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High-risk M yeloma : What do we Know , Where are we Going ? A lot!!! But drifting!!!

High-risk M yeloma : What do we Know , Where are we Going ? A lot!!! But drifting!!!. Bart Barlogie MIRT, UAMS Little Rock, AR, USA. High-risk MM: the Spectrum. Metaphase cytogenetic abnormalities (M-CA) FISH or F-CA High LDH – often signifying extra-medullary disease (EMD)

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High-risk M yeloma : What do we Know , Where are we Going ? A lot!!! But drifting!!!

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  1. High-risk Myeloma: What do we Know, Where are we Going?A lot!!!But drifting!!! Bart Barlogie MIRT, UAMS Little Rock, AR, USA

  2. High-risk MM: the Spectrum • Metaphase cytogenetic abnormalities (M-CA) • FISH or F-CA • High LDH – often signifying extra-medullary disease (EMD) • EMD, plasma cell leukemia (PCL) • PET-defined focal lesions (FL) and metabolic activity (SUVmax) • GEP • UAMS: 70, 80, 5, 2 gene models • HOVON et al

  3. Newly Diagnosed High-risk Myeloma (Malignant Multiple Myeloma, MMM) Major advances in low-risk MM with added thalidomide in TT2 and bortezomib in TT3 No progress in MMM with TT3 over TT2 Started GEP risk-adapted protocols in 2008 TT4 for low-risk and TT5 for high-risk MM Present comparison for GEP70-defined high-risk MM between TT3 and TT5

  4. TT5: Treatment Schema • Induction • Mel10-VTD-PACE and HPC collection • Transplant 1 • Mel80-VRD-PACE • Inter-transplant 1 and 2 • Mel20-VTD-PACE • Transplant 2 • Mel80-VRD-PACE • Maintenance for 3 years • VRD alternating with VMD • Later VRD only • Increased bortezomib to 1.5mg/m2 • Increased lenalidomide to 25mg/d x 21 q 28d

  5. TT5: Characteristics

  6. TT5: Progression on Protocol, Response Rates and Survival

  7. TT5: Survival Outcomes by Age, CA, LDH COD Age CA LDH

  8. TT5: Progression-free Survival by Risk Factors Age CA GEP70 Mol. subgroups

  9. TT5: Survival Outcomes by GEP70/5 Risk Scores GEP70 GEP70/5 GEP5

  10. TT5 v TT3 in GEP70 High-risk MM

  11. Comparison of Outcomes with TT5 versus TT3 Longer OS despite similar PFS in TT5 v TT3 related to better post-relapse therapies such as metronomics, CFZ, POM, PAC-MED+/-MEL

  12. Survival in Combined TT3/TT5 by GEP5

  13. Cox Regression Analysis for OS Data on time to MRD by 8-color FCM forthcoming

  14. TT Protocol Outcomes in GEP70 High Risk

  15. Post-relapse Survival According to Protocol

  16. Long Term Outcomes in TT2: The Cure Issue Earlier plateau in high-risk than low-risk MM

  17. Long Term Outcomes in TT3: The Cure Issue Earlier plateau in high-risk than low-risk MM

  18. GEP5-risk Identifies Further Subgroups within Both Low-risk and High-risk by GEP70 Low risk MM High risk MM TT4 TT5 Ultra-high risk MM New GEP5 risk score peals off additional subsets in both low and high risk MM

  19. GEP5-Based Model for TT3 What’s wrong with 90% survival at almost 10yr???

  20. Intra-tumor Heterogeneity • MRI-defined focal lesions (FL) and interstitial MM growth • Differences in GEP of both PC and stroma when comparing random bone marrow and FL samples • Genomic risk • Low-risk • Predominance of “benign” MM • Upon relapse • Moving up the risk scale as gleaned from serial genomic analyses • High-risk de novo • Predominance of “malignant” MM clone(s) • May regress to “benign” with novel agents

  21. High-risk MM: Final Pathway of Treatment Failure • Dividends of focus on high-risk MM • Superior treatment identifiable within 2-3yr • Testable therapeutic concepts • Avoid dose-intense therapies and minimize potentially MM gowth/survival-promoting cytokine storm during hematopoietic recovery • Metronomic therapy • Novel drug combinations that avoid ‘nadirs’ of myelosuppression • Identify actionable gene mutations (exomics) • Immunotherapy under investigation • Should then be useful in low-risk MM as well

  22. Trametinib in RAS-mutated High-risk MM Metronomic Rx Trametinib VTD-PACE GEP-70 high risk 21 days’ span 3 prior Tx Incl. MEL300

  23. Targeted Sequencing at MIRT Targeted re-sequencing using a panel of ~350 tumor associated genes in relapsed or relapsed/refractory patients for a molecularly guided choice of therapy

  24. Top 6 Actionable Mutations

  25. Ipilimumab, Pomalidomideand Trametinib 10/3/2013 10/18/2013 Light chains markedly down, massive increase in CD4 and CD8 counts

  26. Extra-medullary Disease (EMD):The Achilles Heel of MM • Readily detectable by PET-CT • Present de novo in 1% • Develops in virtually all patients after prolonged salvage therapies • Issue is prediction • Can an EMD PC-GEP signature of bone marrow be developed? • Is blood better source? • Can later EMD onset also be predicted? • Are all EMD equal? • Distinguishing anatomic sites (liver v lymph node v muscle)

  27. Survival According to EMD After Transplant

  28. EMD Development in TT by GEP70 Risk

  29. Baseline Variables Linked to EMDall GEP-derived No other variable survived multivariate model!

  30. Heat-map of Bone Marrow PC GEP EMD Cluster Identified – Red Bars

  31. How to Move Forward? • MIRT’s PACMED therapy for high-risk PET-positive MM • DDP, Ara-C, CTX, Mesna, Etoposide, Dex • Plus VTD or VRD • Day 3-4 F/U PET • Add MEL 50-100mg/m2 • HPC boost 24hr later • Alternate with metro Rx • The challenges • EMD often non-secretory and BM-MRD-negative • Need for frequent PET scanning • Individualize according to level of FDG suppression • Clonal heterogeneity among different EMD sites • Under investigation including exomics

  32. Thanks to • Patients and care givers • Referring MD’s • Colleagues and nurses • Data managers • CRAB statisticians • NIH • Philanthropy

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