Phase to phase: Navigating drug combinations with hypomethylating agents in higher-risk MDS trials for optimal outcomes.

Recent developments in high-risk Myelodysplastic Neoplasms (HR MDS) treatment are confronted with challenges in study design due to evolving drug combinations with Hypomethylating Agents (HMAs). The shift from the International Prognostic Scoring System (IPSS) to its molecular revision (IPSS-M) has notably influenced research and clinical practice. Introducing concepts like the MDS/AML overlap complicate classifications and including chronic myelomonocytic leukemia (CMML) in MDS studies introduces another layer of complexity. The International Consortium for MDS emphasizes aligning HR MDS criteria with the 2022 ELN criteria for AML. Differences in advancements between AML and MDS treatments and hematological toxicity in HR MDS underline the importance of detailed trial designs. Effective therapeutic strategies require accurate reporting of adverse events, highlighting the need for clarity in criteria like the Common Terminology Criteria for Adverse Events (CTCAE). We provide an overview on negative clinical trials in HR MDS, analyze possible reasons and explore possibilities to optimize future clinical trials in this challenging patient population.

Beyond the horizon: emerging therapeutic approaches in myelodysplastic neoplasms.

Management of myelodysplastic neoplasms (MDS) requires a personalized approach, with a focus on improving quality of life and extending lifespan. The International Prognostic Scoring System-Revised and the molecular International Prognostic Scoring System are key tools for risk stratification and management of MDS. They provide a framework for predicting survival and the risk of transformation to acute myeloid leukemia. However, a major challenge in MDS management remains the limited therapeutic options available, especially after the failure of first-line therapies. In lower-risk MDS, the failure of erythropoietin-stimulating agents often leaves few alternatives, although in higher-risk MDS, the prognosis after hypomethylating agent failure is dismal. This highlights the urgent need for novel, more personalized therapeutic approaches. In this review, we discuss emerging novel therapeutic approaches in the treatment of MDS. Several new therapeutic targets are currently being evaluated, offering hope for improved management of MDS in the future.

Spatiotemporal assessment of immunogenomic heterogeneity in multiple myeloma.

Spatial heterogeneity is a common phenomenon in metastatic solid tumors and an evolving concept in multiple myeloma (MM). The interplay between malignant plasma cells (PCs) and the microenvironment has not yet been analyzed in MM. For this purpose, we performed bone marrow aspirates and imaging-guided biopsies of corresponding lesions in newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) patients. PCs were isolated and subjected to whole-exome sequencing (WES). Non-PCs were studied with next-generation flow (NGF) and T-cell receptor sequencing (TCRseq) to analyze the connection between malignant and nonmalignant cells in the bone marrow and in lesions. Although we observed a strong overlap from WES, NGF, and TCRseq in patients with intramedullary disease, WES revealed significant spatial heterogeneity in patients with extramedullary disease. NGF showed significant immunosuppression in RRMM compared with NDMM as indicated by fewer myeloid dendritic cells, unswitched memory B cells, Th9 cells, and CD8 effector memory T cells but more natural killer and regulatory T cells. Additionally, fewer T-cell receptor (TCR) sequences were detected in RRMM compared with NDMM and healthy individuals. After induction therapy, TCR repertoire richness increased to levels of healthy individuals, and NGF showed more regulatory T cells and myeloid-derived suppressor cells, regardless of depth of response. Clinical significance of imaging-guided biopsies of lesions was demonstrated by detection of monoclonal PCs in patients without measurable residual disease (MRD) in aspirates from the iliac crest as well as identification of secondary primary malignancies in MRD- patients. Furthermore, site-specific clones with different drug susceptibilities and genetically defined high-risk features were detected by our workflow.

Deciphering spatial genomic heterogeneity at a single cell resolution in multiple myeloma.

Osteolytic lesions (OL) characterize symptomatic multiple myeloma. The mechanisms of how malignant plasma cells (PC) cause OL in one region while others show no signs of bone destruction despite subtotal infiltration remain unknown. We report on a single-cell RNA sequencing (scRNA-seq) study of PC obtained prospectively from random bone marrow aspirates (BM) and paired imaging-guided biopsies of OL. We analyze 148,630 PC from 24 different locations in 10 patients and observe vast inter- and intra-patient heterogeneity based on scRNA-seq analyses. Beyond the limited evidence for spatial heterogeneity from whole-exome sequencing, we find an additional layer of complexity by integrated analysis of anchored scRNA-seq datasets from the BM and OL. PC from OL are characterized by differentially expressed genes compared to PC from BM, including upregulation of genes associated with myeloma bone disease like DKK1, HGF and TIMP-1 as well as recurrent downregulation of JUN/FOS, DUSP1 and HBB. Assessment of PC from longitudinally collected samples reveals transcriptional changes after induction therapy. Our study contributes to the understanding of destructive myeloma bone disease.

