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MRD in Myeloma: the Future is Here

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Presentation on theme: "MRD in Myeloma: the Future is Here"— Presentation transcript:

1 MRD in Myeloma: the Future is Here
Ola Landgren, M.D., Ph.D. Senior Investigator, Multiple Myeloma Section National Cancer Institute, NIH New York, NY, October 24, 2013 Disclosures: None

2 MRD by Molecular Assays
Outline MRD and Outcomes MRD by Flow Cytometry MRD by Molecular Assays

3 Lahuerta et al. J Clin Oncol 2008
Clinical Response to Therapy and Overall Survival CR nCR PR SD PD Lahuerta et al. J Clin Oncol 2008

4 Flow Cytometry Negativity Post Therapy and Overall Survival
MRD neg FISH low MRD pos or FISH high MRD pos FISH high Paiva B et al. Blood 2012

5 Allele Specific Oligonucleotide (ASO) PCR Negativity and PFS
Progression free survival (PFS) San-Miguel. ASCO 2013

6 MRD by Molecular Assays
Outline MRD and Outcomes MRD by Flow Cytometry MRD by Molecular Assays

7 MRD in Multiple Myeloma: a Survey in the U.S. 2013
Surveyed Directors of Flow Cytometry Laboratories at 30 major medical institutions with active myeloma programs in the U.S. 26 institutions responded Flanders et al. Blood 2013

8 MRD in Multiple Myeloma: a Survey in the U.S. 2013
Number of myeloma specimens per year for flow cytometry? >100 specimens: 19 institutions specimens: 2 institutions N/A: 5 institutions Do you perform myeloma MRD? Yes: 11 institutions No: 15 institutions Flanders et al. Blood 2013

9 MRD in Multiple Myeloma: a Survey in the U.S. 2013
Which bone marrow aspirate is submitted for flow cytometry? All labs (n=26) “MRD” labs (n=11) 1st: 5 institutions 3 institutions 2nd: 4 institutions 2 institutions 3rd: 3 institutions 3 institutions Don’t know: 14 institutions 3 institutions Flanders et al. Blood 2013

10 Precision/concordance
MRD in Multiple Myeloma: a Survey in the U.S. 2013 Number of “colors” in MRD flow analysis? 4 colors: 0 institutions 5 colors: 2 institutions 6-9 colors: 9 institutions Gating strategies: how you determine which cells will be studied? SSC, CD45: 1 institution SSC, CD45, CD38: 2 institutions CD38, CD138: 2 institutions SSC, CD38, CD138, CD45: 6 institutions 67% 92% Precision/concordance as determined by EMN Rawstron et al, Haematologica 2008

11 Rawstron et al, Haematologica 2008
MRD in Multiple Myeloma: a Survey in the U.S. 2013 Which antigens do you study in myeloma MRD? Abnormal Plasma cells: CD38+, CD138+, CD45 -, CD19-, CD56+, CD20+, CD27 dim or-, CD28+, CD81 dim or -, CD117+, monoclonal k/l EMN recommendations Recent studies show that up to 30% normal PCs are CD19- or CD45- and 15% normal PCs are CD56+ Antigen CD38 CD138 CD45 CD19 CD56 CD20 Ic k/l CD27 CD28 CD81 CD117 #Labs 11 10 9 5 3 Antigen CD38 CD138 CD45 CD19 CD56 CD20 Ic k/l CD27 CD28 CD81 CD117 #Labs 11 10 9 5 3 CD38 CD138 CD45 CD19 CD56 CD20 CD27 CD28 CD81 CD117 Rawstron et al, Haematologica 2008

12 MRD in Multiple Myeloma: a Survey in the U.S. 2013
Do you use pre-lyse or post lyse for flow MRD cytometry analysis? Pre-lyse: 4 institutions Post-lyse: 7 institutions How many number of events do you acquire in your MRD myeloma analysis? Your cut-off for MRD positive vs. negative? Flanders et al. Blood 2013

