Minimal Residual Disease-Based End Point for Accelerated Assessment of Clinical Trials in Multiple Myeloma: A Pooled Analysis of Individual Patient Data From Multiple Randomized Trials.

Purpose: Newly approved drugs and combinations treating multiple myeloma (MM) have resulted in substantial improvements in patients' survival. To deliver rapid access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to evaluate the minimal residual disease-negative complete response (MRD-CR) as an intermediate end point for progression-free survival (PFS) and overall survival (OS) in newly diagnosed (ND) transplant-eligible (NDTE) patients, ND transplant-ineligible (NDTinE) patients, and patients with relapsed/refractory (RR) MM.

Bortezomib-releasing silica-collagen xerogels for local treatment of osteolytic bone- and minimal residual disease in multiple myeloma.

Background: Accumulation of malignant plasma cells in the bone marrow causes lytic bone lesions in 80% of multiple myeloma patients. Frequently fracturing, they are challenging to treat surgically. Myeloma cells surviving treatment in the presumably protective environment of bone lesions impede their healing by continued impact on bone turnover and can explain regular progression of patients without detectable minimal residual disease (MRD).

Quantitative Integrative Survival Prediction in Multiple Myeloma Patients Treated With Bortezomib-Based Induction, High-Dose Therapy and Autologous Stem Cell Transplantation.

Purpose: Given the high heterogeneity in survival for patients with multiple myeloma, it would be clinically useful to quantitatively predict the individual survival instead of attributing patients to two to four risk groups as in current models, for example, revised International Staging System (R-ISS), R2-ISS, or Mayo-2022-score.

Patients And Methods: Our aim was to develop a quantitative prediction tool for individual patient's 3-/5-year overall survival (OS) probability. We integrated established clinical and molecular risk factors into a comprehensive prognostic model and evaluated and validated its risk discrimination capabilities versus R-ISS, R2-ISS, and Mayo-2022-score.

Molecular Long-Term Analysis of the GMMG-HD4 Trial in Multiple Myeloma-Patterns of Association of Chromosomal Aberrations with Response and Proliferation Determining Survival in Selecting Treatments in View of Limited Resources in Low- and Middle-Income Countries.

Based on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65/GMMG-HD4 trial (German part; = 395) randomizing VAD induction (vincristin/adriamycin/dexamthasone)/tandem-transplantation/thalidomide-maintenance vs. PAD induction (bortezomib/adriamycin/dexamethasone)/tandem transplantation/bortezomib maintenance, we discern how chromosomal aberrations determine long-term prognosis by different patterns of association with proliferation and treatment-dependent response, whether responses achieved by different regimens are equal regarding prognosis, and whether subpopulations of patients could be defined as treatable without upfront "novel agents" in cases of limited resources, e.g.

Targeting CEACAM5-positive solid tumors using NILK-2401, a novel CEACAM5xCD47 κλ bispecific antibody.

Background: Blocking the CD47 "don't eat me"-signal on tumor cells with monoclonal antibodies or fusion proteins has shown limited clinical activity in hematologic malignancies and solid tumors thus far. Main side effects are associated with non-tumor targeted binding to CD47 particularly on blood cells.

Methods: We present here the generation and preclinical development of NILK-2401, a CEACAM5×CD47 bispecific antibody (BsAb) composed of a common heavy chain and two different light chains, one kappa and one lambda, determining specificity (so-called κλ body format).

Modeling Myeloma Dissemination In Vitro with hMSC-interacting Subpopulations of INA-6 Cells and Their Aggregation/Detachment Dynamics.

Unlabelled: Multiple myeloma involves early dissemination of malignant plasma cells across the bone marrow; however, the initial steps of dissemination remain unclear. Human bone marrow-derived mesenchymal stromal cells (hMSC) stimulate myeloma cell expansion (e.g.

Cytomegalovirus immunoglobulin serology prevalence in patients with newly diagnosed multiple myeloma treated within the GMMG-MM5 phase III trial.

Objectives: The seroprevalence of antibodies against Cytomegalovirus (CMV) is an established poor prognostic factor for patients receiving an allogeneic stem cell transplantation. However, the impact of CMV serology on outcome after autologous stem cell transplantation remains unknown.

Methods: Here, we analyzed the CMV immunoglobulin (Ig) serology of 446 newly-diagnosed multiple myeloma (MM) patients of the GMMG-MM5 phase III trial with a median follow-up of 58 months.

Elotuzumab, lenalidomide, bortezomib, dexamethasone, and autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GMMG-HD6): results from a randomised, phase 3 trial.

Background: The aim of this trial was to investigate the addition of the anti-SLAMF7 monoclonal antibody elotuzumab to lenalidomide, bortezomib, and dexamethasone (RVd) in induction and consolidation therapy as well as to lenalidomide maintenance treatment in transplant-eligible patients with newly diagnosed multiple myeloma.

Methods: GMMG-HD6 was a phase 3, randomised trial conducted at 43 main trial sites and 26 associated trial sites throughout Germany. Adult patients (aged 18-70 years) with previously untreated, symptomatic multiple myeloma, and a WHO performance status of 0-3, with 3 being allowed only if caused by myeloma disease and not by comorbid conditions, were randomly assigned 1:1:1:1 to four treatment groups.

