The choice of first-line therapy is exceptionally challenging when multiple myeloma is associated with advanced renal failure. In this issue of Med, Xiao and colleagues report on results from a randomized phase 2 study[1] indicating that the pomalidomide, bortezomib, and dexamethasone triplet leads to better myeloma disease control, thereby increasing renal function after four cycles.

Advances in the treatment of thalassaemia have led to major improvements in survival and quality of life over the past 30 years. In addition to developments in stem-cell transplantation, transfusion safety, iron overload monitoring, and iron-chelation therapy, novel disease-modifying and gene therapies are also emerging. However, substantial disparities in access to specialised care and novel therapies persist, particularly in low-income and middle-income countries, where most people with thalassaemia reside. This Series paper explores complementary strategies aimed at improving global thalassaemia outcomes beyond conventional therapeutic innovation. We discuss the emerging role of repurposed low-cost therapies, particularly hydroxyurea and thalidomide, as disease-modifying options in resource-limited settings. We further examine opportunities to democratise access to curative gene therapies through technological developments, decentralised manufacturing, regional collaborations, and simplified treatment platforms. In addition, the rapidly expanding role of artificial intelligence in screening, diagnosis, prediction of complications, and remote care delivery is reviewed. Finally, we highlight the importance of international collaborations, multidisciplinary training, and research networks in strengthening equitable global thalassaemia care.

The degradation efficiency of a PROTAC(?)bivalent compounds that link together a ligand for a protein of interest with a ligand for an E3 ligase(?)is governed, in part, by the length and flexibility of its linker ("linkerology"), as well as the accessibility of ubiquitinatable surface lysines. Based on the prior serendipitous discovery of the cyclin-dependent kinase 9 (CDK9)-selective PROTAC degrader "THAL-SNS-032", developed from the multi-CDK2/CDK7/CDK9 inhibitor SNS-032, we speculated that other multi-CDK inhibitors might likewise be transformed into CDK9-selective PROTACs, establishing a "linkerology" platform approach to enhancing CDK family member specificity (and beyond). We tested this hypothesis using AT7519, a multi-CDK2/CDK5/CDK9 inhibitor, and employing cereblon as the targeted E3 ligase. Accordingly, we built candidate PROTACs by linking AT7519 to one of two thalidomide derivatives; those molecules in which AT7519 and the thalidomide derivative were coupled via rigid linkers caused greater degradation of the CDK9 protein than those with more flexible linkers. Western blotting of human acute myeloid leukemia (AML) cells treated with AMC-3-221, our most CDK9-selective PROTAC, resulted in almost-complete reduction of the CDK9 protein, with no detectable degradation of CDK1, CDK2, or CDK5, and minimal degradation of CDK4 and CDK6, corroborated by global proteomics analysis. Subtle shortening or lengthening of AMC-3-221's rigid linker altered the CDK degradation selectivity profile, suggesting that continued linker variation may further enhance selectivity. Molecular modeling provided insight into the observed selectivity through the analyses of ternary complex stabilities. AMC-3-221 treatment rapidly decreased RNA and protein levels of oncogenic downstream targets of CDK9(?)MCL-1 and c-/N-MYC(?)and potently inhibited human AML and other types of human cancer cell lines, with less inhibition of a non-transformed cell line, via an on-target mechanism of apoptosis. AMC-3-221's CDK9 degradation potency (DC50 < 10 nM) approximated its antileukemic inhibitory potency (IC50 < 50 nM). The maximum tolerated dose in mice of AMC-3-221 was higher than that of another PROTAC, AMC-3-225, consistent with AMC-3-221's more selective CDK degradation profile. In summary, we demonstrate that converting a multi-CDK inhibitor into a PROTAC with selectivity for CDK9 over other family members is not an isolated phenomenon. Our findings further support the concept that PROTAC linkerology may serve as a platform for enhancing kinase selectivity.

