Clinicopathological Characteristics of Hyperdiploidy with High-Risk Cytogenetics in Multiple Myeloma

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ISSN 2234-3806 • eISSN 2234-3814

Ann Lab Med 2018;38:160-164

https://doi.org/10.3343/alm.2018.38.2.160

Clinicopathological Characteristics of Hyperdiploidy with High-Risk Cytogenetics in Multiple Myeloma

Naery Yang, M.D.1, Yeung Chul Mun, M.D.2, Chu-Myong Seong, M.D.2, Hee Jin Huh, M.D.3, and Jungwon Huh, M.D.1

Department of Laboratory Medicine1, College of Medicine, Ewha Womans University, Seoul; Department of Internal Medicine2, College of Medicine, Ewha Womans University, Seoul; Department of Laboratory Medicine3, Dongguk University, Ilsan Medical Center, Goyang, Korea

In multiple myeloma (MM), hyperdiploidy (HD) is known to impart longer overall survival.

However, it is unclear whether coexistent HD ameliorates the adverse effects of known high-risk cytogenetics in MM patients. To address this issue, we investigated the clinico- pathological characteristics of HD with high-risk cytogenetics in MM. Ninety-seven patients with MM were included in the study. For metaphase cytogenetics (MC), unstimulated cells from bone marrow aspirates were cultured for either 24 or 48 hours. To detect HD by in- terphase fluorescence in situ hybridization (iFISH), we assessed trisomies of chromosomes 5, 7, 9, 11, 15, and 17. Of the 97 MM patients, 40 showed HD. The frequency of co-oc- currence of HD and high-risk cytogenetics was 14% (14/97). When the clinicopathologi- cal characteristics were compared between the two groups of HD with high-risk cytoge- netics vs. non-HD (NHD) with high-risk cytogenetics, the level of beta 2 microglobulin and stage distribution significantly differed (P =0.020, P =0.032, respectively). This study shows that some of the clinicopathological characteristics of MM patients with high-risk cytoge- netics differ according to HD or NHD status.

Key Words: Hyperdiploidy, Multiple myeloma, Cytogenetics, High risk

Received: February 27, 2017 Revision received: June 25, 2017 Accepted: October 25, 2017 Corresponding author: Jungwon Huh Department of Laboratory Medicine, College of Medicine, Ewha Womans University, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul 07985, Korea Tel: +82-2-2650-5320

Fax: +82-2-2650-5091 E-mail: JungWonH@ewha.ac.kr Co-corresponding author: Hee Jin Huh Department of Laboratory Medicine, Dongguk University School of Medicine, Ilsan Hospital, 27 Dongguk-ro, Ilsandong- gu, Goyang 10326, Korea

Tel: +82-31-961-7893 Fax: +82-31-961-7902 E-mail: hjhuh@duih.org

© Korean Society for Laboratory Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecom- mons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Risk stratification of patients with multiple myeloma (MM) is im- portant to predict survival and define a treatment strategy. Cyto- genetic abnormalities are clinically relevant prognostic factors in MM [1, 2]. Patients with MM can be categorized into hyperdip- loidy (HD) and non-hyperdiploidy (NHD) groups according to the primary cytogenetic abnormalities. The definition of HD in MM has varied across studies; one study defined HD as numer- ous chromosomal trisomies and low prevalence of IgH translo- cations [3], and another as a chromosome count of 48–65, with a gain of at least two odd chromosomes [4]. HD in this study was defined by a chromosome count of 47 or more, with gain of

one or more odd-numbered chromosomes (chromosome 3, 5, 7, 9, 11, 15, or 17). Previous studies have shown that abnor- malities such as t(4;14), t(14;16), and deletion of the short arm of chromosome 17 (17p) are predictive of significantly short- ened survival (defined as high-risk cytogenetics), whereas HD is associated with cytogenetics with a favorable outcome [1, 2].

There is a small subset of patients with MM that shows evidence of both HD and high-risk cytogenetics, but its clinical significance and prognostic impact is controversial [5-8].

