t(4;14) and genomic instability in
high-risk myeloma
P. Leif Bergsagel, MD
Mayo Clinic Arizona
Scottsdale, Arizona
Rochester, Minnesota
Jacksonville, Florida
t(4;14) dysregulates MMSET and FGFR3
FGFR3
MMSET
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Chesi et al, Nat Genet 1997
Chesi et al, Blood 1998
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Clinical detection of t(4;14) in MM
Flow, cIg-FISH, RT-PCR
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C2
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S1
S1
M1
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KM
UT
MM5
H
JIM
KM
OP
MMT
MMT
MMT
MM.
PB
tonsi
I/JH-MMSET on der(4)
Co-expression of FGFR3 and MMSET in MM patients
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Better OS in t(4;14) with bortezomib induction
Bortezomib-Dexamethasone
VAD
AVET-LOISEAU, JCO 2010
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MMSET regulates histone H4K20 methylation and
53BP1 accumulation at DNA damage sites
Pei H, Zhang L, Luo K, Qin Y, Chesi M, Fei F, Bergsagel PL, Wang L, You Z & Lou Z.
Nature 2011 (470)124
Patient Tumors are Stable Over Time
Three changes in one patient and no changes in second patient
Keats JJ et al, unpublished
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Summary of the Paired Analysis
First Hit
Progenitor
Diagnosis
Relapse
No Changes (36%)
1-38 Months (Median 13)
Gains & Losses (36%)
Only New Changes (29%)
6-29 Months (Median 21)
3-65 Months (Median 18)
9-61 Changes (Median 26)
1-15 Changes (Median 5)
Relapse
Relapse
Keats JJ et al, unpublished
Relationship Between Changes and Subtype
Keats JJ et al, unpublished
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Clinical course of a patient with t(4;14) MM
Keats JJ et al, unpublished
Chromosome 8
Keats JJ et al, unpublished
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Keats JJ et al, unpublished
Effective re-treatment of MM with full dose bortezomib
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Suboptimal bortezomib treatment alters disease course
Chesi et al, unpublished
Aggressive MM can stimulate or eradicate indolent MM
Chesi et al, unpublished
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Drug response in transplanted Vk*MYC MM
Remarkable activity of HDACi+Bortezomib
Chesi et al, unpublished
Possible clinical implications of genomic instability
and intra-clonal heterogeneity in high-risk MM
· Argues for combination vs sequential therapy (E.g., RVd instead
or Rd followed by Vd)
· Selection of pre-existing resistant clones by low-dose
maintenance therapy more likely with high-risk MM
· For drugs used in maintenance, the initial exposure should be
when the tumor burden is lowest
· There are more genetic changes following relapse from
melphalan then from agents that do not target DNA
· Melphalan may be harmful to high-risk MM (that are not in CR)
· Melphalan is best used following a maximal cytoreduction so that
the fewest possible MM cells are exposed to its mutagenic
effects
· Early treatment (e.g., smoldering MM) may preferentially
eradicate "good" myeloma, making room for "bad" myeloma
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Collaborators
Bergsagel Lab
Marta Chesi
Jonathan Keats
Mayo Clinic
Mike Kuehl
Keith Stewart
Jonathan Licht
Rafael Fonseca
Zhenkun Lou 19
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