Over the past decades, therapeutic advances have significantly improved survival outcomes in patients with Multiple Myeloma (MM); however, the high biological heterogeneity and genetic complexity remain major challenges in disease management (1, 2). In this context, genetic alterations have gained relevance due to both their high prevalence and prognostic impact.

Among genetic alterations, gain or amplification of the long arm of chromosome 1 (+1q), is one of the most frequent and has consistently been associated with inferior outcomes. The presence of +1q is defined by the acquisition of additional copies of genetic material on chromosome 1q by malignant plasma cells and may occur as whole-arm trisomy or by partial duplications, mostly including the 1q21 region (3). It is important to distinguish between “gain 1q”, defined as one additional copy (three total copies), and “amplification 1q, “ defined as two or more additional copies (four or more total copies) (4). The prevalence of +1q increases across the MM spectrum: it is reported in approximately 17-23% of patients with monoclonal gammopathy of undetermined significance (MGUS), 28-49% of newly diagnosed multiple myeloma (NDMM) patients, and up to 42-80% of relapsed/refractory multiple myeloma (RRMM) cases (4, 5). Studies have shown that the acquisition of +1q is a driver event in MM pathogenesis, but it is also the most common secondary cytogenomic abnormality described during disease progression. This could be explained by the presence of several notable genes located at 1q21, the most frequently implicated region, such as CKS1B, PSMD4, BCL9 and MCL1 (3). Numerous studies have associated +1q with the activation of various genes involved in MM development and cell proliferation. Some of these genes are associated with immune evasion mechanisms, such as the regulation of the complement system. Specifically, overexpression of complement-inhibitory proteins and reduced CD38 expression on the surface of myeloma cells, often driven by 1q alterations, have been associated with resistance to anti-CD38 monoclonal antibodies (4). Furthermore, the extent of 1q gain or amplification and the clonal proportion of cells carrying this alteration correlate with greater disease aggressiveness and suboptimal response to conventional therapies (4, 6).

The current prognostic model for MM incorporates several cytogenetic markers, including deletion of chromosome 17p and the t(4;14) and t(14;16) translocations, which have traditionally been considered high-risk. Recently, 1q gain/amplification has been recognized as another significant adverse factor. In this regard, +1q has emerged as a risk marker, as its presence is associated with shorter progression-free survival (PFS) and, in many cases, reduced overall survival (OS) (7). Its inclusion in staging systems such as the second revision of the International Staging System (R2−ISS) underscores the importance of this alteration for risk stratification and therapeutic decision-making (8). However, the prognostic relevance of +1q appears to be modulated by the presence of co-occurring high-risk features rather than acting as an isolated determinant of outcome (9).

In the current therapeutic landscape, anti-CD38 monoclonal antibodies have become a cornerstone of modern MM therapy. Currently, two anti-CD38 monoclonal antibodies, daratumumab, a fully human IgG1 monoclonal antibody, and isatuximab, a humanized chimeric anti-CD38, are approved and widely used in clinical practice.

Direct comparative evidence between daratumumab and isatuximab in patients with 1q alterations is limited. Nevertheless, some studies have suggested that isatuximab may be more effective in this subgroup, possibly due to its mechanism of action, which relies on antibody-dependent cytotoxicity and other immunomodulatory mechanisms, potentially resulting in a more consistent response in patients with 1q abnormalities. By contrast, daratumumab exerts its activity primarily via complement-dependent cytotoxicity, and for this reason it has been suggested that it may be less effective in this patient subgroup (4).

In retrospective studies and post hoc analyses, the addition of daratumumab to standard regimens has been shown to improve PFS in patients with +1q. However, the magnitude of this benefit may be attenuated in cases involving additional 1q copies or other high-risk cytogenetic abnormalities (10). For instance, some analyses have shown that while patients with gain 1q demonstrate improvement, those with amplification may experience a less favorable response, suggesting that the extent of the alteration has both prognostic and therapeutic implications (3). On the other hand, preliminary data with isatuximab have shown promising results in terms of response and survival in the RRMM setting, even in subgroups with +1q, raising the hypothesis that its mechanism of action may counteract, at least partially, the adverse effects of this alteration (4).

Our aim was to evaluate the impact of 1q gain or amplification in multiple myeloma patients treated with anti-CD38 monoclonal antibodies in a real-life cohort of patients treated in a third level center.

