Meu paciente realizou um TACTH na 1a linha, e agora...
Transcript of Meu paciente realizou um TACTH na 1a linha, e agora...
Meu paciente realizou um TACTH na 1a linha, e agora? Tandem, Manutenção, Consolidação?
Marcelo C Pasquini, MD, MS
Medical College of Wisconsin
Post Auto HCT Options for MM
• Maintenance Lenalidomide vs. no maintenance
• Bortezomib maintenance
• Consolidation (Second HCT or triple drug combination)
• Considerations:
– Patient-, response-, or risk adapted-therapy
Lenalidomide Maintenance
4
CALGB 100104: A Phase III Randomized, Double-
Blind Study of LEN vs PBO Maintenance Therapy
Following ASCT for MM
McCarthy PL, et al. N Engl J Med. 2012;366:1770-1781.
5
CALGB 100104: Study Design and
Endpoints
• Primary endpoint: TTP (time from ASCT to PD/death)
• Secondary endpoints: OS, post-ASCT response, long-term LEN
feasibility
a All patients received thromboprophylaxis; b LEN dose adjustments between 5-15 mg permitted.
ASCT, autologous stem cell transplant; β2-M, β2-microglobulin; CALGB, Cancer and Leukemia Group B; CR, complete response; LEN, lenalidomide; MEL200, melphalan 200
mg/m2; MR, minimal response; OS, overall survival; PD, progressive disease; PR, partial response; R, randomization; SD, stable disease; THAL, thalidomide; TTP, time to
progression; Tx, treatment.
McCarthy PL. N Engl J Med. 2012;366:1770-1781.
R 1:1CR, PR,
MR, SDPlacebo
(n = 229)
MEL200
ASCT
N = 460
• ≤ 70 years of age
• ≤ 1 yr from start of Tx
• Stratified by β2-M and
THAL and LEN use
during induction
LEN
10 mg/dayb
(n = 231)
MaintenanceaRestaging(Within 100 days)
6
CALGB: OS From Randomization
Holstein S, et al. ASCO 2015. Abstr 8523.
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60 72 84 96 108
Pro
po
rtio
n o
f P
ati
en
ts
Overall Survival Time (months)
1: Lenalidomide
2: Placebo
Lenalidomide vs Placebo
Log-rank p-value =<0.001 (2-sided)
HR (95% CI) 0.565 (0.419, 0.761)
KM median Lenalidomide=NE [NE, NE]
KM median Placebo=79.04 [70.17, 88.37]
Events Lenalidomide =72/231 Placebo=109/229
1 231 223 213 195 178 160 90 38 15 1
2 229 215 196 171 157 124 75 24 7 0
Number of Subjects at Risk:
7
CALGB 100104
2015/2016 Analysis
Revlimid® (lenalidomide) [package insert]. Summit, NJ: Celgene Corporation. 2017.
8
CALGB 100104: Progression-Free Survival
CALGB, Cancer and Leukemia Group B; HR, hazard ratio; LEN, lenalidomide; PBO, placebo; PFS, progression-free survival.
Revlimid (lenalidomide) [package insert]. Summit, NJ: Celgene Corporation. 2017.
• At the updated data cut-off (median follow-up 72.4 months), LEN
maintenance prolonged median PFS vs placebo
Cut-off: March 1, 2015
PFS, months
1.0
0.8
0.6
0.4
0.2
0.0
0 12 24 36 48 60 72 84 96 108
Su
rviv
al P
rob
ab
ilit
y
HR (95% CI): 0.38 (0.28, 0.50)
Number of patients at risk:
LEN 231 194 158 121 102 82 40 16 5 0
PBO 229 116 57 29 20 18 11 3 0
Median PFS Events, n (%)
LEN 68.6 months 97 (42)
PBO 22.5 months 116 (51)
9
CALGB 100104: Overall Survival
• With a median follow-up of 81.6 months at a Feb 1, 2016, cut-off, LEN
maintenance prolonged OS vs placebo
CALGB, Cancer and Leukemia Group B; HR, hazard ratio; LEN, lenalidomide; NE, not estimable; OS, overall survival.