This study aimed to investigate clinicopathological character- istics associated with HD with high-risk cytogenetics in MM, com-

2017-03-16 https://crossmark-cdn.crossref.org/widget/v2.0/logos/CROSSMARK_Color_square.svg

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pared with those of NHD with high-risk cytogenetics in MM. In- terestingly, del(5q) was detected in two patients, which corre- sponded to an EGR1 deletion. We examined the clinical signifi- cance of either del(5q) or an EGR1 mutation in MM and reviewed the literature.

A total of 97 patients were newly diagnosed as having MM, according to the International Myeloma Working Group diagnos- tic criteria [9], at two institutions in Korea (93 from Ewha Wom- ans University Mokdong Hospital, Seoul, Korea; four from Dong- guk University Ilsan Hospital, Goyang, Korea) between 2010 and 2015. The demographics, laboratory, and clinical data of the patients were retrospectively reviewed. This study was ex- empted from approval from the institutional review board, as it was a retrospective review of existing medical records, and all information was de-identified. Demographic and laboratory characteristics of the patients are summarized in Supplemental Data Tables S1 and S2.

HD was confirmed by metaphase cytogenetics (MC) and/or interphase fluorescence in situ hybridization (iFISH). For MC, unstimulated cells from bone marrow aspirates were cultured for either 24 or 48 hours. All data were retrospectively reviewed and reanalyzed according to the International System for Hu- man Cytogenetic Nomenclature (ISCN 2013) guidelines [10].

iFISH was performed using the following probes (Abbott/Vysis, Downers Grove, IL, USA; Metasystems, Heidelberg, Germany;

or Kreatech, Amsterdam, the Netherlands): IgH dual color break apart rearrangement probe, TP53 dual color probe, CEP7/D7S486 dual color probe, 13q14/13q34 dual color probe, IgH/CCND1 dual color probe, dual fusion probe, IgH/FGFR3 dual color probe, dual fusion probe, IgH/MAF dual color probe, dual fusion probe, 1q21/1p32 dual color probe, EGR1/D5S721,D5S23 dual color probe, p16/CEP9 dual color probe, and/or CEP15 single color probe. To detect HD by iFISH, we assessed trisomies of chro- mosomes 5, 7, 9, 11, 15, and 17, using targeted probes. At least 200 interphase cells from each case were counted.

Of the 97 patients with MM, 57 (59%) were classified into the NHD group, and HD was detected in 40 patients (41%) by MC and/or iFISH. At diagnosis, iFISH in two patients (See Supple- mental Data Table S1; cases 6 and 9) revealed HD, whereas a normal karyotype was revealed by MC. However, after the dis- ease progressed, HD was also detected by MC.

We defined high-risk cytogenetics as the presence of t(4;14), t(14;16), or del(17p), based on the revised International Staging System proposed by the International Myeloma Working Group [1]. Among patients newly diagnosed with MM, the frequency of co-occurrence of HD and high-risk cytogenetics was 14%

(14/97); t(4;14), (14;16), and del(17p) were observed in 7%

(7/97), 2% (2/97), and 8% (8/97) of the patients, respectively (Table 1). Three patients presented concurrent, multiple high- risk cytogenetics (See Supplemental Data Table S1; cases 12, 18, and 35). We also reviewed the frequencies of high-risk cyto- genetics in the NHD group (See Supplemental Data Table S2) and compared them with those in the HD group. The difference in the frequencies of high-risk cytogenetics was not statistically

Table 1. Comparison of clinical and laboratory characteristics of patients with hyperdiploidy with high-risk cytogenetics and non-hy- perdiploidy with high-risk cytogenetics

Variable HD with high- risk cytogenetics

(n=14)

