Presentation and outcomes of patients with multiple myeloma harboring gain or amplification of 1q21 and receiving novel agent therapies: results from a single-center study

ABSTRACT Objective Gain or amplification 1q21 (1q21+) is one of the most common recurrent cytogenetic abnormalities in multiple myeloma (MM). Our aim was to explore the presentation and outcomes of patients with MM harboring 1q21 + . Methods We retrospectively analyzed the clinical features and survival outcomes in 474 consecutive patients with MM receiving immunomodulatory drugs or proteasome inhibitor-based regimens as first-line therapies. Results 1q21 + was detected in 249 (52.5%) patients. Patients with 1q21 + had a higher proportion of subtypes of IgA, IgD, and λ-light chain than non-1q21 + . 1q21 + was associated with more advanced ISS stage and was more frequently accompanied by del(13q), elevated lactate dehydrogenase and lower levels of hemoglobin and platelets. Patients with 1q21 + had shorter PFS (21 months vs. 31 months, P = 0.001) and OS (43 months vs. 72 months, P < 0.001) than those without 1q21 + . Multivariate Cox regression analysis confirmed that 1q21 + was an independent prognostic factor for both PFS (HR 1.277, P = 0.031) and OS (HR 1.547, P = 0.003). Patients with 1q21 + del(13q) double-abnormality had shorter PFS (P < 0.001) and OS (P = 0.001) than those with no FISH abnormalities, and they also had shorter PFS (P = 0.018) and OS (P = 0.026) than those with del(13q) single abnormality. No significant difference in PFS (P = 0.525) or OS (P = 0.245) was found between patients with 1q21 + del(13q) double-abnormality and 1q21 + del(13q) multiple-abnormality. Conclusions Patients with 1q21 + were more likely to have coexisting negative clinical features and del(13q). 1q21 + was an independent prognostic factor associated with poor outcomes. Concurrence with such unfavorable features may account for poor outcomes given 1q21 + .


Introduction
Multiple myeloma (MM) is a clonal plasma cell malignancy and is characterized by significant biological and genetic heterogeneity resulting in a wide range of disease courses [1,2].With the advent of novel therapeutic agents, immunomodulators (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies, survival outcomes have rapidly improved over the last two decades [1,3].However, MM is still incurable, and almost all patients experience disease progression or relapse.Screening for high-risk cytogenetic abnormalities (HRCAs) by fluorescent in situ hybridization (FISH) is a routine means to identify patients with poor outcomes.Several studies have demonstrated that chromosome aberrations referring to del(17p), 4 (4;14), and t(14;16) are independent prognostic factors associated with poor survival and are defined as HRCAs by the Revised International Staging System (R-ISS) [4][5][6].1q21 + is not considered an HRCA in the R-ISS, which is extensively used as a standard risk-stratification system in MM [4].However, 1q21 + is one of the most common recurrent cytogenetic abnormalities (CAs) in patients with MM, with an incidence of approximately 40-50% at diagnosis and up to nearly 70% at disease relapse [7][8][9].The search for potential genetic drivers on chromosome 1q has identified many candidates.One of them is cyclin kinase subunit 1B (CKS1B), which activates both MEK/ERK and JAK/STAT3 signaling pathways and promotes the proliferation of myeloma cells and tumor progression [9].MCL-1 and ADAR1 have been identified as potentially important genes located at 1q21, and their overexpression in MM patients apparently leads to abnormal cell proliferation [10,11].The exact driving gene on 1q21 is still unknown.Before the widespread use of IMiDs and PI-based induction therapies, 1q21 + was identified as a prognostic factor associated with early death in the IFM99-02 and IFM99-04 trials [12].One study evaluated the impact of 1q21 + in patients treated with lenalidomide, bortezomib and dexamethasone and found that those with 1q21 + had worse PFS and OS than those without 1q21 + [13].One meta-analysis evaluated the prognostic value of gain (1q) (3 copies) and amp (1q) (≥4 copies) in 2,596 patients with newly diagnosed MM from three phase III trials (GMMG HD4, GMMG MM5 and Myeloma XI) [14].The study found that both gain (1q) and amp (1q) were associated with shorter PFS and OS, and no statistically significant difference in survival existed between the two copy numbers [14].Until recently, the European Myeloma Network developed a new robust risk-stratification system, R2-ISS, taking 1q21 + into account as a high-risk variable [15].However, the prognostic value of 1q21 + in MM is largely debated.A main argument focuses on whether 1q21 + itself is a driver of poor prognosis or merely occurs as a byproduct of genetic instability [13].To better understand the clinical features and survival outcomes of patients with MM carrying 1q21+, we conducted a retrospective investigation in our single center.

Patients
A total of 474 consecutive patients with NDMM who were treated in our hospital between January 2010 and January 2022 and had available cytogenetic results detected by FISH were included in this retrospective study.All information related to demographic and clinical characteristics and laboratory tests was collected and assembled through our database of electronic medical records.The diagnostic criteria for MM were according to the International Myeloma Working Group [16].All patients received 4-6 courses of induction therapy containing at least an immunomodulatory drug (thalidomide and lenalidomide) and/or a proteasome inhibitor (bortezomib).When patients achieved an optimal therapeutic effect, patients started on maintenance therapy using IMiDs or PIs until disease progression or intolerance of drug toxicity.The study complied with the Helsinki Declaration of the World Medical Association and was approved by the ethics committee of Shanghai Jing'an District Zhabei Central Hospital (ZBLL2022011204).Because of the retrospective nature of the study, the requirement for patient consent for inclusion was waived.

