Summary
Del(1p32.3) by FISH detection in multiple myeloma (MM) has not been routinely carried out in China. Its clinical significance was not clearly demonstrated. This study analysed clinical characteristics, treatment response and prognostic significance of del(1p32.3). We analysed 345 newly diagnosed multiple myeloma (NDMM) samples, and cytogenetic analysis was performed using Cytoscan and FISH results, enabling comprehensive disease‐specific cohort analysis and prognostic model development. The total proportion of chromosomal 1 abnormality was 64.1%, including 189 cases of 1q21 gain/amplification and 88 cases of 1p deletion, 40 patients had 1p32.3/CDKN2Cdeletion. Del(1p32.3) patients were strongly correlated with 1q21 gain/amplification and 17p deletion. Del(1p32.3) patients were more likely accompanied with extra‐medullary multiple myeloma (EMM) and complex karyotype. Del(1p32.3) had a worse effect on progression‐free survival (PFS) and overall survival (OS), alongside other high‐risk cytogenetic abnormalities that further worsened prognosis, especially 1q gain/amplification. Patients with 1p32.3 in the main clone or with a single monoallelic deletion had significantly poorer survival outcomes. Autologous stem cell transplantation (ASCT) cannot completely overcome its adverse effects on prognosis. In multivariate analysis, 1p32.3 was an important independent adverse PFS factor. Patients harbouring single monoallelic del(1p32.3) and/or main clone deletions demonstrated inferior outcomes despite lenalidomide, bortezomib and dexamethasone (VRD) induction and transplantation. Del(1p32.3) had synergistic effects frequently co‐occurring with 1q21 gain/amplification, thus, we strongly advocate for routine del(1p32.3) testing in clinical practice.
Keywords: 1p32.3 deletion, main clone, multiple myeloma, single monoallelic deletion, VRD
BACKGROUND
Multiple myeloma (MM) is an incurable haematological malignancy characterized by abnormal monoclonal plasma cell proliferation, 1 predominantly affecting the elderly, with an incidence of approximately 1.03 per 100 000 annually in China. 2 Chromosomal abnormalities, notably chromosome 14 translocations involving the immunoglobulin heavy chain (IgH) gene, hyperdiploidy and other copy number alterations, 3 , 4 significantly contribute to patient heterogeneity and disease progression. Traditional genetic markers (del(17p13), t(4;14), t(14;16)) insufficiently explain this variability, necessitating identification of additional cytogenetic markers for accurate risk stratification.
Chromosome 1, containing numerous cancer‐related genes, 5 exhibits abnormalities in 35%–50% of MM patients, 6 predominantly gain/amplification of 1q21 (~35%) and deletion of 1p (~30%). Critical loci, including 1p32.3 (CDKN2C), 1p22.1–1p21.3 and 1p12, are strongly associated with poor prognosis, 7 , 8 particularly the tumour suppressor gene CDKN2C at 1p32.3. The International Myeloma Society (IMS) 2024 guidelines identify genetic indicators for high‐risk MM as del(17p), P53 mutations, biallelic del(1p32.3), combinations of specific translocations with 1q gain/amplification or single allelic del(1p32.3) and 1q gain/amplification with single allelic del(1p32.3). Clinical factors like age, organ function, immunoglobulin type, circulating tumour cells and gene expression profiles also significantly impact prognosis. Despite recognition of del(1p32.3)/CDKN2C as a vital prognostic marker, 9 its clinical detection remains limited, especially in China, where routine FISH testing commonly includes 1q21 but rarely 1p32.3 deletions. This study aims to comprehensively analyse chromosome 1 abnormalities, particularly del(1p32.3)/CDKN2C, using FISH and Cytoscan arrays across diverse NDMM patient subgroups.
METHODS
Patients
This study included samples from 345 newly diagnosed multiple myeloma (NDMM) patients from The First Affiliated Hospital of Soochow University, enrolled in a real‐world prospective lenalidomide, bortezomib and dexamethasone (VRD)+/− autologous stem cell transplantation (ASCT) study between September 2018 and August 2022. Diagnoses, staging, treatment evaluations and risk stratification followed the 2016 International Myeloma Working Group (IMWG) criteria and 2017 Chinese MM Guidelines. 10 Ethics approval and patient consent were obtained, and samples came from the Haematological Biobank.
Transplant‐eligible patients underwent ASCT after four cycles of VRD induction therapy and two cycles of consolidation. The chemotherapy regimen was administered in 28‐day cycles: bortezomib (1.3 mg/m2, days 1, 4, 8, 11), lenalidomide (25 mg/day or adjusted to 10 mg, days 1–14) and dexamethasone (20 mg intravenously, days 1–2, 4–5, 8–9, 11–12). Transplant‐ineligible patients received eight VRD cycles. Maintenance therapy consisted of lenalidomide for standard‐risk patients and combined lenalidomide and bortezomib for high‐risk patients (t(4;14), t(14;16) or del(17p)), as illustrated in Figure 1.
