Original Article

Cytogenet Genome Res Received: October 28, 2022

Accepted: January 11, 2023
DOI: 10.1159/000529191 Published online: February 13, 2023

Cytogenetic Abnormalities in Multiple Myeloma:

Incidence, Prognostic Significance, and Geographic
Heterogeneity in Indian and Western Populations
Pratibha Kadam Amare a Shraddha Nikalje Khasnis a Pranita Hande a

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Hrushikesh Lele a Nishigandha Wable a Snehal Kaskar a Nikita Nikam Gujar a

       

Nilesh Gardi b Aniket Prabhudesai a Karishma Todi a Rohit Waghole a

       

Pritha Roy a  

aOncocytogenetics and Oncomolecular Department, Lilac Insights Pvt. Ltd, Navi Mumbai, India; bACTREC, Tata
Memorial Center, Navi Mumbai, India

Keywords was performed on isolated plasma cells. Karyotype analysis

Multiple myeloma · Cytogenetics · FISH · Geographic was done as per ISCN 2016 and 2020. FISH could detect cy-
heterogeneity togenetic abnormalities in 67.6% of the cases with an inci-
dence of 59% non-hyperdiploidy. The incidence of IGH trans-
location was 26% versus literature frequency of 40–50%
Abstract which was mainly due to a low incidence (6%) of t(11;14) in
Multiple myeloma (MM) is a genetically complex and hetero- contrast to 15–20% in other series. Additionally, the associa-
geneous neoplasm in which cytogenetics is a major factor tion of secondary progressive aberrations in the hyperdip-
playing an important role in the risk stratification of disease. loid group rather than the non-hyperdiploid group in our
High-risk MM based upon cytogenetic classification includes patients is not a common finding. A biallelic inactivation of
primary IGH translocations t(4;14), t(14;16), t(14;20), and sec- TP53 as an ultra-high risk factor was detected in old-aged
ondary progressive aberrations such as gain/amp(1q), 1p de- patients. These observations disclose the novel findings and
letion, del(17p), and hypodiploidy. Several studies have strongly indicate the racial disparity which leads to geo-
proved that interphase FISH can detect primary as well as graphic heterogeneity. In contrast to FISH, conventional
secondary cryptic aberrations very efficiently in lowest karyotyping could detect MM-related aberrations in 50% of
5–10% abnormal plasma cell population. The present large- cases, of which 44% revealed highly complex karyotypes
scale study was undertaken to evaluate the incidence of cy- with common aberrations of chromosome 1q. Overall, FISH
togenetic abnormalities, to analyse the correlation of con- was found to be a novel, easy approach with high success
ventional karyotyping with FISH, and to seek the geograph- rate and capability of detection of all cytogenetic abnormal-
ic heterogeneity in the incidence of primary as well as ities that add valid information for the risk stratification of
secondary aberrations in our Indian versus Western popula- disease. This, in future, in combination with mutation profile
tions. We conducted prospective studies of 1,104 patients and gene expression profile will help in further refinement
consecutively referred from the primary, secondary, and ter- of disease and identification of actionable targets.
tiary oncology centres from all over India. Interphase FISH © 2023 The Author(s).
Published by S. Karger AG, Basel

[email protected] © 2023 The Author(s). Correspondence to:

www.karger.com/cgr Published by S. Karger AG, Basel Pratibha Kadam Amare, pamare @ lilacinsights.com
This article is licensed under the Creative Commons Attribution 4.0
International License (CC BY) (http://www.karger.com/Services/
OpenAccessLicense). Usage, derivative works and distribution are
permitted provided that proper credit is given to the author and the
original publisher.
 Introduction amplification, 1p deletion, and trisomies of odd num-
bered chromosomes in 60–90% of MM patients [Avet-
Multiple myeloma (MM) is a genetically complex and Loiseau et al., 2007; Fonesca et al., 2009; Rajan and Raj-
heterogeneous neoplasm in which cytogenetic abnormal- kumar, 2015; Kadam Amare et al., 2016; Kumar and Ra-
ities are major genetic factors in the prognostication of jkumar, 2018; Abdallah et al., 2020].
disease; hence cytogenetics is considered as an integral The present large-scale study was undertaken to (1)
part of disease management [Fonesca et al., 2004; Avet- evaluate the incidence of cytogenetic abnormalities, (2)
Loiseau et al., 2007; Sawyer, 2011; Rajan and Rajkumar, assess the frequency of double-hit and triple-hit myelo-
2015; Kadam Amare et al., 2016; Sonneveld et al., 2016; ma, (3) analyse the correlation of metaphase cytogenetics
Abdallah et al., 2020]. The identification of high-risk and with FISH analysis, and, most importantly, (4) seek the
low-risk cytogenetic abnormalities either single or in geographic heterogeneity in the incidence of the abnor-
group plays an important role in the therapeutic decision malities in Indian and western countries’ populations.
[Kumar and Rajkumar, 2018; Abdallah et al., 2020;
Hanamura, 2022]. Hence, cytogenetics is included in the

