To the Editor,
Multiple myeloma (MM) patient outcomes have dramatically improved over recent decades, and this is largely attributable to the development of novel targeted therapies. 1 However, some patients continue to experience suboptimal outcomes due to several different clinical and disease‐specific factors. 2 Certain cytogenetic abnormalities—translocations t(4;14), t(14;16) and 17p deletion (del(17p))—have historically been associated with poorer progression‐free survival (PFS) and overall survival (OS). 3 , 4 Del(17p) is associated with shorter survival in MM and is present in approximately 10% of MM patients. Furthermore, it is becoming clear that patients with more than one high‐risk cytogenetic abnormality (HRCA) belong to an ‘ultra‐high risk’ group and have even shorter PFS and OS. 5
The standard of care for a transplant‐eligible patient with newly diagnosed MM (NDMM) is quadruplet therapy followed by upfront autologous haematopoietic stem cell transplantation (AHSCT). Given the increasing importance placed on developing personalized therapeutic approaches, further understanding of the impact of these high‐risk cytogenetic lesions on survival is needed. We therefore sought to characterize outcomes in a large cohort of patients with del(17p) MM.
Adult MM patients with del(17p) undergoing a first AHSCT between 2016 and 2022 inclusive were selected from the EBMT registry. This excluded any cases with missing cytogenetic data or cases where testing was not done. Testing for del(17p), t(4;14) and t(14;16) was standard of care in EBMT centres between 2016 and 2022. On this basis, if t(4;14) or t(14;16) was not registered when del(17p) had been, they were assumed to be absent.
EBMT centres commit to obtaining informed consent according to the local regulations and EBMT approval was granted for this retrospective analysis. Patient demographics, transplant strategies, cytogenetic profiles, PFS and OS were characterized. The prevalence of additional cytogenetic abnormalities was evaluated, specifically assessing the effect of the concurrent presence of t(4;14) and/or t(14;16) in addition to del(17p). PFS and OS at 1 and 3 years and causes of death were reported. In multivariable analysis, the effect of t(4;14) on OS was adjusted for the presence of t(14;16), patient sex, patient age, ISS, disease stage, conditioning and Karnofsky score. Model‐based survival estimates are calculated using direct standardization. A p value of <0.05 was considered statistically significant.
A total of 2460 MM patients with del(17p) underwent AHSCT between 2016 and 2022 inclusive. Descriptive variables are shown in Table 1. The median age of this cohort was 61 years (interquartile range [IQR]; 55.9–66.7) and 1373 (55.8%) were male. A total of 1210 (49.9%) had immunoglobulin G (IgG) MM, 490 (20.2%) immunoglobulin A (IgA) MM and 671 (27.6%) light chain MM. Patients were stratified according to the standardized International Staging System (ISS) with 36.6% having ISS stage III disease. A total of 415 patients (17.3%) achieved a complete remission (CR) pre‐AHSCT, 1105 (46.2%) a very good partial response (VGPR), 747 (31.2%) a partial response (PR), 60 (2.5%) a minimal response/stable disease (MR/SD) and 61 patients (2.5%) had relapsed/progressive disease. Performance status based on the Karnofsky score revealed that most patients had a good functional status with only 733 (32.2%) having a score of < /=80.
TABLE 1.
Baseline variables.