NHD with high- risk cytogenetics

(n=16) P * Male:female, number (% male) 12:2 (85.7) 8:8 (50.0) 0.042 Age (yr)

median (range) 66 (57–85) 67 (48–82) 0.546 Albumin (g/dL)

median (range) 3.1 (2.2–4.5) 3.1 (1.6–3.9) 0.755 β2 microglobulin (mg/L)

median (range) 4.5 (2.4–39.6) 11.8 (2.7–71.2) 0.020 Serum LDH (IU/L)

median (range) 189 (114–611) 254 (170–1,250) 0.056 t(4;14)

number (%) 7 (50.0) 3 (18.8) 0.075

t(14;16)

number (%) 2 (14.3) 1 (6.3) 0.472

del(17p)

number (%) 8 (57.1) 12 (75.0) 0.309

1q21 amplification

number (%) 11 (78.6) 8 (50.0) 0.111

ISS stage number (%) 0.051

I 3 (21.4) 0 (0.0)

II 5 (35.7) 3 (18.8)

III 6 (42.9) 13 (81.3)

ISS-R stage number (%) 0.032

I 0 (0.0) 0 (0.0)

II 8 (57.1) 3 (18.8)

III 6 (42.9) 13 (81.3)

*P values were calculated by the χ2 test for categorical variables and the Mann-Whitney U test for continuous variables in a comparison between pa- tients with HD with high-risk cytogenetics and those with NHD with high-risk cytogenetics. Significant values are shown in bold.

Abbreviations: HD, hyperdiploidy; ISS, International Staging System; ISS-R, Revised International Staging System; LDH, lactate dehydrogenase; NHD, non-hyperdiploidy.

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significant (P =0.467) between the two groups.

Table 1 summarizes the comparative analysis between the two groups of HD with high-risk cytogenetics vs. NHD with high- risk cytogenetics.

The difference in stage distribution, determined according to the International Staging System (ISS), did not reach statistical significance (P =0.051), but stage distribution determined ac-

cording to the revised International Staging System (ISS-R) [11]

was significantly different between the two groups (P =0.032) (Table 1). It is noteworthy that 57% of patients with HD and high- risk cytogenetics belonged to ISS-R stage II, whereas 81% of pa- tients with NHD and high-risk cytogenetics belonged to stage III.

Gain of chromosome 9 (22 patients) was the most commonly observed aneuploidy in the HD group, identified by iFISH, fol-

Fig. 1. Karyotype and interphase fluorescence in situ hybridization* using a D5S721/

D5S23/EGR1 probe in multiple myeloma patients with chromosome 5 aberrations. (A) Case 9 showing partial trisomy 5; two normal chromosome 5s and one del(5q). (B) Case 38 showing del(5q). (C) Case 38 showing one red signal loss (2G1R), suggestive of del(5q).

(D) Case 6 showing three green and red signals (3G3R), suggestive of trisomy 5 (left panel); and four green and three red signals (G4R3), suggestive of partial tetrasomy 5 (three normal chromosome 5s and one del(5q)) (right panel). (E) Case 16 showing G4R3, suggestive of partial tetrasomy 5. *FISH probe design is as follows: Chromosome 5p15 shows a green signal (G), and 5q31 shows a red signal (R). The normal FISH pattern of chromosome 5 is two green signals and two red signals (2G2R).

A B

C

E

Left Right D

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lowed by gain of chromosome 5 (n=21), 15 (n=19), similar to the frequencies reported in previous studies [12, 13]. iFISH us- ing probes targeting chromosomes 5, 9, and 15 for the detec- tion of HD showed various patterns. In one patient (See Supple- mental Data Table S1; case 20), iFISH showed trisomy of chro- mosome 5 (43.5%), whereas both trisomy and tetrasomy were observed for chromosomes 9 (trisomy, 13.0%; tetrasomy, 48.5%) and 15 (trisomy, 18.5%; tetrasomy, 22.5%). In another patient (See Supplemental Data Table S1; case 32), trisomies of chro- mosomes 9 (72.0%) and 11 (61.0%) were revealed by iFISH, whereas both trisomy and tetrasomy were observed for chromo- some 15 (trisomy, 30.0%; tetrasomy, 29.5%). In one patient (See Supplemental Data Table S1; case 6), both trisomies and tetrasomies of chromosome 5 (trisomy 26.5%, tetrasomy 78.5%) and 9 (trisomy 14.5%, tetrasomy 73.5%) were observed at re- lapse by iFISH, whereas only trisomies of chromosome 5 (28.0%), 9 (77.5%), and 15 (61.5%) were observed at diagnosis.