FIGURE 1.
Study population inclusion and exclusion process diagram.
Cytogenetic testing techniques
Fluorescence in situ hybridization (FISH)
CD138‐sorted bone marrow plasma cells were analysed by fluorescence in situ hybridization (FISH) using specific fluorescein‐labelled DNA probes to detect 1q21 gain/amplification, 13q14 deletion, Rb1 deletion, IgH rearrangement and 17p deletion. Additional probes were used for t(4;14), t(11;14) and t(14;16) in IgH rearrangement‐positive cases. After sorting, fixation and hybridization, at least 200 interphase cells per case were examined under fluorescence microscopy. Positive thresholds were conservatively set at 10% for fusion/break‐apart probes and 20% for numerical abnormalities, in line with European Myeloma Network guidelines. A bone marrow volume of 10 mL was required.
Cytoscan
CD138‐sorted plasma cells were also analysed using a high‐density 750 K Cytoscan DNA array (Affymetrix) with 200 000 SNP probes and 550 000 copy number probes spaced evenly across the genome. Hybridization signals were rapidly and accurately quantified using laser confocal scanning or charge‐coupled device imaging, detecting genomic copy number variations, UPD and LOH. Genome‐wide polymorphisms and mosaicisms were analysed using Chromosome Analysis Suite (CHAS) software. The assay required >10% abnormal cells, achieving >99% sensitivity and specificity, and utilized 10 mL of bone marrow.
Chromosome copy numbers were classified as normal (two), single monoallelic deletion (one), chimeric monoallelic deletion (one–two) or biallelic deletion (zero). Subclones were identified if abnormal clone proportions differed by over 30%, defining larger groups as main clones and smaller groups as subclones.
Follow‐up
All 345 patients were analysed, with follow‐up conducted from diagnosis until 31 March 2025. Follow‐up data were collected from inpatient and outpatient medical records and telephone contacts. Deaths were verified through medical records or family interviews. Outcomes included overall survival (OS), defined from diagnosis to death or last follow‐up, and progression‐free survival (PFS), from diagnosis to disease progression or death.
Statistical analysis
Analyses were performed using SPSS 25.0. Continuous variables were compared using independent‐sample t‐tests or ANOVA; categorical variables via chi‐squared tests. OS and PFS were analysed by Kaplan–Meier curves with log‐rank tests to compare survival across risk groups. Multivariate analyses were conducted using Cox regression. Propensity Score Matching (PSM) matched individuals based on propensity scores to minimize confounding, balance covariates and reduce selection bias. Statistical significance was set at p < 0.05.
RESULTS
Patient characteristics
Table 1 summarizes clinical and biological characteristics of 345 NDMM patients (median age: 58 years; range: 31–82; male‐to‐female ratio: 1.17). IgG was the predominant M protein type (45.6%). Most patients (95.1%) were DS stage III, with intermediate risk predominating in ISS, R‐ISS and R2‐ISS staging systems. All patients received VRD induction therapy; approximately 70% proceeded to ASCT. Maintenance therapy differed slightly between groups; those without del(1p32.3) more often received lenalidomide monotherapy (55.1% vs. 45.7%), while del(1p32.3)‐positive patients more frequently received combined lenalidomide and proteasome inhibitor therapy (42.8% vs. 31.4%; p = 0.3068).
TABLE 1.
Analysis of del (1p32.3) with clinical and laboratory characteristics.
