Bhavana Bhatnagar

The bispecific CD19/CD3 T-cell engaging antibody blinatumomab is efficacious in front-line therapy in B-cell acute lymphoblastic leukemia (B-ALL) but the biological determinants of response and resistance are incompletely understood. To examine the genomic determinants of outcome, we analyzed genomic and clinical data of 569 adults registered to the ECOG-ACRIN E1910 study of blinatumomab in BCR::ABL1-negative B-ALL (ClinicalTrials.gov NCT02003222). We identified 23 molecular subtypes including the high-risk subtypes BCR::ABL1 (20%), BCR::ABL1-like (18%), low hypodiploid (14%) and KMT2A-R (12%), and 267 putative driver genes. We identified a subtype characterized by CEBPA overexpression or elevated CEBPB expression due to chromosomal translocation-mediated enhancer hijacking, or insertions downstream of CEBPA that generate neoenhancers. Attainment of MRD-negativity patients after induction and intensification chemotherapy was more common in PAX5alt, TCF3::PBX1 and ZNF384-R B-ALL, and less common in BCR::ABL1-like and KMT2A-R B-ALL. Integration of genomic and clinical data suggested that the addition of blinatumomab to chemotherapy was associated with improved relapse-free and overall survival for several B-ALL subtypes, including hyperdiploid, PAX5alt, PAX5 P80R, BCR::ABL1-like JAK-STAT and KMT2A-R B-ALL, although small sample sizes for several subtypes indicate that confirmation is required. Alteration of TP53 or mutations associated with myeloid clonal hematopoiesis of indeterminate potential (CHIP) were identified in 15.3% and 9.8% of patients, respectively. The presence of these mutations was associated with older age at diagnosis and inferior outcome to chemotherapy. In summary, we define the landscape of genomic alterations of adult B-ALL, and identify genomic subtypes that may influence the efficacy of blinatumomab when combined with chemotherapy.

As the role of cellular therapies in myeloma evolves and their utilization expands, several alternative CAR-T targets, beyond BCMA, are being explored. G protein-coupled receptor class C group 5 (GPRC5D) is the foremost CAR-T target among the emerging options with efficacy even after BCMA failure. In their meta-analysis of eighteen early-phase clinical trials investigating CAR-T targeting BCMA or GPRC5D, Yang et al offer valuable insights into their safety and efficacy in RRMM. This analysis reports a clear efficacy advantage of GPRC5D CAR-T with a higher overall response rate, complete response rate, with similar MRD negativity rate compared to BCMA CAR-T. It is of note that both products seem to be equally efficacious in patients with traditional high-risk features such as extramedullary disease and adverse cytogenetics. However, significantly fewer patients treated with GPRC5D CAR-T cell therapy relapsed, likely due to the receptor's expression being independent of BCMA and its non-shedding pattern that could lead to stronger CAR-T engagement, even with BCMA-low or -negative disease. Both therapies showed favorable toxicity profiles; however, rates of high-grade cytokine release syndrome (CRS) were higher with BCMA CAR. Given these findings and the recognition of antigen escape as a wellknown mechanism of treatment failure, GPRC5D stands as a viable option for patients relapsing after BCMA CAR. While being a promising option in RRMM, the superior efficacy and safety of GPRC5D CAR-T reported in this analysis needs to be validated in phase II and III trials, before changing the treatment paradigm.While advances in CAR-T therapy have undoubtedly shaped the treatment landscape in MM, other plausible cellular therapy options continue to be explored. In a notable retrospective analysis, Lei and colleagues report outcomes in 20 patients with multiple myeloma treated with HLA-mismatched peripheral blood stem cell microtransplant over a 16-year period. Although microtransplants have been previously explored in acute leukemia and non-Hodgkin lymphoma, this study represents the first report of its application in myeloma. Despite the modest cohort size, the study introduces a novel, lowintensity therapeutic strategy that appears well tolerated, with lower toxicity compared with high-dose chemotherapy followed by autologous stem cell rescue or CAR-T cell therapy, and with the potential for broader clinical accessibility.The reported overall response rate was 85% (17 of 20 patients). Six-year overall survival approached 65%, and six-year progression-free survival was 35%-notable outcomes given that nearly half of the cohort harbored high-risk cytogenetic abnormalities, including 1q gain, t(4;14), and del(17p). Importantly, in a subset of patients, the authors observed evidence of immune reconstitution, reflected by improvements in T-cell and natural killer cell function following microtransplantation.While limited by its retrospective design and small sample size, this analysis is both provocative and hypothesis-generating. It provides a foundation for prospective evaluation of HLA mismatched peripheral blood microtransplantation as a potential therapeutic strategy in MM.Lastly, the role of targeted immune therapy, specifically, the CD38 monoclonal antibody, daratumumab is highlighted by Garg and Devarakonda in their comprehensive review of smoldering myeloma-a condition historically managed with observation rather than intervention in the pre-FDA approval era. The authors describe the evolving landscape of management options, particularly for patients with high-risk smoldering disease. Smoldering multiple myeloma is generally considered to be a "gray zone" plasma cell disorder situated between monoclonal gammopathy of undetermined significance and overt MM, for which most patients have traditionally been monitored without therapy. This concise and highly informative review addresses the contemporary complexities surrounding smoldering myeloma, including variability in diagnostic definitions, challenges in disease classification, and the long-standing controversy regarding the timing of therapeutic intervention. With the recent approval of daratumumab for patients with highrisk smoldering myeloma, the decision of whom to treat has become increasingly nuanced. The authors provide a systematic framework for approaching these patients, highlighting emerging data demonstrating survival benefit and delayed progression to overt myeloma. The insights offered in this review equip clinicians with a modern understanding of management strategies in the post-daratumumab approval era and contribute meaningfully to ongoing discussions regarding optimal care for patients with this complex and evolving entity.Over the past decade, drug development in MM has undergone a transformative evolution, yielding unprecedented depths of response and meaningful gains in survival. Advances in cellular and immune-based therapies have been central to these improvements. Yet, despite this progress, the challenges of clonal evolution and therapeutic resistance remain. Most patients ultimately experience relapse and continue to succumb to the disease, underscoring the urgent need for ongoing investigation and innovation.