As for chromosome 5 abnormalities, the del(5q) was observed in two patients by MC (See Supplemental Data Table S1; cases 9 and 38). One patient (case 9) showed a normal karyotype at diagnosis, but partial trisomy 5 (two normal chromosome 5s and one with a 5q deletion) was detected by MC at nine months (Fig. 1A). In another patient (case 38), del(5q) was identified by MC and 5q signal loss, corresponding to an EGR1 deletion of 5q31 (21.6%), was confirmed by iFISH (Fig. 1B and C). Fur- thermore, in one patient (case 40), iFISH indicated two clones:

one with trisomy 5 (15.0%), and the other with partial trisomy 5 [two normal and one with del(5q)] (11.5%), whereas only trisomy 5 was revealed by MC. Two patients (cases 6 and 16) showed partial tetrasomy 5 by iFISH: three normal and one with del(5q) (78.5% in case 6; 22.0% in case 16) (Fig. 1D and E).

Similar to our findings, one study showed partial trisomy 5 (two normal and one with a 5q deletion) in clonal plasma cells of patients newly diagnosed as having MM [14]. EGR1 as a can- didate gene for del(5q) in MDS has been associated with an in- dividual’s response to lenalidomide [15]. However, another study showed that an EGR1 mutation is highly associated with HD in MM [16]. In MM, EGR1 was recently shown to be involved in recruiting MYC to the promoters of NOXA and BIM and induc- ing p53-independent apoptosis [17, 18]. The clinical significance of del(5q) or an EGR1 mutation on 5q in MM remains to be as- certained.

There is no consensus on the prognostic impact or risk asso- ciated with concurrent HD and high-risk cytogenetics. A few studies have shown that the poor outcomes observed in patients with high-risk cytogenetics are not ameliorated by the co-occur-

rence of HD [7, 8]. In contrast, one study showed that patients with high-risk cytogenetics have higher survival rates when triso- mies are present than when they are absent [6]. Another study showed that trisomy 15 increases the rate of progression-free survival in patients with del(17p), whereas HD does not improve clinical outcomes in patients harboring t(4;14) [5]. These dis- crepant findings may be attributed to different treatment regi- mens. Certain therapies (i.e., bortezomib-based therapies) can mitigate the risk associated with specific abnormalities, as in the case of t(4;14) or del(17p) [1, 2].

Our study showed that a considerable subset—14% (14/97)—

of all MM patients had HD and coexistent high-risk cytogenet- ics. Of the 40 HD patients, 35% (14/40) presented high-risk cy- togenetics, whereas 28% (16/57) of NHD patients presented high-risk cytogenetics. Moreover, the distribution of stages ac- cording to ISS-R differed between the groups with HD with high- risk cytogenetics and NHD with high-risk cytogenetics. This study indicates that the clinicopathological characteristics of MM pa- tients with high-risk cytogenetics may differ according to HD or NHD status.

Further comprehensive studies in larger cohorts, using the same treatment strategies, are needed to delineate the prognos- tic impact of concurrent HD and high-risk cytogenetics com- pared with that of NHD and high-risk cytogenetics. Assessment of HD by MC and iFISH may be mandatory for patients newly diagnosed as having MM.

Authors’ Disclosure of Potential Conflicts of Interest

No potential conflicts of interest relevant to this article were re- ported.

Acknowledgements

This study was supported by the Basic Science Research Pro- gram through the National Research Foundation of Korea, funded by the Ministry of Education, Science, and Technology (NRF- 2012R1A1A2044138).