| Total population (n = 345) | Patients with del(1p32.3) (n = 40) | Patients without del(1p32.3) (n = 305) | p‐value | ||
|---|---|---|---|---|---|
| Patients with 1p12 and 1p22 deletion (n = 48) | Patients without 1p deletion (n = 257) | ||||
| Age [year, range] | 58 (31–82) | 58 (37–82) | 58 (46–73) | 58 (46–73) | 0.9656 |
| Gender [male (%)] | 186 (53.9) | 23 (57.4) | 25 (52.0) | 138 (53.7) | 0.6284 |
| Type [number (%)] | 0.4448 | ||||
| IgA | 75 (21.7) | 5 (12.5) | 13 (27.0) | 57 (22.2) | |
| IgG | 157 (45.6) | 19 (47.5) | 18 (37.5) | 120 (46.7) | |
| IgD | 17 (4.9) | 3 (7.5) | 0 (0) | 14 (5.4) | |
| Light chain | 91 (26.4) | 13 (32.5) | 17 (35.4) | 61 (23.7) | |
| Nonsecretory | 5 (1.4) | 0 (0) | 0 (0) | 5 (2.0) | |
| DS stage [number (%)] | 0.7506 | ||||
| I–II | 17 (4.9) | 1 (2.5) | 5 (10.4) | 11 (4.3) | |
| IIIA | 234 (67.8) | 28 (70.0) | 34 (70.8) | 172 (66.9) | |
| IIIB | 94 (27.3) | 11 (27.5) | 9 (18.75) | 74 (28.7) | |
| ISS sage [number (%)] | 0.7975 | ||||
| I | 68 (19.7) | 7 (27.5) | 6 (12.5) | 55 (21.4) | |
| II | 147 (42.6) | 19 (47.5) | 23 (47.9) | 105 (40.8) | |
| III | 130 (37.7) | 14 (35.0) | 19 (29.5) | 97 (37.7) | |
| R‐ISS stage [number (%)] | 0.5377 | ||||
| I | 53 (15.4) | 4 (10.0) | 4 (8.3) | 45 (17.5) | |
| II | 228 (66.1) | 27 (67.5) | 34 (70.8) | 167 (65.0) | |
| III | 64 (18.5) | 9 (22.5) | 10 (20.8) | 45 (17.5) | |
| R2‐ISS stage [number (%)] | 0.0163 | ||||
| I–II | 101 (29.2) | 4 (10.0) | 13 (27.1) | 84 (32.7) | |
| III | 185 (53.6) | 28 (70.0) | 23 (47.9) | 134 (52.1) | |
| IV | 59 (17.1) | 8 (20.0) | 12 (25.0) | 39 (15.2) | |
| Extra‐medullary multiple myeloma (EMM) [number (%)] | 40 (11.6) | 10 (25) | 3 (6.3) | 27 (10.5) | 0.0032 |
| Circulating tumour cell (≥0.165%) [number (%)] | 90/328 (27.4) | 9/38 (23.7) | 15/44 (34.9) | 66/246 (26.8) | 0.7003 |
| Haemoglobin [<100 g/L, (%)] | 225 (65.2) | 29 (72.5) | 30 (62.5) | 166 (64.6) | 0.3037 |
| Platelet [<100 g/L, (%)] | 50 (14.5) | 8 (20) | 5 (10.4) | 37 (14.4) | 0.2927 |
| Albumin [<25 g/L, (%)] | 35 (10.2) | 2 (5) | 6 (12.5) | 27 (10.5) | 0.2517 |
| Creatine [>177 μmol/L, (%)] | 73 (21.1) | 10 (25) | 7 (14.6) | 56 (21.8) | 0.5271 |
| Serum corrected calcium [>2.75 mmol/L, (%)] | 40 (11.6) | 2 (5) | 4 (8.3) | 34 (13.2) | 0.1659 |
| β2‐microglobulin [>5.5 mg/L, (%)] | 122 (35.3) | 13 (32.5) | 19 (39.6) | 90 (35.0) | 0.6872 |
| 24‐h urinary protein [>150 mg/24 h, (%)] | 252 (73.0) | 28 (70) | 34 (70.8) | 190 (73.9) | 0.6445 |
| LDH [>245 U/L, (%)] | 53 (15.3) | 6 (15) | 7 (14.6) | 40 (15.5) | 0.9461 |
| ASCT (≥PR, n = 320) [number (%)] | 0.8804 | ||||
| Yes | 232 (72.5) | 25 (71.4) | 30 (66.7) | 177 (73.7) | |
| No | 88 (27.5) | 10 (28.6) | 15 (33.3) | 63 (26.2) | |
| Maintenance treatment (n = 320) [number (%)] | 0.3068 | ||||
| Lenalidomide | 184 (57.5) | 16 (45.7) | 27 (60.0) | 141 (58.7) | |
| Lenalidomide+proteasome inhibitor | 111 (34.7) | 15 (42.8) | 16 (35.5) | 80 (33.3) | |
| Other | 25 (7.8) | 4 (11.4) | 2 (4.4) | 19 (8.0) | |
Abbreviation: ASCT, autologous stem cell transplantation.
Statistical significance was set at p < 0.05, the bold values mean that there was significance difference between Patients with del(1p32.3) (n = 40) and Patients without del(1p32.3) (n = 305).
Del(1p32.3) was identified in 40 patients (11.6%), associated with a higher incidence of extra‐medullary multiple myeloma (EMM) at diagnosis (25% vs. 9.8%, p = 0.0032) and advanced R2‐ISS stage III–IV (90% vs. 68.1%, p = 0.0163). No significant differences were found for baseline haemoglobin, platelet count, albumin, calcium, creatinine, β2‐microglobulin, Lactate Dehydrogenase (LDH), 24 h urinary protein or circulating tumour cell presence(≥0.165%), 11 indicating comparable clinical baselines between groups.
