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Treatment For Newly Diagnosed Myeloma

A. Keith Stewart

Risk Adapted Therapy

AgeRenal

functionCo morbidconditions

Geography Access PatientPreference

RiskProfile

mSMART 2.0: Classification of Active MM

FISH Del 17p t(14;16) t(14;20)

GEP High risk

signature

All others including: Hyperdiploid t(11;14)*** t(6;14)

FISH t(4;14)*

Cytogenetic Deletion 13 or hypodiploidy

PCLI >3%

High-Risk 20% Intermediate-Risk 20% Standard-Risk 60% **

* Prognosis is worse when associated with high beta 2 M and anemia** LDH >ULN and beta 2 M > 5.5 in standard risk may indicate worse prognosis*** t(11;14) is associated with plasma cell leukemia

Clearly not a transplant candidate

Can include melphalan-based combinations

Potential transplant candidate

Non-alkylator based induction

Stem cell harvest

Initial Approach to Treatment

Therapy Options: NonTransplant Candidate

• Melphalan + Prednisone (MP)

• Melphalan + Prednisone + Thalidomide (MPT)

• Melphalan + Prednisone + Bortezomib (MPV)

• Dexamethasone (Dex)

• Thalidomide + Dexamethasone (Thal/Dex)

• Lenalidomide + Dexamethasone (Rev/Dex)

NCCN Practice Guideline-v.2.2008NCCN Practice Guideline-v.2.2008

Figure 2

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60

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80

90

100

VAD TD RD PAD VTD CVD RVD CVRD VTD andTandem

Induction Regimen

Percent Response

ORRVGPRCR/nCR

Therapies for younger patients

Figure 2

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10

20

30

40

50

60

70

80

90

100

VAD TD RD PAD VTD CVD RVD CVRD VTD andTandem

Induction Regimen

Percent Response

ORRVGPRCR/nCR

Transplant ?

What About Maintenance

N Thalidomide CR rate PFS (year) OS (year)

Barlogie 668 400 mgTaper

62% vs. 43%5-year

56% vs. 44%

6-yearSuperior for Thal in CA abnormal

Attal 597400 mg

Until progression or adverse event

67% vs. 55%4-year

52% vs. 36%4-year

87% vs. 77%

Spencer 243 200 mg12 months

63% vs. 40%3-year

63% vs. 36%3-year

90% vs. 81%

Barlogie, Tricot, et al, 2006; Attal et al, 2003; Spencer et al, 2009.

IFM 2005-02: Study design

Arm A=

Placebo

(N=307)

until relapse

Arm A=

Placebo

(N=307)

until relapse

Patients < 65 years, with non-progressive disease, 6 months after ASCT in first line

Arm B=

Lenalidomide

(N=307)

10-15 mg/d until relapse

Arm B=

Lenalidomide

(N=307)

10-15 mg/d until relapse

Primary end-point: PFS.Secondary end-points: CR rate, TTP, OS, feasibility of long-term lenalidomide….

Phase III randomized, placebo-controlled trialN= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008

Consolidation:Lenalidomide alone 25 mg/day p.o.

days 1-21 of every 28 days for 2 months

Consolidation:Lenalidomide alone 25 mg/day p.o.

days 1-21 of every 28 days for 2 months

Randomization: stratified according to Beta-2m, del13, VGPRRandomization: stratified according to Beta-2m, del13, VGPR

PFS according to Response Pre-Consolidation

HR= 0.37 - CI 95% [0.25-0.58] HR= 0.54 - CI 95% [0.37-0.78]

PR or SD VGPR or CR

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36

Placebo Revlimid

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36

Placebo Revlimid

p<10-5 p=0.001

Lenalidomide Maintenance: TTP

Median Follow up from randomization is 12 months

Median TTP: Not yet reached

Median TTP 25.5 mos

CALGB 100104, Nov 2009

Palumbo et al, 2009

MPR-R vs. MPRMPR-R vs. MPR

Progression-Free SurvivalProgression-Free Survival

MPR-R

MPR

Median PFS

Not reached13.2 months

HR 0.530

100

75

50

25

0

0 5

PFS Time (months)