Serological Response to Vaccination after Autologous Transplantation for Multiple Myeloma Is Associated with Improved Progression-Free and Overall Survival.

Revaccination after autologous hematopoietic cell transplantation (AHCT) is recommended in post-HCT survivorship guidelines to restore humoral immunity. Data on seroconversion after AHCT and vaccination in multiple myeloma (MM) patients are limited. We investigated the feasibility and effectiveness of vaccination post-AHCT and analyzed the restoration of humoral immunity and patient prognosis. Anti-pathogen titers were measured within a median of 2 days before and 96 days after AHCT and following revaccination in 139 MM patients who had a first AHCT from 2013 to 2016. Most (84%) patients received at least one dose of any planned vaccines. High-dose melphalan with AHCT restored measurable immunity in 18% of patients. In an additional >60% of patients, seroconversion occurred after vaccination; however, despite vaccination, 20% of patients remained seronegative for most pathogens. Attainment of MM complete response post-AHCT was associated with higher rates of seroconversion which yielded significantly longer progression-free and overall survival. Our study demonstrates the feasibility of post-AHCT vaccination, supporting measurement of post-vaccination titers to determine which patients should be considered for antimicrobial prophylaxis, as seroconversion does not occur in all patients. Titer seroconversion is a potential indicator of the immunological effects of AHCT, with restoration of humoral immunity demonstrating improved survival.

EASIX for prediction of survival in lower-risk myelodysplastic syndromes.

Patients with myelodysplastic syndromes (MDS) are at risk of early death from cardiovascular complications due to the link between clonal hematopoiesis and endothelial dysfunction. EASIX (Endothelial Activation and Stress Index) has been established to predict endothelial complications after allogeneic transplantation. We investigated the impact of EASIX measured at first diagnosis on survival of patients with lower- and higher-risk MDS (no allogeneic transplantation) in two independent institutions: n = 192 (training cohort) and n = 333 (validation cohort). Serum markers of endothelial cell distress were measured and correlated to EASIX. While no effects of EASIX on survival were observed in higher-risk patients, EASIX was associated with shorter survival in patients with lower-risk MDS in both cohorts (univariate: Cohort I: hazard ratio (HR): 1.46; 95% confidence interval (CI) 1.24-1.71; p-value < 0.001/Cohort II: HR 1.31 [1.17-1.48]; p-value < 0.001). Multivariate Cox regression analysis and prediction error analyses confirmed that EASIX remained a significant predictor of survival after adjustment for age, sex, cytogenetic abnormalities and bone marrow blasts in lower-risk patients. The model of the training cohort could be validated. Serum levels of Angiopioetin-2 correlated significantly with EASIX. We introduce EASIX as an easily accessible and independent predictor for survival in patients with lower-risk MDS.

The evolving role of maintenance therapy following autologous stem cell transplantation in multiple myeloma.

Introduction: Maintenance therapy after autologous transplantation is a standard of care in newly diagnosed myeloma. However, there is no universal answer to the question of which maintenance strategy should be pursued after ASCT? Areas covered: We conducted a MEDLINE search using the medical subject headings 'multiple myeloma', 'autologous transplantation' and 'maintenance' to identify available data from clinical trials on the role of different maintenance strategies after autologous transplantation for the newly diagnosed disease. Expert opinion: A large meta-analysis demonstrated that lenalidomide prolongs progression-free and overall survival after autologous transplantation compared to observation/placebo. Further trials confirmed that lenalidomide maintenance increases rates of high-quality responses and one study demonstrated that lenalidomide maintenance improves outcomes regardless of cytogenetic risk. Although lenalidomide can cause side effects and is associated with an increased risk of second primary malignancies, its benefits outweigh the mentioned risks. The proteasome inhibitors ixazomib and bortezomib may partially overcome the negative effects of high-risk cytogenetics. Future trials will combine different agents and monoclonal antibodies during maintenance and will investigate whether minimal residual disease status can guide maintenance duration.