Early intervention with daratumumab improves survival for patients with high-risk smouldering myeloma
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Daratumumab/lenalidomide/dexamethasone in transplant-ineligible newly diagnosed myeloma: MAIA long-term outcomes
In the MAIA study, daratumumab plus lenalidomide and dexamethasone (D-Rd) improved progression-free survival (PFS) and overall survival (OS) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). We report updated efficacy and safety from MAIA (median follow-up, 64.5 months), including a subgroup analysis by patient age (<70, ≥70 to <75, ≥75, and ≥80 years). Overall, 737 transplant-ineligible patients with NDMM were randomized 1:1 to D-Rd or Rd. The primary endpoint, PFS, was improved with D-Rd versus Rd (median, 61.9 vs 34.4 months; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.45–0.67; P < 0.0001). Median OS was not reached in the D-Rd group versus 65.5 months in the Rd group (HR, 0.66; 95% CI, 0.53–0.83; P = 0.0003); estimated 60-month OS rates were 66.6% and 53.6%, respectively. D-Rd achieved higher rates of complete response or better (≥CR; 51.1% vs 30.1%), minimal residual disease (MRD) negativity (32.1% vs 11.1%), and sustained MRD negativity (≥18 months: 16.8% vs 3.3%) versus Rd (all P < 0.0001). D-Rd demonstrated clinically meaningful efficacy benefits across age groups. No new safety concerns were observed. Updated results (median follow-up, >5 years) continue to support frontline use of D-Rd in transplant-ineligible patients with NDMM.
Enhancing children’s numeracy and executive functions via their explicit integration
Executive functions (EF) are crucial to regulating learning and are predictors of emerging mathematics. However, interventions that leverage EF to improve mathematics remain poorly understood. 193 four-year-olds (mean age = 3 years; 11 months pre-intervention; 111 female, 69% White) were assessed 5 months apart, with 103 children randomised to an integrated EF and mathematics intervention. Our pre-registered hypotheses proposed that the intervention would improve mathematics more than practice as usual. Multi-level modelling and network analyses were applied to the data. The intervention group improved more than the control group in overall numeracy, even when controlling for differences across settings in EF and mathematics-enhancing practices. EF and mathematics measures showed greater interconnectedness post-intervention. In addition, disadvantaged children in the intervention group made greater gains than in the control group. Our findings emphasise the need to consider EFs in their integration with co-developing functions, and in their educational and socio-economic context.
CD38 in the pathobiology of cutaneous T-cell lymphoma and the potential for combination therapeutic intervention
Cutaneous T-Cell Lymphoma (CTCL) is a non-Hodgkin’s lymphoma involving malignant skin-homing T-cells, characterized by variable severity and limited treatment options. Our study shows that patient samples and derived cell lines express CD38 on CTCL cells, and αCD38 antibodies effectively target CD38 in a mouse model. In vivo αCD38 antibody treatment led to the loss of CD38 expression in residual tumor cells, highlighting the need for innovative strategies to improve CTCL outcomes despite the CD38 loss in residual tumor cells. To investigate the role of CD38 in CTCL pathology, we used CRISPR-Cas9 to create CD38-deficient (CD38KO) CTCL cells. These CD38KO cells showed higher expression of oncogenes B-catenin, TCF7, and BCL6, along with reduced migration. Elevated NAD+ levels in CD38KO cells increased cellular respiration after CD38 inhibition in CD38WT cells. In vivo, CD38KO cell transplants led to more aggressive tumors, likely due to elevated β-catenin, Bcl6, and Tcf-1 signaling. Prior research in multiple myeloma showed αCD38 antibody efficacy relies on CD38 expression. We discovered that panobinostat, a histone deacetylase inhibitor, increased surface CD38 expression in CTCL cells dose-dependently. Combining panobinostat with αCD38 antibody in a CTCL mouse model significantly improved survival compared to the antibody alone, underscoring CD38’s therapeutic potential in CTCL.
The clinical journey of belantamab mafodotin in relapsed or refractory multiple myeloma: lessons in drug development
Patients with relapsed/refractory multiple myeloma (RRMM) have a poor prognosis and a need remains for novel effective therapies. Belantamab mafodotin, an anti–B-cell maturation antigen antibody-drug conjugate, was granted accelerated/conditional approval for patients with RRMM who have received at least 4 prior lines of therapy, based on response rates observed in DREAMM-1/DREAMM-2. Despite the 41% response rate and durable responses observed with belantamab mafodotin in the Phase III confirmatory DREAMM-3 trial, the marketing license for belantamab mafodotin was later withdrawn from US and European markets when the trial did not meet its primary endpoint of superiority for progression-free survival compared with pomalidomide and dexamethasone. This review reflects on key lessons arising from the clinical journey of belantamab mafodotin in RRMM. It considers how incorporating longer follow-up in DREAMM-3 may have better captured the clinical benefits of belantamab mafodotin, particularly given its multimodal, immune-related mechanism of action with responses deepening over time. A non-inferiority hypothesis may have been more appropriate rather than superiority in the context of a monotherapy versus an active doublet therapy. Further, anticipation of, and planning for, non-proportional hazards arising from response heterogeneity may have mitigated loss of statistical power. With the aim of improving the efficacy of belantamab mafodotin, other Phase III trials in the RRMM development program (DREAMM-7 and DREAMM-8) proceeded to evaluate the synergistic potential of combination regimens in earlier lines of treatment. The aim was to increase the proportion of patients responding to belantamab mafodotin (and thus the likelihood of seeing a clear separation of the progression-free survival curve versus comparator regimens). Protocol amendments reflecting DREAMM-3 learnings could also be implemented prospectively on the combinations trials to optimize the follow-up duration and mitigate risk. The wider implications of the lessons learned for clinical research in RRMM and in earlier treatment settings are discussed.
Feasibility and efficacy of therapeutic drug monitoring of abiraterone in metastatic castration resistant prostate cancer patients
Previous studies demonstrated better outcomes for mCRPC (metastatic castration resistant prostate cancer) patients with higher abiraterone exposure (minimal plasma concentration (Cmin) > 8.4 ng/mL), but around 40% of patients experience exposure below this target. Pharmacokinetic (PK)-guided interventions following Therapeutic Drug Monitoring (TDM) could optimise exposure and outcomes. We aimed to evaluate the feasibility and effect on treatment outcomes of abiraterone TDM.
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