Cytogenetic abnormalities by fish and cytoscan
Prevalence of karyotype abnormalities
Chromosome 1 abnormalities were most frequent (64.1%), including gain/amplification (1q21) in 189 cases (54.8%) and del(1p) in 88 cases (25.5%). Other common abnormalities included del(13q14) (55.3%) and del(17p13) (14.5%). Key translocations included t(4;14) (20.6%), t(11;14) (13.3%) and t(14;16) (1.5%). Only 16 patients (4.5%) showed no chromosomal or Copy Number Variation (CNV) abnormalities (Table 2).
TABLE 2.
Analysis of cytogenetic abnormalities detected by FISH and Cytoscan.
| Total population (n = 345) | Patients with del(1p32.3) (n = 40) | Patients without del(1p32.3) (n = 305) | p‐value | |
|---|---|---|---|---|
| Cytogenetic abnormalities [n, (%)] | ||||
| Gain/amplification(1q21) | 189 (54.8) | 34 (85.0) | 155 (50.8) | <0.0001 |
| Del(17p) | 50 (14.5) | 11 (27.5) | 39 (12.8) | 0.0280 |
| Del(13q14) | 191 (55.3) | 24 (60.0) | 167 (54.8) | 0.6130 |
| t(4,14) | 71 (20.6) | 6 (15.0) | 65 (21.3) | 0.4123 |
| t(11,14) | 46 (13.3) | 4 (10.0) | 42 (13.7) | 0.6271 |
| t(14,16) | 5 (1.5) | 1 (2.5) | 4 (1.3) | 0.4621 |
| mSMART3.0 stage [n, (%)] | 0.0005 | |||
| Low risk | 111 (32.2) | 3 (7.5) | 109 (35.7) | |
| High risk (with one hit) | 156 (45.2) | 24 (60.0) | 131 (43.0) | |
| High risk (with double or triple hit) | 78 (22.6) | 13 (32.5) | 65 (21.3) | |
| Karyotype [n, (%)] | 0.0286 | |||
| Diploid | 111 (32.2) | 7 (17.5) | 104 (34.1) | |
| Hypodiploid | 120 (34.8) | 21 (52.5) | 99 (32.5) | |
| Hyperdiploid | 114 (33.0) | 12 (30.0) | 102 (33.4) | |
| Subclone [n, (%)] | 0.0003 | |||
| 0 | 118 (34.2) | 6 (15.0) | 112 (36.7) | |
| 1 | 158 (45.8) | 17 (42.5) | 141 (46.2) | |
| 2 | 69 (20.0) | 17 (42.5) | 52 (17.1) | |
| Complex karyotype (≥6 chromosomes) [n, (%)] | 227 (65.8) | 38 (95) | 189 (61.9) | <0.0001 |
| CNV abnormalities (>3 with more than 5 Mb) [n, (%)] | 259 (75.1) | 40 (100) | 219 (71.8) | <0.0001 |
| Prognostic index stage [n, (%)] | <0.0001 | |||
| ≤0 score (low risk) | 116 (33.6) | 0 (0) | 116 (38.0) | |
| 0–1 score (middle risk) | 157 (45.5) | 7 (17.5) | 150 (49.1) | |
| ≥1 score (high risk) | 72 (20.9) | 33 (82.5) | 39 (12.8) | |
Abbreviation: FISH, fluorescence in situ hybridization.
Statistical significance was set at p < 0.05, the bold values mean that there was significance difference between Patients with del(1p32.3) (n = 40) and Patients without del(1p32.3) (n = 305).
Specific chromosome 1p deletion loci
Cytoscan complemented FISH findings by identifying specific chromosome 1p deletions. Among 88 cases with del(1p), 40 (11.6%) involved the critical 1p32.3/CDKN2C locus. Other deletions primarily affected 1p12 or 1p22 loci, including two cases of complete chimeric deletion of chromosome 1 (1p36.33q44), resulting in sub‐diploid chromosomes (−1) (Appendix S1).
The most frequently involved fragments were 1p21‐31 (15/88), 1p11‐36 (10/88) and 1p12‐31 (8/88). The highest individual locus involvement was at 1p22 (22.0%), followed by 1p12 (13.0%) and 1p32 (11.6%). Additionally, 22 patients (6.3%) exhibited small‐fragment gains at 1p36, suggesting chromosome 1p predominantly undergoes deletions rather than gains (Appendix S1).
Monoallelic deletions and clone analysis of 1p32.3 by Cytoscan
Among 40 patients with del(1p32.3), Cytoscan identified 11 cases with single monoallelic deletion (one copy loss, including 2 cases of LOH), and 29 with chimeric monoallelic deletions (partial one‐copy loss). No biallelic deletions were found. Similar deletion patterns occurred at other loci (e.g. 1p12: 6 cases; 1p22: 10 cases; Appendix S2). Subclone analysis showed 18 cases (including all single monoallelic deletions) with 1p32.3 deletion in the main clone, 15 in median subclones and 7 in smaller subclones.
