Update on transplantineligible patients:
Which regimens are best?
Suzanne Lentzsch MD, PhD
Columbia University, New York
Disclosures for
Suzanne Lentzsch, MD, PhD
Research Support/P.I.
Celgene
Employee
No relevant conflicts of interest to declare
Consultant
No relevant conflicts of interest to declare
Major Stockholder
No relevant conflicts of interest to declare
Speakers Bureau
No relevant conflicts of interest to declare
Honoraria
No relevant conflicts of interest to declare
Scientific Advisory Board
Amgen, Bristol-Myers Squibb, Celgene,
Janssen, Millenium, Onyx
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?)
Expectations
Understanding
Life Expectancy
Treatment Decision in Transplant
Ineligible Patients
• Frailty ???
• Melphalan based regimens ???
• Doublets ???
• Triplets ???
• Maintenance ???
Frailty score
Variable
AGE
HR (CI 95%)
P
SCORE
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 <1
1
-
0
Charlson >2
1.6 (1.07-2.39)
0.021
1
ADL >4
1
-
0
ADL<4
1.76 (1.14-2.71)
0.01
1
IADL >5
1
-
0
IADL<5
1.53 (1.03-2.27)
0.036
1
Age <75 years
CHARLSON INDEX
ADL SCORE
IADL SCORE
ADDITIVE TOTAL SCORE
PATIENT STATUS
0
FIT
1
UNFIT
>2
FRAIL
Slide courtesy of Palumbo, ASH 2013
Fit vs. Unfit vs. Frail
Patients (%)
Overall Survival
1-yr OS
Fit
96%
Unfit
93%
Frail
78%
Unfit vs Fit, HR=1.61 p=0.042
Frail vs Fit, HR=3.57 p<0.001
Fit defined as: score=0
Multivariate Analysis
Unfit vs Fit
1.24 (0.74, 2.08)
Frail vs Fit
3.11 (1.97, 4.90)
ISS 3 vs ISS 1-2
1.77 (1.23, 2.54)
HR vs SR Fish
1.83 (1.26, 2.63)
ECOG 2-3 vs 0-1
1.19 (0.81, 1.76)
Lower risk Death
FIT
ISS 1-2
FISH neg
Higher risk Death
FRAIL
ISS 3
FISH pos
Unfit defined as: score=1 Frail defined as: score>2
Slide courtesy of Palumbo, ASH 2013
Slide courtesy of Palumbo, ASH 2013
Treatment algorithm for elderly MM
PATIENT STATUS ASSESSMENT
Age (score 0 – 1 – 2)
Charlson (score 0 – 1)
ADL (score 0 – 1)
FIT
UNFIT
FRAIL
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
25 mg/d
15 mg/d
10 mg/d
1.3 mg/m2/wk
1.0 mg/m2/wk
1.3 mg/m2/2wk
40 mg/wk
20 mg/wk
10 mg/wk
300 mg/m2 d 1,8,15
50 mg/d
50 mg/qod
Additive total score = 0
Lenalidomide
Bortezomib
Dexamethasone
Cyclophosphamide
IADL (score 0 – 1)
Slide courtesy of Palumbo, ASH 2013
Unanswered Question for Transplant
Ineligible Patients
• Frailty-Adjust Treatment Intensity
• Melphalan ???
• Doublets ???
• Triplets ???
• Maintenance ???