Development and characterization of NILK-2301, a novel CEACAM5xCD3 κλ bispecific antibody for immunotherapy of CEACAM5-expressing cancers.

Background: T-cell retargeting to eliminate CEACAM5-expressing cancer cells via CEACAM5xCD3 bispecific antibodies (BsAbs) showed limited clinical activity so far, mostly due to insufficient T-cell activation, dose-limiting toxicities, and formation of anti-drug antibodies (ADA).

Methods: We present here the generation and preclinical development of NILK-2301, a BsAb composed of a common heavy chain and two different light chains, one kappa and one lambda, determining specificity (so-called κλ body format).

Results: NILK-2301 binds CD3ɛ on T-cells with its lambda light chain arm with an affinity of ≈100 nM, and the CEACAM5 A2 domain on tumor cells by its kappa light chain arm with an affinity of ≈5 nM.

RNA-sequencing based first choice of treatment and determination of risk in multiple myeloma.

Background: Immunotherapeutic targets in multiple myeloma (MM) have variable expression height and are partly expressed in subfractions of patients only. With increasing numbers of available compounds, strategies for appropriate choice of targets (combinations) are warranted. Simultaneously, risk assessment is advisable as patient's life expectancy varies between months and decades.

Implications and prognostic impact of mass spectrometry in patients with newly-diagnosed multiple myeloma.

Mass spectrometry (MS) is a promising tool for monitoring monoclonal protein in plasma cell dyscrasias. We included 480 transplant-eligible newly-diagnosed multiple myeloma (MM) patients from the GMMG-MM5 trial (EudraCT No. 2010-019173-16) and performed a retrospective MS analysis at baseline (480 patients) and at the pre-defined, consecutive time points after induction (444 patients), prior to maintenance (305 patients) and after one year of maintenance (227 patients).

The BLM helicase is a new therapeutic target in multiple myeloma involved in replication stress survival and drug resistance.

Multiple myeloma (MM) is a hematologic cancer characterized by accumulation of malignant plasma cells in the bone marrow. To date, no definitive cure exists for MM and resistance to current treatments is one of the major challenges of this disease. The DNA helicase BLM, whose depletion or mutation causes the cancer-prone Bloom's syndrome (BS), is a central factor of DNA damage repair by homologous recombination (HR) and genomic stability maintenance.

Beyond medicines' barriers: exploring the true cost of multiple myeloma.

Aim: The goal of this research was to quantify and qualify all the costs associated with multiple myeloma (MM) from a healthcare and societal perspective and to highlight certain costs that are often underestimated.

Materials And Methods: The study used a mixed methods approach that consisted of three phases: a systemic literature review (SLR), a virtual roundtable discussion based on the results of the SLR, and an online survey.

Results: In total, 4321 records were identified by literature and snowball searches.

Systematic literature review of health economic models developed for multiple myeloma to support future analyses.

Aims: The goal of this study was to review the economic evaluations of health technologies in multiple myeloma (MM) and provide guidance and recommendations for future health economic analyses.

Materials And Methods: A systemic literature review (SLR) was conducted on original economic assessment studies and structured review papers focusing on the studies in MM. The search was limited to English language papers published from 1 January 2000 onwards.

Patient and Caregiver Experience Decision Factors in Treatment Decision Making: Results of a Systematic Literature Review of Multiple Myeloma Decision Aids.

Objectives: Decision-aids (DAs) may facilitate shared decision-making for patients and caregivers, by providing evidence-based information to assist healthcare professionals, patients, and caregivers in making choices about aspects of care, and/or highlighting decision factors to discuss with the potential of altering the treatment decision. These decision factors may not be well integrated in DAs.

Methods: A systematic literature review was conducted in the field of multiple myeloma (MM) on peer-reviewed publications, extended with a gray literature search.

Resemblance-Ranking Peptide Library to Screen for Binders to Antibodies on a Peptidomic Scale.

A novel resemblance-ranking peptide library with 160,000 10-meric peptides was designed to search for selective binders to antibodies. The resemblance-ranking principle enabled the selection of sequences that are most similar to the human peptidome. The library was synthesized with ultra-high-density peptide arrays.

Pyrroline-5-Carboxylate Reductase 1: a novel target for sensitizing multiple myeloma cells to bortezomib by inhibition of PRAS40-mediated protein synthesis.

Background: Multiple myeloma (MM) remains an incurable cancer despite advances in therapy. Therefore, the search for new targets is still essential to uncover potential treatment strategies. Metabolic changes, induced by the hypoxic bone marrow, contribute to both MM cell survival and drug resistance.

Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single-cell transcriptomics.

Virtually all patients with multiple myeloma become unresponsive to treatment over time. Relapsed/refractory multiple myeloma (RRMM) is accompanied by the clonal evolution of myeloma cells with heterogeneous genomic aberrations and profound changes of the bone marrow microenvironment (BME). However, the molecular mechanisms that drive drug resistance remain elusive.

CS1-specific single-domain antibodies labeled with Actinium-225 prolong survival and increase CD8+ T cells and PD-L1 expression in Multiple Myeloma.

Multiple myeloma (MM) is a hematological malignancy characterized by the presence of clonal plasma cells in the bone marrow niche. Despite significant therapeutic advances, MM remains incurable for the majority of patients. Targeted radionuclide therapy (TRNT) has emerged as a promising treatment option to eradicate residual cancer cells.