Concurrent cytogenetic abnormalities with del(1p32.3)
Del(1p32.3) was significantly associated with gain/amplification (1q21) (p < 0.001) and del(17p) (p = 0.0280), aligning patients into mSMART 3.0 high‐risk subgroups, with increased likelihood of double or triple hits (p = 0.0005). The Cytoscan‐based Prognostic Index also classified most del(1p32.3)‐positive cases as high risk (p < 0.001).
All del(1p32.3)‐positive cases exhibited extensive CNV abnormalities, and 95% had complex karyotypes. Hypodiploid karyotypes, associated with poor prognosis, were more frequent (52.5%, p = 0.0286), while hyperdiploidy rates did not differ significantly. Patients with del(1p32.3) also showed significantly greater subclonal heterogeneity (p = 0.0003; Table 2).
Treatment response evaluation
After four cycles of VRD induction therapy, response rates were sCR 10.7%, CR 30.7%, VGPR 40.9%, PR 10.4% and PD 7.2%. Responses among del(1p32.3)‐positive patients were sCR 10.0%, CR 27.5%, VGPR 45.0%, PR 5.0% and PD 12.5%. Although response distributions were similar between groups (p = 0.4892), del(1p32.3)‐positive patients showed trends towards increased disease progression (12.5% vs. 6.5%) and fewer deep responses (≥CR: 37.5% vs. 41.9%; p > 0.05).
At day 100 post‐transplantation (n = 232), no significant differences in response rates were observed between del(1p32.3)‐positive (n = 25) and negative (n = 207) groups: sCR (16% vs. 19.3%), CR (40% vs. 46.4%), VGPR (32% vs. 31.4%), PR (8% vs. 2.9%) and PD (4% vs. 0%). Both groups showed substantial increases in deep responses after transplantation (≥CR in the del(1p32.3)‐positive group: 56%; negative group: 63.3%; p > 0.05).
Survival analysis
All 345 NDMM patients were followed up until 31 March 2025, with a median follow‐up of 40 months (range: 1–78). Median PFS was 66 months; median OS was not reached. At 60 months, cumulative PFS was 52.6% and OS was 75.2% (Figure 2A,B).
FIGURE 2.
(A, B) PFS and OS analyses of the total population. (C, D) PFS and OS analyses of del(1p) and involvement of 1p32.3 locus. (E, F) PFS and OS analyses of del(1p32.3) in the main clone or subclone. (G, H) PFS and OS analyses of single monoallelic and chimeric monoallelic del(1p32.3). OS, overall survival; PFS, progression‐free survival.
Prognosis by 1p deletion loci
Patients with del(1p32.3) exhibited significantly worse outcomes, with median PFS of 33 months (p = 0.0033) and inferior OS (p = 0.0403) compared to del(1p)‐negative patients. No difference was observed between del(1p)‐positive patients without the 1p32.3 deletion and del(1p)‐negative patients (p > 0.05). At 60 months, PFS rates were 34.4%, 52.8% and 55.5%, respectively, and OS rates were 58.6%, 77.8% and 76.6% respectively (Figure 2C,D).
Prognosis by clone size and Monoallelic deletion type of del(1p32.3)
Del(1p32.3) in the main clone significantly worsened outcomes (PFS: 17 vs. 42 months, p = 0.0170; OS: 53.4% vs. 69.4% at 60 months, p = 0.0419), compared to smaller subclones (Figure 2E,F).
Patients with single monoallelic del(1p32.3) exhibited rapid progression (median PFS: 15 months, p = 0.0183) and shorter survival (median OS: 27 months, p = 0.0036), representing the subgroup with the poorest outcomes. Notably, all 11 single monoallelic deletions were in the main clone, suggesting a primary evolutionary role (Figure 2G,H).
Synergistic effects of del(1p32.3)
High‐risk cytogenetic abnormalities (HRCAs: del(17p), t(4;14), t(14;16), gain/amplification(1q21)) showed cumulative negative effects on outcomes. Median PFS decreased from not reached to 49, 35 and 12.5 months, and median OS from not reached to 62 and 27.5 months with increasing HRCAs (p < 0.0001; Figure 3A,B). Among del(1p32.3) patients, 38/40 had concurrent HRCAs (34 with gain/amplification of 1q21). Patients with multiple abnormalities (12 double‐hit, 1 triple‐hit) had particularly poor outcomes (median PFS: 19 months; 60‐month OS: 40.3%; PFS p = 0.0350, OS p = 0.1624; Figure 3C,D).
FIGURE 3.