Revlimid (lenalidomide) [package insert]. Summit, NJ: Celgene Corporation. 2017.
OS at Updated Analysis (1 Feb 2016)LEN
(n = 231)
Placebo
(n = 229)
OS events, n (%) 82 (35) 114 (50)
Median, months (95% CI) 111.0 (101.8-NE) 84.2 (71.0-102.7)
HR (95% CI) 0.59 (0.44-0.78)
10
IFM 2005-02: Maintenance Treatment With
Lenalidomide After Transplantation for MM
Attal M, et al. N Engl J Med. 2012;366:1782-1791.
IFM, Intergroupe Francophone du Myélome; MM, multiple myeloma.
11
IFM 2005-02: Study Design and
Endpoints• Primary endpoint: PFS
• Secondary endpoints: response rate, EFS, OS
• Approximately 60% of pts came from study IFM 2005-01
a As measured by FISH; b Consolidation phase added at first protocol amendment (Sept 2006).
ASCT, autologous stem cell transplant; β2-M, β2-microglobulin; del, deletion; EFS, event-free survival; FISH, fluorescence in situ hybridization; IFM, Intergroupe Francophone du
Myélome; LEN, lenalidomide; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PFS, progression-free survival; pts, patients; R, randomization; SD, stable
disease; VGPR, very good partial response.
Attal M. N Engl J Med. 2012;366:1782-1791.
LEN 25 mg/day
days 1-21
Placebo
(n = 307)
N = 614
• NDMM; < 65 yrs of age
• ≥ SD within 6 months
of ASCT
• Stratified according to
β2-M (≤ 3 or > 3,
del(13),a ≥ VGPR post-
ASCT
LEN
10-15 mg daily
(n = 307)
Maintenanceuntil progression
Consolidationb
2 × 28-day cycles
R 1:1
12
IFM 2005-02
2015/2016 Analysis
Revlimid (lenalidomide) [package insert]. Summit, NJ: Celgene Corporation. 2017.
Lenalidomide improves TTP and OS
Intent-to-treat analysis, data cut-off Oct 2016Median follow-up for OS of 91 mosPrimary Objective: TTP (PFS); Secondary Objectives: OS, CR, Toxicity Lancet Haematology 4:e431-442, 2017
Median: 113.8 vs 84.1 mos
Median: 57.3 vs 28.9 mos
14
IFM 2005-02: Overall Survival
• With a median follow-up of 96.7 months at a Feb 1, 2016, cut-off,
median OS was 105.9 vs 88.1 months for LEN vs placebo
HR, hazard ratio; IFM, Intergroupe Francophone du Myélome; LEN, lenalidomide; NE, not estimable; OS, overall survival.
Revlimid (lenalidomide) [package insert]. Summit, NJ: Celgene Corporation. 2017.
OS at Updated Analysis (1 Feb 2016)LEN
(n = 307)
Placebo
(n = 307)
OS events, n (%) 143 (47) 160 (52)
Median, months (95% CI) 105.9 (88.8-NE) 88.1 (80.7-108.4)
HR (95% CI) 0.90 (0.72-1.13)
15
Abstract 8001
Lenalidomide Maintenance After High-Dose
Melphalan and Autologous Stem Cell
Transplant in Multiple Myeloma:
A Meta-Analysis of Overall Survival
Michel Attal,1 Antonio Palumbo,2 Sarah A. Holstein,3 Valérie Lauwers-Cances,1
Maria Teresa Petrucci,4 Paul Richardson,5 Cyrille Hulin,6 Patrizia Tosi,7
Kenneth C. Anderson,5 Denis Caillot,8 Valeria Magarotto,9 Philippe Moreau,10
Gerald Marit,11 Zhinuan Yu,12 Philip L. McCarthy13
1Institut Universitaire du Cancer, Toulouse-Oncopole, France; 2The Myeloma Unit, Department of Hematology,
University of Turin, Turin, Italy; 3Roswell Park Cancer Institute, Buffalo, NY; 4University La Sapienza, Rome, Italy; 5Dana-Farber Cancer Institute, Boston, MA; 6Bordeaux Hospital University Center (CHU), Bordeaux, France; 7Seràgnoli
Institute of Hematology and Medical Oncology, Bologna University, Bologna, Italy; 8Dijon University Hospital Center,
Dijon, France; 9University of Torino, Torino, Italy; 10University Hospital Hôtel-Dieu, Nantes, France; 11Centre Hospitalier
Universitaire, Bordeaux, France; 12Celgene Corporation, Summit, NJ; 13Blood and Marrow Transplant Program, Roswell
Park Cancer Institute, Buffalo, NY
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LEN Maintenance After ASCT in MM: OS AnalysisStudies Included in the Meta-Analysis
a Starting dose of 10 mg/day on days 1-28/28 was increased to 15 mg/day if tolerated and continued until PD. b Patients received 10 mg/day on days 1-21/28 until PD.