| Group | Total | |
|---|---|---|
| Missing | N (%) | |
| Total | 2460 (100%) | |
| Age at this treatment | ||
| Median (IQR) | 61.4 (55.9–66.7) | |
| Sex | ||
| Male | 1373 (55.8%) | |
| Female | 1087 (44.2%) | |
| High‐risk abnormalities | ||
| del(17p) | 1988 (80.8%) | |
| t(4;14) | 335 (13.6%) | |
| t(14;16) | 109 (4.4%) | |
| t(4;14) + t(14;16) | 28 (1.1%) | |
| t(4;14) present | ||
| No | 2097 (85.2%) | |
| Yes | 363 (14.8%) | |
| t(14;16) present | ||
| No | 2323 (94.4%) | |
| Yes | 137 (5.6%) | |
| Gain 1q present | ||
| No | 2436 (99%) | |
| Yes | 24 (1%) | |
| MM type | ||
| Common type | 25 (1%) | 1725 (70.8%) |
| Light chain | 671 (27.6%) | |
| Non‐secretory | 39 (1.6%) | |
| Ig type in MM | ||
| IgG | 743 (30.2%) | 1210 (70.5%) |
| IgA | 490 (28.5%) | |
| IgD | 11 (0.6%) | |
| IgM | 6 (0.3%) | |
| Chain type in MM | ||
| Kappa | 76 (3.1%) | 1497 (62.8%) |
| Lambda | 879 (36.9%) | |
| Both kappa and lambda | 8 (0.3%) | |
| MM classification | ||
| IgG | 33 (1.3%) | 1210 (49.9%) |
| IgA | 490 (20.2%) | |
| Light chain | 671 (27.6%) | |
| Other Ig | 17 (0.7%) | |
| Non‐secretory | 39 (1.6%) | |
| ISS (International Staging System) | ||
| I | 482 (19.6%) | 579 (29.3%) |
| II | 675 (34.1%) | |
| III | 724 (36.6%) | |
| HSCT variables | ||
|---|---|---|
| Group | Total | |
| Missing | N (%) | |
| Total | 2460 (100%) | |
| Interval diagnosis‐TX in months | ||
| Median (IQR) | 6.6 (5.3–8.7) | |
| Categorized disease status at TX1 | ||
| CR | 66 (2.7%) | 415 (17.3%) |
| VGPR | 1105 (46.2%) | |
| PR | 747 (31.2%) | |
| MR/SD | 60 (2.5%) | |
| Rel/Prog | 61 (2.5%) | |
| Other | 6 (0.3%) | |
| Karnofsky score | ||
| >80 | 184 (7.5%) | 1543 (67.8%) |
| <=80 | 733 (32.2%) | |
| Conditioning groups | ||
| Mel140 | 11 (0.4%) | 304 (12.4%) |
| Mel200 | 1825 (74.5%) | |
| Mel other/unknown dose | 195 (8.0%) | |
| Other conditioning | 125 (5.1%) | |
| Stem cell source | ||
| PB | 2460 (100%) | |
Abbreviations: CR, complete remission; HSCT, haematopoietic stem cell transplantation; IgA, immunoglobulin A; IgD, immunoglobulin D; IgG, immunoglobulin G; IgM, immunoglobulin M; IQR, interquartile range; MM, multiple myeloma; MR/SD, minimal response/stable disease; PB, peripheral blood; PR, partial response; VGPR, very good partial response.
A total of 1988 (80.8%) patients had del(17p) as their sole high‐risk cytogenetic abnormality whereas 335 (13.6%) also had t(4;14) and 109 (4.4%) had a co‐occurring t(14;16). Twenty‐eight (1.1%) patients had both t(4;14) and t(14;16).
All patients received peripheral blood stem cells as their stem cell source. Of 1668 patients for whom data were available, 939 (56.3%) had an upfront single AHSCT (relapse/progression before subsequent transplant) and 729 (43.7%) had a tandem AHSCT (</=6 m interval, no relapse/progression registered).
Estimated PFS was 77% (75%–79%) and 46% (43%–49%) at 1 and 3 years respectively. Estimated OS was 90% (89%–92%) and 68% (65%–71%) at 1 and 3 years respectively.
Disease characteristics and cytogenetic abnormalities associated with poorer OS on multivariate analysis (MVA) were as follows: Del(17p) and co‐occurring t(4;14) (Hazard Ratio [ HR] 1.38 (1.09–1.74), p = 0.007) (Figure 1), ISS stage III disease (HR 1.87 (1.46–2.40); p < 0.001) and disease status of </=PR (HR 1.40 (1.08–1.81); p < 0.01). Older age, conditioning regimen, Karnofsky score, ISS <stage III and co‐occurrence of t(14;16) were not associated with shorter OS. The main cause of death was relapse/progression of disease (64.7%), followed by infection (13.6%) and organ damage/failure (9.9%).
FIGURE 1.
Comparative overall survival of myeloma patients with del (17p) with or without co‐existing t(4;14) translocation.
This registry analysis of the ‘real‐world’ post‐AHSCT outcomes of almost 2500 patients with del(17p) MM is one of the largest to date and provides further evidence of the adverse effect of del(17p) and, more specifically, the compounding deleterious effect of the presence of additional concurrent HRCA. In addition, a suboptimal disease response (≤PR) prior to AHSCT was associated with poorer OS, highlighting the need for more effective induction strategies in this cohort to ensure maximal disease control prior to AHSCT.
A previous EBMT study evaluated the outcomes of 623 patients with del(17p) and/or t(4;14) undergoing either upfront single autologous (auto) (n = 446), tandem autologous (auto‐auto) (n = 105) or tandem autologous/reduced‐intensity allogeneic (auto‐allo) (n = 72) haematopoietic stem cell transplantation between 2000 and 2015. 6 Forty‐five per cent had del(17p) while 9% were reported as having both abnormalities. For those with isolated del(17p), 5‐year PFS and OS were 20% and 44%, respectively, with no significant difference in OS between the treatment groups, highlighting the historically poor survival in this cohort.