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consensus statement of the European Myeloma Network Materials and Methods
and International Myeloma Working Group as well as
Patients
treatment guidelines of the National Comprehensive
We conducted prospective studies on 1,104 consecutive pa-
Cancer Network [Avet-Loiseau et al., 2007; Fonseca et al., tients (675 males, 429 females, age range 30–96 years) who were
2009]. newly diagnosed MM cases from all the zones of Indian population
Trisomies of 3, 5, 7, 9, 11, and 15 are the most com- which included the tertiary oncology hospitals, polyclinics, indi-
monly observed trisomies in hyperdiploidy which is one vidual clinics, since January 2016 to December 2022. The diagnosis
of MM was evaluated and confirmed by bone marrow pathology
of the major cytogenetic groups and is generally consid-
and immunobiochemical parameters. The exclusion criteria were
ered as low-risk cytogenetic category in MM [Wuilleme history of other primary malignancies, administration of chemo-
et al., 2005; Barilàet al., 2020]. therapy or radiotherapy before diagnosis of MM.
High-risk MM is defined as having at least one of the Plasma cell isolation was performed by purification of plasma
cytogenetic abnormalities related with poor prognosis, cells using CD138-coated magnetic beads according to the manu-
facturer’s instructions (Miltenyi Biotec, Paris, France).
which include IGH translocations t(4;14), t(14;16), and
t(14;20), del (17p), p53 mutation, 1q gain/amplification, FISH on Plasma Cells
and 1p deletion. The genes dysregulated in the high-risk Mononuclear cells from bone marrow aspirate were enriched
translocations are: 4p16.3 (FGFR3 and MMSET), 16q23 by Ficoll Hypaque gradient centrifugation. Plasma cells were puri-
(c-MAF), and 20q11 (MAFB) [Bergsagel et al., 2013; Goz- fied by using CD138-coated magnetic beads according to the man-
ufacturer's instructions. Enriched plasma cells were identified by
zetti et al., 2014; Sonneveld et al., 2016].
FITC-conjugated anti-human Kappa Lambda Light Chain stain-
Recently, the Mayo Clinic has proposed a concept sim- ing and the purity was 95% (range 70–99%).
ilar to high-grade lymphomas which is described as dou- Interphase FISH was performed on isolated plasma cells using
ble-hit MM, having two high-risk, and triple-hit MM, locus-specific probes SPEC RB1/13q12 dual colour probe/LSI
with three high-risk abnormalities which seem to be ad- 13q34 (control), SPEC TP53 (17p13)/CEN17 dual colour probe,
SPEC CKS1B, CDKN2C dual colour, LSI break apart dual colour
ditional adduct, helpful prognostic indicators in the un-
5′-3′ IGH probe, dual fusion IGH translocation probes CCND1/
derstanding of the MM prognosis [Walker et al., 2019; IGH, MAF/IGH, IGH/MAFB, MYC 5′-3′ break apart probe (Zyto-
Abdallah et al., 2020]. Light Spec, Germany), Metasystem XL IGH/FGFR3 DF, CCND3/
Biallelic inactivation of TP53, occurring in 2–4% of IGH probe. Hyperdiploidy was analysed by using a set of probes
newly diagnosed MM patients, was identified as an ultra- specific for CEN3, CEN7 (ZytoLight), and XL5p15/9q22/15q22
(Metasystems). Hyperdiploid MM was defined as presence of tri-
high-risk feature of MM, being associated with a median somy of ≥2 odd numbered chromosomes [Ashby et al., 2019; Ab-
survival of less than 2 years [Ashby et al., 2019; Munawar dallah et al., 2020]. FISH procedure was followed as per manufac-
et al., 2019]. turer's protocol. A total of 200 interphase plasma cell nuclei were
In comparison to conventional metaphase cytogenet- evaluated by two observers. The cut off threshold for ∆13
ics which yields a poor mitotic index, unable to give a true (del(13q)/–13), del(17)(p13.1), 1q gain/amp was 5%, t(14q32) was
10%, for dual fusion translocation probes (CCND1/IGH, FGFR3/
picture of cytogenetics, several groups have proved that IGH, MAF/IGH, MAFB/IGH, CCND3/IGH), MYC (5′-3′ MYC
interphase FISH can efficiently detect more than 90% of break-apart) and trisomy was 5%. Results were considered abnor-
cytogenetic abnormalities including cryptic 13q deletion, mal if the percentage of nuclei with the abnormal hybridization
various IGH translocations, aberrations of 17p, 1q gain/ signals was >3 SD from the mean. Two technologists scored the