Statistical analysis
The chi-squared test was used to compare categorical clinical features and cytogenetic aberrations between groups.PFS was defined as the period from the diagnosis of MM to the first disease progression or death from any reason.OS was defined as the duration from the initiation of diagnosis to death from any cause.The Kaplan-Meier method was applied to plot the survival curves using the log-rank test to assess the differences between groups.Multivariate Cox proportional hazard regression was performed to evaluate the prognostic value of the factors.We used SPSS version 22.0 (SPSS, Inc.) for all statistical analyses.Statistical significance was defined as a P value < 0.05.

Discussion
This study was an unselected retrospective analysis of patients with NDMM in our single center.Del(17p), t (4;14), and t(14;16) are thought to be HRCAs by international consensus [4].Furthermore, elevated LDH and ISS-III are also predictors associated with poor survival outcomes in MM.Only recently 1q21 + has been identified as a poor prognostic factor under R2-ISS to adapt to the constantly improved therapies in MM.The frequency of 1q21 + gradually increases as the disease runs its course from smoldering MM to symptomatic MM and then to relapse refractory MM [7,9,18].Several studies have found that 1q21 + has an unfavorable impact on the survival of patients with MM.Meanwhile, studies also demonstrate that 1q21 + is associated with higher frequency of the IgA subtype and advanced ISS/R-ISS stage and more often coexists with additional cytogenetic abnormalities, especially del(13q) or monosomy and del(17p) [18,19].Some scholars think that the predictive value of 1q21 + in MM is dependent on the concurrent HRCAs [8,18].One study indicated that 1q21 + alone, in the absence of other cytogenetic aberrations, showed similar survival outcomes to patients without HRCAs [20].Consequently, there remains a debate as to whether 1q21 + itself is a driver factor resulting in worse survival or merely co-occurs as a byproduct of other pathogenic factors [13].In our study, patients with 1q21 + had worse PFS and OS than those without 1q21, and 1q21 + was an independent prognostic factor associated with poor survival in multivariate Cox regression.Subgroup analyses indicated that 1q21 + was more prone to be accompanied by del(13q).Patients with 1q21 + del(13q) double-abnormality had both shorter PFS and OS than patients with no FISH abnormalities as seen in one study [19], and patients with 1q21 + del(13q) double-abnormality or 1q21 + del(13q) multiple-abnormality both showed poor survival outcomes.Although no significant difference was seen between OS curves for patients with no FISH abnormalities and 1q21 + single-abnormality/del(13q) singleabnormality, the groups of no FISH abnormalities and the 1q21 + single-abnormality curves were obviously separated after 40 months, and the del(13q) singleabnormality curve completely overlapped with the no FISH abnormalities curve.The results indicated that 1q21 + del(13q) double-abnormality was associated with poor disease outcomes and that 1q21 + may play a greater role in the disease process than del (13q).According to the results of our study, it is  reasonable to consider more intensive treatments and exploration of innovative agents with different mechanisms for such patients with 1q21+, especially for those with 1q21 + del(13q) double/multiple-abnormality, who should be strongly encouraged to participate in clinical trials.
As seen in some studies [8,14,21], our study also found that 1q21 + was more likely to coexist with specific negative clinical features: stage ISS-II/III, elevated LDH and more serious anemia.In addition, the subtypes of IgA, IgD, and λ-light chain were more common in patients with 1q21 + .The close relationships between 1q21 + and these clinical characteristics have been less investigated and need to be further explored in the future.
However, retrospective studies inevitably have limitations.First, the patients included in our investigation were all Chinese from a single center, and the results indicate patient selection bias and should be further evaluated in other populations.Second, the sample size of the patients was small, which limits more detailed subgroup analyses.Third, very few patients underwent ASCT, and our conclusion is more representative of patients who do not undergo transplantation.
In conclusion, 1q21 + in MM patients was more frequently accompanied by del(13q) and specific negative clinical features, and it was an independent prognostic indicator associated with poor survival outcomes.1q21 + alters MM disease biology, and, thus, patients with MM harboring 1q21 + have poorer clinical features of the disease.

Figure 1 .
Figure 1.PFS and OS based on 1q21 + or not.(A) PFS and (B) OS between patients with 1q21 + and non-1q21+.

Figure 2 .
Figure 2. Survival analysis according to 1q21 + or not in patients treated with IMiDs-based or PIs-based therapeutic regimens as first-line treatments.(A) PFS and (B) OS in patients receiving IMiDs-based therapeutic regimens.(C) PFS and (D) OS in patients receiving PIs-based therapeutic regimens.

Table 1 .
Baseline characteristics between patients with or without 1q21+.

Table 2 .
Multivariate analysis of variables associated with patient outcomes.