ASCT, autologous stem cell transplant; DEX, dexamethasone; LEN, lenalidomide; MM, multiple myeloma; MNTC, maintenance; MPR, melphalan, prednisone, and lenalidomide; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PD, progressive disease; Tx, treatment.
Attal M, et al. ASCO 2016. Abstr 8001.
Target population of patients with NDMM who received LEN maintenance or
placebo/no maintenance after ASCT
CALGB 100104
(accrual 8/2005 – 11/2009)
INDUCTION
ASCT
1:1 RANDOMIZATION
“NO EVIDENCE OF PD”
LEN MNTCa
(n = 231)
PLACEBO
(n = 229)
INTERIM ANALYSIS AND
UNBLINDING
Dec 2009
CROSSOVER
BEFORE PD
ALLOWED
CONTINUED
TX
IFM 2005-02
(accrual 6/2006 – 8/2008)
INDUCTION
ASCT
1:1 RANDOMIZATION
“NO EVIDENCE OF PD”
LEN: 2 COURSES
LEN MNTCa
(n = 307)
PLACEBO
(n = 307)
ALL TX
DISCONTINUED
Jan 2011
CONTINUED
TX
NO
CROSSOVER
BEFORE PD
ALLOWED
INTERIM ANALYSIS AND UNBLINDING
Dec 2009 Jan 2010
GIMEMA (RV-MM-PI-209)
(accrual 11/2007 – 7/2009)
MPR: 6 COURSES
2 × 2 DESIGN
LEN + DEX × 4 INDUCTION
LEN MNTCb
(n = 67)NO TX
(n = 68)
LEN
MNTCbNO TX
ASCT
CONTINUED
TXCONTINUED
TX
PRIMARY ANALYSIS
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LEN Maintenance After ASCT in MM: OS AnalysisOS
a Median for LEN treatment arm was extrapolated to be 116 months based on median of the CTL arm and HR (median, 86 months; HR = 0.74).
ASCT, autologous stem cell transplant; CTL, control; HR, hazard ratio; LEN, lenalidomide; MM, multiple myeloma; NE, not estimable; OS, overall survival; pts, patients.
Attal M, et al. ASCO 2016. Abstr 8001.
0.0
0 10 20 30 40 50 60 70 80 90 100 1 10 120
0.2
0.4
0.6
0.8
605 578 555 509 474 431 385 282 200 95 20 1 0
604 569 542 505 458 425 350 271 174 71 10 0
Overall Survival, months
Su
rviv
al P
rob
ab
ilit
y
Pts at risk
7-yr OS
62%
50%
N = 1209 LEN CTL
Median OS,
(95% CI), mos
NE
(NE-NE)
86.0
(79.8-96.0)
HR (95% CI)
P value
0.74 (0.62 – 0.89)
.001
• 26% reduction in risk of death, with an estimated 2.5-year increase in
median survivala
1.0
18
LEN Maintenance After ASCT in MM: OS AnalysisSubgroup Analysis
a Number of patients. b Cytogenetic data were only available for the IFM and GIMEMA studies. c CrCl post-ASCT data were only available for the CALGB and IFM studies.
