Christian Sebastian Michel

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.

The lysine acetyltransferase (KAT) activity of p300/CREBBP has traditionally been linked to transcriptional activation. This has been attributed largely to acetylation of histone residues such as H3K27ac, a defining hallmark of active regulatory elements. Here we show that, in acute myeloid leukemia (AML), inhibition of p300/CREBBP catalysis can paradoxically increase transcription. We combined time-resolved dynamics of nascent and total transcription with chromatin binding dynamics of p300/CREBBP and their associated TFs/co-regulators (inferred from chromatin pull-down proteomics, acetyl-proteomics and motif enrichment) to uncover mechanisms of transcriptional rewiring after p300/CREBBP catalytic inhibition. In parallel, we dissected the functional contribution of individual p300/CREBBP acetyl-interactome members to KAT inhibition using genome-wide CRISPR-Cas9 dropout and focused Perturb-seq screens. Together, these approaches revealed that KAT inhibition paradoxically retains p300/CREBBP and promotes cooperative TF assembly and increased H3K27 acetylation at a subset of regulatory elements. The effect was most pronounced at IRF motif-enriched loci, including interferon-stimulated genes (ISGs), where KAT inhibition triggered p300/CREBBP accumulation and enhanced combinatorial TF binding, enabling recruitment of the ISG activator STAT1. Consequently, ISG loci were converted into transcriptionally active states that induced cell-cycle arrest, differentiation and apoptosis. Therapeutically, combining KAT inhibition with interferon-alpha augmented ISG expression, synergistically drove AML cell death in vitro and significantly extended survival in both AML xenografts and murine models. These findings refine our understanding of p300/CREBBP KAT activity, demonstrating that cooperative TF assembly can reconfigure p300/CREBBP-containing complexes under catalytic inhibition to induce transcription, with translational implications for reprogramming interferon-driven programs through catalytic inhibition in AML and beyond.

Whole-body imaging plays a critical role in assessing multiple myeloma (MM). The structured scoring systems MY-RADS and KIM score have primarily been developed for newly diagnosed patients (NDMM). However, their application and prognostic significance in relapsed/refractory multiple myeloma (RRMM) remains uncertain. To clarify this, we evaluated whole body magnetic resonance imaging (MRI) data from 46 RRMM patients and compared findings to 68 NDMM patients from the GMMG-HD7 trial using both scoring systems. Despite similar overall disease burden, RRMM patients showed significant differences, characterized by increased paramedullary and extramedullary disease and reduced diffuse marrow infiltration compared to NDMM. Both MY-RADS and KIM scores independently correlated with progression-free and overall survival in RRMM. These results highlight distinct biological patterns in RRMM, emphasizing a shift towards bone marrow-independent growth. Our findings suggest that in RRMM, iliac crest biopsies may underestimate disease burden, underlining the importance of imaging complementing bone marrow diagnostics.

Response assessment during treatment of multiple myeloma (MM) typically relies on immunofixation and serum electrophoresis. However, low levels of IgG and especially IgA paraprotein are difficult to quantify reliably. The Hevylite Assay quantifies the kappa and lambda fractions of IgG and IgA separately and is useful to determine response to therapy. Using serum samples of 360 evaluable patients from the prospective GMMG‐MM5 trial (EudraCT‐No. 2010–019173‐16) we assessed the normalization of the kappa/lambda ratio with the Hevylite Assay (HLCr) at baseline, after induction, mobilization, autologous blood stem cell transplantation, consolidation and every three months during maintenance or follow‐up within two years after the end of consolidation. We observed a steady increase in the proportion of patients with normalized HLCr over the course of therapyAchieving HLCr normalization any time until the end of consolidation was associated with a trend towards a prolonged progression‐free survival (PFS; hazard ratio (HR) = 0.75, 95% confidence interval (95% CI) = 0.56–1.01, p = 0.06) but not overall survival (OS; HR = 0.94, 95% CI = 0.69–1.26, p = 0.66) in multivariable time‐dependent Cox regression analyses. Using a landmark analysis from the end of consolidation there was again a marginally statistically significant effect of HLCr normalization by the end of consolidation on PFS using a multivariable Cox model on the subset of the two study arms with continuous lenalidomide maintenance (HR 0.61, 95% CI 0.37–1.02, p = 0.06). No such effect was observed in study arms in which maintenance was only applied to patients not in CR at the end of consolidation. In conclusion, our analysis of the Hevylite Assay in patients with IgG or IgA myeloma from the GMMG‐MM5 study did not find evidence to support the general use of HLCr normalization as a response parameter for predicting PFS or OS. However, the differential effects of HLCr normalization depending on the way in which treatment was adapted to response may be of interest for future study designs on response‐adapted therapy. Trial Registration: ISRCTN05622749.

