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Clonality in Multiple Myeloma
DANA‐FARBER CANCER INSTITUTE
Nikhil C. Munshi, MD
Professor of Medicine Harvard Medical School
Director Basic and Correlative SciencesJerome Lipper Myeloma Center
Dana-Farber Cancer Institute
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John Shaughnessy, Jr et al. Blood 2000;96:1505-1511©2000 by American Society of Hematology
• Bone marrow cells simultaneously hybridized with probes for D13S272 (red) and D13S31 (green).
• 5% cells were normal (i)• 48% cells demonstrated
monosomy (ii)• 12% cells showed
monosomy for D13S272 and complete loss of the D13S31 signal (iii)
• 23% of the cells had no signal for either probe (iv).
Clonal heterogeneity and dispersed interstitial deletions in myeloma
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More than 60% sub clonality in 17p predicts for poor outcome
PFS OS
Avet-loiseau et al. Blood 2013
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Neha Korde et al. Blood 2011;117:5573-5581
©2011 by American Society of Hematology
Evolution of Multiple Myeloma –Genomic Changes
Normal Plasma Cells
Myeloma Cells
ExtramedullaryDisease
MGUSCells
Spontaneous Evolution• Inherent• Microenvironmental• Immune effects
Spontaneous Evolution• Inherent• Microenvironmental• Immune effects
Therapy Effects• Clonal selection• Clonal induction• Mutation promotion• Effcet on repair
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Clonal progression in cancer
Normal Preclinical Overtmalignan cy
Frequent Subclonal Variants in MM
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Complex Landscape of Rearrangements and clonal evolution in Smoldering and Multiple Myeloma Revealed By Whole‐
Genome Sequencing
WGS of 100 matched paired myeloma samples (SMM, ND, relapse/normal) in a cohort of 30 patients:
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Complex Genomic
Changes Even at Early stage
Disease
Bolli et al. Nature Comm In Press
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Branching Evolution may Drive Subset of SMM progression into symptomatic MM
Bolli et al. Nature Comm In Press
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Two Types of SMM Associated with Distinct Evolution and Pattern of Progression to
symptomatic MM
Bolli et al. Nature Comm In Press
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Complex landscape of chromosome rearrangements in MM
Del
Gain
ITD
inversion
translocation
% of p
atients
coordinnates
Chr 1
Chr 6
Chr 16
Chr 15
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Chromosomal changes occur over the time in MM
HD1q+Del Xt(8p12;Xq23)
CN‐LOH X8p‐3q‐
Xq27‐
NDMM4
HD1q+Del Xt(8p12;Xq23)
CN‐LOH Xt(8q11.21;Xq25)
8p‐
t(8q11.21;Xq25)delXq25*5q‐3q‐
RMM4
HD1q+Del X
t(8p12;Xq23)8p‐CN‐LOH X
SMM4
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Multiple genetically distinct subclones occur in multiple myeloma
• Multiple genetically distinct subclones are present at diagnosis, increase during the course of disease1–4
– These evolve over time due to selective pressures from treatment and factors in the microenvironment1,4
– This clonal evolution can result in disease progression and treatment resistance5
1. Bahlis N et al. Blood 2012;120:927–282. Keats JJ et al. Blood 2012;120:1067–763. Bianchi G, Ghobrial IM. Curr Cancer Ther Rev 2014;10:70–9
4. Bolli N et al. Nat Commun 2014;5:29975. Brioli A et al. Br J Haematol 2014;165:441–54.
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Marc S. Raab et al. Blood 2016;127:2155-2157
©2016 by American Society of Hematology
The clinical course and management of a patient with BRAFV600E-mutant MM developing resistance to treatment
with vemurafenib.
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RAS‐RAF mutations often late and convergent
Bolli et al. Nature Comms, 2014
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Trametinib +Dabrafenib for BRAF/NRAS/KRAS mutant MM
Determine if mutation in BRAF, KRAS, NRAS
Braf mutated Braf with KRASOr NRAS mutated
KRAS or NRAS mutated
Treat with Dabrafenib
Treat with Dabrafenib+ Trametinib
Treat with Trametinib
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Conclusion & Clinical Implications• Clonal heterogenity and sub clonal evolution are
fundamental to malignant cells – myeloma no exception
• Different patterns of disease evolution over time across patients ‐ Need for repeated genomic analysis
• So what are the mechanisms driving early versus late clones may be different
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From Whole Exome Sequencing NNMF extracted 2 main mutational
signatures in myeloma
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AID May Drive MGUS/SMM While APOBEC May Act at A Later Time During MM Evolution
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Deeper WGS Identifies Additional Mutational Processes
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In Myeloma Transcribed Region is Under Pressure of DNA Repair Related Mutational Processes:
Composite Analysis Using RNA‐seq, ATAC‐seq and WGS
Whole Genome Sequencing
ATACseq
RNAseq
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Transcribed Region is Under Pressure of DNA Repair Related Mutational Processes in
Multiple Myeloma
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Subclonal Mutations Shows >85% Contribution from DNA Repair Signatures
in The Coding Region
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APOBEC is An Important Mutational Processes in Myeloma
Walker et al Nat Comm 2015 Bolli et al. Leukemia 2018
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Elevated Functional Deaminase Activity in MM
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Impact of elevated APOBEC 3 G expression on genomic instability in MM cells
APOBECs may be a good target for therapy !!
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Conclusion & Clinical Implications• Clonal heterogeneity and sub clonal evolution
are fundamental to malignant cells – myeloma no exception
• Different patterns of disease evolution over time across patients ‐ Need for repeated genomic analysis
• Mechanisms driving early versus late clones may be different
• Number of factors determine clonal selection and therapy may have significant impact on genome -need to consider types of agents and combinations used and lengthy of therapy
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WGS at diagnosis
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WGS at relapse
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WGS at diagnosis andrelapse – Significant increase in complexity
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Conclusion & Clinical Implications• Sub clonal variants and clonal evolution
o A moving Target
oTry and eliminate the clones aggressively
oA sensitive clone mat remerge
o Is Targeted therapy really possible?
oNeed for multi target therapy
oRise of immunotherapy!
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Masood Shammas, PhDPrabhala Rao, PhDMariateresa Fulciniti, PhDWeihua Song, MDJagannath Pal, MD, PhDPuru Nanjappa, PhDJianhong Lin, MDMaria Gkotzamanidou , MD, PhDAdan Soerling, MD, PhDWeihong Zhang, MDTeresa Calimari, MDAriel Kwart, BSSophia Adamia, PhDRajya Bandi, MSYuTzu Tai, MDJooeun Bae, PhD
Kenneth Anderson, MD
Giovanni Parmigiani, PhDMehmet Samur, PhDYi Li, PhDNaim Rashid, PhD and Bioinformatics Group
Dr. Herve Avet-LousieuDr Stephane Miniville, Dr. Philippe MoreauDr. Florence MAGRANGEASDr. Michel Attal and IFM
Peter CampbellAndy FutrealGraham BignellNiccolo BoliDavid Wage
DANA-FARBER CANCER INSTITUTE