ASCT, autologous stem cell transplant; CR, complete response; CrCl, creatinine clearance; CTL, control; HR, hazard ratio; ISS, International Staging System; LEN, lenalidomide;
MM, multiple myeloma; OS, overall survival; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response.
Attal M, et al. ASCO 2016. Abstr 8001.
0 . 2 5 0 . 5 1 2
5 0 m L / m i n
< 5 0 m L / m i n
N o
Y e s
N o n - L E N
L E N
P R / S D / P D
C R / V G P R
C R
I I I
I o r I I
F e m a l e
M a l e
6 0
< 6 0
H R
ISS stage
Response
after ASCT
Prior induction
therapy
Adverse-risk
cytogeneticsb
CrCl post ASCTc
Favors CTLFavors LEN
LENa CTLa HR (95% CI)
372 375 0.68 (0.54-0.86)
233 229 0.83 (0.63-1.10)
322 349 0.65 (0.52-0.83)
283 255 0.91 (0.69-1.19)
411 440 0.65 (0.52-0.81)
113 90 1.04 (0.72-1.51)
66 80 0.63 (0.35-1.16)
320 339 0.70 (0.54-0.90)
218 210 0.86 (0.65-1.15)
147 146 0.48 (0.31-0.75)
458 458 0.82 (0.67-1.00)
56 36 1.18 (0.66-2.10)
231 243 0.79 (0.59-1.06)
33 25 0.73 (0.33-1.60)
379 404 0.74 (0.59-0.92)
Age
Sex
19
LEN Maintenance After ASCT in MM: OS AnalysisCumulative Incidence of SPMs
a HR based on Cox proportional hazards model. b P value is based on log-rank test.
ASCT, autologous stem cell transplant; CTL, control; HR, hazard ratio; LEN, lenalidomide; MM, multiple myeloma; OS, overall survival; pts, patients; SPM, second primary
malignancy.
Attal M, et al. ASCO 2016. Abstr 8001.
0 12 24 36 48 60 72 84 96 1080.0
586 559 514 465 422 365 251 139 38 1
602 559 525 468 428 340 248 119 28 0
Time to Hematologic SPM Onset (mos)
Cu
mu
lati
ve
In
cid
en
ce
LEN
CTL
HR (95% CI): 2.03a (1.14-3.61)
P = .015b
0.20
0.40
0.60
0.80
1.00
Hematologic
Pts at
risk
0 12 24 36 48 60 72 84 96 108
586 554 508 458 415 360 251 136 35 0
602 559 520 461 417 328 241 117 28 0
Time to Solid Tumor SPM Onset (mos)
Cu
mu
lati
ve
In
cid
en
ce LEN
CTL
HR (95% CI): 1.71a (1.04-2.79)
P = .032b
0.0
0.20
0.40
0.60
0.80
1.00
Solid Tumor
Pts at
risk
20
Lenalidomide Is a Highly Effective Maintenance
Therapy in Myeloma Patients of All Ages;
Results of the Phase III Myeloma XI Study
Jackson GH, et al. ASH 2016. Abstr 1143.
21
Myeloma XI: LEN Maintenance in NDMMStudy Design
LEN, lenalidomide; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PD, progressive disease; PFS, progression-free survival; pts, patients; TE, transplant-
eligible; TNE, transplant non-eligible.
Jackson GH, et al. ASH 2016. Abstr 1143.
No
Maintenance
LEN Maintenance
LEN 10 mg d1-21
28 d cycles
TE and TNE pts
(N = 1551)
CTDCVD
CRD
ASCT
(TE only)
Induction Consolidation
< VGPR
≥ VGPR
R 1:1
R 1:1
No Further Tx
Maintenance
R 1:1
• Primary endpoints: PFS and OS
• N = 1551 (TE = 828; TNE = 723)
• Median follow-up: 27 months*TE pts could also receive KRD induction and
proceed directly to ASCT.