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Fig. 1. a G-banded karyotype. 42,XX,+1der(1)del(1)(p13)dup(1) DAPI metaphase image after FISH with WCP1 showing duplica-
(p22q42),t(1;3)(q22;p21)t(1;10;3)(p22;p13;q22)t(1;4)(p32;p14),– tions (gain of 1q copy number) followed by translocation and in-
2,–3,+5?t(5;8)(q31;q22),–7,–8,–9,t(11;?)(p15;?),t(12;17) sertion to other chromosomes indicating the mechanism of chro-
(p11.2;p11.2),–13,t(14;16)(q32;q23),t(1;16)(?p13;q23),–17,– mothripsis. c WCP14 (green) and WCP16 (red) showing IGH/
20,+21i(21)(q10). The complex karyotype was checked and con- MAF co-localization: t(14;16)(q32;q23). d Inverted DAPI image of
firmed by FISH with WCP14 and 16 probes. Arrows indicate the same metaphase.
structural and numerical chromosome abnormalities. b Inverted

Cytogenetics in Multiple Myeloma from Cytogenet Genome Res 3

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Fig. 2. G-banded karyotype. 43,X,–Y,+1,+der(1)t(?;1)(?;p32),del(1)(p13)×2,del(2)(p23),t(4;14;?)(p16;q32;?),+6del(6)
(q21)×2,t(?;9)(?;q22),–12,–13,–14,–16,–17,t(?;17)(?;p13),+mar. Arrows indicate structural and numerical chromo-
some abnormalities.

Table 1. Incidence of chromosome abnormalities in 1,104 multiple results. For biallelic TP53 inactivation TP53 mutation analysis was
myeloma cases performed by Sanger sequencing in 48 cases with del(17p).
Bone marrow samples from 30 individuals without apparent
Chromosome abnormality Frequency, % haematological diseases and with normal karyotypes were used as
controls. Means and SD of the percentages of nuclei with one, two,
del(13q) 3.4 three, or break apart hybridization signals were obtained and cal-
Monosomy 13 31.3 culated on at least 200 cells.
Gain(1q) 19
amp(1q) 13 Conventional Karyotyping
Gain/amp(1q) 32 The karyotypes were obtained by culturing bone marrow aspi-
del(17p) 8 rate for 4–5 days in complete medium with B-cell mitogens inter-
Monosomy 17 1.3 leukin 4 (250 ng) and CD40L (400 ng). The cultures were har-
dup(17p) 0.9 vested by hypotonic KCl treatment followed by methanol:acetic
del(1p) 5.7 acid fixative, and mitotic preparation were made for GTG staining
IGH translocations 26 [Ding et al., 2013]. A minimum of 20 cells were karyotyped and
IGH partial deletion 7.4 abnormalities were defined as per ISCN 2016 and ISCN 2020 [Mc-
Gowan-Jordan et al., 2016, 2020]. GTG-banded karyotype analy-
sis was confirmed by WCP on metaphase cells and interphase
FISH.

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Fig. 3. High-risk markers in the non-hyperdiploid (NHD) and hyperdiploid group (HD).

Statistical Analysis cases with hypodiploid and diploid karyotypes. MM FISH

Results of all 1,104 cases were enrolled for statistical analysis to panel was negative in 32 of 65 (50%) cases. Twenty-one
investigate frequency of cytogenetic abnormalities, association of
hyperdiploidy and non-hyperdiploidy with IGH translocation and out of 65 (32.3%) cases were either hyperdiploid or had
other high-risk markers, incidence of dual- and triple-hit myeloma 1–2 non-recurrent abnormalities which were not related
along with incidence of frequent high-risk markers in dual and to MM. Overall, 29 of 65 cases (44.6%) had highly com-
triple-hit MM. Fisher’s exact test at a significance level of 0.05 was plex karyotypes with abnormalities of chromosome 1 and
used to compare the groups. All statistical analyses were carried del(17)(p11.2). Abnormalities of chromosome 1 included
out in R software. A comparison of incidence among different
chromosome abnormality groups was analysed using a proportion homogeneously staining regions (HSR) and multiple
test. events of chromosome 1 such as deletion of 1p, duplica-
tion of 1q, 1q translocation, and insertion into other chro-
mosomes at random (Fig. 1, 2). Overall 17/32 cases (53%),
those with 1q gain/amp showed either extra copies of 1 or
Results duplication of 1q through i(1q) or HSR on 1q followed by
translocation, insertion at other chromosomes at random
Conventional Karyotyping (Fig. 1, 2). Hyperdiploid karyotypes revealed gain of al-
In conventional cytogenetic preparations, successful most all chromosomes, of which gain of odd numbered
results were obtained in 65 of 80 cases (80%). Diploid, chromosomes like 3, 5, 7, 9, 15, 19, 21 was common. The
hyperdiploid (47–59 chromosmes), hypodiploid (40–45 interesting observation was that all complex karyotypes
chromosomes) and triploid-tetraploid (61–90 chromo- with chromosome 1 abnormalities revealed gain/amplifi-
somes) karyotypes were observed in 13 (20%), 19 (29.2%), cation of 1q. Hypodiploid karyotypes revealed losses of
12 (18.4%), and 4 (6%) cases, respectively. Abnormalities chromosomes 13, 14, 16, and 20.
of inv(9), inv(Y) or loss of Y were common findings in 16

