Highlighted Research Articles

In the largest study to date, Razzo and colleagues analyzed real-world data from 509 multiple myeloma patients treated with the CD3/BCMA-targeting bispecific antibody teclistamab. The cohort was enriched for high-risk cases, with more than half of patients relapsed on at least 6 lines of therapy and with nearly 90% of patients ineligible for the initial teclistamab clinical trial. Among the ineligibility factors were cytopenia and prior BCMA-targeting CAR-T therapy. In the real-world setting, these clinical variables anticorrelated with teclistamab response depth and duration. However, the negative association was not seen with belantamab mafodotin or if more than 9 months passed since prior anti-BCMA exposure. In addition to documenting the real-world safety and efficacy of teclistamab in the US population, the study offers insights into optimal sequencing of BCMA-targeting therapies.See article, p. 561.Multiple myeloma relapsed on T-cell immunotherapy targeting BCMA and GPCR5D often presents with genetic loss of these antigens. However, it has remained unclear whether these genomic lesions are selected from a pre-existing clone or got newly acquired under therapeutic pressure. The authors leveraged chemotherapy-induced mutational signatures as molecular barcodes to deconvolute the relative timing of these events. For myeloma cases with previous exposure to high-dose melphalan, antigen escape variants appeared after immunotherapy. The findings identify a relevant window for surveillance of resistance to immunotherapy and pave the way to studying clinical antigen escape in other cancer types.See article, p. 572.Characterizing DLBCL co-culture with CAR-T cells, Lüönd and colleagues uncover unexpected dynamic interplay of antigen levels, apoptosis sensitivity, and yet uncharacterized factors in mediating lymphoma cell resistance to CAR-T. Strikingly, once DLBCL acquired resistance to CD19-CAR-T, they became cross-resistant: refractory to killing by CAR-T targeting other expressed antigens. These resistant DLBCL cells expressed a signature that was enriched in pre-infusion DLBCL biopsies of CAR-T non-responder patients. Furthermore, resistant DLBCL could restore CD19 surface levels, but not sensitivity to CAR-T. Nonetheless, cross-resistant DLBCL remained targetable by MCL1 inhibitor. The findings offer important implications for CAR-T strategies, favoring dual antigen co-targeting over sequential CAR-T cell therapies.See article, p. 580.Minimal residual disease drives relapse in multiple myeloma but has rarely been dissected at single-cell resolution. In this work, Kamiya and colleagues integrated single-cell RNA sequencing with VDJ profiling to map disease heterogeneity across stages, including post-therapy. They uncovered plasticity of cells along a CD138-axis and defined therapy-resistant subpopulations within the CD138-negative compartment. CRISPR screens and perturbation assays revealed dependency of myeloma cells on members of core splicing machinery, with RBM39 overexpression as a critical vulnerability. Genetic and pharmacologic RBM39 inhibition impaired myeloma cells. These findings establish splicing-pathway intervention as a potential strategy to eradicate residual disease and highlight single-cell analysis as a powerful approach for profiling therapy-resistant populations.See article, p. 602.Approximately 20% of patients with follicular lymphoma (FL) relapse early with poor outcomes, but the underlying mechanisms remain unclear. Dasari and colleagues correlated higher IRF4 (IRF4hi) with increased transformation risk and with gene signatures of aberrant immune signaling and suppressive tumor microenvironment in FL biopsy samples. In cultured lymphoma cell lines, IRF4 repressed antigen presentation and co-receptor genes and promoted cytokines with known T-cell-modulatory functions. IRF4 also increased glucose utilization by lymphoma cells, while silencing IRF4 reduced cell growth and restored Treg numbers. These findings link IRF4hi B cells to more aggressive disease via gene program shaping B-T helper interactions.See article, p. 623.