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Update on transplant-ineligible patients: Which regimens are best?. Suzanne Lentzsch MD, PhD Columbia University, New York. Research Support/P.I. Celgene. Employee. No relevant conflicts of interest to declare. Consultant. Major Stockholder. No relevant conflicts of interest to declare. - PowerPoint PPT Presentation
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Update on transplant-ineligible patients: 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 declareMajor Stockholder
Consultant
No relevant conflicts of interest to declareEmployee
CelgeneResearch 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 declare
Treatment Decision in Older Patients
Patients• ADL• IADL• Comorbidities• Hospitalization• Medications• Social Support
Multiple Myeloma • Cytogenetics• Stage• Tumor burden• Optimal Chemo• Supportive meds
Goals of Care (CR vs Disease Control?) ExpectationsUnderstandingLife Expectancy
Treatment Decision in Transplant Ineligible Patients
• Frailty ???
• Melphalan based regimens ???
• Doublets ???
• Triplets ???
• Maintenance ???
Frailty score
Variable HR (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<5 1.53 (1.03-2.27) 0.036 1
ADDITIVE TOTAL SCORE PATIENT STATUS
0 FIT
1 UNFIT
>2 FRAIL Slide courtesy of Palumbo, ASH 2013
Pat
ien
ts (
%)
Overall Survival Multivariate Analysis
Lower risk DeathFIT
ISS 1-2FISH 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 3
FISH pos
Unfit vs Fit, HR=1.61 p=0.042
Frail vs Fit, HR=3.57 p<0.001
Slide courtesy of Palumbo, ASH 2013
Slide courtesy of Palumbo, ASH 2013
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/m2/wk 1.0 mg/m2/wk 1.3 mg/m2/2wk
Dexamethasone 40 mg/wk 20 mg/wk 10 mg/wk
Cyclophosphamide 300 mg/m2 d 1,8,15 50 mg/d 50 mg/qod
Treatment algorithm for elderly MM
Slide courtesy of Palumbo, ASH 2013
Unanswered Question for Transplant Ineligible Patients
• Frailty-Adjust Treatment Intensity
• Melphalan ???
• Doublets ???
• Triplets ???
• Maintenance ???
MP betterMPT better
Progression-free survival
MPT better MP better
Overall 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)
10.5 0.75 1.5
NOTE: weights are from random effects analysis
Overall (I-squared = 60.6%, p = 0.026)
NMSG
Study
Italy
FR < 75
HOVONFr ≥ 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)
10.5 0.75 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;118:1239-1247
MPT MP
mOS 39.3 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;118:1239-1247
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;31:448-455
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 Agents
Unanswered Question for Transplant Ineligible Patients
• Frailty – Adjust Treatment Intensity
• Melphalan or Novel Drugs ???
• Doublets or Triplets ???
• Maintenance ???
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 2013
RESULTSPatients
• 502 patients were randomized to – VD (n=168),
– VTD (n=167),
– VMP (n=167)
• Baseline characteristics were well balanced across the treatment arms
– Median age was 73 years (range 38–91)
– 48% of patients had comorbidities at baseline
• The most common were diabetes mellitus (21%), renal disease (15%), and chronic pulmonary disease (8%)
Slide Courtesy Niesvizky, R; ASH 2013
Response*
• ORRs after 13 cycles were 73% (VD), 80% (VTD), and 70% (VMP) including:– 30%, 40%, and 32% CR/nCR, respectively– 37%, 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 2013
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 2013
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 2013
UPFRONT TRIAL CONCLUSIONS
• After ~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 arms
• VD 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 2013
Unanswered Question for Transplant Ineligible Patients
• Frailty – Adjust Treatment Intensity
• Melphalan or Novel Drugs!
• Doublets! or Triplets
• Maintenance ???
Facon T, et al. Blood. 2013;122:abstract 2.
RA
ND
OM
IZA
TIO
N 1
:1:1
Arm BRd18
Arm CMPT
LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28
MEL + PRED + THAL 12 Cycles1 (72 wks)MELPHALAN 0.25mg/kg D1-4/42PREDNISONE 2mg/kg D1-4/42THALIDOMIDE 200mg D1-42/42
PD
, OS
an
d
Su
bse
qu
ent
anti
-MM
Tx
PD
or
Un
acce
pta
ble
To
xici
ty
Active Treatment + PFS Follow-up PhaseScreening LT Follow-Up
Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 (100 mg D1-42/42); MEL2 0.2 mg/kg D1–4
• Stratification: age, country and ISS stage
1Facon T, et al. Lancet 2007;370:1209-18; 2Hulin C, et al. JCO. 2009;27:3664-70.
FIRST Trial: Study Design
LEN + Lo-DEX ContinuouslyLENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28
Arm AContinuous 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.
mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone.
Median PFS
Rd (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)
Pat
ien
ts (
%)
100
80
60
40
20
00 6 12 18 24 30 36 42 48 54 60
72 w
ks
FIRST Trial: Final Progression-free Survival
28% reduced risk of disease progression
Benboubker L et al. N Engl J Med 2014;371:906-917.
FIRST Trial: Overall Survival Interim AnalysisP
atie
nts
(%
)
RdRd18MPT
535541547
488505484
457465448
433425418
403393375
338324312
224209205
121124106
434430
563
000
4-year OS
Rd (n= 535)
59%
Rd18 (n= 541)
56%
MPT (n= 547)
51%
Overall survival (months)
100
80
60
40
20
00 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)
Responsea (%)
Continuous Rd
(n=535)Rd18
(n=541)MPT
(n=547)
ORR (≥ PR)b75 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
aIMWG 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.
FIRST Trial: Conclusions
• Continuous Rd significantly extended PFS and OS vs. MPT– PFS:
• HR= 0.72 (P= 0.00006)• Consistent benefit across most subgroups• Rd better than Rd18 (HR= 0.70, P= 0.00001)• 3 yr PFS: 42% Rd vs 23% Rd18 and MPT
– Planned interim OS: HR= 0.78 (P= 0.0168)– Rd was superior to MPT across all other efficacy secondary endpoints
• Safety profile with continuous Rd was manageable – Hematological and non-hematological AEs were as expected for Rd and
MPT– Incidence of hematological SPM was lower with continuous Rd vs. MPT
• In 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.
Unanswered Question for Transplant Ineligible Patients
• Frailty – Adjust Treatment Intensity
• Melphalan or Novel Drugs !!
• Doublets or Triplets !!
• Maintenance !!
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=511
Survival outcomes in the intention-to-treat population, according to study group.
PFS
OS
TNT
OS after Relapse
Palumbo A et al. JCO 2014;32:634-640
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 patients
VT-Maintenance for Non-Transplant Patients
Palumbo A et al. JCO 2014;32:634-640
UnAnswered Question for Transplant Ineligible Patients?
• Frailty – Adjust Treatment Intensity– Determine the goals of care !!
• Melphalan or Novel Drugs !!
• Doublets or Triplets !!– Less toxic treatment allows longer treatment
• Maintenance !!
32
Thank You !!