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Treatment For Newly Diagnosed Myeloma

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Presentation on theme: "Treatment For Newly Diagnosed Myeloma"— Presentation transcript:

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 patients

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

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