Cytogenetics in Multiple Myeloma from Cytogenet Genome Res 5

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Fig. 4. IGH translocations in the non-hyperdiploid (NHD) and hyperdiploid group (HD).

Incidence of Overall Abnormalities, Hyperdiploidy, malities 384/1,104 (34.7%) which included del(13q):
IGH Translocations, and High-Risk Abnormalities by 38/1,104 (3.4%) and monosomy 346/1,104 (31.3%); gain/
FISH amp(1q): 357/1,104 (32%), gain(1q): 209/1,104 (19%),
Among 1,104 cases, 160 cases (14.55%) were in the age amp(1q): 148/1,104 (13%); aberration of chromosome 17:
range of 30–50 years and 944 cases (85.5%) were between 112/1,104 (10.2%), del(17p): 87/1,104 (8%), −17: 15/1,104
51 and 96 years. The male:female ratio was 1.57:1. (1.3%), dup(17p): 10/1,104 (0.9%); del(1p): 63/1,104
Of the 1,104 patients, 746 (67.6%) had chromosome (5.7%); IGH translocations: 289/1,104 (26%) and IGH
abnormalities, which included hyperdiploidy, IGH trans- partial deletion 82/1,104 (7.4%) (Table 1).
locations, and high-risk abnormalities. Abnormal clone Clustering of abnormalities viz, del(13q), −13, gain/
size was 5–100%. amp(1q), del(17p), −17, dup(17p), del(1p), IGH translo-
Finally, 655 (59.2%) cases had non-hyperdiploidy and cations, IGH partial deletion, was detected in both the
40.8% had hyperdiploidy. Hyperdiploidy revealed com- non-hyperdiploid as well as in the hyperdiploid group.
mon gain of odd numbered chromosomes 3, 7, 9, and 15, There was no significant association of high-risk markers
of which gain of chromosome 3 was 28.4%, chromosome with the non-hyperdiploid group. It was noted that aber-
7: 22.2%, chromosome 9: 33.05%, and chromosome 15: ration of 17 (p ≤ 0.00135) and gain/amp(1q) (p = 0.00001)
36.2%. In a separate cohort of 743 cases, chromosome 5 and IGH partial deletion (p < 0.014) were associated with
aneuploidy was checked along with chromosomes 3, 7, 9, the hyperdiploid group (Fig. 3).
and 15. Gains of chromosomes 5, 9, 15 were higher, i.e., Recurrent IGH translocations were detected as fol-
33%, 33.6%, and 55%, respectively as compared to gains lows: t(11;14): 66/1,104 (6%), t(4;14): 99/1,104 (9%),
of chromosomes 3 and 7 (27.6% and 20.4%, respectively). t(14;16): 24/1,104 (2.1%), t(6;14): 3/1,104 (0.27%),
Gain of chromosome 15 was highest (55%) among the t(14;20): 10/1,104 (0.9%), MYC translocations: 11/1,104
gains of 3, 7, 5, 9, and 15. (1%), and variant IGH translocations: 19/1,104 (1.7%)
(Fig. 4).
Incidence of Chromosome Abnormalities in Our Series Although IGH translocations including t(4;14) were
The incidence of chromosome abnormalities among more frequent in non-hyperdiploid group than in the hy-
the 1,104 cases was as follows: chromosome 13 abnor- perdiploid group, there was no significant association of

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DOI: 10.1159/000529191
 a1 a2

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b1 b2

Fig. 5. FISH on interphase cells. a Double-

hit myeloma. a1 1q amplification; a2 IGH/
MAFB colocalization: t(14;20)(q32;q12).
b Triple-hit myeloma. b1 IGH/FGFR3 co-
localization: t(4;14)(p16;q32); b2 monoso-
my of chromosome 13; b3 17p deletion; b4 b3 b4
1q amplification as well as 1p deletion.