More recently, Marcoux et al. conducted a retrospective single‐centre analysis of patients with NDMM with del(17p) who underwent upfront AHSCT in the MD Anderson Cancer Centre between 2008 and 2018. 7 One hundred and fifteen patients (median age 62 years) had a median PFS and OS of 19.9 and 71.5 months respectively. As in our study, the concurrent presence of del(17p) and t(4;14) was associated with poorer outcomes with a PFS of 11.5 months and an OS of 22.4 months. The adverse effect on OS was confirmed on MVA.
PFS and OS rates in our contemporary EBMT cohort (2016–2022) were 77% and 90% at 1 year and 46% and 68% at 3 years respectively. For the purposes of comparison, OS in the IFM‐2009 trial transplant arm (Revlimid (Lenalidomide), Velcade (Bortezomib), dexamethasone + AHSCT) was 81% at 4 years, demonstrating that del(17p) continues to be associated with poorer outcomes in the modern era. 8
The International Myeloma Society/International Myeloma Working Group recently published consensus recommendations on the definition of high‐risk MM. 9 The Panel proposes that del(17p) and/or a TP53 mutation be considered high risk. To establish that isolated del(17p) remains high risk in the absence of a TP53 mutation, Corre et al. studied 121 del (17p) patients treated with a consistent intensive approach and assessed for TP53 mutations. 10 Outcomes were then compared with 2505 patients lacking del(17p). They confirmed that the ‘double hit’ (bi‐allelic TP53 deletion) cohort had the shortest survival (median OS 36 months), but that del(17p) alone was still associated with poorer outcomes when compared with those of the control cohort (median survival 52.8 months vs. 152.2 months respectively).
The cumulative adverse effect of HRCA has been reported by several groups. In a study of 79 NDMM AHSCT patients who had had two or more HRCA and who were treated between 2008 and 2018, the median PFS was 22.9 months and median OS was 71.5 months. 11 Moreover, patients with three HRCA had a median PFS of 15.6 months and a median OS of 28.0 months. In a similar recent report on 73 patients with del (17p) treated in consecutive PETHEMA‐GEM trials, 26 (35.6%) had one other HRCA and 15 (20.5%) had two or more other HRCAs. 12 Although no significant differences in PFS or OS were found when patients with del(17p) alone were compared with those with co‐occurrence of one or more other HRCA, this may reflect the small sample size.
Kaiser and colleagues performed a systematic review of randomized controlled trials in MM between 2000 and 2021 to investigate the consistency of association of co‐occurrence of HRCA with prognosis in patients with both NDMM and relapsed/refractory MM across a range of treatment modalities. 5 Twenty‐four trials including 13 926 patients were included. The HR for PFS was 2.28 (95% CI, 2.05–2.54) for patients with two or more HRCA and 1.51 (95% CI, 1.38–1.65) for patients with only one HRCA. The HR for OS was 2.94 (95% CI, 2.49–3.47) and 1.69 (95% CI, 1.52–1.88) for the two subgroups respectively.
We acknowledge that our study has inherent weaknesses as testing for del (1p) or gain (1q) were not recommended as standard of care between 2016 and 2022. It therefore remains unclear how many of the patients identified as having had del (17p) as their only high‐risk lesion may, in fact, have had additional adverse cytogenetic abnormalities. There is no remedy for this lack of testing so the additional insight our cohort can provide for the care of patients going forward, with wider genetic testing now being standard, is limited.
In conclusion, our large registry study highlights that AHSCT‐eligible patients with MM and del(17p) continue to have poorer outcomes with standard approaches to therapy and that patients with t(4;14) and del(17p) (two high‐risk cytogenetic abnormalities) represent an ultra‐high‐risk cohort.