22
Myeloma XI: LEN Maintenance in NDMMBaseline Characteristics
a Available for 196/857 pts in the LEN arm and 209/694 pts in the no maintenance arm. b High risk includes presence of an adverse translocation [t(4;14), t(14;16)], gain(1q), or del(17p). Ultra-high risk includes > 1 adverse lesion.
ISS, International Staging System; LEN, lenalidomide; NDMM, newly diagnosed multiple myeloma; TE, transplant-eligible; TNE, transplant non-eligible.
Jackson GH, et al. ASH 2016. Abstr 1143.
CharacteristicLEN Maintenance
(n = 857)
No Maintenance
(n = 694)
Pathway, n (%)
TE
TNE
451 (53)
406 (47)
377 (54)
317 (46)
Age, median (range), yrs 68 (29-89) 68 (30-90)
Sex, n (%)
Male 531 (62) 435 (63)
ISS stage, n (%)
I
II
III
Unknown
224 (26)
342 (40)
231 (27)
60 (7)
196 (28)
291 (42)
163 (24)
44 (6)
Cytogenetics, n (%)a
Standard risk
High risk/ultra-high riskb
Ultra-high riskb
97 (49)
99 (51)
31 (16)
118 (56)
91 (44)
21 (10)
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Myeloma XI: LEN Maintenance in NDMMPFS in TE Patients
• Among TE pts, median PFS was significantly prolonged by 22 months
with LEN maintenance vs no maintenance
HR, hazard ratio; LEN, lenalidomide; NDMM, newly diagnosed multiple myeloma; PFS, progression-free survival; pts, patients; TE, transplant-eligible.
Jackson GH, et al. ASH 2016. Abstr 1143.
Median PFS,
months [95% CI]
Lenalidomide (n=451) 50 [44, ∞]
Observation (n=377) 28 [23, 32]
HR=0.47; 95% CI 0.38, 0.60
Log-rank p<0.0001
No. of patients at risk:
Lenalidomide
Observation
451
377
397
326
356
306
330
261
285
237
254
198
215
175
196
143
163
121
144
105
130
86
107
70
92
52
76
39
61
32
43
21
30
16
17
8
10
2
5
1
2
1
1
1
0
0
Time since maintenance randomization (months)
100
0
Pa
tie
nts
aliv
e a
nd
pro
gre
ssio
n-f
ree
(%
)
80
60
40
20
0
18 33 51 663 6 9 12 15 21 24 27 30 36 39 42 45 48 54 57 60 63
NOTE: Weights are from random effects analysis
Overall (I-squared = 54.6%, p = 0.085)
Study
GIMEMA-RVMM-PI209
Myeloma XI
IFM 2005-02
CALGB 100104
0.72 (0.56, 0.91)
Ratio (95% CI)
0.72 (0.37, 1.38)
0.69 (0.52, 0.93)
Hazard
0.91 (0.72, 1.15)
0.56 (0.42, 0.76)
100.00
Weight
10.52
28.38
%
33.18
27.92
0.72 (0.56, 0.91)
Ratio (95% CI)
0.72 (0.37, 1.38)
0.69 (0.52, 0.93)
Hazard
0.91 (0.72, 1.15)
0.56 (0.42, 0.76)
100.00
Weight
10.52
28.38
%
33.18
27.92
1.2 .5 1 2
24Transplant eligible meta-analysis Demonstrates improved OS with maintenance lenalidomide
OS: overall survival
Attal M, et al. N Engl J Med. 2012;366:1782-91
McCarthy PL, et al. N Engl J Med. 2012;366:1700-81
Palumbo A, et al. N Engl J Med. 2014;371:895-905
McCarthy PL et al., J Clin Oncol. 2017 Oct 10;35(29):3279-3289
Jackson et al ASH 2017
Bortezomib Induction and Maintenance in
Patients with Newly Diagnosed Multiple
Myeloma: Long-Term Follow-up of the HOVON-
65/GMMG-HD4 Trial
Sonneveld P, et al. ASH 2015. Abstr 27.
