Highlighted Research Articles

Primary resistance to teclistamab occurs in 30% to 40% of relapsed/refractory multiple myeloma patients. In this study, Sharma and colleagues develop a composite variable Hi-MM score that correlates with lack of response to teclistamab in two independent cohorts. Hi-MM is defined by any one of extramedullary disease, plasma cell leukemia, bone marrow plasmacytosis ≥50%, or transfusion within 30 days. Furthermore, debulking chemotherapy can convert Hi-MM–positive to Hi-MM–negative status and improve subsequent response to teclistamab, even in patients who were primary refractory to BCMA bispecifics in the immediate prior line of therapy. By overcoming or preventing Hi-MM–associated primary resistance, this strategy holds promise to expand the patient population beneftting from bispecific therapy.See article, p. 394.The venetoclax plus hypomethylating agent (HMA/VEN) regimen has become standard front-line therapy for older or unfit patients with acute myeloid leukemia (AML), yet survival outcomes remain highly variable. Drekolias, Tuz Zahra, and colleagues analyzed 506 AML patients treated with HMA/VEN to develop a genetic risk model integrating somatic mutations and cytogenetic abnormalities. Their point-based scoring system stratifies patients into low-, intermediate-, and high-risk groups with markedly distinct survival outcomes. External validation in 126 patients supports its potential to guide personalized treatment decisions for this growing population.See article, p. 403.Recent diagnostic criteria recognize oligomonocytic chronic myelomonocytic leukemia (OM-CMML) as an early form of CMML but risk misclassifying some myelodysplastic syndrome cases as CMML. Through analysis of a large patient cohort, Montalban-Bravo and colleagues show that key genomic patterns, such as biallelic loss of TET2 or SRSF2+TET2 co-mutations and bone marrow monocytosis, define true OM-CMML biology and forecast progression to full-blown CMML. Their proposed clinic-ready workflow, which incorporates genetics and pathology, enhances precision in early detection, reduces errors, and guides better patient management across this heterogeneous disease spectrum.See article, p. 414.Ibrutinib with venetoclax is an effective treatment in both treatment-naïve and relapsed/refractory chronic lymphoblastic leukemia (R/R CLL). Here, Swaminathan and colleagues report the results of a phase II study of combined ibrutinib and venetoclax in 79 patients with R/R CLL. At a median follow-up of 95.5 months, the estimated 7-year progression-free survival rate was 63.3%. Even after an approximately 8-year follow-up—the longest reported for this combination in R/R CLL—24 cycles of ibrutinib and venetoclax led to durable remissions.See article, p. 431.Chimeric antigen receptors (CAR) are designed to enhance effector T-cell activity through combining the CD3ζ T-cell activating domain with either the co-stimulatory domain of CD28 or 4-1BB. Here, Lieberman and colleagues discovered that endogenous CD28 on 4-1BB co-stimulated CAR T cells is important for their fitness and anti-tumor activity. While continued disruption of CD28 limited CAR T efficacy in vivo, short-duration CD28 blockade reduced pro-inflammatory cytokine levels without affecting efficacy against B-lineage tumor models. These findings have important implications for ongoing efforts to improve CAR T therapy for the broader anti-tumor immunotherapy field.See article, p. 441.Multiple myeloma development depends on the bone marrow microenvironment, but the spatial organization of cells within this niche is not well characterized. Using imaging mass cytometry of diagnostic bone marrow biopsies, Roseth and colleagues show that plasma cells near bone surfaces display a quiescent state and, in patients with bone disease, exhibit distance-to-bone–dependent IL-32 expression. They also identify two distinct plasma cell neighborhoods characterized by endothelial/oxidative or immune/glycolytic features, and imaging-inferred interactions between plasma cells and CD4+ T cells negatively correlated with progression-free survival. These data highlight spatial analysis as a promising tool for understanding disease biology and informing risk stratification.See article, p. 460.For patients considering CAR T-cell therapy, likelihood of response versus relapse and adverse events can be prospectively estimated by risk scoring systems including CAR-HEMATOX and EASIK. Here, Frenking and colleagues apply these models to two real-world cohorts of myeloma patients treated with T-cell engager (TCE) therapies, aiming to develop a stratification model for its risks and benefits. The results identify several parameters correlating with poor outcomes, highlighting determinants of outcomes shared between CAR-T and TCE therapies. With further validation, these findings could pave the way to a risk stratification system to guide clinical decisions on TCE therapy.See article, p. 479.