multiple myeloma: high risk cytogenetics
TRANSCRIPT
References1. Sonneveld P, et al. Blood 2016;127:2955–62; 2. Nooka AK, et al. Am Soc Clin Oncol Educ Book 2016;35:e431–41; 3. Dimopoulos MA, et al. Cancer Treat Rev 2015;41:827–35;4. Richardson PG, et al. Blood Cancer J 2018;8:109; 5. Lancman G, et al. Clin Adv Hematol Oncol 2017;15:870–9; 6. Castaneda O and Baz R. Acta Medica Academica 2019;48:57–67;7. Kumar S, et al. Blood 2012;119:2100–5; 8. Bianchi G & Ghobrial IM. Curr Cancer Ther Rev 2014;10:70–9; 9. Brioli A, et al. Br J Haematol 2014;165:441–54;10. Keats JJ, et al. Blood 2012;120:1067–76; 11. Manier S, et al. Nat Rev Clin Oncol 2017;14:100–13; 12. Saxe D, et al. Int J Lab Hem 2019;41:5–14;13. NCCN Guidelines Multiple Myeloma V3.2020. Available at: https://www.nccn.org/; 14. Moreau P, et al. Ann Oncol 2017;28 (suppl_4):iv52–61;15. Palumbo A, et al. J Clin Oncol 2015;33:2863–9; 16. Schmidt TM, et al. Blood Cancer J 2019;9:94; 17. Rajkumar SV. Am J Hematol 2016;91:720–34; 18. Boyd KD, et al. Leukemia 2012;26:349–55; 19. Jian et al. Medicine (Baltimore) 2016;95:e3521
MAT-GLB-2101543 (v1.0) – 04/21© 2021 sano�-aventis U.S. LLC
MULTIPLE MYELOMA:HIGH RISK CYTOGENETICS
The presence of high-risk cytogenetic features has been well documentedas a negative prognostic factor and these patients typically have poorer
outcomes compared with standard risk patients1,2
Patients with high-riskcytogenetics are not always captured in
clinical trials or real-world studies resulting in
subgroup analyses on a relatively small
sample size3–5
Consequently, there isa paucity of data for
the targeted treatment of patients with
high-risk cytogenetics and randomized trials are needed in these
populations5
Cytogenetic analysis of bone marrow samples by �uorescence in situ hybridization (FISH) is recommend-
ed at diagnosis for risk strati�cation1,13,14
The IMWG use the following cytogenetic abnormalities identi-�ed by FISH to de�ne multiple myeloma with poor prognosis:1
Nearly all patients withmultiple myeloma haveone or more geneticaberrations and thepattern of abnormalities can change due toclonal evolution1,6,7
Intra-clonal heterogeneity may affecttreatment response; differential selectivepressure of the treatment may result inthe disappearance of some clones but not others allowing these to proliferate and cause relapse of disease8,9
Duplications ofentire chromosomes
Typically involves chromosomes 3, 5, 7, 9, 11, 15, 19 or 21
Gain 1q is a poor prognostic factor with a negative impact on survival outcomes particularly when there
are more than 4 copies present or if it is associated with other high-risk cytogenetic abnormalities
A clearde�nition of a high-risk
diagnosis is needed
Median overall survival is approximately 3 years vs 7–10 years
Patients may acquire additionalhigh risk chromosomalabnormalities throughout courses of treatment that could esult in a more aggressivedisease course8,11
The genomes of patients with high-risk cytogenetics are less stable and showmore variation than those with standard risk cytogenetics10
General population Trial population
*Included in the Revised International Staging System for multiple myeloma as high-risk15
t(14;20)
1%of MM cases
t(14;16)
4%of MM cases*
del(17/17p)
7%of MM cases*
t(4;14)
15%of MM cases*
gain(1q)
40%of MM cases
Gain of chromosome 1q is commonlyfound in patients with MM and frequency
increases with disease progression16
The presence of multiple cytogenetic abnormalities further decreasesprognosis compared with individual high-risk abnormalities1,18,19
There is inconsistency in clinical trials in the cut-off used tode�ne the existence of a high-risk abnormality ranging fromdetection in a single cell to 60% of cells4,5
Response rates and survival outcomes are lower for patients withgenetic abnormalities versus those with standard risk cytogenetics2,17
Median OS
7–10 years:Trisomies,t(11;14),t(6;14)
Genomic instabilityand heterogeneityare hallmarks ofmultiple myeloma1,6
Trisomies ~50% of cases
Normal
Translocationsinvolving the immunoglobulin heavy-chain gene on chromosome 14
Translocations 40–70% of cases
Deletions 7–50% of cases Gains ~40% of cases
Duplication of chromosomes orsections
Frequently affects chromosome 1q
Loss of chromosomes or sections, resultingin haploinsuf�ciency
Typically involves chromosomes 1, 6, 8, 13, 11, 14, 16 or 17
~50%
~40%
40–70%
40–70%
Multiple myeloma: cytogenetic abnormalities1,6,12
D B
C
A
1Initiating mutations Secondary
mutations
D B
C
EA
1
PFS 41.9months
Patients with 1q gain at diagnosis:
Patients with 4 or morecopies of 1q at diagnosis:
PFS 34.6months
Patients with 1q + t(4;14),t(14;16) or del(17p)
at diagnosis:PFS 25.1
months
Overall survivalYears0 1 2 3 4 5 6 7 8 9 10
Median OS
3 years:t(14;16),t(14;20),
del(17/17p)
Median OS
5 years: t(4;14), gain(1q)
Patients without 1qgain at diagnosis:
PFS 65.1months
E
D B
C
A
1
FTreatment
D B
C
A
1
No adverse lesions n=4511 adverse lesion n=2892 adverse lesions n=1133 adverse lesions n=16
Survival (months)
0
0.0
0.2
0.4
0.6
0.8
1.0
10 40 60 70
Pro
po
rtio
n o
f pa
tien
ts
503020
FISH standard risk
P<0.001
FISH high risk
Follow-up from Diagnosis (months)
00.0
0.1
0.2
0.3
0.4
0.6
0.5
0.8
0.9
0.7
1.0
12 48 72
Pro
po
rtio
n s
urv
ivin
g
603624
There remains a detrimental gap between high-risk andstandard risk cytogenic patients5,7