Impact of 1q gain/amplification in multiple myeloma patients treated with daratumumab-based regimens: A retrospective single-center study

Abstract INTRODUCTION Gain/amplification of chromosome arm 1q (+1q) is among the most frequent cytogenetic abnormalities (CAs) in multiple myeloma (MM), now widely recognized as a marker of poor prognosis and included in modern risk stratification systems. The introduction of anti-CD38 monoclonal antibodies (moAbs), particularly daratumumab, has significantly improved outcomes and reshaped the MM treatment landscape. However, data on patients with +1q treated with daratumumab-based regimens remain limited. Pivotal trials often did not report outcomes for this subgroup, and existing evidence - largely from small real-world series or post-hoc analyses - has been conflicting. We conducted a retrospective single-center study to assess the prognostic impact of +1q in a large cohort of daratumumab-treated MM patients. Progression-free survival (PFS) from daratumumab initiation was the primary endpoint. METHODS We included all MM patients treated with daratumumab-based regimens at our center in Reggio Emilia, Italy, from May 2018 to December 2023. Clinical data were extracted from electronic medical records. CAs were assessed by interphase FISH. Time-to-event outcomes were analyzed using Kaplan-Meier estimates and log-rank tests. Multivariate analyses for PFS, time to next treatment (TTNT) and overall survival (OS) were conducted using Cox proportional hazards models. Analyses were performed in Python 3.11.2. The study was approved by the local Ethics Committee. RESULTS A total of 174 patients were included. Median age was 72.0 years; 31% had renal impairment (CrCl <60 mL/min), 20% had ISS stage 3, and 11.5% had at least one high-risk (HiR) clinical feature (e.g., extramedullary disease, secondary plasma cell leukemia, or circulating plasma cells <5%). The median line of daratumumab administration was 2 (range 1–4); 46% of patients received it as first- and 42% as second-line therapy. Most patients (71.8%, n=125) received daratumumab-lenalidomide-dexamethasone (DaraRd). Cytogenetic data were available for 92 patients (52.9%): 18 had isolated +1q, 20 had +1q plus ≥1 HiR CAs (+1q+HiRCAs), 11 had non-1q HiRCAs, and 43 had standard-risk (SR) disease. After a median follow-up of 30.7 months, patients with isolated +1q had significantly shorter PFS than SR patients (28.1 vs 66.8 mo; HR 4.77, 95% CI 1.68–13.53). The poorest outcomes were observed in non-1q HiRCA (24.8 mo; HR 6.29, 95% CI 2.10–18.88) and +1q+HiRCA patients (20.3 mo; HR 7.67, 95% CI 2.84–20.72). TTNT was also significantly shorter in isolated +1q vs SR patients (35.6 vs 67.4 mo; HR 3.83, 95% CI 1.33–11.09), while OS showed only a non-significant trend (NR vs NR; HR 2.69, 95% CI 0.72–10.01). +1q+HiRCA patients had the worst TTNT and OS (TTNT: HR 5.81, 95% CI 2.09–16.16; OS: HR 6.03, 95% CI 1.78–20.27). Multivariate analysis confirmed isolated +1q as an independent predictor of inferior PFS (HR 4.56, 95% CI 1.61–12.95) and TTNT (HR 3.64, 95% CI 1.26–10.55), with a non-significant trend for OS (HR 2.62, 95% CI 0.70–9.79). +1q+HiRCA conferred the highest risk across all endpoints (PFS: HR 8.36, 95% CI 3.08–22.70; TTNT: HR 6.37, 95% CI 2.28–17.82; OS: HR 6.18, 95% CI 1.84–20.79). Similar findings emerged in the DaraRd subgroup. Compared to SR, patients with isolated +1q had inferior PFS (28.2 vs 66.7 mo; HR 8.26, 95% CI 2.14–31.87) and TTNT (HR 5.84, 95% CI 1.50–22.75), with a trend for OS (HR 3.75, 95% CI 0.69–20.49). Again, the worst outcomes were seen in non-1q HiRCA and +1q+HiRCA subgroups. Multivariate analysis confirmed isolated +1q as an independent adverse factor for PFS (HR 8.20, 95% CI 2.12–31.66) and TTNT (HR 5.77, 95% CI 1.48–22.46), with a non-significant trend for OS (HR 3.75, 95% CI 0.69–20.50). +1q+HiRCA retained the strongest impact across all endpoints (PFS: HR 11.50, 95% CI 3.03–43.60; TTNT: HR 7.28, 95% CI 1.86–28.51; OS: HR 7.59, 95% CI 1.51–38.02). Notably, while daratumumab administration in later lines (≥2) was associated with inferior PFS and TTNT in the overall cohort, this effect was not observed in DaraRd-treated patients. CONCLUSION Our findings highlight the role of +1q as an independent factor of adverse prognosis in daratumumab-treated MM patients, with further outcome deterioration when associated with other HiRCAs.