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.


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


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.


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

16

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

17

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.


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.


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.


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.


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.


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)

23

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.


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


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)


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


Auto/Maint: 83.4 (77.9, 87.7)

Auto/Auto: 82.0 (76.3, 86.5)

Auto/RVD: 85.7 (80.5, 89.5)


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


Auto/Maint: 52.2 (45.4, 58.6)

Auto/Auto: 61.3 (53.6, 68.9)

Auto/RVD: 57.8 (50.7, 64.2)


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

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?

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