Impact of 1q vulnerabilities in patients treated with anti-CD38 monoclonal antibodies

Multiple myeloma (MM) is a genetically heterogeneous malignancy in which cytogenetic abnormalities, including gain or amplification of chromosome 1q (+1q), have been associated with adverse outcomes. We conducted a retrospective single-center study evaluating the impact of 1q alterations in MM patients treated with anti-CD38 monoclonal antibodies (daratumumab or isatuximab) between 2015 and 2024. Fluorescence <i>in situ</i> hybridization was performed to detect 1q gain or amplification and other high-risk cytogenetic abnormalities. A total of 149 patients were analyzed, with 115 receiving daratumumab and 34 isatuximab. In the daratumumab cohort, 51.3% harbored 1q alterations, with comparable baseline characteristics across groups. Patients with 1q alterations showed a lower rate of MRD negativity (20.3% vs 39.3%; p = 0.04) and a trend toward shorter PFS (26.3 vs 43.4 months; p = 0.05), while OS was similar overall (61.2 vs 68.7 months; p = 0.24), although 1q amplification was associated with poorer OS (42 vs 74 months; p = 0.029). These findings were not confirmed in multivariate analysis, where the line of anti-CD38 therapy emerged as the main variable significantly associated with both PFS and OS. In the isatuximab-treated group, 41% exhibited 1q alterations, with no significant differences in response rates, MRD negativity (28.6% vs 55%; p = 0.171), PFS (56.9 vs 58.2 months; p = 0.67), or OS (median not reached in either group; p = 0.27). The small sample size and low number of events precluded meaningful multivariate analysis. Overall, our findings suggest that 1q alterations are not independent prognostic factors in MM patients treated with anti-CD38 antibodies. The poorer outcomes observed in univariate analyses among daratumumab-treated patients with 1q alterations likely reflect a more advanced disease profile, including later lines of therapy and greater underlying disease risk, rather than the isolated effect of 1q alterations themselves. Comprehensive cytogenetic profiling and achieving MRD negativity remain critical for risk stratification and optimizing therapeutic strategies in MM patients receiving anti-CD38 therapies.