25
26
HOVON-65/GMMG-HD4: Study Design
• Randomized, open-label phase III trial
• HDM 200 mg/m2: 1 cycle for HOVON-65, 2 cycles for GMMG-HD4
• Primary endpoint: PFS adjusted for ISS stage
• Secondary endpoints: Response after induction, HDM, and on protocol; OS from
randomization; PFS from HDM; safety
VAD: Vincristine 0.4 mg/day IV D1-4 +
Doxorubicin 9 mg/m2 IV D1-4 +
Dexamethasone 40 mg D1-4,9-12,17-20
(n = 414)
Transplant-
eligible pts
18 yrs of age
or older with
stage II or III
NDMM
(N = 827)
PAD: Bortezomib 1.3 mg/m2 IV D1,4,8,11 +
Doxorubicin 9 mg/m2 IV D1-4 +
Dexamethasone 40 mg D1-4,9-12,17-20
(n = 413)
INDUCTION MAINTENANCE
Thalidomide
50 mg/day
Bortezomib
1.3 mg/m2 q2wk
HDMASCT
x 3 28-day cycles 2 yrs
Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955. Sonneveld P, et al. ASH 2015. Abstr 27.
HDM, high-dose melphalan; ISS, International Staging System; OS, overall survival; PFS, progression-free survival; pts, patients.
Tandem Autologous HCT
• Not routinely performed in the US outside clinical trials.
• Phase III HOVON-65/GMMG-HD4 (Bortezomib)
• GIMEMA – Single vs. Tandem + Bort and high risk features (4 groups based on ISS 3, cyto, not in CR):– Tandem superior in patients with at least two high risk
features
nCR/CR(PAD vs. VAD)
Median PFS(PAD vs. VAD)
OS at 5y(PAD vs. VAD)
HOVON (Single) 47%vs. 29% 32 mon vs. 24 mon 55% both
GMMG (Double) 51% vs. 39% 36 mon vs. 31 mon 70% vs. 54%
Sonneveld et al JCO 2012/ Cavo M et al ASH 2013
28
50
HOVON-65/GMMG-HD4: Survival From
Randomization
• Subgroup analysis: bortezomib + double-cycle HDM before ASCT improved
OS vs single cycle of HDM before ASCT
– 96-mo OS: 55% vs 42%; HR: 0.071 (95% CI, 0.54-0.94; P = .018)
– No significant difference in PFS between subgroups
96-mo
PFS, %
PAD/Bort (n = 413) 17
VAD/Thal (n = 414) 10
PFS OS
HR: 0.77 (95% CI: 0.65-0.90)
P = .001
100
75
25
00 24 48 72 96
Mos
Cum
ula
tive p
erc
en
tage
50
100
75
25
00 24 48 72 96
MosC
um
ula
tive p
erc
en
tage
96-mo
OS, %
PAD/Bort (n = 413) 48
VAD/Thal (n = 414) 45
HR: 0.87 (95% CI: 0.71-1.04)
P = .22
Sonneveld P, et al. ASH 2015. Abstr 27.
ASCT, autologous stem cell transplant; Bort, bortezomib; del, deletion; HDM, high-dose melphalan; HR, hazard ratio; ISS, International Staging System; OS, overall
survival; PAD, bortezomib, doxorubicin, dexamethasone; PFS, progression-free survival; pts, patients; Thal, thalidomide; VAD, vincristine, doxorubicin, dexamethasone.
29
HOVON-65/GMMG-HD4: Survival From
Start of Maintenance
P < .01
PFS100
75
50
25
00 24 48 72 96
Mos
Cum
ula
tive p
erc
en
tage
283
303
141
164
67
92
32
61
5
10
VAD
PAD
At risk:
PAD (n = 283)
VAD (n = 303)
Sonneveld P, et al. ASH 2015. Abstr 27.
PAD, bortezomib, doxorubicin, dexamethasone; PFS, progression-free survival; VAD, vincristine, doxorubicin, dexamethasone.