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Supplemental Data Table S1. Characteristics of patients with multiple myeloma and hyperdiploidy, identified by a G-banded chromosome study and/or interphase FISH Case no.SexAgeDate (mo.)G-banded chromosome studyAberrations identified by interphase FISH ISSISS-R HDt(4;14)1) (%)t(14;16)1) (%)del(17p)1) (%)1q21 ampl1) (%)Other 1F49 046,XX[20]+7negnegnegnegIIII 2F79 046,XX[20]+5, +9, +11, +15negnegnegnegIIIIII 3M41 046,XY[20]+5, +9, +11, +15negnegnegnegMAF gainIIII 4M81 046,XY[20]+5negnegnegnegIIIIII 5F82 046,XX[20]+7, +1317negneg20-13IIII 6F57 046,XX[20]+5, +9, +11, +15negnegneg95-13, MAF deletionII 2052,X,-X,del(1)(q41),?inv(1)(p22q11),+2,-4,+5,-6,add(6)(q22),-8, +9,+11,+12,+12,add(12)(p10),add(13)(p10),+14,+15,-16,+19, add(22)(p12),+mar1,+mar2[2]/46,XX[7]

NTNTNTNT-13IIII 3453~60,X,-X,+1,add(1)(p13), del(1)(q41),+2,+3,+4,del(4)(q21q25),+5,+6, add(6)(q22),+7,add(7)(p15)x2,+9,+9,+11,-12,+13,add(13) (p10),+14,+14,+15,-17,+18,+19,+20,+21,+21,+22,add(22)(p12),+mar1, +mar2,+mar3[cp10]//46,XY[6]

+5, +9, +11 negnegneg76del(5q), t(11;14), IgH gain, MAF deletionIIIIII 7F52 046,XX[20]+9negnegnegnegdel(13q)IIII 8F55 046,XX[20]+5, +9, +15negnegneg63MAF deletionIII 9M62 046,XY[20]+7, +11negneg39negdel(8p)IIIIII 953,X,del(X)(q22), der(1)t(1;?8)(p13;?q13),+5,del(5)(q22q33),+7,-8,+9,+9, der(9)t(9;11)(p13;q13),add(10)(q22),del(13)(q12q22),+15,add(17) (q25),+19,+21,+mar[3]/46,XX[17]

+7, +9, +15negneg37negdel(8p), del(13q)IIIIII 10M63 046,XY[20]+15negnegnegnegdel(1p), t(11;14), 5´ IgH deletion, -13, -15II 11M57 046,XY[20]+5, +11, +15negnegnegnegIgH rearr., MAF deletionIIII 12M66 046,XY[20]+5, +9, +15, +174710neg18del(13q)III 13M57 046,XY[20]+9, +15negneg717IgH rearr.IIIIII 14M69 046,XY[20]+5, +9negnegneg61-13IIII 15M56 046,XY[20]+5, +9, +15negnegnegneg-13IIII (Continued to the next page)

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Case no.SexAgeDate (mo.)G-banded chromosome studyAberrations identified by interphase FISH ISSISS-R HDt(4;14)1) (%)t(14;16)1) (%)del(17p)1) (%)1q21 ampl1) (%)Other 16M70045,X,-Y[11]/46,XY[9]+5negnegneg145´ IgH deletion -13, -15, MAF deletionII 17M70046,XY[20]+9, +11, +17negnegnegnegIgH rearr.IIII 18M73046,XY[20]+1546neg7neg-13IIII 19M75046,XY[20]+9negneg3643del(13q)IIIIII 20M66046,XY[20]+5, +9, +11, +1534negneg53IIII 21M82046,XY[20]+5, +11negnegnegnegdel(1p), IgH rearr., 5' IgH deletionIIIIII 22M60046,XY[20]+5, +9negnegneg67Whole IgH deletion IIIII 23M98046,XY[20]+5, +9, +15negnegneg13del(13q), IgH rearr.IIII 24M63046,XY[20]+1763negneg14-13IIII 25M64068,XXY,+Y,+1,+2,+3,add(4)(q12),add(4)(q21),add(6)(q13)x3,+9,-10,-10, +11,-12,-13,-14,-14, +15,der(15)t(15;17)(q22;q21)x2,-16,+17, der(17) add(17)(p11.2)t(15;17)x2,+18,-19,-21,-22[2]/46,XY[18]

+5, +9, +11, +15negneg6neg-13, whole IgH deletion III 26F75063~66,X,-X,-X,del(1)(q21), -2,add(2)(31),+3,add(3)(q27), del(3) (q21q23),i(3)(p10), add(4)(p16),-6,add(6)(q21),-7,add(7)(p22), del(7)(q31), -8,add(9)(p24),+10,-13,-14,-17, +18,+18,-19, +1~9mar[cp4]/46,XX[10]

