Lancet Haematology最新文献

β-thalassaemia is an inherited haemoglobinopathy characterised by ineffective erythropoiesis and chronic anaemia of varying severity, which is predominant in the region extending from the Mediterranean basin and Middle East towards southeast Asia. Patients with severe phenotypes require lifelong transfusions, iron overload monitoring, and chelation. Suboptimal management due to access challenges continues to be directly linked to increased morbidity and mortality in many regions. In the past few decades, an improved understanding of the underlying pathogenesis of β-thalassaemia has led to the development of several disease-modifying therapies and curative gene manipulation techniques. However, global disparities in access and the need for specialised expertise hinder their wide implementation, especially in resource-limited countries where more than 80% of patients live. Uncertainty about which biomarkers can predict patient response further complicates the selection of patients for treatment. Beyond the need for access programmes and pragmatic national health policies, patient prioritisation by treating physicians, informed by available evidence and expert opinion, is crucial for ensuring that a resource-cautious management approach is implemented. This Viewpoint provides a decision matrix to prioritise interventions by need, benefit, and risk in settings with inadequate access, and to identify alternatives when standard options are unavailable. It draws on the Thalassaemia International Federation guidelines, best available trial and real-world evidence, and expert consensus from virtual discussions among the authors (haematologists, bone marrow transplantation physicians, patient group representatives, translational scientists, and trialists).

Background: Iberdomide is an oral cereblon E3 ligase modulator with higher affinity to cereblon than immunomodulatory drugs, leading to improved direct anti-myeloma activity and enhanced immunostimulatory effects. We aimed to evaluate the safety and activity of iberdomide plus low-dose cyclophosphamide and dexamethasone (IberCd) in patients with relapsed and refractory multiple myeloma.

Methods: The ICON study is a prospective, single-arm, phase 2, open-label study conducted in eight hospitals in the Netherlands. We enrolled patients (aged ≥18 years) with relapsed and refractory multiple myeloma (lenalidomide-refractory) who had received two to four previous lines of therapy and had a WHO performance status of 0-2. Patients were treated with oral iberdomide (1·6 mg/day on days 1-21 of each 28-day cycle), oral low-dose cyclophosphamide (50 mg/day on days 1-28), and oral dexamethasone (40 mg [20 mg in patients age >75 years] once a week) until progression. All patients received thrombosis prophylaxis daily: 80 mg oral aspirin or 100 mg oral carbasalate calcium. Patients with a previous history of venous thromboembolism received only low molecular-weight heparin by subcutaneous injection. The primary endpoint was progression-free survival, defined as time from the start of treatment to the date of progression or death. Activity and safety were assessed in all patients who started treatment. This trial was registered at ClinicalTrials.gov (NCT04392037) and is ongoing.

Findings: Between Feb 17, 2021, and July 7, 2023, 61 patients were enrolled and received IberCd treatment (29 [48%] were female and 32 [52%] patients were male). The median number of previous lines of therapy was 3 (range 2-5); 52 (85%) patients were triple-class exposed and 27 (44%) had triple-class refractory disease. 50 patients discontinued study treatment, 39 of whom due to progressive disease, but all 61 patients were included in the main analysis population. After a median follow-up of 25·4 months (IQR 19·7-31·6), the median progression-free survival was 17·6 months (one-sided 95% CI 16·6-19·9). In all 61 patients, the most common grade 3-4 adverse events were neutropenia (34 [56%] patients) and infections (21 [34%] patients). Treatment-related serious adverse events were reported in 25 (41%) patients, with infections being the most common (34 [71%] of 48 serious adverse events). Treatment-related death occurred in one (2%) patient due to COVID-19.

Interpretation: IberCd is an all-oral and active combination for patients with relapsed and refractory multiple myeloma that showed clinically meaningful activity. This regimen offers a valuable treatment option for patients who have received two to four previous lines of therapy and compares favourably with other available treatments.

Funding: Bristol Myers Squibb.