Background: Decitabine efficacy in acute myeloid leukemia (AML) may be enhanced by the pharmacologic upregulation of microRNA miR-29b, a regulator of DNA methyltransferase (DNMT) expression. Bortezomib and sorafenib have been shown preclinically to increase miR-29b levels, providing a biologically informed strategy to sensitize leukemic blasts to DNMT inhibition. Objectives: To evaluate the safety, tolerability, biological activity, and preliminary efficacy of combining bortezomib and sorafenib followed by decitabine in patients with newly diagnosed or relapsed/refractory AML. Methods: This phase I, dose-escalation study enrolled 15 patients (11 untreated, 4 relapsed/refractory) who received fixed-dose bortezomib and sorafenib across three dose levels prior to decitabine. Dose escalation was guided by dose-limiting toxicities (DLTs) and an increase in miR-29b expression. Results: The regimen was generally well tolerated with the most frequent grade ≥3 adverse events of hypertension and febrile neutropenia. At the highest dose level, a ≥2-fold increase in miR-29b expression was observed in two of the six evaluable patients. The overall response rate was 33.3%, with clinical responses observed in both newly diagnosed and relapsed/refractory patients. However, changes in miR-29b expression did not consistently correlate with clinical response. Conclusions: Sequential treatment with bortezomib and sorafenib followed by decitabine is feasible and demonstrates acceptable safety in AML. Although the biologic modulation of miR-29b was variable, this trial provides a proof of concept for pharmacodynamic-guided dose finding in epigenetic therapy combinations.

Representativeness of Study Participants

Pharmacokinetic exposure versus toxicity/response. (A) Steady-state plasma levels of TP-0903 parent drug in non-responders and responders (CR, CRh, CRi, MLFS). Percent decrease in (B) absolute neutrophil count (ANC) or (C) platelets in patients with a steady state plasma level above or below the median.

Sequencing data. Serial sequencing versus response.

Inclusion and Exclusion Criteria

TP-0903 and metabolite pharmacokinetic parameters on days 1 and 10 of course 1