1. Treatment For Newly Diagnosed Myeloma
Scottsdale, Arizona
Rochester, Minnesota
Jacksonville, Florida
Treatment For Newly Diagnosed Myeloma
A. Keith Stewart
There are many factors which must be considered when developing a treatment plan for a patient with myeloma…first among those is the age of the patient

2. Risk Adapted Therapy Renal function Co morbid conditions Age Risk
Profile
Geography
Access
Patient
Preference

3. mSMART 2.0: Classification of Active MM
High-Risk 20%
Intermediate-Risk 20%
Standard-Risk 60% **
FISH
Del 17p
t(14;16)
t(14;20)
GEP
High risk
signature
FISH
t(4;14)*
Cytogenetic Deletion 13 or hypodiploidy
PCLI >3%
All others including:
Hyperdiploid
t(11;14)***
t(6;14)
* 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

4. Initial Therapy Considerations
Ensure patient does not have smoldering (asymptomatic) MM
Approach to therapy is based on whether a pt is a transplant candidate
Consider clinical trials if available
Improving complete response rates is a key goal of current trials

5. Initial Approach to Treatment
Clearly not a transplant
candidate
Potential transplant
candidate
Can include melphalan-
based combinations
Non-alkylator based
induction
Stem cell harvest

6. 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

7. Therapies for younger patients7

8. Transplant ? 8

9. What About Maintenance
Thalidomide
CR rate
PFS (year)
OS (year)
Barlogie
668
400 mg
Taper
62% vs. 43%
5-year
56% vs. 44%
6-year
Superior for Thal in CA abnormal
Attal
597
Until progression
or adverse event
67% vs. 55%
4-year
52% vs. 36%
87% vs. 77%
Spencer
243
200 mg
12 months
63% vs. 40%
3-year
63% vs. 36%
90% vs. 81%
Barlogie, Tricot, et al, 2006; Attal et al, 2003; Spencer et al, 2009.

10. IFM : Study design
Phase III randomized, placebo-controlled trial
N= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008
Patients < 65 years, with non-progressive disease,  6 months after ASCT in first line
Randomization: stratified according to Beta-2m, del13, VGPR
Consolidation:
Lenalidomide alone 25 mg/day p.o.
days 1-21 of every 28 days for 2 months
We thus designed the IFM protocol. Patients under the age of 65, with a non progressive disease, within 6 months after a transplant performed as part of their first line therapy were randomized to receive a consolidation treatment with revlimid 25 mg/d , 21 days per month for 2 months followed by maintenance treatment with low dose of revlimid mg/ until relapse or placebo
Randomization was stratified according to beta 2, del 13, and VGPR
Arm A=
Placebo
(N=307)
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…. 10

11. PFS according to Response Pre-Consolidation
VGPR or CR
PR or SD
p<10-5
p=0.001
HR= CI 95% [ ]
HR= CI 95% [ ]

12. Lenalidomide Maintenance: TTP
Median TTP: Not yet reached
Median TTP 25.5 mos
Median Follow up from randomization is 12 months
CALGB , Nov 2009

13. MPR-R vs. MPR Progression-Free Survival
Median PFS
Not reached
13.2 months
HR 0.530
100 75 50 25 5
PFS Time (months) 10 15 20 30
Patients without Event (%)
At time of data cut-off (April 15, 2009) 50% of patients had continued to maintenance therapy phase
Median duration of therapy was 9 cycles
Only 8% of patients receiving lenalidomide maintenance required dose reduction suggesting continued treatment is well tolerated
Palumbo et al, 2009

14. How to treat standard risk disease
1. 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)
Choice of induction should acknowledge long survival
At times transplant can be deferred

15. How to Treat Standard Risk Disease
All others including:
Hyperdiploid
t(11;14)***
t(6;14)
150 transplant eligible standard risk patients treated
with RD, CRD or CBD +/- HDM.

16. How to treat Intermediate Risk Disease
FISH
t(4;14)
Cytogenetic Deletion 13 or hypodiploidy
PCLI >3%
Bortezomib-Dex better than VAD
Pre transplant

17. Short remission post transplant despite high response rates
All others
Del 17
t(4;14)
Despite the high responses with CyBorD, high risk cytogenetics by FISH still predicts for early relapse and progression in this population.
4 cycles of CyborD induction and high dose melphalan

18. Prolonged use of Bortezomib may help overcome intermediate risk
FISH
t(4;14)*
Cytogenetic Deletion 13 or hypodiploidy
PCLI >3%
VMP standard risk (N=142): not reached (16 events)
VMP high risk (N=26): not reached (3 events)

19. IFM2005: Len maintenance improves PFS even with elevated ß2-m
ß2-m  3 mg/l
ß2-m > 3 mg/l
p<10-5
p=0,0002
Attal et al. 2010

20. How to treat Intermediate Risk Disease
A bortezomib based multi-agent chemotherapy (CyborD, VRD, VTD, MPV) which maximizes CR
Longer duration of bortezomib
Autologous transplant
Consider Consolidation if not in CR
IMID based Maintenance
Consider targeted therapy approach on trials
Intermediate-Risk
FISH
t(4;14)*
Cytogenetic Deletion 13 or hypodiploidy
PCLI >3%

21. High Risk Disease: Not very effective
Velcade Dex
Tandem Autologous Transplant
Allogeneic Transplant
Maintenance Thalidomide

22. POSSIBLY HELPFUL Chemotherapy targeting proliferation ?
Longer duration bortezomib ?
Lenalidomide maintenance ?
New drugs

23. How to treat High risk disease
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
High-Risk
FISH
Del 17p
t(14;16)
t(14;20)
GEP
High risk
signature

24. mSMART 2.0: Treatment of Active MM
High-Risk
Intermediate-Risk
Standard-Risk
Novel approaches
New drugs
“TT3 like” approach for p53 deletion ?
Prolonged Bortezomib based combination
HDM +/- consolidation
Lenalidomide
maintenance
Targeted therapy
Regimen which provides a high ORR and which minimizes early toxicity
HDM could be delayed in patients achieving CR
Lenalidomide maintenance

25. The Debate Will Continue
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