(A, B) PFS and OS analyses of different number of HRCAs. (C, D) PFS and OS analyses of del(1p32.3) with other HRCAs. (E, F) PFS and OS analyses of different PI scores. HRCAs, high‐risk cytogenetic abnormalitiesPFS, progression‐free survival; OS, overall survival; PFS, progression‐free survival.
The Cytoscan‐based Prognostic Index (PI) ([0.4 × t(4;14)] + [1.2 × del(17p)] – [0.3 × trisomy 5] + [0.3 × trisomy 21] + [0.5 × gain(1q21)] + [0.8 × del(1p32)]) effectively identified risk groups, with significantly worse outcomes in the high‐risk subgroup (PFS and OS p < 0.0001; Figure 3E,F).
Impact of ASCT
Of 345 patients, 320 completed four cycles of VRD induction (25 progressed during induction). Among those completing induction, 232 underwent ASCT and 88 did not. The ASCT group had not reached median PFS versus 37 months in the non‐ASCT group, and significantly better 60‐month OS (94% vs. 84%; PFS p < 0.0001; OS p = 0.0011) (Figure 4A,B).
FIGURE 4.
(A, B) PFS and OS analyses of ASCT in patients with total population. (C, D) PFS and OS analyses of ASCT in patients with del(1p32.3). (E, F) PFS and OS analyses of ASCT in patients with EMM. ASCT, autologous stem cell transplantation; EMM, extra‐medullary multiple myeloma; OS, overall survival; PFS, progression‐free survival.
Within the del(1p32.3) subgroup (25 transplanted, 10 non‐transplanted), median PFS was 38 vs. 22.5 months. Although ASCT trended towards improved outcomes, differences did not reach significance (PFS p = 0.0996; OS p = 0.3719). Sixty‐month PFS and OS were 39.5% vs. 30% and 65.3% vs. 58.3% respectively (Figure 4C,D).
There was a significant age difference between transplanted (median 54 years) and non‐transplanted (median 65 years) patients (p < 0.05), reflecting real‐world practice. Of 25 patients who progressed during induction, 6 (24%) presented with EMM. In 34 total EMM patients, transplantation significantly improved both PFS (median PFS 16 months vs. 41 months, p = 0.0377) and OS (median OS 35 months vs. not reach, p = 0.0223) (Figure 4E,F).
Multivariate prognostic analysis
In a Cox regression model including all 345 NDMM patients and key cytogenetic variables, del(1p32.3) emerged as an independent adverse factor for PFS (HR 1.597; 95% CI: 1.006–2.535; p = 0.047) but not for OS (HR 1.408; 95% CI: 0.752–2.635; p = 0.284). Deletions at other 1p loci showed no significant effect on PFS or OS (p > 0.05) (Table 3).
TABLE 3.
Multivariate prognostic analysis of PFS and OS in NDMM patients.
| PFS | OS | |||||||
|---|---|---|---|---|---|---|---|---|
| HR | HR (95% CI) | p‐value | HR | HR (95% CI) | p‐value | |||
| Del(1p) with 1p32.3 | 1.597 | 1.006 | 2.535 | 0.047 | 1.408 | 0.752 | 2.635 | 0.284 |
| Del(1p) without 1p32.3 | 1.073 | 0.657 | 1.753 | 0.777 | 0.801 | 0.402 | 1.595 | 0.528 |
| Gain/amplification(1q21) | 2.146 | 1.462 | 3.149 | 0.001 | 1.731 | 1.007 | 2.975 | 0.047 |
| Del(17p) | 1.587 | 1.023 | 2.460 | 0.039 | 2.130 | 1.235 | 3.674 | 0.007 |
| t(4,14) | 1.551 | 1.034 | 2.327 | 0.034 | 2.518 | 1.513 | 4.191 | 0.001 |
| t(11,14) | 1.721 | 1.078 | 2.748 | 0.023 | 0.992 | 0.441 | 2.231 | 0.984 |
| t(14,16) | 1.555 | 0.474 | 5.109 | 0.467 | 3.023 | 0.879 | 10.402 | 0.079 |
| Del(13q14) | 1.242 | 0.866 | 1.781 | 0.238 | 1.341 | 0.789 | 2.269 | 0.279 |
| ISS‐III stage | 1.462 | 1.047 | 2.042 | 0.026 | 1.983 | 1.256 | 3.131 | 0.003 |
Abbreviations: NDMM, newly diagnosed multiple myeloma; OS, overall survival; PFS, progression‐free survival.
Statistical significance was set at p < 0.05, the bold values mean that the facotr is an independent prognostic factor in PFS or OS.
Established risk factors—gain/amplification of 1q21, del(17p), t(4;14) and ISS stage III—were independently associated with worse outcomes for both PFS and OS (p < 0.05).