Thalidomide for previously untreated elderly patients with
multiple myeloma: meta-analysis of 1685 individual patient
data from 6 randomized clinical trials
Progression-free survival
Study
MPT better
HR (95% CI)
MP better
Overall survival
Study
MPT better
HR (95% CI)
MP better
FR < 75
0.50 (0.39– 0.65)
FR < 75
0.61 (0.45– 0.81)
Turkey
0.59 (0.35–0.99)
0.68 (0.48– 0.96)
Fr ≥ 75
0.61 (0.46–0.82)
Fr ≥ 75
HOVON
Italy
0.62 (0.48–0.80)
Turkey
0.87 (0.46–1.67)
HOVON
0.79 (0.62–1.00)
Italy
1.04 (0.75–1.44)
NMSG
0.89 (0.70–1.13)
NMSG
1.12 (0.85–1.47)
Overall
(I-squared = 61.7%,
p = 0.023)
0.67 (0.55– 0.80)
Overall
(I-squared = 60.6%,
p = 0.026)
0.82 (0.66–1.02)
0.5 0.75 1
1.5
NOTE: weights are from random effects analysis
0.75 (0.57–1.00)
0.5
0.75 1
1.5
NOTE: weights are from random effects analysis
Fayers P M et al. Blood 2011;118:1239-1247
Thalidomide for previously untreated elderly patients with
multiple myeloma: meta-analysis of 1685 individual patient
data from 6 randomized clinical trials
MPT
MP
mOS
39.3 m
32.7 m
mPFS
20.3 m
14.9 m
Fayers P M et al. Blood 2011;118:1239-1247
Overall survival in patients randomized to bortezomibmelphalan-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
Initial Therapy in Older Adults With MM: Randomized
Trials of MP With or Without the Addition of Novel Agents
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.
Wildes T M et al. JCO 2014;32:2531-2540
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
RESULTS
Patients
• 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
Best confirmed response after 8 (induction) and
13 (induction + maintenance) cycles
*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)
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 ???
FIRST Trial: Study Design
Active Treatment + PFS Follow-up Phase
Arm B
Rd18
LEN + Lo-DEX: 18 Cycles (72 wks)
Arm C
MPT
LENALIDOMIDE
Lo-DEX
LENALIDOMIDE
Lo-DEX
25mg D1-21/28
40mg D1,8,15 & 22/28
25mg D1-21/28
40mg D1,8,15 & 22/28
MEL + PRED + THAL 12 Cycles1 (72 wks)
MELPHALAN
PREDNISONE
THALIDOMIDE
0.25mg/kg D1-4/42
2mg/kg D1-4/42
200mg D1-42/42
Subsequent anti-MM Tx
LEN + Lo-DEX Continuously
PD, OS and
Arm A
Continuous Rd
LT Follow-Up
PD or Unacceptable Toxicity
RANDOMIZATION 1:1:1
Screening
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
ISS, International Staging System; LT, long-term; PD, progressive disease; OS, overall survival
1Facon
T, et al. Lancet 2007;370:1209-18; 2Hulin C, et al. JCO. 2009;27:3664-70.
Facon T, et al. Blood. 2013;122:abstract 2.
Benboubker L et al. N Engl J Med 2014;371:906-917.
FIRST Trial: Final Progression-free Survival
100
Rd
80
Patients (%)
Median PFS
28% reduced risk of disease progression
(n=535)
25.5 mos
Rd18 (n=541)
20.7 mos
MPT (n=547)
21.2 mos
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
60
40
72 wks
20
0
0
6
12
18
24
30
36
42
48
54
60
Time (months)
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
mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone.
Benboubker L et al. N Engl J Med 2014;371:906-917.
FIRST Trial: Overall Survival Interim Analysis
100
4-year OS
Rd
Patients (%)
80
(n= 535)
59%
Rd18 (n= 541)
56%
MPT (n= 547)
51%
60
40
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
20
574 deaths (35% of ITT)
0
Rd
Rd18
MPT
0
6
12
18
24
30
36
42
Overall survival (months)
535
541
547
488
505
484
457
465
448
433
425
418
403
393
375
338
324
312
224
209
205
121
124
106
48
54
60
43
44
30
5
6
3
0
0
0
Benboubker L et al. N Engl J Med 2014;371:906-917.
FIRST Trial: Response Endpoints
Continuous Rd
(n=535)
Rd18
(n=541)
MPT
(n=547)
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
Responsea (%)
ORR (≥ PR)b
aIMWG
Criteria; CR, complete response; mos, months ORR, overall response rate; PR, partial response; SD, stable disease; VGPR, very good PR.
assessment for Rd obtained every 4 wks and for MPT every 6 wks; Response and progression rate based on IRAC assessment.
bResponse
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 !!
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
Palumbo A et al. JCO 2014;32:634-640
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
VT-Maintenance for Non-Transplant Patients
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%).
Conclusion
Bortezomib and thalidomide maintenance significantly improved
OS in multiple myeloma 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 !!
3
2
Thank You !!