NTnegnegnegnegMAF gain, +18, -XIIII 27M52062~65,XXY,+Y,-1, t(1;12)(q32;q24),-2,-6,-8, add(11)(q25),-12,-15, -16[cp13]/46,XY[7]NTnegnegnegnegIIII 28F80058,X,-X,-X, der(1)t(1;5)(p12;p13),-2,-5,-8,-10,-12,-13,-14,+15,-16,-20, -22[6]/46,XX[14]negnegneg14MAF gainIIIIII 29F52057~59,X,-X, ?psu dic(1;5)(p13;q35),+2,+3, +del(6)(q14q25),+7,+9,+9, +11,+15,add(16)(q13~q21),+17,+19, +20,+21[cp6]/46,XX[14]+5, +9, +11, +15, +17

negnegneg28MAF deletionIIIIII 30F66057,XX,+3,+4,+7,+9,+11,+11,+15,+19,+20,+21,+22[5]/46,XX[15]negnegnegnegdel(1p)IIIIII 31F85056,XX,+3,+3,+5,+6,+9, add(9)(p24),+10,+10,+11,+12,-13,dic(14;15) (q32;q26),+16, add(17)(q25),-17,+18, +19,+19[1]/46,XX[19]+5, +9, +1125negneg23-13, MAF gainIIIIII 32M71054,XY,+1,del(1)(p13), t(1;11)(p22;q14),+3,+7,-8,+9, +11,del(12)(p11.2), -13,add(13)(p10),+15,+15,-17,+19,?del(20)(q13.1),+21,+21, +mar[5]/46,XY[15]

+9, +11, +15negnegneg71-13IIIIII (Continued to the next page)

Supplemental Data Table S1. Continued

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Case no.SexAgeDate (mo.)G-banded chromosome studyAberrations identified by interphase FISH ISSISS-R HDt(4;14)1) (%)t(14;16)1) (%)del(17p)1) (%)1q21 ampl1) (%)Other 33F72050~55,X,-X,+3, der(3;15)(q10;q10),+5,+7,+9, +11,+15,+18,+19,+21,+22[cp6]/46,XX[14]+5, +9, +11, +15negnegnegnegIIIII 34M77050~52,XY,+1,der(1;22)(q10;q10),+3,+5,+6, der(6)t(6;9)(q13;q12), +7,add(7)(p21),+9, +mar1,+mar2[cp15]/46,XY[5]negnegneg33IgH rearr.IIIIII 35M71050,XY,+5,del(6)(q13q21),+7,+9,+11,-13,+15, der(16) t(1;16)(q12;q24), -17,add(19) (p13.3),-20,-22,+mar1,+mar2,+mar3[2]/46,XY[18]+5, +9, +11, +15neg11513-13IIIIII 36F66049,XX,del(1)(p13.2),del(1)(p21),+6,-8,-10,+11,+12, +15,+16,del(17)(p13), -20,+21[5]/46,XX[15]negnegnegnegIIII 37F66049,X,-X,der(1)t(1;?)(p22;?),+9,+11,del(12)(p13),+14,+15,-16, +22[11]/46,XX[9]negnegnegnegdel(1p), del(13q), whole IgH deletion, MAF deletion

IIII 38M58047~48,XY,del(5)(q31~q32),+11,der(14)t(11;14)(q13;q32),+19, der(19) t(1;19)(q21;q13.3)[cp12]/46,XY[8]negneg356del(5q), t(11;14), 5´ IgH deletion, -15IIIIII 39M62045~48,XY,add(1)(q23),+8,add(8)(p11.2),-13,+15,add(16) (q12~q13),add(17)(q24)der(17) del(17)(p11.2),der(19)t(1;19) (q21;q13.4), -22,+mar1,+mar2[cp3]/76,XXY,+Y,add(1)(q23),+2,+3,-7,+8,+add(8) (p11.2),+10,-13,-14,+15,add(15)(p10~p11.2),add(16)(q13),+19,der(19) t(1;19)(q21;q13.4),+20,add(21)(p11.1),-22,+mar1,+mar2[2]/46,XY[15]