DISCUSSION
In this single‐centre real‐world analysis combining FISH and Cytoscan, we observed a high incidence of chromosome 1 abnormalities (64.1%), including 1q21 gain/amplification in 54.8% and 1p deletions in 25.5% of 345 NDMM patients. Among those with 1p deletions, 11.6% (n = 40) specifically involved the 1p32.3/CDKN2C locus, while the remaining 48 cases affected 1p12 or 1p22 without CDKN2C involvement. These frequencies align with previously reported rates of 7.3–15%. 12 , 13 , 14
Patients harbouring del(1p32.3) displayed more aggressive features, a higher rate of extra‐medullary disease (25% vs. 9.8%, p = 0.0032) and more frequent advanced R2‐ISS staging (90% vs. 68.1%, p = 0.0163) and higher Prognostic Index scores (p < 0.0001). Extra‐medullary spread is often associated with treatment resistance and poorer survival 15 and reflects ongoing clonal evolution.
Del(1p32.3) co‐occurred with other high‐risk abnormalities, particularly 1q21 gain/amplification (85%, p < 0.0001) and del(17p) (27.5%, p = 0.0280), consistent with prior reports by Hebraud 9 and Qazilbash. 16 Cytoscan added critical resolution; it detected sub‐diploid karyotypes (p = 0.0286), complex CNV patterns (p < 0.0001) and subclonal populations (p = 0.0003) that FISH alone would miss. High‐density SNP/CNV probes permit simultaneous detection of UPD/LOH, fusion genes and low‐level chimeric abnormalities, enabling precise breakpoint mapping and discovery of novel lesions.
Prior work has identified 1p12 (containing FAM46C), 1p22 (containing EVI5 and RPL5) and 1p32.3 (CDKN2C) as key loci. 17 FAM46C plays a tumour‐suppressive role by stabilizing mRNA and triggering apoptosis via autophagy disruption. 18 , 19 EVI5 regulates cell‐cycle progression and cytokinesis, while RPL5 is critical for ribosomal biogenesis, with reduced expression correlating with poorer survival. 20 , 21 CDKN2C halts cell‐cycle progression in late‐stage B cells; its loss leads to unchecked CCND1 expression and accelerated proliferation. 13
In our cohort, del(1p32.3) was associated with markedly shorter PFS (median 33 vs. 66 months; p = 0.0033) and decreased OS (p = 0.0403) compared to patients without 1p32.3 involvement. Subgroup analyses confirmed that deletions at other 1p loci had no significant prognostic impact. These findings mirror the French Myeloma Collaboration Group's analysis of 2551 NDMM patients, which also linked del(1p32.3) to worse outcomes. 22
We uniquely evaluated the size of the del(1p32.3) clone; patients with main‐clone involvement had a median PFS of only 17 months (p = 0.0170) versus 42 months in smaller subclones, and lower 60‐month OS (53.4% vs. 69.4%, p = 0.0419). This parallels our previous work showing that 1q21 gain in the main clone also portends a poorer prognosis. 23 Clonal heterogeneity increases over time and drives disease progression, 24 and del(1p) appears as a secondary event; it is found in 25.5% of NDMM, 31.1% of relapsed/refractory MM and 62.5% of secondary plasma cell leukaemia(sPCL), but not in monoclonal gammopathy of undetermined significance (MGUS). 25
Schavgoulidze A 22 pioneered the analysis of del(1p32.3) copy number variations, demonstrating that biallelic del(1p32.3) carries a particularly dismal prognosis, though we identified no such cases among 345 patients. In our larger centre database of ~650 MM patients, only one (0.15%) exhibited biallelic loss (1p32.3: 51050055–51 616 630; 0 copy). This extremely low incidence explained the absence of biallelic deletions in our cohort. Nevertheless, our findings revealed that single monoallelic deletions were associated with worse outcomes compared to partial chimeric monoallelic deletions (Median PFS 15 months, p = 0.0183, Median OS 27 months, p = 0.0036). Notably, all 11 patients with single monoallelic 1p32.3 deletions harboured these abnormalities in their main clone, suggesting that single monoallelic deletion serves as a crucial determinant in disease progression.
Del(1p32.3) also exerted a cumulative adverse effect, which was linked to the combination with other HRCAs (del(17p), t(4;14), t(14;16) or 1q21 gain/amplification). Among 40 del(1p32.3) patients, 38 had ≥1 concurrent HRCA, most commonly 1q21 gain/amplification (34/38). Those with multiple hits (12 double hit, 1 triple hit) demonstrated a statistically significant and clinically meaningful influence in prognosis, with a median PFS of 19 months and 40.3% 60‐month OS (PFS p = 0.0350; OS p = 0.1624). In the Chinese population, where 1q abnormalities are more frequent, 23 this co‐occurrence can be especially prognostic. The Cytoscan‐derived Prognostic Index stratified patients into low, intermediate and high risk, and the poorest PFS and OS were particularly notable given the high‐risk group (p < 0.0001); from another perspective, it illustrated the accuracy and guiding significance of a prognostic stratification system that included 1p32 abnormalities.