10 15 20 25 30

Pat

ient

s w

ithou

t E

vent

(%

)

How to treat standard risk disease

Standard-Risk1. OS is 80% at 5 years (before routine maintenance adopted)

2. No difference in induction regimens (needs further study)

3. A drug regimen which results in high overall response rates and which avoids extremes of toxicity (Rd, weekly bortezomib, MPT)

4. Transplant indicated in younger but may be deferred

5. Maintenance likely helps

All others including: Hyperdiploid t(11;14)*** t(6;14)

How to Treat Standard Risk Disease

All others including: Hyperdiploid t(11;14)*** t(6;14)

Standard-Risk**

150 transplant eligible standard risk patients treated with RD, CRD or CBD +/- HDM.

How to treat Intermediate Risk Disease

FISH t(4;14)

Cytogenetic Deletion 13 or hypodiploidy

PCLI >3%

Intermediate-Risk

Vel/Dex

VADp=.0004

Bortezomib-Dex better than VADPre transplant

Short remission post transplant despite high response rates

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40

60

80

100

0 5 10 15 20 25 30 35

Time (months)

%A

live a

nd

Pro

gre

ssio

n F

ree

del17 or t(4;14) all others

Del 17

t(4;14)

All others

4 cycles of CyborD induction and high dose melphalan

FISH t(4;14)*

Cytogenetic Deletion 13 or hypodiploidy

PCLI >3%

Intermediate-Risk

VMP standard risk (N=142): not reached (16 events)VMP high risk (N=26): not reached (3 events)

Prolonged use of Bortezomib may help overcome intermediate risk

IFM2005: Len maintenance improves PFS even with elevated ß2-m

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36

Placebo Revlimid

ß2-m 3 mg/l ß2-m > 3 mg/l

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36

Placebo Revlimid

p=0,0002 p<10-5

Attal et al. 2010

How to treat Intermediate Risk Disease

Intermediate-Risk

FISH t(4;14)*

Cytogenetic Deletion 13 or hypodiploidy

PCLI >3%

1. A bortezomib based multi-agent chemotherapy (CyborD, VRD, VTD, MPV) which maximizes CR

2. Longer duration of bortezomib

3. Autologous transplant

4. Consider Consolidation if not in CR

5. IMID based Maintenance

6. Consider targeted therapy approach on trials

High Risk Disease: Not very effective

• Velcade Dex

• Tandem Autologous Transplant

• Allogeneic Transplant

• Maintenance Thalidomide

POSSIBLY HELPFUL

• Chemotherapy targeting proliferation ?

• Longer duration bortezomib ?

• Lenalidomide maintenance ?

How to treat High risk disease

FISH Del 17p t(14;16) t(14;20)

GEP High risk

signature

High-Risk 1.This population needs novel ideas and therapeutic concepts

2. A multi drug regimen incorporating all available drugs which emphasizes durable CR and uses longer duration of therapy may improve outcomes for p53 deletion

3. Transplant contribution is however of dubious benefit and IMID based maintenance still uncertain

mSMART 2.0: Treatment of Active MM

Novel approaches

New drugs

“TT3 like” approach for p53 deletion ?

Regimen which provides a high ORR and which minimizes early toxicity

HDM could be delayed in patients achieving CR

Lenalidomide maintenance

Prolonged Bortezomib based combination

HDM +/- consolidation

Lenalidomide maintenance

Targeted therapy

High-Risk Intermediate-Risk Standard-Risk

While risk adapted therapy is appealing, randomized trial data is largely lacking:

Minimize toxicity argument: High risk patients do less well even with very aggressive therapy so quality of life more important. Lower risk patients should be treated with focus on lower toxicity as survival long anyway.

Maximize therapy argument: Although less aggressive therapy for standard risk disease may result in good outcomes most patients still relapse so all deserve the most intensive therapy

The Debate Will Continue