 m
mPFS
20.3 m
14.9 m
Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials
Fayers
P M et al. Blood 2011;118:1239-1247Slide12
Overall survival
in
patients
randomized to
bortezomib
-
melphalan
-prednisone (VMP) or
melphalan
-prednisone (MP) after a median follow-up of 5
years
San Miguel J F et al. JCO 2013;31:448-455Slide13
Wildes
T M et al. JCO 2014;32:2531-2540
Abbreviations: MM, multiple myeloma; MP,
melphalan
and prednisone; MPR,
melphalan
, prednisone, and
lenalidomide
; MPR-R,
melphalan
, prednisone, and
lenalidomide
with
lenalidomide
maintenance; MPT, melphalan, prednisone, and thalidomide; MPV, melphalan, prednisone, and bortezomib
; NR, not reported; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide and low-dose dexamethasone; RD, lenalidomide and high-dose dexamethasone. ↵* Discontinuation rate because of toxicity, specifically during induction where applicable. Global (ie, “any” or “
nonhematologic”) toxicity incidence not reported. ↵† Statistically significant for MPR-R v MP and MPR-R v MPR only.
Initial Therapy in Older Adults With MM: Randomized Trials of MP With or Without the Addition of Novel AgentsSlide14
Unanswered Question for Transplant Ineligible Patients
Frailty – Adjust Treatment IntensityMelphalan or Novel Drugs ???Doublets or Triplets ???Maintenance ??? Slide15
Efficacy and Safety of Three
Bortezomib-Based Induction and Maintenance Regimens in Previously Untreated, Transplant-Ineligible Multiple Myeloma Patients: Final Results from the Randomized, Phase 3b, US Community-Based UPFRONT Study
Slide Courtesy
Niesvizky
,
R
;
ASH 2013Slide16
RESULTSPatients502 patients were randomized to
VD (n=168), VTD (n=167), VMP (n=167)Baseline characteristics were well balanced across the treatment armsMedian age was 73 years (range 38–91)48% of patients had comorbidities at baselineThe most common were diabetes mellitus (21%), renal disease (15%), and chronic pulmonary disease (8%)Slide Courtesy Niesvizky, R; ASH 2013Slide17
Response* ORRs after 13 cycles were 73% (VD), 80% (VTD), and 70% (VMP) including:
30%, 40%, and 32% CR/nCR, respectively37%, 51%, and 41% ≥VGPR, respectively*Response-evaluable population (n=425 patients who received at least one dose of study drug, had measurable disease at baseline, and had at least one post-baseline M-protein measurement)Best confirmed response after 8 (induction) and 13 (induction + maintenance) cycles Slide Courtesy Niesvizky, R; ASH 2013Slide18
PFS (intent-to-treat population) After a median follow-up of 42.7 months, 265 (53%) patients had progressed and/or died
Median PFS (95% CI) was 14.7 months (12.0, 18.6), 15.4 months (12.6, 24.2), and 17.3 months (14.8, 20.3), for VD, VTD, and VMP, respectively, with no global difference among arms (p=0.458)Slide Courtesy Niesvizky, R; ASH 2013Slide19
OS (intent-to-treat population)Median OS (95% CI) was 49.8 months (35.7, not estimable [NE]),
51.5 months (38.5, NE), and 53.1 months (41.1, NE) for VD, VTD, and VMP, respectively, with no global difference among arms (p=0.789)Slide Courtesy Niesvizky, R;
ASH 2013Slide20
UPFRONT TRIAL CONCLUSIONSAfter ~3.5 years’ follow-up, no significant differences in PFS or OS were seen among arms
VTD had the highest toxicity rates and the lowest mean bortezomib dose intensity among the armsVD doublet therapy may be as effective as VTD or VMP triplet therapy in elderly pat (due less toxicity with higher bortezomib intensity?)In accordance with: Recent analysis of VMP data from VISTA suggests that a higher cumulative bortezomib dose, reflecting prolonged treatment duration and/or dose intensity, is associated with superior OS (Mateos MV, et al. ASH 2013, abstract #2155)Slide Courtesy Niesvizky, R; ASH 2013Slide21
Unanswered Question for Transplant Ineligible P
atients Frailty – Adjust Treatment IntensityMelphalan or Novel Drugs!Doublets! or Triplets Maintenance ??? Slide22
Facon T, et al. Blood. 2013;122:abstract 2.
RANDOMIZATION 1:1:1
Arm B
Rd18
Arm C
MPT
LEN + Lo-DEX: 18 Cycles (72 wks)
LENALIDOMIDE 25mg D1-21/28
Lo-DEX 40mg D1,8,15 & 22/28
MEL + PRED + THAL 12 Cycles
1
(72 wks)
MELPHALAN 0.25mg/kg D1-4/42
PREDNISONE 2mg/kg D1-4/42
THALIDOMIDE 200mg D1-42/42
PD, OS and
Subsequent anti-MM Tx
PD or Unacceptable Toxicity
Active Treatment + PFS Follow-up Phase
Screening
LT Follow-Up
Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL
2
(100 mg D1-42/42); MEL
2
0.2 mg/kg D1–4
Stratification: age, country and ISS stage
1
Facon T, et al. Lancet
2007;370:1209-18
;
2
Hulin C, et al. JCO.