A consistent benefit was observed in both PFS and OS due to the combination of autologous stem cell transplantation (ASCT) across the entire cohort (PFS p < 0.0001; OS p = 0.0011); the median PFS was NR with the transplant group compared with 37 months with the non‐transplant group. The 60‐month OS was 84% vs. 94%. The trend of improved outcomes could be reflected by the 60‐month cut‐off results (PFS: 39.5% vs. 30%; OS: 65.3% vs. 58.3%), but it only partially mitigated the adverse impact of the 1p32 deletion (PFS p = 0.0996; OS p = 0.3719). In patients with extramedullary disease, who had a median PFS of only 16 months and a median OS of only 35 months with VRD treatment only , ASCT demonstrated a clinically meaningful improvement in median PFS by 40 months (p = 0.0377), with median OS not yet reached (p = 0.0223). All of these strongly emphasized the unshakable position of transplantation, especially with high risks, as stated by Rocchi S. 26
Multivariate analysis confirmed del(1p32.3) as an independent adverse factor for PFS (HR = 1.597; 95% CI: 1.006–2.535; p = 0.047), showing a 59.7% enhancement in the risk of progression, but not for OS (HR = 1.408; 95% CI: 0.752–2.635; p = 0.284). Other 1p deletions lacked prognostic significance. Established risk factors—1q21 gain/amplification, del(17p), t(4;14) and ISS stage III—remained independently associated with worse PFS and OS (p < 0.05).
This real‐world study provides the most comprehensive evaluation of del(1p32.3) in Chinese NDMM patients to date. Given its strong prognostic relevance, we recommend incorporating routine del(1p32.3) testing into clinical practice. Limitations include the single‐centre, moderate sample size, variable follow‐up and potential selection bias. Importantly, the absence of biallelic del(1p32.3) in our cohort underscores its rarity; larger multicentre prospective studies are needed to confirm these findings and better define the role of 1p32.3 in MM pathogenesis and risk stratification.
AUTHOR CONTRIBUTIONS
HY, WY and LY designed the study, collected the data, analysed the data and wrote the article. YZ, ZY and JS contributed to data collection and analysis. SY, XS, SJ, XG, DW, HS and JP contributed to the data collection and verification. DW and CF contributed to the research design article composition and study supervision. All authors read and approved the final article.
FUNDING INFORMATION
This study was supported by the Translational Research Grant of NCRCH (Grant No. 2020ZKPB01), Suzhou Project of Science and Technology 2021 (Grant No. SLJ2021004), National Natural Science Foundation of China General Project Approval 2022 (Grant No.82270210/H0811), Young Scientists Fund of the Natural Science Foundation of Jiangsu Province (grant no. BK20230213), Jiangsu Province Science and Technology Resources (Major Disease Biological Samples) Coordination Service Platform 2022 Open Project (TC2022B007).
CONFLICT OF INTEREST STATEMENT
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
ETHICS STATEMENT
The studies involving human participants were reviewed and approved by the First Affiliated Hospital of Soochow University Research Ethics Board. The patients/participants (or legal guardian/next of kin) provided written informed consent to participate in this study.
PATIENT CONSENT STATEMENT
Informed consent was obtained from all patients and kept in the First Affiliated Hospital of Soochow University Research Ethics Board.
PERMISSION TO REPRODUCE MATERIAL FROM OTHER SOURCES
No permission to reproduce material from other sources was necessary.
Supporting information
Appendix S1–S3.
ACKNOWLEDGEMENTS
All samples were from Hematologic Biobank, National Clinical Research Center for Hematologic Diseases, Jiangsu Provincial Science and Technology Resources (Clinical Resources) Coordination Service Platform, The First Affiliated Hospital of Soochow University.
You H, Yao W, Yan L, Zhai Y, Yan Z, Shang J, et al. Poor prognosis of newly diagnosed multiple myeloma patients with 1p32.3 deletion in single monoallelic deletion and/or in main clone. Br J Haematol. 2025;207(3):869–880. 10.1111/bjh.70015
Hongying You, Weiqin Yao, and Lingzhi Yan have contributed equally to this work and share first authorship.
Contributor Information
Depei Wu, Email: wudepei@suda.edu.com.
Chengcheng Fu, Email: fuchengchengsz@163.com.
DATA AVAILABILITY STATEMENT
All data generated or analysed during this study are included in this published article and its supplementary information files.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Appendix S1–S3.
Data Availability Statement
All data generated or analysed during this study are included in this published article and its supplementary information files.