30
Post-ASCT LEN Maintenance Trials
DaratumumabMMY3004 Ph II DRVd vs RVd
ind, consol, maint (dara+R vs R
– 26 months)
DurvalumabMEDI4736-MM-002 Ph I Durva
+R post-SCT maint (R 21/218 –
10 mg to progression)
ElotuzumabSWOG1211 Ph I/II RVd +/- E ind
+ RVd or RVdE maint (R 21/28 –
dose unknown)
GMMG HD-6 Ph III RVdE ind
+ R or RE maint (R 28/28 10-
15 mg to prog)
NCI-2015-00762 Ph II Post-
ASCT ER maint (R 28/28 10-
15 mg to prog)
Ph II ERD induction,
consolidation, maintenance
(24 months)
CarfilzomibU of Chicago Ph III Post-ASCT
KRd vs R mono (dose/duration
TBD)
FORTE Ph II KCyD vs KRd
ind/consol + KR or R maint
to prog (R dose unknown)
MMRC Ph I/II KRd ind/consol
+ maint 10 cycles followed by
R maint to prog (R dose
unknown)
Ixazomib
EM2014MAIN Ph III Post-ASCT
IRd vs Rd maint (R 21/28 15 mg
– if MRD+ at 2 yrs, R maint up to
5 yrs)
Wash U Ph II
Post-ASCT alternating Ixa
and Rev maint 24 cycles (R
dose unknown)
LenalidomideBMT CTN0702 Ph III Post-ASCT
R maint (R10-15 mg frequency
unspecified – up to 3 yrs)
DFCI-10-106 Ph III RVd + R
maint vs RVd+ASCT + R
maint (R 10-15 mg 28/28 for
12 mos)
Myeloma XI Ph III RCyD vs
TCyD + R maint +/- vorinostat
(R 10 mg 21/21)
Ph I/Ib FRVd ind + Rd maint
(R 21/28 25 mg to prog)
Click to edit Master Presentation Date
DRAMMATIC STUDYPhase III Study of Daratumumab + Lenalidomide (LD) or
Lenalidomide (L) as Post-Autologous Stem Cell Transplant Maintenance Therapy in Patients with Multiple Myeloma (MM)
Using Minimal
SWOG1803/BMT CTN 1706Amrita Krishnan/ Parameswaran Hari
Treatment/Schema
33
CONSOLIDATION
BMT CTN 0702 Stem Cell Transplantation for
Multiple Myeloma Incorporating Novel Agents: SCHEMA
Register and
Randomize
MEL
200mg/m2 VRD x 4*Lenalidomide
Maintenance**
Lenalidomide
Maintenance**
Lenalidomide
Maintenance
MEL
200mg/m2
**Lenalidomide x 3years :
10mg/d for 3 cycles , then 15 mg/dAmendment in 2014 changed Lenalidomide
maintenance until disease progression after
report of CALGB 100104.
