Induction Therapy in Transplant Eligible MM

2 December 2017

Tontanai Numbenjapon, M.D.

What we need from induction therapy in NDMM

• Depth of response: MRD-negative, sCR, CR

• Longest response

• Acceptable toxicity

• Good quality of life

• Maximize the depth of response• Minimize the burden of the residual cells

New treatment paradigm for transplant candidate MM

NDMM-transplant candidate

Induction regimen

High dose melphalan and

ASCT

Post ASCT consolidation

Post ASCT maintenance

Agents to make induction combination regimen for NDMM-transplant eligible

• 6 different classes of agents

– Sterioids

– Alkylators

– PIs: 2nd generation-carfilzomib and ixazomib

– IMiDs: 3rd generation-pomalidomide

– DACIs: panobinostat

– mAbs: elotuzumab and daratumumab

Novel agent-based induction therapies for transplant eligible MM

Combination Thalidomide-based

Bortezomib-based

Lenalidomide-based

PI + IMiD-based

2-drug TD VD RdRD

3-drug TADCTD

PADVCD

RADCRD

VTDVRD

KRd/KTDIxa-RD

4-drug - - - VTDCRVCD

VTD-DaraVRD-Elo

Efficacy of induction regimens

Role of ASCT in MM (non-novel agent era)

Group/trial NAge

(years)Median F/U

CR rate (%)

Median EFS (months)

Median OS (months)

CCT HDT CCT HDT CCT HDT

IFM-90 200 <65 7 years 5 22 18 28 44 57

MAG91 190 55-65 56 months 5 19 19 24 50 55

PATHEMA 164 <65 44 months 11 30 33 42 66 61

Italian MMSG 195 <70 39 months 6 25 15.6 28 42 58+

MRC7 407 <65 42 months 8 44 19 31 42 54

MAG95 190 55-65 10 years 20 48 19 25 48 48

US S9321 516 ≤70 76 months 15 17 14 17 38 38

J Clin Oncol 2011;29:1898-906.

Meta-analysis: Bortezomib-based vs. non-bortezomib-based induction prior to ASCT

Response rate Bortezomib-based

induction(n = 775)

Non-bortezomibbased induction

(n = 772)

OR 95%CI p

Post-transplant (%)

CR+nCR 38 24 2.05 1.64-2.56 <0.001

Response rate

Bortezomib-based

induction(n = 775)

Non-bortezomib

based induction

(772)

HR 95%CI p

PFS, mos 35.9 28.6 0.75

CR+nCR 50 41.1 0.75 0.65-0.85 <0.001

Sonneveid et al. J Clin Oncol 2013;31:3279-87.

Phase III VTD vs. TD: response and survival with ASCT and consolidation therapy

VCD vs. VTD induction: response

VTD (4-cycles) VCD (4 cycles) P-value

≥CR 13.0% 8.9% 0.22

≥VGPR 66.3% 56.2% 0.05

IFM 2013-04 trial (prospective, intention-to-treat analysis)1

VTD (4-cycles) VCD (4 cycles) P-value

≥CR 13.0% 8.9% 0.22

≥VGPR 66.3% 56.2% 0.05

GIMEMA MMY-3006 and EMN-02 studies (retrospective, case-matched analysis)2

Moreau P, et al. Blood 2016;127:2569-74.Cavo , et al. Leukemia 2015;29:2429-31.

Evolving role of high-dose melphalanand ASCT in the era of novel agents

and antibodies• Novel agents

– Improved induction

– Improved consolidation

– Improved maintenance

• Early vs. late transplant

• Single vs. Tandem transplant

• Role of transplants in high-risk disease

Upfront ASCT vs. late ASCT

Palumbo A, et al. N Engl J Med 2014;371:895.

Attal M, et al. N Engl J Med 2017;376:1311-20.

NDMMAge ≤ 65 years

(n=700)R

Vd

x 3

cyc

les

R1:1

Cyc

lop

ho

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amid

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ob

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nP

BSC

co

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ion

RVd (n=350)Five 21-day cyclesV 1.3 mg/m2 D1,4,8,11R 25 mg D1-14d 10 mg daily

HDT-ASCT +

RVd x 2 cycles

(n=350)Melphalan 200 mg/m2

ASCT

R m

ain

ten

ance

R 1

0 m

g/d

x 3

mo

nth

s th

en

titr

ate

to 1

5 m

g/d

if t

ole

rate

dco

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up

to

1 y

ear

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ease

pro

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sio

n

3 weeks

3 weeks

Primary endpoint: Progression free survival

Secondary endpoint: Response rate, time to disease

progression, overall survival, adverse events

IFM 2009: Role of ASCT in novel agent era

Upfront ASCT is important in novel agent era

RVD arm Transplant arm P value

CR 49% 59%

VGPR 29% 29% 0.02

PR 20% 11%

At least VGPR 78% 88% 0.001

Neg MRD by FCM 65% 80% 0.001

4-y PFS 35% 47% HR: 0.69 (0.56-0.84; P<0.001)

