Systemic immunoglobulin light-chain (AL) amyloidosis is a rare plasma cell disorder caused by a clone producing unstable misfolded light chains that form amyloid fibrils, causing organ damage, mostly in kidneys and heart. The disease is progressive and early treatment is crucial to prevent irreversible injury. In January 2021, based on the ANDROMEDA trial, the anti-CD38 antibody Daratumumab combined with the CyBorD regimen (bortezomib/cyclophosphamide/dexamethasone) became the new up-front standard of care for AL amyloidosis. Few real-world studies assessed Daratumumab alone or with bortezomib or lenalidomide; however, data on its combination with CyBorD outside clinical trials remain limited. The “CyBor_Dq trial” was designed to retro- and prospectively evaluate the efficacy and safety of Daratumumab-CyBorD in newly diagnosed Italian AL amyloidosis patients. We present data from the first interim analysis.

A multicenter observational study across multiple haematology Italian Centers started in June 2024. Eligible patients had biopsy-confirmed systemic AL amyloidosis, with deposits verified by immunohistochemistry and/or immune-electron microscopy. All patients received “CyBor_Dq” regimen upfront (subcutaneous bortezomib 1.3 mg/m², cyclophosphamide 300 mg/m² orally or IV, and dexamethasone 40 mg orally or IV weekly for six 28-day cycles, plus subcutaneous Daratumumab 1800 mg—weekly in cycles 1-2, every two weeks in cycles 3-6, then monthly up to 24 cycles or progression—in a real-world setting). Hematological responses were assessed at 3 and 6 months; cardiac and renal responses at 6 months post treatment initiation. Responses followed consensus criteria: Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), with cardiac and renal response (International Society of Amyloidosis criteria). Age, sex, Charlson comorbidity index, fluorescence in situ hybridization (FISH) abnormalities, European modification of the Mayo 2004 staging system, NYHA functional class, and creatinine clearance were also recorded as baseline variables. Hematologic and non-hematologic adverse events were also monitored. Logistic regression was used for associations; p<0.05 was significant.

Between June 2024 to June 2025, 117 patients were enrolled at 22 Italian Centers. Up to July 2025, data were available from 95 patients showing a median age of 64 years, with a prevalence of lambda chain isotype (77%). Cardiac involvement was seen in 39 (41%) patients; of them, 12 (12.6%) were IIIa and 7 (7.4%) IIIb stage. Kidney involvement was seen in 54 patients (56.8%). A total of 35 patients (36.8%) had both cardiac and renal injury, while 6 patients (6.3%) having 3 or more organs involved. FISH was available in 43 (45%) subjects of whom 21 (48.8%) harbored the t(11;14). The overall hematologic response rate (ORR) was 91.4% with 27 (32.9%) patients obtaining a VGPR, 3 (3.7%) a PR and 45 (54.8%) a CR. Overall, 44.4% achieved hematologic response within 6 months. At 6 months, renal response was observed in 14 of 36 evaluable patients (38.8%) and cardiac response in 16 of 39 patients (41%). None of the classical baseline variables was significantly associated with hematological, cardiac, or renal response. As of today, no serious adverse events (AE) were reported and the most commonly treatment-associated symptoms (diarrhoea, fatigue, peripheral edema, anemia, constipation, dyspnea, thrombocytopenia, worsening of renal function) were reported in <7% of patients. No AE resulted in permanent treatment discontinuation.

To our knowledge, the present study describes one of the largest RW cohort of newly diagnosed AL amyloidosis patients treated with Daratumumab-CyborD. The study population reflects the clinical heterogeneity of real-life patients, including those with severe cardiovascular conditions and/or critical renal impairment, who would not have met the inclusion criteria of the “ANDROMEDA” trial. Nevertheless, this interim evidence confirms “CyBor_Dq” as an effective and manageable frontline treatment for AL amyloidosis, resembling results of the “ANDROMEDA” trial. The challenge is to find early predictors of treatment response and improve patient outcomes. Additional follow-up data are needed to confirm these initial results and guide the development of future personalized treatment approaches.

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2025
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