*Bortezomib 1.3mg/m2
days 1, 4, 8,11
Lenalidomide 15mg days 1-15
Dexamethasone 40mg
days 1, 8, 15
Every 21 days
**N=750 pts (250 in each arm)
N=257
N=254
N=247
N at risk
Auto/Auto 247 200 153 87
Auto/RVD 254 215 172 99
Auto/Maint 257 213 158 80
Primary Endpoint: Progression-free Survival
35
100
0
20
40
60
80
Pro
ba
bili
ty, %
0 12 3824
Months from Randomization
Auto/Maint: 52.2 (45.4, 58.6)
Auto/Auto: 56.5 (49.4, 62.9)
Auto/RVD: 56.7 (50.0, 62.8)
38 Month Estimate and 95% CI
N at risk
Auto/Auto 247 231 204 147
Auto/RVD 254 246 229 166
Auto/Maint 257 247 227 148
Overall Survival
36
100
0
20
40
60
80
Pro
babili
ty, %
0 12 3824
Months from Randomization
Auto/Maint: 83.4 (77.9, 87.7)
Auto/Auto: 82.0 (76.3, 86.5)
Auto/RVD: 85.7 (80.5, 89.5)
38 Month Estimate and 95% CI
Compliance with each intervention
Auto/Auto
(N=247)
Auto/RVD
(N=254)
Auto/Maint
(N=257)
N % N % N %
Received 2nd Intervention
No 79 32.0 30 11.8 - -
Yes 168 68.0 224 88.2 - -
Started maintenance
No 41 16.6 43 16.9 14 5.4
Yes 206 83.4 211 83.1 243 94.6
37
Progression-Free Survival – as
treated/per protocol Analysis
38
N at risk
Auto/Auto 247 149 121 70
Auto/RVD 254 195 160 91
Auto/Maint 257 212 157 79
100
0
20
40
60
80
Pro
ba
bili
ty, %
0 12 3824
Months from Randomization
Auto/Maint: 52.2 (45.4, 58.6)
Auto/Auto: 61.3 (53.6, 68.9)
Auto/RVD: 57.8 (50.7, 64.2)
38 Month Estimate and 95% CI
Design of EMN02 trial
4 × VCD +
Stem cell apheresis
R1
4 × VMP HDM 1/2
2 × VRD None
Lenalidomide Lenalidomide
HDM/ASCT at 1st relapse
Registration
Induction
Stem cell mobilization in all pts
Consolidation
Maintenance
until relapse
R2MRD
Early or late ASCT, once
or twice
https://clinicaltrials.gov/ct2/show/NCT01208766 [Accessed March 2015]Slide courtesy Sonneveld P, ASH 2016
EMN02 / HO95 MM 40
no consolidationVRDCox LR P=0.045 (adjusted for 1st random.)
N435450
F137115
no consolidation
VRD
At risk:435450
336371
187196
4952
no consolidation
VRD
0
25
50
75
100
Cum
ulat
ive
perc
enta
ge
months0 12 24 36
Progression free survival
HR = 0.78 (0.61-1.00)
Progression-free survival
BMT CTN 0702: Regimens prior to
Transplant
Auto/Auto
(N=247)
Auto/RVD
(N=254)
Auto/Maint
(N=257)
N % N % N %
Initial Therapy
141 57.1 134 52.8 143 55.6Bort/Len/Dex
Cy/Bort/Dex 33 13.4 35 13.8 40 15.6
Len/Dex 24 9.7 28 11.0 22 8.6
Bort/Dex 28 11.3 32 12.6 32 12.5
Other21 8.5 25 9.8 20 7.8
41
Bort, bortezomib; Cy, cyclophosphamide; Dex, dexamethasone; Len, lenalidomide
Pre-transplant induction regimens in
the US
42
0%
10%
20%
30%
40%
50%
60%
2004/05 2006/07 2008/09 2010/11 2012/14
Year of transplant
VAD/Similar TD VTD RD VD VCD VRD
VAD- Vincristine/Adriamycin/Dexamethasone
T- Thalidomide V- Bortezomib R- Lenalidomide C- Cyclophosphamide D- Dexamethasone
PRIMeR- Baseline MRD Status
Auto/Auto
N=91 (%)
Auto/Maint
N1=06 (%)
Auto/RVD
N=99 (%)
High Risk Disease 20 21 24
VGPR or better 49 44 41
MRD Negative 47 42 40
43
MRD- MRD+
sCR/CR/nCR 64 15
Other 60 136
Kappa=0.43 [0.33, 0.53]
PRIMeR: OS by Disease Status and MRD
at 1 year after enrollment
Unpublished Data 44
sCR/CR/nCR/VGPR vs. Other
at one year
MRD Status at one year
Considerations on Selecting post
Transplant Therapy
• All interventions appear to have a PFS
benefit.
• Upfront treatment and disease status at time
of transplant
• Accessibility to agents
• Response post transplant
• Disease risk
45
46
Considerations
• Consider disease risks: are poor risk markers present?
• Response adapted approach
– Maximize disease control prior to transplant
– Consider post transplant treatment in the setting of suboptimal response (caution).
• Does achieving the best response (CR /MRD-) be the main goal of therapy?