Current treatment strategies for multiple myeloma (MM) are highly effective, but most patients develop relapsed/refractory disease (RRMM). The anti-CD38/CD3xCD28 trispecific antibody SAR442257 targets CD38 and CD28 on MM cells and co-stimulates CD3 and CD28 on T cells (TCs). We evaluated different key aspects such as MM cells and T cells avidity interaction, tumor killing, and biomarkers for drug potency in three distinct cohorts of RRMM patients. We found that a significantly higher proportion of RRMM patients (86%) exhibited aberrant co-expression of CD28 compared to newly diagnosed MM (NDMM) patients (19%). Furthermore, SAR442257 mediated significantly higher TC activation, resulting in enhanced MM killing compared to bispecific functional knockout controls for all relapse cohorts (Pearson’s r = 0.7). Finally, patients refractory to anti-CD38 therapy had higher levels of TGF-β (up to 20-fold) compared to other cohorts. This can limit the activity of SAR442257. Vactoserib, a TGF-β inhibitor, was able to mitigate this effect and restore sensitivity to SAR442257 in these experiments. In conclusion, SAR442257 has high potential for enhancing TC cytotoxicity by co-targeting CD38 and CD28 on MM and CD3/CD28 on T cells.

In order to meet the challenges in data evaluation and comparability between studies in multiple myeloma (MM) minimal residual disease (MRD) assessment, the goal of the current study was to provide a step-by-step evaluation of next-generation sequencing (NGS) and multicolor flow cytometry (MFC) data. Bone marrow (BM) sample pairs from 125 MM patients were analyzed by NGS and MFC MM MRD methods. Tumor load (TL) and limit of detection (LOD) and quantification (LOQ) were calculated. The best-fit MRD cut-off was chosen as 1 × 10⁻⁵, resulting in an overall 9.6% (n overall = 12 (NGS n = 2, MFC n = 10)) nonassessable cases. The overall concordance rate between NGS and MFC was 68.0% (n = 85); discordant results were found in 22.4% (11.2% (n = 14) of cases in each direction. Overall, 55.1% (n = 60/109) and 49.5% (n = 54/109) of patients with a serological response ≥ very good partial response (VGPR) showed BM MRD negativity by NGS and MFC, respectively. A good correlation in the TL assessed by both techniques was found (correlation coefficient = 0.8, n = 40, p < 0.001). Overall, our study shows good concordance between MM BM MRD status and TL when comparing NGS and MFC at a threshold of 10^–5. However, a sufficient number of analyzed events and calculation of MRD key metrics are essential for the comparison of methods and evaluability of data at a specific MRD cut-off.

Mass spectrometry (MS) offers a minimally invasive approach for detecting monoclonal proteins in multiple myeloma (MM), but large prospective evaluations remain limited. We analyzed 3,301 serum samples from 617 patients enrolled in the phase III GMMG-HD7 trial to characterize the analytical performance and clinical relevance of MS-based measurable residual activity. MS reliably distinguished therapeutic antibodies, tracked diagnostic M proteins longitudinally, and demonstrated strong prognostic value across defined time points. MS negativity was associated with superior progression-free survival (PFS), with the greatest separation at later time points (12 months of maintenance: hazard ratio, 0.25 [95% CI, 0.15 to 0.43]; adjusted P < .001). Combined assessment with bone-marrow measurable residual disease (MRD) further refined risk stratification: MS/MRD double-positive patients exhibited the worst PFS, whereas all other groups showed comparably favorable outcomes. MS/MRD concordance increased over time and was influenced by immunoglobulin isotype, with expected immunoglobulin G-recycling–associated early discordance. MS provided accurate M-protein detection and outperformed serum protein electrophoresis at low concentrations, reliably quantifying low-level residual disease. These findings establish serum MS as a sensitive, reproducible, and practical biomarker that complements MRD and supports minimally invasive disease monitoring in MM, with potential integration into future response assessment and risk-adapted treatment strategies.

Key Points. High dietary fiber intake increases gut microbiome diversity and specific fibers link to MRD negativity in NDMM patients.Microbial signatures a