Langerhans cell histiocytosis (LCH) is a rare clonal proliferative disorder that frequently mimics common inflammatory dermatoses, often resulting in delayed diagnosis. We report a highly deceptive clinical presentation. A 36-year-old man presented with a five-year history of painful, refractory ulcerated plaques on his bilateral groins. Previous empirical therapies failed completely. A targeted skin biopsy eventually revealed classic atypical Langerhans cells with reniform nuclei, demonstrating striking immunohistochemical positivity for CD1a and CD207. Comprehensive systemic investigations confirmed isolated cutaneous involvement. Although subsequent trials of systemic agents-including thalidomide, methotrexate, and upadacitinib-were poorly tolerated and offered limited benefit, surgical excision ultimately achieved complete resolution. The patient has not presented recurrence at 18-month follow-up. This case highlights the critical necessity of an early biopsy for chronic intertriginous ulcers. Furthermore, it demonstrates that surgical management serves as a safe and durable definitive strategy for recalcitrant, localized cutaneous LCH.

Despite substantial improvements in survival over recent decades, multiple myeloma (MM) remains largely incurable, and most patients ultimately experience relapsed or refractory disease, highlighting the need for novel therapeutic strategies. Immunomodulatory drugs (IMiDs) have transformed MM treatment through direct antitumor and immune-enhancing effects mediated by cereblon modulation, while their ability to stimulate T-cell and NK-cell function has provided a strong rationale for combination with modern immunotherapies, including bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapies. More recently, cereblon E3 ligase modulators (CELMoDs), such as iberdomide and mezigdomide, have emerged as next-generation cereblon-targeting agents with enhanced potency, deeper substrate degradation, and activity in lenalidomide- and pomalidomide-resistant settings. Clinical studies have demonstrated promising efficacy and manageable safety profiles across newly diagnosed and relapsed/refractory MM, including in heavily pretreated patients. In parallel, novel degraders such as cemsidomide have shown encouraging preliminary activity, further expanding the therapeutic potential of cereblon-directed approaches in MM. In this review, we aim to summarize the evolution of oral therapies in MM, focusing on the efficacy and safety of next-generation cereblon modulators and emerging cereblon-directed degraders.

Background/Objectives: RELA encodes the p65 subunit of NF-κB and plays a critical role in immune regulation, epithelial protection, and anti-apoptotic signaling. Pathogenic RELA variants cause monogenic immune dysregulation with heterogeneous clinical manifestations. However, genotype-phenotype relationships and optimal treatment strategies remain incompletely defined. Methods: We conducted a comprehensive literature-based analysis of reported individuals with RELA variants and additionally described a family carrying a RELA c.706C>T (p.R236*) variant, including a clinically affected proband and his variant-positive father with isolated vitiligo. Clinical, immunological, genetic, endoscopic, and therapeutic data were extracted and summarized using a module-based phenotypic framework. Exploratory analyses were performed to examine potential genotype-phenotype patterns and reported treatment responses. Results: A total of 72 individuals with RELA variants, including the proband and his variant-positive father from the present family, were analyzed. RELA-associated disease exhibited marked clinical heterogeneity, encompassing mucocutaneous, systemic inflammatory, autoimmune, gastrointestinal, hematologic, allergic/eosinophilic, and infection-related manifestations. Exploratory analyses suggested that truncating or splice-site variants were more frequently observed among individuals with mucocutaneous lesions, whereas missense variants appeared to be more common among those with autoimmune manifestations. Tumor necrosis factor (TNF) inhibitors were among the therapies associated with favorable reported responses. In the present family, the proband presented with early-onset Behçet-like intestinal inflammation and achieved clinical and endoscopic remission after thalidomide and dose-escalated infliximab treatment. Conclusions: This study expands the clinical spectrum of RELA-associated disease and highlights preliminary variant-related clinical patterns that require confirmation in larger independent cohorts. The available treatment experience suggests that TNF blockade may be considered as a therapeutic option in selected patients, although comparative efficacy cannot be established from the available data.