In our study, in the daratumumab-treated cohort, patients with 1q gain or amplification showed a trend towards a shorter PFS and patients with 1q amplification presented with a shorter OS, consistent with the concept that amplification reflects a more advanced cytogenetic event. These differences were not evident in the isatuximab-treated group, suggesting that the adverse prognostic impact of 1q alterations may be less pronounced in this cohort, a finding consistent with previous reports (13). However, once additional risk markers were considered in the multivariate analysis in daratumumab group, the isolated prognostic impact of 1q alterations was largely abrogated. This finding implies that the inferior outcomes observed in some daratumumab-treated patients are likely due to the cumulative burden of adverse cytogenetic events and other high-risk factors rather than the effect of +1q alone.

In our cohort, patients with 1q gain or amplification, although generally comparable to the general cohort, also presented with other high‐risk features like deletion of 17p, t(4;14), and higher ISS‐R scores in general, though statistically significant differences were noted only for t(4;14), which was present in a very low number of patients (11.3% in daratumumab group and 23.5% in isatuximab group). These additional abnormalities have been associated with shorter PFS and reduced OS in previous studies (5), although when evaluated together in our multivariate analysis, none reached statistical significance as independent factors.

Moreover, as outlined in the introduction, the extent of 1q gain or amplification and the clonal proportion of cells carrying this alteration may correlate with greater disease aggressiveness and suboptimal response to conventional therapies (4, 6). This suggests that patients with 1q amplification, rather than simple gain, may have a worse prognosis, reflecting a more advanced acquired cytogenetic alteration. This trend was observed in the univariate analysis of our daratumumab cohort, where patients with 1q amplification had poorer overall survival, a pattern not seen in patients with 1q gain alone. Additionally, MRD negativity was less frequently achieved in patients with 1q amplification, whereas in those with 1q gain, response rates were like the overall cohort.

Importantly, in an exploratory analysis, MRD negativity emerged as a robust prognostic marker, showing a strong association with both PFS and OS in daratumumab-treated patients. These findings support the role of MRD as a powerful indicator of treatment benefit in MM (14).

In daratumumab-treated patients, multivariate analysis showed that 1q status (including both gain and amplification) was not confirmed as an independent prognostic factor. In contrast, the line of treatment in which patients received daratumumab had a strong and significant impact on both PFS and OS. Additionally, the presence of extramedullary disease demonstrated a trend toward shorter overall survival, although this did not reach statistical significance. These results suggest that the differences observed in the univariate analysis (including a trend toward shorter PFS in +1q patients) may reflect a more advanced disease state with a higher-risk profile, including the presence of greater cumulative cytogenetic burden and later line of treatment.

This observation highlights the importance of evaluating the complete cytogenetic profile rather than focusing on a single alteration. It is plausible that the overall genetic complexity, rather than the presence of a solitary 1q gain or amplification, underlies the reduced efficacy of daratumumab in certain subgroups of MM. In support of this notion, other studies have demonstrated that the intensity of the adverse prognostic impact increases with the number of high-risk alterations present, suggesting a cumulative effect rather than a singular driver (3, 8).

In summary, it has been suggested that the high risk associated with +1q could be mitigated with the use of isatuximab instead of daratumumab. However, our analysis suggests that the less favorable outcomes observed among patients receiving daratumumab are not driven by 1q alterations alone, but by the cumulative burden of additional high-risk cytogenetic abnormalities.

While our study contributes to the growing body of evidence that the adverse impact on outcomes in daratumumab-treated MM patients is more complex than the presence of +1q alone, further research is warranted. Prospective randomized trials that include detailed cytogenetic analyses will be pivotal to validate these findings.

Emerging technologies such as next-generation sequencing and single-cell analysis may offer deeper insights into the clonal evolution of MM and help refine our understanding of how multiple high-risk events interact to influence therapeutic efficacy.

The main limitations of this study include its retrospective design, the heterogeneous patient population, and the relatively small sample size, which may limit the generalizability of the findings and the statistical power to detect certain associations.

In summary, while +1q alterations are associated with adverse outcomes in MM, our findings strongly suggest that the less favorable outcomes observed in some daratumumab-treated patients are not driven solely by the presence of 1q gain or amplification, but rather by a higher-risk profile, including greater cumulative cytogenetic burden and later line of treatment. Consequently, comprehensive cytogenetic evaluation is essential for risk stratification and therapy selection, and future studies should focus on stratifying patients based on the entire spectrum of high-risk genetic alterations to optimize the use of anti-CD38 monoclonal antibodies in MM and other novel therapies.