AUTHOR CONTRIBUTIONS
Annoek Broers: Writing – review and editing. Tobias Gedde‐Dahl: Writing – review and editing. Britta Besemer: Writing – review and editing. Claire Comerford: Conceptualization; writing – original draft; writing – review and editing; methodology; project administration; formal analysis; supervision. Sandra Sauer: Writing – review and editing. Patrick J. Hayden: Conceptualization; writing – original draft; writing – review and editing; methodology; project administration; formal analysis; supervision. Diderik‐Jan Eikema: Methodology; writing – original draft; conceptualization; writing – review and editing; data curation; project administration; formal analysis; supervision; resources. Linda Koster: Data curation; methodology; conceptualization; project administration; formal analysis; supervision; resources. Deborah Richardson: Writing – review and editing. Jean Noel Bastie: Writing – review and editing. Robert Zeiser: Writing – review and editing. Luisa Giaccone: Writing – review and editing. Christine Schuermans: Writing – review and editing. Laure Vincent: Writing – review and editing. Anne Cairoli: Writing – review and editing. Joanna Drozd‐Sokolowska: Writing – review and editing. Laurent Garderet: Writing – review and editing; conceptualization; methodology. Thomas Pabst: Writing – review and editing. Donal P. McLornan: Conceptualization; methodology; writing – review and editing; project administration. Monica Poiani: Writing – review and editing. Kristina Carlson: Writing – review and editing. Meral Beksac: Conceptualization; methodology; writing – review and editing. Kavita Raj: Writing – review and editing. Inas El Najjar: Writing – review and editing. Neil Rabin: Writing – review and editing. Jean‐Marc Schiano de Colella: Writing – review and editing.
CONFLICT OF INTEREST STATEMENT
The authors have no conflicts of interest to disclose.
ACKNOWLEDGEMENTS
The authors would like to acknowledge the EBMT centres who shared their data for this research and our patients for whom we hope to improve future management with these data.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
REFERENCES
- 1. Dimopoulos MA, Terpos E, Boccadoro M, Moreau P, Mateos MV, Zweegman S, et al. EHA‐EMN evidence‐based guidelines for diagnosis, treatment and follow‐up of patients with multiple myeloma. Nat Rev Clin Oncol. 2025;22(9):680–700. [DOI] [PubMed] [Google Scholar]
- 2. Usmani SZ, Hoering A, Cavo M, Miguel JS, Goldschimdt H, Hajek R, et al. Clinical predictors of long‐term survival in newly diagnosed transplant eligible multiple myeloma—An IMWG Research Project. Blood Cancer J. 2018;8(12):123. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Chalopin T, Vallet N, Theisen O, Ochmann M, Tiab M, Godmer P, et al. No survival improvement in patients with high‐risk multiple myeloma harbouring del(17p) and/or t(4;14) over the two past decades. Br J Haematol. 2021;194(3):635–638. [DOI] [PubMed] [Google Scholar]
- 4. Abdallah N, Rajkumar SV, Greipp P, Kapoor P, Gertz MA, Dispenzieri A, et al. Cytogenetic abnormalities in multiple myeloma: association with disease characteristics and treatment response. Blood Cancer J. 2020;10(8):82. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Kaiser MF, Sonneveld P, Cairns DA, Raab MS, San‐Miguel Izquierdo J, Zhang R, et al. Co‐occurrence of cytogenetic abnormalities and high‐risk disease in newly diagnosed and relapsed/refractory multiple myeloma. J Clin Oncol. 2025;43(24):2679–2691. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Gagelmann N, Eikema DJ, de Wreede LC, Rambaldi A, Iacobelli S, Koster L, et al. Upfront stem cell transplantation for newly diagnosed multiple myeloma with del(17p) and t(4;14): a study from the CMWP‐EBMT. Bone Marrow Transplant. 2021;56(1):210–217. [DOI] [PubMed] [Google Scholar]
- 7. Marcoux C, Pasvolsky O, Milton DR, Tanner MR, Bashir Q, Srour S, et al. Real‐world outcomes of upfront autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma with deletion 17p. Transplant Cell Ther. 2025;31(1):12.e1–12.e10. [DOI] [PubMed] [Google Scholar]
- 8. Attal M, Lauwers‐Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311–1320. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Avet‐Loiseau H, Davies FE, Samur MK, Corre J, D'Agostino M, Kaiser MF, et al. International myeloma society/international myeloma working group consensus recommendations on the definition of high‐risk multiple myeloma. J Clin Oncol. 2025;43(24):2739–2751. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Corre J, Perrot A, Caillot D, Belhadj K, Hulin C, Leleu X, et al. del(17p) without TP53 mutation confers a poor prognosis in intensively treated newly diagnosed patients with multiple myeloma. Blood. 2021;137(9):1192–1195. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Pasvolsky O, Ghanem S, Milton DR, Masood A, Tanner MR, Bashir Q, et al. Outcomes of autologous stem cell transplantation in patients with ultra‐high‐risk multiple myeloma. Transplant Cell Ther. 2023;29(12):757–762. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Gonzalez‐Calle V, Rodriguez‐Otero P, Calasanz MJ, Guijarro M, Martinez‐Lopez J, Rosinol L, et al. High‐risk cytogenetic abnormalities in multiple myeloma: PETHEMA‐GEM experience. Hema. 2024;8(12):e70031. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.