2009;27:3664-70.
FIRST Trial: Study Design
LEN + Lo-DEX Continuously
LENALIDOMIDE 25mg D1-21/28
Lo-DEX 40mg D1,8,15 & 22/28
Arm A
Continuous Rd
ISS,
International Staging System; LT, long-term; PD, progressive disease; OS, overall survival
Benboubker
L et al. N
Engl
J Med 2014;371:906-917.Slide23
mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone.
Median PFSRd (n=535)
25.5 mos
Rd18 (n=541)
20.7 mos
MPT (n=547)
21.2 mos
Rd
535
400
319
265
218
168
105
55
19
2
0
Rd18
541
391
319
265
167
108
56
30
7
2
0
MPT
547
380
304
244
170
116
58
28
6
1
0
Hazard ratio
Rd vs. MPT: 0.72;
P
= 0.00006
Rd vs. Rd18: 0.70; P = 0.00001 Rd18 vs. MPT: 1.03; P = 0.70349
Time (months)
Patients (%)
100
80
60
40
20
0
0
6
12
18
24
30
36
42
48
54
60
72 wks
FIRST Trial: Final Progression-free Survival
28% reduced risk of disease progression
Benboubker
L et al. N
Engl
J Med 2014;371:906-917.Slide24
FIRST Trial: Overall Survival Interim Analysis
Patients (%)RdRd18MPT535541547
488
505
484
457
465
448
433
425
418
403
393
375
338
324
312
224
209
205
121
124
106
43
44
30
5
6
3
0
0
0
4-year OS
Rd (n= 535)
59%
Rd18 (n= 541)
56%
MPT (n= 547)
51%
Overall survival (months)
100
80
60
40
20
0
0
6
12
18
24
30
36
42
48
54
60
Hazard ratio
Rd vs. MPT: 0.78;
P
=
0.02
Rd vs. Rd18: 0.90;
P
=
0.31
Rd18 vs. MPT: 0.88;
P
=
0.18
Benboubker
L et al. N
Engl
J Med 2014;371:906-917.
574 deaths (35% of ITT)Slide25
Response
a (%)Continuous Rd (n=535)Rd18
(n=541)
MPT
(n=547)
ORR (
≥ PR)
b
75
73
62
CR
15
14
9
VGPR
28
28
19
PR
32
31
34
SD
19
21
27
VGPR or better
43
42
28
Time to response (median,
mos
)
1.8
1.8
2.8
Duration of response (median,
mos
)
35.0
22.1
22.3
FIRST Trial: Response Endpoints
a
IMWG
Criteria; CR, complete response; mos, months ORR, overall response rate; PR, partial response; SD, stable disease; VGPR, very good PR. bResponse assessment for Rd obtained every 4 wks and for MPT every 6 wks; Response and progression rate based on IRAC assessment. Benboubker L et al. N Engl J Med 2014;371:906-917.Slide26
FIRST Trial: ConclusionsContinuous Rd significantly extended PFS
and OS vs. MPTPFS: HR= 0.72 (P= 0.00006)Consistent benefit across most subgroupsRd better than Rd18 (HR= 0.70, P= 0.00001)3 yr PFS: 42% Rd vs 23% Rd18 and MPTPlanned interim OS: HR= 0.78 (P= 0.0168)Rd was superior to MPT across all other efficacy secondary endpointsSafety profile with continuous Rd was manageable Hematological and non-hematological AEs were as expected for Rd and MPTIncidence of hematological SPM was lower with continuous Rd vs. MPTIn NDMM transplant-ineligible patients, the FIRST Trial establishes continuous Rd as a new standard of care
Benboubker
L et al. N
Engl
J Med 2014;371:906-917.Slide27
Unanswered Question for Transplant Ineligible Patients
Frailty – Adjust Treatment IntensityMelphalan or Novel Drugs !!Doublets or Triplets !!Maintenance !! Slide28
Palumbo A et al. JCO 2014;32:634-640
Bortezomib
-
Melphalan
-Prednisone Followed by Maintenance With
Bortezomib
-Thalidomide (VMP-VT) Compared With
Bortezomib
-
Melphalan
-Prednisone (VMP) for Initial Treatment of Multiple Myeloma
N=511Slide29
Survival outcomes in the intention-to-treat population, according to study group.
PFS
OS
TNT
OS after Relapse
Palumbo A et al. JCO 2014;32:634-640Slide30
VMP vs. VMPT-VT: 3-year PFS: 41
% vs 56% median PFS: 24.8 vs 35.3 months (P .001)TNT 27.8 vs 46.6 months (P .001)5-year overall survival (OS) was greater with VMPT-VT (61%) than with VMP (51%; HR, 0.70; P .01). VMPT-VT group, more grade 3 to 4 adverse events including neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%). ConclusionBortezomib and thalidomide maintenance significantly improved OS in multiple myeloma patientsVT-Maintenance for Non-Transplant Patients
Palumbo A et al. JCO 2014;32:634-640Slide31
UnAnswered Question for Transplant Ineligible Patients?
Frailty Adjust Treatment IntensityDetermine the goals of care !!Melphalan or Novel Drugs !!Doublets or Triplets !!Less toxic treatment allows longer treatment
Maintenance !! Slide32
32
Thank You !!