+5, +9, +11, +15, +17

86negneg80IgH gain, MAF deletionIIII 2846,XY,add(1)(q23),+8,-13,+15, add(16)(q12~q13),der(19)t(1;19) (q21;q13.4),-21-22,+mar[2]/46,XY[18]+5, +9, +1589negneg98-13, MAF deletionIIIIII 40M68048~49,XY,del(1)(q32q42), der(1)dup(1)(q21q32), add(3)(q27)x2,-4,+5, add(6)(q15),-8,+9,+11,add(12) (p11.2),+15,add(16)(p12),-17,+19,+mar1, +mar2[cp3]/46,XY[17]

+5, +9, +11, +15negneg3316FGFR3 deletion, -13IIII 1)Positive cut-off values for t(4;14), t(14;16), del(17p), and 1q amplification were 0.6%, 0.6%, 1.8%, and 1.8%, respectively. Abbreviations: ampl, amplification; F, female; FISH, fluorescence in situ hybridization; HD, hyperdiploidy; ISS, International Staging System; ISS-R, Revised International Staging System; M, male; mo., months; neg, negative; NT, not tested; rearr., rearrangement.

Supplemental Data Table S1. Continued

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Supplemental Data Table S2. Characteristics of patients with multiple myeloma and non-hyperdiploidy, identified by a G-banded chromosome study and/or interphase FISH Case no.SexAgeG-banded chromosome study Aberrations identified by interphase FISH ISSISS-Rt(4;14)1) (%)t(14;16)1) (%)del(17p)1) (%)1q21 ampl1) (%)Other 41M5346,XY[20]negnegneg5del(13q),IgH rearr.,-15, MAF gain

IIII 42F7046,XX,inv(9)(p11q13)c[20]negnegnegnegMAF gainII 43M7046,XY,dup(1)(q44q11)[14]/46,XY[6]negnegneg47IIII 44F8146,XX[20]negnegneg4IIII 45M5346,XY,del(13)(q12q14),del(17)(p13)[1]/46,XY[19]negneg5949del(13q)IIII 46F5146,XX[20]negnegnegnegdel(13q)IIII 47M8244~46,XY,der(1;14)(q10;q10),add(2)(p13),add(3)(q29),add(4)(p14~p16),add(8) (p12~p21),add(9)(p13~p22),del(12)(q24.1),-13,del(14)(q32),-16,+17,der(17)del(17) (p11.2),del(17)(q25), +add(19)(p13),+mar1,+mar2[cp5]/46,XY[35]

neg25neg51del(1p), p16 deletion,-13IIIIII 48M7946,XY[20]negnegnegnegIgH rearr.IIIII 49M4846,XY[20]39negneg19del(13q)IIIIII 50F7846,XX[20]negneg6234-13, IgH rearr., -15IIIIII 51M5246,XY[20]negnegnegnegdel(13q),-15II 52F4646,XX,del(1)(p21)[2]/46,XX[18]negnegneg19del(8p), del(13q)IIIIII 53F6646,XX[20]negneg9negdel(1p), 5´ IgH deletionIIII 54M8946,XY[20]negnegnegnegIIII 55M7846,XY[20]negnegnegnegIIIII 56M7545,X,-Y[9]/46,XY[11]negneg8negdel(13q), IgH rearr.IIIIII 57F6746,XX[20]negneg9negIIII 58M5346,XY[20]negnegnegnegII 59F5546,XX[20]negnegnegnegIII 60M6946,XY[20]negneg615IgH rearr.,IIIIII 61F7246,XX[20]negnegnegnegt(11;14)IIIIII 62F6546,XX[20]negnegneg97FGFR3 deletionIIIIII 63M5545,X,-Y,-11,der(14)t(11;14)(q13;q32),der(16)t(1;16)(q21;q12.1),+mar[9]/46,XY[11]negneg547del(13q), t(11;14)IIIIII 64M6846,XY[20]negnegnegnegII (Continued to the next page)