Chimeric antigen receptor (CAR) T-cell (CAR-T) therapy represents a major advance in the treatment of relapsed/refractory multiple myeloma (RRMM). However, the long time span from leukapheresis to actual CAR-T infusion often necessitates bridging therapies. Because of limited knowledge about the effects of bridging on post–CAR-T clinical course and outcomes, the selection of treatment options is challenging. In this multicenter international observational study, we explored the impact of bridging therapy on hematopoietic reconstitution in 158 patients with RRMM treated with B-cell maturation antigen (BCMA)–directed CAR-T therapy. Based on exposure to classical cytotoxic (CTX) chemotherapy, we classified bridging regimens as non-CTX, intermediate CTX (1-2 CTX agents), or intensive CTX (≥3 CTX agents or high-dose therapy with stem cell transplantation). We found associations between the number of CTX agents used and impaired post–CAR-T hematopoietic reconstitution, evident across hematopoietic cell lineages and particularly manifesting during the late post–CAR-T period. Intensive CTX bridging was associated with a prolonged time to neutrophil and platelet recovery, distinct patterns of hematopoietic recovery (eg, an intermittent phenotype characterized by a second drop), an increased susceptibility to severe infections and a significantly increased risk for severe late cytopenias in univariate and multivariate models. Taken together, these results highlight that bridging intensity distinctly shapes the trajectory of hematopoietic recovery after BCMA CAR-T therapy. Targeted and novel immunotherapies could provide alternatives for bridging, and high-risk patients may particularly benefit from enhanced monitoring, prophylaxis, and supportive care.

Previously, addition of isatuximab (Isa) to standard-of-care lenalidomide-bortezomib-dexamethasone (RVd) in transplant-eligible patients with newly diagnosed multiple myeloma in the GMMG-HD7 trial (ClinicalTrials.gov identifier: NCT03617731 ) resulted in a significant increase of minimal residual disease negativity (MRD–) rates after induction therapy. A total of 662 patients were randomly assigned to receive induction therapy with Isa-RVd (n = 331) or RVd (n = 329), followed by single or tandem autologous stem-cell transplant and second random assignment to maintenance with lenalidomide alone or Isa-lenalidomide. We report updated results for part 1 from first random assignment to post-transplant. As of January 31, 2024, MRD– rates continued to deepen after transplant (66% Isa-RVd v 48% RVd). Isa-RVd induction therapy significantly prolonged progression-free survival (PFS) compared with RVd regardless of maintenance therapy (hazard ratio, 0.70 [95% CI, 0.52 to 0.95]; P = .0184). Weighted risk set estimator analysis accounting for second random assignment followed by maintenance with only lenalidomide confirmed a statistically significant benefit for Isa-RVd followed by lenalidomide maintenance versus RVd followed by lenalidomide maintenance (stratified weighted log-rank test P = .016). In conclusion, after 18-week induction therapy followed by transplant without consolidation therapy, adding Isa to RVd resulted in a significant PFS benefit, regardless of maintenance strategy.

Background: Chimeric antigen receptor (CAR) T-cell therapy has demonstrated significant benefits in the treatment of relapsed/refractory multiple myeloma (RRMM). However, these outcomes can be compromised by severe complications, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS) and immune effector cell-associated hematotoxicity (ICAHT), predisposing for life-threatening infections. Methods: This retrospective observational study examined a total of 129 patients with RRMM who had received idecabtagene vicleucel (ide-cel) at two major myeloma centers in Germany and one center in the USA to assess the Endothelial Activation and Stress Index (EASIX) as a risk marker for an unfavorable clinical course and outcome after CAR T-cell therapy. EASIX is calculated by lactate dehydrogenase (U/L) × creatinine (mg/dL) / platelets (10⁹ cells/L) and was determined before lymphodepletion (baseline) and at the day of CAR T-cell infusion (day 0). The analysis was extended to EASIX derivatives and the CAR-HEMATOTOX score. Results: An elevated baseline EASIX (>median) was identified as a risk marker for severe late ICAHT, manifesting with an impaired hematopoietic reconstitution and pronounced cytopenias during the late post-CAR-T period. Patients with high EASIX levels (>upper quartile) were particularly at risk, as evidenced by an increased rate of an aplastic phenotype of neutrophil recovery, severe late-onset infections and ICANS. Finally, we found associations between baseline EASIX and an inferior progression-free and overall survival. Moreover, the EASIX at day 0 also demonstrated potential to serve as a risk marker for post-CAR-T complications and adverse outcomes. Conclusions: In conclusion, EASIX aids in risk stratification at clinically relevant time points prior to CAR T-cell therapy with ide-cel. Increased EASIX levels might help clinicians to identify vulnerable patients to adapt peri-CAR-T management at an early stage.

Monoclonal gammopathy‐associated pure red cell aplasia (MG‐PRCA) is characterized by the absence or pronounced hypoplasia of erythroid precursors in the bone marrow, causing reticulocytopenia and a normocytic, normochromic anaemia in a patient with a monoclonal plasma cell dyscrasia. We report here on the successful treatment of MG‐PRCA with isatuximab, pomalidomide, and dexamethasone after multiple lines of immunosuppressive and anti‐plasma cell‐directed treatments.