Pain and inflammation are protective responses; however, when persistent, they can cause damage and reduce the quality of life. The limitations of current therapies underscore the importance of investigating new agents that are effective and have fewer adverse effects. Therefore, the present study aimed to evaluate the anti-inflammatory and antinociceptive activities of LASSBio-753 in rats. The animals were pretreated with LASSBio-753 at doses of 0.1, 1.0, and 10 mg/kg, p.o., and subjected to carrageenan-induced paw edema to determine the optimal dose for combating inflammation caused by this agent. Subsequently, paw edema was induced using inflammatory mediators: histamine, compound 48/80, serotonin, prostaglandin E2, and bradykinin. Carrageenan-induced peritonitis was induced to assess neutrophil migration, as well as the levels of TNF-α, IL-1β, myeloperoxidase, malondialdehyde, and glutathione in the peritoneal fluid. Acetic acid-induced abdominal writhing and formalin-induced paw licking were used to evaluate antinociceptive activity. The 10 mg/kg dose of LASSBio-753 demonstrated the best anti-inflammatory and antinociceptive effects, reducing carrageenan-induced edema and edema induced by inflammatory mediators, as well as reducing neutrophil migration, TNF-α and IL-1β, myeloperoxidase, and malondialdehyde, while preserving glutathione in the peritoneal fluid. In addition, it reduced the number of abdominal contractions and the duration of paw licking that were chemically induced. The results obtained demonstrate that LASSBio-753 possesses significant anti-inflammatory and antinociceptive potential and may be a promising candidate for the treatment of inflammatory diseases; however, studies in inflammatory disease models are needed to better elucidate its therapeutic potential.

Background Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant, multisystem vascular disorder characterized by mucocutaneous telangiectasias and visceral arteriovenous malformations (AVMs). Pathogenic variants in ENG (endoglin), ACVRL1 (activin receptor-like kinase 1, ALK1), and SMAD4 (SMAD family member 4) disrupt signaling in the bone morphogenetic protein (BMP) 9/10 and transforming growth factor-beta (TGF-β) pathways, resulting in dysregulated angiogenesis and excess vascular endothelial growth factor (VEGF) activity. Clinically, HHT most commonly presents with recurrent epistaxis and chronic gastrointestinal (GI) bleeding, frequently leading to iron deficiency anemia and reduced quality of life (QoL). Complications from visceral AVMs involving the lungs, brain, and liver may also occur. Early diagnosis and systematic screening are essential to reduce preventable morbidity. Methods This narrative review synthesizes current primary literature on the diagnosis, screening, and treatment of HHT, with particular emphasis on evolving systemic therapies, supportive care strategies, and procedural interventions. Evidence from international guidelines, randomized trials, observational cohort studies, and narrowly focused systematic reviews was evaluated to summarize contemporary management approaches. Results HHT diagnosis is made with the Curaçao clinical criteria, genetic testing, and targeted imaging to identify visceral vascular malformations. Screening recommendations emphasize early detection of pulmonary and cerebral AVMs and ongoing surveillance for anemia and other complications. Therapeutic strategies increasingly prioritize systemic therapy over repeated local procedures. Antiangiogenic agents including intravenous bevacizumab, pomalidomide, thalidomide, and oral pazopanib have demonstrated efficacy in reducing bleeding severity, improving hemoglobin levels, and decreasing transfusion requirements in moderate-to-severe disease. Supportive care remains foundational and includes iron replacement, selective blood transfusion, routine monitoring, and assessment of patient-reported QoL. In patients with refractory epistaxis, surgical interventions such as septodermoplasty or nasal closure may provide durable bleeding control. Endovascular and neurosurgical management may also be required for selected vascular complications. Conclusions Management of HHT is undergoing a paradigm shift toward mechanism-based systemic therapy integrated with multidisciplinary care. Advances in antiangiogenic and precision-medicine approaches are improving bleeding control and long-term outcomes. Early recognition, comprehensive screening, individualized therapy, and coordinated management across specialties are critical for optimizing care in this complex multisystem disease.