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Case no.SexAgeG-banded chromosome study Aberrations identified by interphase FISH ISSISS-Rt(4;14)1) (%)t(14;16)1) (%)del(17p)1) (%)1q21 ampl1) (%)Other 65F5746,XX[20]negnegneg10III 66F7843~45,X,-X,-1,+8,add(8)(q22),i(8)(q10), add(12)(p11.2~13),-13,-18,-20,add(21)(p11.2), +mar1,+mar2[cp6]/46,XX[14]62negneg65-13IIIIII 67M6946,XY[20]negnegnegneg-13, t(11;14)IIII 68F5946,XX[20]negnegnegnegIII 69M8546,XY[20]negnegnegnegIIIIII 70M5746,XY[20]negnegnegnegII 71F6843,X,-X,del(1)(p13p22),der(1)t(1;1)(p36.3;q12),del(8)(q11.1q22),der(9)t(1;9)(q12;p22),-13, -14[3]/46,XX[7]29negneg37-13, -14, MAF gainIIIIII 72M7846,XY[20]negnegnegnegIIII 73M5746,XY[20]negnegnegnegIIIIII 74F7246,XX[20]negnegneg7IgH rearr. IIII 75M5346,XY[20]negnegnegneg-13IIII 76M3546,XY[20]negnegnegnegII 77M5246,XY[20]negnegnegnegt(11;14)IIII 78F5646,XX[20negnegnegnegt(11;14)IIIII 79F8846,XX,t(11;14)(q13;q32),-16,+mar[12]/46,XX[8]negnegnegnegt(11;14)IIII 80M7946,XY[20]negnegnegnegIIII 81F7446,XX[20]negnegneg11del(1p), FGFR3 deletion,-17IIII 82F6646,XX[20]negnegnegnegdel(13q), IgH rearr.IIII 83F6046,XX[20]negneg9negdel(1p), -13, IgH rearr.IIIIII 84F5946,XX[20]negnegneg3del(13q)IIII 85F7746,XX[20]negnegnegnegIIII 86M6046,XY[20]negnegnegnegIIII 87F7246,XX[20]negnegnegnegdel(13q), IgH rearr.IIII 88F7846,XX[20]negnegnegnegIIII

Supplemental Data Table S2. Continued (Continued to the next page)

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Supplemental Data Table S2. Continued Case no.SexAgeG-banded chromosome study Aberrations identified by interphase FISH ISSISS-Rt(4;14)1) (%)t(14;16)1) (%)del(17p)1) (%)1q21 ampl1) (%)Other 89M6146,XY[20]negneg3negdel(1p), -13, t(11;14), whole IgH deletion

IIIIII 90F7046,XX[20]negneg9negt(11;14)IIIIII 91M5946,XY[20]negneg7neg-13, IgH rearr., 5´ IgH deletion, -15, -17

IIIIII 92M7945,X,-Y[18]/46,XY[2]negnegnegnegIII 93F6044~45,X,-X,-1,del(2)(q33),+7,add(7)(p22), del(7)(p21),add(8)(q24),?ins(11;?)(q13;?),-12, -13,der(14)t(11;14)(q13;q32),add(16)(p13.3),?der(17)add(17)(p12)add(17)(q21),add(19) (p13.3),+mar[cp6]/46,XX[5]

negneg6negt(11;14)IIIIII 94M7546,XY[20]negnegnegnegIIIII 95M8746,XY[20]negnegnegnegIIII 96M6246,XY[20]negnegnegnegFGFR3 deletion, t(11;14), 5´ IgH deletion

IIII 97M8046,XY[20]negnegnegnegdel(1p), p16 deletion, t(11;14)IIII 1)Positive cut-off values for t(4;14), t(14;16), del(17p), and 1q amplification were 0.6%, 0.6%, 1.8%, and 1.8%, respectively. Abbreviations: ampl, amplification; F, female; FISH, fluorescence in situ hybridization; ISS, International Staging System; ISS-R, Revised International Staging System; M, male; mo., months; neg, negative; rearr., rearrangement.

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