t(4;14), t(14;16), t(6;14), t(14;20), MYC translocations, tion of gain/amp (1q) was seen in t(4;14) (p ≤ 0.00001),
variant IGH translocations with the non-hyperdiploid t(14;16) (p ≤ 0.000017), t(14;20) (p ≤ 0.016), MYC trans-
group except t(11;14) which was more prevalent in the locations (p ≤ 0.001), and variant IGH translocation (p ≤
non-hyperdiploid group (p ≤ 0.002) (Fig. 4). 0.025) positive cases. The del(1p) occurred frequently in
t(14;16) (p ≤ 0.043) positive cases.
Association of High-Risk Markers and Monosomy 13
with IGH Translocations Characteristics of Double- and Triple-Hit Myeloma
Clustering of monosomy 13 was detected in t(4;14)- The incidence of double-hit MM was 13.3% (147/1,104
positive cases (p ≤ 0.00001). The del(17p)/–17/dup(17p) cases) and triple-hit MM was 5% (55/1,104 cases). We did
abnormalities were associated with t(11;14) (p ≤ 0.0178), not find significant association of double- and triple-hit
t(4;14) (p ≤ 0.00001), t(14;16) (p ≤ 0.0005), and variant MM with ploidy group (double-hit with hyperdiploidy,
IGH translocations (p ≤ 0.00001). The significant associa- p ≤ 0.096; triple-hit with hyperdiploidy, p ≤ 0.3; double

Cytogenetics in Multiple Myeloma from Cytogenet Genome Res 7

Indian Population DOI: 10.1159/000529191
hit with non-hyperdiploidy, p ≤ 0.096; and triple-hit with from those reported by others, except frequency of del(1p)
non-hyperdiploidy, p ≤ 0.306). Further, there was no was comparatively low (5.7%) as compared with 15–30%
prevalence of double- and triple-hit MM in old aged cas- reported frequency [Hebraud et al., 2014; Walker et al.,
es [≤60 years, p < 0.92 vs. ≥60 years, p ≤ 0.74) (Fig. 5a, b). 2015].
Double-hit MM was more prevalent in t(4;14) (p ≤ IGH partial deletion studies are scarce in the literature.
0.00001), t(14;16) (p ≤ 0.0001), t(14;20) (p ≤ 0.0007), The present study found that the low frequency (7.4%) of
MYC translocations (p ≤ 0.0013), and variant IGH trans- IGH partial deletion either telomeric 5′ or 3′ centromeric
locations (p ≤ 0.05). Similarly, triple-hit MM occurred is due to an IGH fusion most frequently in t(11;14),
frequently in t(4;14) (p ≤ 0.00001), t(14;16) (p ≤ 0.00001), t(4;14), and t(14;16) [Rajkumar, 2020; Smith et al., 2020].
and MYC translocations (p ≤ 0.014). As reported by Rajkumar [2020], we also found that the
All high-risk abnormalities such as abnormalities of majority of these IGH partial deletions were more com-
del(17p)/–17, gain/amp(1q), and del(1p) were most com- mon in t(11;14), t(4;14), and t(14;16) cases which are gen-
mon in double-hit MM (p ≤ 0.000036, p ≤ 0.00001, and erally associated with worse outcome except t(11;14) [Ra-
p ≤ 0.00001, respectively) and triple-hit MM (p ≤ 0.00001, jkumar, 2020; Smith et al., 2020].