4-y OS 83% 86% HR: 1.2(0.7-1.8; P = NS)

Attal M, et al. Blood 2015;126:391a

Attal M, et al. N Eng J Med 2017;376:1311-20.ç

PFS OS

Upfront ASCT is important in novel agent era

Attal M, et al. Blood 2015;126:391a

Attal M, et al. N Eng J Med 2017;376:1311-20.ç

Blood 2016;128:LBA-1

NDMM symptomatic

Age ≤ 70 years,

(n=758)

R1:1:1

Second ASCTMel 200 mg/m2

Consolidation

VRd x 4 cycles

BMT CTN0702 StaMINA trial

Firs

t A

SCT

Mel

20

0 m

g/m

2

R m

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ance

R 1

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g/d

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• Median follow up from randomization: 38 months• 38-month PFS: ACM 57% vs. TAM 56% vs. AM 52% • Median OS not been reached; 38-month ACM 86% vs. TAM 82% vs. AM 83%• Cumulative incidence of disease progression is not different**Addition of second ASCT or RVd consolidation was NOT superior to single ASCT followed by Lenalidomide maintenance**

ACM

TAM

AM

No improvement of PFS and OS using tandem ASCT or post ASCT consolidation over single ASCT

With more effective induction, consolidation and maintenance, ASCT is still required

Zimmerman T, et al. ASH 2016. abstract 675

Treatment arm Induction ASCT Consolidation Post maintenance

≥VGPR ≥CR ≥CR ≥VGPR ≥CR ≥VGPR ≥CR

ASCT 73% 16% 27% 91% 67% 94% 86%

No ASCT 69% 18% 89% 34% 90% 59%

Transplant increases MRD-neg CR

Autograft 1 vs. 2

EMN02/HO95 MM trial: study design

Cavo M, et al. ASH 2016. abstract 673.

Stratification: ISS I vs. II vs. IIIRandomization to VMP or HDM was 1:1 in centers with a fixed single ASCT policyRandomization to VMP or HDM-1 or HDM-2 was 1:1:1 in centers with a double ASCT policy

1192 pts eligible for randomization 1

1 transplant is essential but 2 transplants improve outcomes in HR-NDMM

Cavo M, et al. ASH 2016. abstract 673. Sonneveid P, et al. ASH 2016. abstract 242.

Single vs. double ASCT for patients who failed CR after bortezomib-based induction regimens and had del(17p) and or t(4;14)

Harousseau et al. JCO 2010;28:4621-9.Cavo M, et al. Lancet 2010;376:2075-85.Rosinof L, et al. Blood 2012;120:1589-96.

Cavo M, et al. ASH 2013 abstract 768

OS by study group and by treatment arm (single vs. double HDM/ASCT)

• HOVON PAD and VAD arms:

single ASCT

• GMMG PAD and VAD arms:

double ASCT

• PAD: single vs. double HDM/ASCT

at 96 moths: 42% vs. 55%

• Cox all arms:

HR: 0.71, 95% CI = 0.54-0.94;

P = 0.018

Double ASCT subanalysis

PFS at 5 years, % OS at 5 years, %

FISH n Bor p standard Bor p Standard

Del(17p) y/n

39/312 22% vs. 27%

0.47 5% vs. 24%

65% vs. 72%

0.48 18% vs. 66%

Sonneveid P, et al. ASH 2015 abstract 27

Conclusions: Management of transplant candidate in the era of new drugs

• 3-drug combinations are recommended induction regimens, with the recent EMA-approval of VTD in this setting

• ASCT should remain as standard of care in 2017 in the frontline treatment of patients eligible for high-dose therapy– Double tandem transplant is of use, particularly in high-risk patients?

• Conventional CR is inadequate to predict outcomes since in most of the cases may logs of residual tumor cells still persist

• MRD negativity should be the current treatment endpoint, but not in Thailand now

• Consideration of the whole treatment sequence, including induction regimen and post-ASCT therapy, will maximize the depth of response.

• 4-drug regimens may possibly be the next standard of care.