13 MRD in Multiple Myeloma: a Survey in the U.S. 2013
Flanders et al. Blood 2013

14 Stetler-Stevensen et al, unpublished data
MRD in Multiple Myeloma: a Survey in the U.S. 2013 53 year-old female with myeloma Abnormal plasma cells at diagnosis: CD19-, CD45-, CD38 dim, CD20-, CD56+, CD81-, CD27 dim Now MRD work-up post therapy 100,000 cells 500,000 cells 1 Million cells 3 Million cells No abnormal plasma cells 6 abnormal plasma cells 12 abnormal plasma cells 30 abnormal plasma cells Stetler-Stevensen et al, unpublished data

15 Summary and Conclusions
MRD testing by flow cytometry in myeloma varies greatly in the U.S. with maximum possible sensitivity ranging from % to 0.02% 5/11 MRD laboratories are using gating strategies proven to have low precision/concordance by EMN 1/11 MRD lab does not use one of the EMN essential antibodies Consensus guidelines are necessary and process is initiated

16 MRD by Molecular Assays
Outline MRD and Outcomes MRD by Flow Cytometry MRD by Molecular Assays

17 MRD by Molecular Assays
ASO-PCR for VDJ rearrangements High throughput VDJ sequencing Targeted/whole exome sequencing

18 1. Allele Specific Oligonucleotide (ASO) PCR
Detection of clonal plasma cells by ASO-PCR for VDJ rearrangements Patient specific customization, or use BIOMED-2 consensus primers (covers 70-80% of pts) Strong correlation between ASO PCR and flow cytometry (r=0.88) ASO PCR negativity associated with better PFS (p=0.001) San-Miguel. ASCO 2013

19 2. High Throughput VDJ Sequencing
Extract DNA Add known quantity of reference IgH Amplify IgH molecules Sequence molecules  quantify tumor VDJ sequences

20 2. VDJ Sequencing in Spanish Multiple Myeloma Clinical Trials
Bone marrow samples assessed by VDJ sequencing and flow cytometry in 56/68 (82%) multiple myeloma pts in VGPR/CR Strong correlation between VDJ sequencing and flow cytometry (r2=0.86) Based on small numbers, MRD negative by VDJ sequencing associated with significantly better overall survival (NR vs. 86 months) Martinez-Lopez. ASCO 2013

21 2. VDJ Sequencing: the NCI Experience
Tumor specific VDJ gene rearrangement identified in bone marrow supernatant/CD138+ cells in 13/14 (93%) MM patients treated with Carfilzomib, Lenalidomide and Dexamethasone (CRd) MRD assessment by VDJ sequencing in blood and flow cytometry of the marrow for 7 patients with VGPR/CR One patient was MRD negative by flow cytometry of the marrow and positive by VDJ sequencing in blood Another patient was MRD positive by flow cytometry of the marrow and negative by VDJ sequencing in blood

22 Clonogenic Evolution in Recurrent Myeloma
3. Detection of Tumor Specific Mutations: Beyond VDJ Clonogenic Evolution in Recurrent Myeloma Keats et al. Blood 2012

23 3. Detection of Tumor Specific Mutations: Beyond VDJ
Identify tumor specific mutations in biopsy specimen using targeted/whole exome sequencing Quantify identified mutations in peripheral blood (circulating cell free DNA) using targeted sequencing Validated in breast cancer (NEJM 2012) and colorectal cancer (ASCO 2013)

24 Summary and Conclusions

25 Assay Related Facts 1. ASO-PCR 2. VDJ Sequencing 3. Exome Sequencing
Flow cytometry Universal assay No (patient specific primers) Yes “Yes/No” Sensitivity 10-5 Unknown 10-4 (to 10-5) Sample analyzed Bone marrow aspirates Bone marrow aspirates or plasma Inter-observer variation Likely Significant Study clonal evolution No detection Limited detection Can overcome sampling error Maybe overcome with plasma samples

26 Disease Related Facts Patchy bone marrow involvement Extramedullary disease Clonal heterogeneity Do only plasma cells matter?

27 FDG PET-CT Negativity Post Therapy and Overall Survival
Ant MIP FDG PET Zamagni et al. Blood 2011

28 MRD in Myeloma: the future [technology] is here…
…we need to develop consensus guidelines!

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