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p ≤ 0.00001, p ≤ 0.00001, respectively). Monosomy 13 was The incidence of overall IGH translocations (26%) is
also frequently detected in double-hit (p ≤ 0.00001) and lower than the reported frequencies of 40–50% [Fonesca
triple-hit MM (p ≤ 0.0024) (Fig. 5a, b) There was no age- et al., 2004; Avet-Loiseau et al., 2007; Schmidt-Hieber et
related prevalence of high-risk abnormalities as the fre- al., 2012; Rajan and Rajkumar, 2015; Kumar and Rajku-
quencies of single-hit, double-hit, and triple-hit MM mar, 2018]. The main reason for lower IGH translocation
were almost the same in cases ≤60 years and ≥60 years frequency is due to very low frequency of t(11;14) (6%) as
(p ≤ 0.363, p ≤ 0.92, p ≤ 0.74, respectively). compared to other series (15–20%). Greenberg et al.
While screening for the IGH translocation, IGH partial [2015] reported significantly lower frequency of t(11;14)
deletion was noted in all IGH translocation-positive cases in blacks compared with whites. They also found low fre-
with frequency 2.3–39%. The association of IGH partial quency of t(4;14) in blacks as compared with whites [Fon-
deletion was more common in t(4;14) (39%). esca et al., 2004, 2009; Greenberg et al., 2015]. Our previ-
A biallelic TP53 mutation study in 48 cases with ous study has also reported the low frequency of t(11;14)
del(17p) revealed 7 cases (14.6%) with a biallelic TP53 in Indian population [Kadam Amare et al., 2016].
mutation. Out of 7 cases, 6 were above 60 years, indicat- The association of high-risk markers, i.e., aberration of
ing total inactivation of TP53 is a very high risk factor that chromosome 17 [del(17p)/–17/dup(17p)], only del(17p),
could emerge during the ageing process, which might gain/amp(1q), and IGH partial deletion with the hyper-
cause further progression of the disease. diploid group rather than the non-hyperdiploid group
observed in our large cohort has not been reported by
previous studies [Fonesca et al., 2004; Sawyer; 2011; Bari-
Discussion là et al., 2020], which further supports and strongly indi-
cates the racial disparity which leads to geographic het-
Fluorescence in situ Hybridization erogeneity.
In the present study of 1,104 cases, sensitive FISH on As reported in published studies, various IGH translo-
purified plasma cells could detect genomic abnormalities cations preferably occurred in the non-hyperdiploid
in 67.6% of cases which was almost comparable to the in- group. However, our study highlights that only t(11;14)
cidence (50–90%) reported in literature [Avet-Loiseau et showed significant association with the non-hyperdip-
al., 2007; Jacobus et al., 2011; Rajan and Rajkumar, 2015; loid group (Fig.  4) [Avet-Loiseau et al., 2002, 2007;
Sonneveld et al., 2016]. The incidence of higher frequen- Sonneveld et al., 2016]. Further, our study revealed that
cies of chromosomes 5, 9, and 15 than chromosomes 3 the frequency of occurrence of high-risk markers like ab-
and 7 in hyperdiploidy is in agreement with reported erration of 17p, gain/amp(1q), including monosomy 13,
studies [Kumar et al., 2012]. Losses of chromosomes 13, was associated with t(11;14), t(4;14), t(14;16), t(14;20),
14, 16 observed in hypodiploid karyotypes by conven- and variant IGH translocations, which further supports
tional karyotyping are generally common losses in hypo- the concept of primary IGH translocation which later on
diploid MM [Smadja et al., 2001; Van Wier et al., 2013]. develops high-risk abnormalities as secondary, progres-
The frequencies of del(13q), monosomy 13, gain/amp(1q), sive events. MYC was associated only with gain/amp(1q),
del(17p) observed in our cohort do not differ markedly which suggests that MYC translocations are themselves

8 Cytogenet Genome Res Kadam Amare et al.

DOI: 10.1159/000529191
secondary rather than primary changes [Avet-Loiseau et seems to be the result of pericentromeric instability which
al., 2007; Walker et al., 2015; Weinhold et al., 2016]. results in increase in the 1q copy number followed by
The frequent occurrence of t(4;14), t(14;16), t(14;20), translocation, insertion, inverted duplication randomly
MYC translocations in double-hit MM, and t(4;14), to various chromosomes by jumping rearrangements
t(14;16), and MYC translocations in triple-hit MM indi- (Fig.  1a, b). The mechanism is called chromothripsis,
cates that t(14;16), t(14;20), and MYC translocations are which involves chromosomal shattering and random re-
high-risk translocations. assembly and localized clustering of breakpoints in re-
There is a controversy whether monosomy 13 can be sponse to one catastrophic event rather than accumula-
considered as a high-risk abnormality [Rajan and Rajku- tion of a series of subsequent events. This results in copy
mar, 2015; Rajkumar, 2015; Binder et al., 2017; Kumar number changes of 1q genes, described as gain/amp(1q)
and Rajkumar, 2018]. The strong association of mono- here, which can be very well studied by application of
somy 13 in double- and triple-hit MM like the association FISH [Cai et al., 2014; Morishita et al., 2016; Le Baccon et
of other high-risk abnormalities such as aberrations of al., 2001; Maura et al., 2022]. There is also a chance of
17p, gain/amp(1q), and del(1p), supports the notion that missing cryptic translocations like t(4;14)(p16;q32) and

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monosomy 13 can also be considered as a high-risk ab- t(14;16)(q32;q23) at chromosome level. The karyotyping
normality. A biallelic inactivation of TP53 as an ultra- revealed hypodiploidy with losses of chromosomes 13,
high risk factor was detected more in cases above 60 years, 14, and 16 which one cannot detect by FISH studies, and
indicating progressive changes in old-aged patients. detection of hypodiploidy in MM is very important be-
Gain/amp(1q) leads to gain/amplification of several cause it is associated with very poor prognosis [Van Wier
genes such as ANP32E, MCL1, PSMD4, ILF2, IL6R, and et al., 2013; Sawyer et al., 2017]. There are always some
PBX1 apart from CKS1B which leads to overexpression of advantages and disadvantages with either FISH or con-
these genes which may affect the resistance to different ventional karyotyping. However, considering the easy ap-
drugs [Sawyer et al., 2005; Shaughnessy, 2005; Hanamura proach, the success rate even at an early stage and expect-
et al., 2006; Shah et al., 2017; Zeng et al., 2019; Hanamura, ed important valid information from the prognostic,
2022]. Similarly, FISH studies in MM show deletion of therapeutic point of view, FISH seems to be a gold stan-
CDKN2C on 1p. There are several deletion loci on 1p arm. dard technique to study the genomic picture in MM.
The candidate genes on del(1p) are CDKN2C and FAF1 In conclusion, the present study represents the first
at 1p32, RRLP and EVI5 at 1p22 and FAM46C at 1p12. large-scale evaluation of cytogenetic abnormalities in
CDKN2C performs an important function in cell cycle MM in an Indian cohort by conventional karyotyping
inhibition, hence 1p deletion plays an important role in complemented by FISH.
cell proliferation in MM [Hebraud et al., 2014; Barbieri et FISH could detect 59% of non-hyperdiploidy which
al., 2016; Walker et al., 2019]. Whole-genome screening was higher than the incidence reported in the literature.
by oligo-based microarrays and aCGH technique have The association of secondary abnormalities with all IGH
identified CNAs >100 kb in 100% of cases. Most common translocations supports the concept that primary IGH
CNAs were found in 1p, 1q, 6p, 8p, 13q, 14q, 16q, and 22q translocations later on develop high-risk abnormalities as
along with gain of extra copies of odd-numbered chro- secondary progressive events. The strong association of
mosomes [Smetana et al., 2014]. monosomy 13 like other high-risk abnormalities in dou-
ble- and triple-hit MM indicate that monosomy 13 can
Conventional Karyotyping also be considered as a high-risk abnormality, which is
Conventional karyotyping studies in MM have been still a dilemma.
able to detect only 20–30% cells with abnormal karyo- The incidence of IGH translocations was 26% versus a
types due to low proliferative index of G0 plasma cells in literature frequency of 40–50%. The said frequency was
which cryptic translocations/insertions like t(4;14), mainly affected by low occurrence of t(11;14) (6%) in
t(14;16) were missed [Sawyer et al., 1998; Chang et al., contrast to 15–20% in other studies. Additionally, the as-
2004]. On the other hand, karyotyping gives a global view sociation of high-risk markers such as abnormalities of
of most of the known and unknown aberrations [Sawyer chromosome 17, gain/amp(1q), and IGH partial deletion
et al., 1998, 2014; Chang et al., 2004; Soekojo et al., 2019]. in the hyperdiploid group rather than non-hyperdiploid
We could detect copy number changes in 1q along with group in our patients is not a common finding. These
translocation/insertion to multiple chromosomes, which findings support and strongly indicate the racial disparity
cannot be detected by FISH. The amplification of 1q which leads to geographic heterogeneity. As reported by

Cytogenetics in Multiple Myeloma from Cytogenet Genome Res 9

Indian Population DOI: 10.1159/000529191
many other studies, the conventional karyotyping could Dr. Randeep Singh (Narayana Superspeciality Hospital, Guru-
not reveal the true picture of MM cytogenetics in all cases. gram), Dr. Ajay Sharma (Paras Hospital, Panchkula), Dr. Jasjit
Singh, Dr. Nitin Gupta, Dr. Shyam Aggarwal (Sir Ganga Ram Hos-
The detection of 1q copy number changes along with pital), Dr. Rajib De (NRS Medical college, Kolkata), Dr. Joydeep
translocation, insertion to multiple chromosomes, also Chakrabartty (HCG EKO Cancer Center, Kolkata), Dr. Vivek
hypodiploidy with losses of chromosomes 13, 14, and 16 Agarwala, Dr. Sharmila Chandra (Narayana Superspeciality Hos-
cannot be detected by interphase FISH. However, due to pital, Howrah), Dr. Sisir Kumar Patra, Dr. Ujjal Mani, Dr. M.V.
its overall easy approach, success rate, capability of iden- Chandrakanth (Rabindranath Tagore International Institute of
Cardiac Science, Kolkata), Dr. Anupam Chakrapani (Apollo Gle-
tifying cryptic aberrations that add valid information neagles Hospital), Dr. Prantar Chakrabarty (Fortis Hospital Anan-
from the prognostic, risk stratification, and therapeutic dapur, Kolkata), Dr. Swarnabindu Banerjee (Calcutta Medical
decision point of view, FISH seems to be the gold stan- College).
dard, indispensable technique to study the cytogenomic
status in MM. Further, in future, prognostication in MM
needs involvement of an international staging system, cy- Statement of Ethics
togenetics, mutation profile in combination with genome

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expression profile which will help refinement of prognos- All experimental procedures were approved by the ethics com-
mittee of the Lilac insights Pvt Ltd. headed by Mr. Subhamoy Das-
tication and implementation of genome-guided targeted tidar (Director), Dr. Pratibha Kadam Amare (Chief and Lab Direc-
therapies. tor), Dr. Chaitanya Datar (Consultant), Dr. Balkrishna Padate
(Consultant), Reference No. LIPL/EC/001. As the study was con-
ducted on specimens received in a lab for diagnosis purpose, no
Acknowledgements clinical trial was involved. Support regarding specimen consent
was given by clinicians mentioned in the acknowledgement. Writ-
The authors would like to thank and acknowledge the following ten informed consent was obtained from participants prior to the
clinicians who referred the patient specimens recruited in the study.
study. Dr. S.H. Advani (Shushrut Hospital/AOH Services Pvt.
Ltd.), Dr. M.B. Agarwal (Dr. M.B. Agarwal Haematology Centre-
Dadar), Dr. B.K. Smruti (Bombay Hospital), Dr. Tapan Saikia Conflict of Interest Statement
(Prince Aly Khan Hospital), Dr. S.P. Sanyal (Fortis Hospital,
Mumbai), Dr. S. Chandrakala (K.E.M Hospital, Mumbai), Dr. All the authors have no conflict of interest to disclose.
Balkrishna Padate, Dr. Adwaita Gore, Dr. Muzammil Shaikh
(Nanvati Max Hospital, Mumbai), Dr. Farah Jijina, Dr. Sachin
Almel, Dr. Asha Kapadia (Hinduja Hospital, Mumbai), Dr. Ritu
Jain (Jaslok Hospital), Dr. Kunal Sehgal (Sehgal Path Lab Pvt. Ltd., Funding Sources
Mumbai), Dr. Prathmesh Kulkarni, Dr. Ashish Bakshi (Hiranan-
dani Hospital, Mumbai), Dr. Mukesh Desai (Hematology & Im- This study was funded by Lilac Insights Pvt. Ltd.
munology Cell), Dr. Dipanjan Halder, Dr. Supriya Dutta (Jupiter
Hospital), Dr. Ashish Bakshi (Bethany Hospital), Dr. Deep Kumar
Mahajan (Doctors Planet, Mumbai), Dr. Anand Pathak, Dr. Mur- Author Contributions
taza Bohra (National Cancer Institute, Nagpur), Dr. Siddhesh Ka-
lantri (Blood Care Hematology Clinic), Dr. Pushpak Chirmade P. Kadam Amare: Conceived and designed the experiments
(Oncura Hematology & Oncology Care), Dr. Ashay Karpe (Sun- and wrote the manuscript. S. Nikalje Khasnis, P. Hande, H. Lele,
rise Oncology Centre), Dr. Nilesh Wasekar (Nashik Haematology N. Wable, S. Kaskar, N. Nikam Gujar, A. Prabhudesai, K. Todi, R.
Services), Dr. Riya Ballikar (Kingsway Hospital), Dr. Hari Menon Waghole, and P. Roy: Performed the experiments and analysed the
(St. John's Medical College and Hospital), Dr. K.D. Santhosh, Dr. data. N. Gardi: Performed statistical analysis.
Vinayak Maka, Dr. P. Rashmi (HCG Ramaiah Cancer Centre, Ban-
galore), Dr. Ashish Dixit, Dr. Amit Rauthan, Dr. Mallikarjun Ka-
lashetty (Manipal Hospital, Bangalore), Dr. Pavan Kumar, Dr.
Senthil Rajappa, Dr. Rakesh Pinninti, Dr. Pallavi Suresh (Basava- Data Availability Statement
tarakam Indo American Cancer Hospital & Research Institute),
Dr. Sai Vivek (Sri Shankara Cancer Hospital and Research Centre), The data corresponding to the above research article are pres-
Dr. Shekar Patil, Dr. Ravi T. (HCG Comprehensive Cancer Care ent with Lilac insights Pvt. Ltd.
Hospital, Bangalore), Dr. Vineet Gupta (Sakra World Hospital),
Dr. Vindhya Vasini (Omega Hospitals), Dr. P.S. Dattatreya (Reno-
va Soumya Cancer Centre, Telangana), Dr. Deepan Rajamanick-
am (Thangam Hospital), Dr. Sadashivudugundeti (Nizam's Insti-
tute Of Medical Sciences), Dr. Suparno Chakrabarty, Dr. Sarita
Rani Jaiswal (Dharamshila Narayana Superspeciality Hospital),

10 Cytogenet Genome Res Kadam Amare et al.

DOI: 10.1159/000529191
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12 Cytogenet Genome Res Kadam Amare et al.

DOI: 10.1159/000529191