The Role of CELMoD Agents in Multiple Myeloma.

Although recent decades have seen continued improvements in survival for patients with multiple myeloma, the disease remains largely incurable, and most patients will experience relapse and/or become refractory to treatment. There thus remains an urgent unmet need for novel treatments, particularly for those patients with relapsed or refractory multiple myeloma. Novel treatment modalities, such as targeted protein degradation, have attracted particular interest due to their ability to expand the range of druggable protein targets in myeloma cells.

Treatment Patterns of Patients With Multiple Myeloma in a Real-World Setting in Spain. How are Triple-Class Exposed Patients Being Managed?

Objective: We aim to describe multiple myeloma (MM) characteristics and treatment patterns in Spain, focusing on triple-class exposed (TCE) population.

Methods: In this non-interventional, cross-sectional, retrospective study, real-world treatment data between October 2022 and September 2023 were collected from Oncology Dynamics and Oncology Advantage datasets. The proportion of TCE patients was described by line of therapy (LOT).

Induction therapy with bortezomib, melphalan, and prednisone followed by lenalidomide and dexamethasone versus carfilzomib, lenalidomide, and dexamethasone with or without daratumumab in older, fit patients with newly diagnosed multiple myeloma (GEM-2017FIT): a phase 3, open-label, multicentre, randomised clinical trial.

Background: Triplet and quadruplet regimens based on bortezomib, melphalan and prednisone (VMP) and lenalidomide and dexamethasone (Rd) with anti-CD38 antibodies are potential treatments for transplant-ineligible patients with newly diagnosed multiple myeloma. However, the high risk of toxic effects in this population requires frailty-based therapy adaptation. We aimed to compare the response of carfilzomib-based triplet and quadruplet regimens with a VMP-Rd regimen in newly diagnosed transplant-ineligible patients with multiple myeloma, considering patient frailty.

Modification of Belantamab Mafodotin Dosing to Balance Efficacy and Tolerability in the DREAMM-7 and DREAMM-8 Trials.

Belantamab mafodotin (belamaf) combined with standard therapies demonstrated significant progression-free survival (PFS) and overall survival benefits in DREAMM-7 and PFS benefit in DREAMM-8 in relapsed/refractory multiple myeloma. Belamaf dose modifications managed adverse events, including belamaf-related ocular events. Ocular events included ocular adverse reactions (eg, dry eyes, photophobia, eye irritation) and protocol-mandated ophthalmic examination findings.

Practical Guidance on Clinical Management of Belantamab Mafodotin-Associated Ocular Events.

Importance: Belantamab mafodotin (belamaf)-containing regimens are effective treatment options for patients with relapsed and/or refractory multiple myeloma. Ocular events are a common adverse effect of belamaf treatment, which can be managed by physicians, following appropriate training, to minimize their impact on the patient.

Objective: To develop clinical recommendations for the identification, monitoring, and management of ocular events associated with belamaf therapy, and guidance for any required dose modification.

Factors Increasing the Risk of Infection in Patients With Multiple Myeloma: From Biology to Prevention.

New therapies for multiple myeloma (MM) have improved survival rates but also increased infection risks, particularly during the early treatment of newly diagnosed disease (NDMM) and in cases of relapsed/refractory disease (RRMM). Understanding the factors contributing to Grade ≥3 infections in MM patients and identifying risk factors is critical for implementing effective prevention strategies and reducing infection incidence and severity. These factors can vary based on the disease, the patient's condition, and the anti-MM therapies employed.

Belantamab mafodotin plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM-7): updated overall survival analysis from a global, randomised, open-label, phase 3 trial.

Background: In the primary (first interim) analysis of the DREAMM-7 trial (median follow-up 28·2 months), belantamab mafodotin, bortezomib, and dexamethasone (BVd) showed a statistically significant and clinically meaningful progression-free survival benefit versus daratumumab, bortezomib, and dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma (RRMM) after at least one line of therapy. The aim of this study is to report overall survival from the second interim analysis, with extended follow-up.

Methods: In the ongoing global, open-label, randomised, phase 3 DREAMM-7 trial done at 142 study centres (research facilities, hospitals, and institutions) in 20 countries across North America, South America, Europe, and the Asia-Pacific region, eligible patients were aged at least 18 years and had confirmed multiple myeloma (according to International Myeloma Working Group criteria), an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and progression on or after at least one previous line of therapy.

Patient-reported outcomes with belantamab mafodotin, bortezomib, and dexamethasone versus daratumumab, bortezomib, and dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM-7): results from a phase 3, open-label, randomised controlled trial.

Background: Belantamab mafodotin, bortezomib, and dexamethasone showed significant progression-free survival benefit compared with daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma in the phase 3 DREAMM-7 study. We aimed to evaluate the effect of belantamab mafodotin, bortezomib, and dexamethasone compared with daratumumab, bortezomib, and dexamethasone on health-related quality of life (HRQOL) using various patient-reported outcomes in patients who participated in DREAMM-7.

Methods: This phase 3, open-label, randomised controlled trial, done at 142 hospitals in 20 countries included adult patients aged 18 years or older with relapsed or refractory multiple myeloma who received at least one previous line of therapy and progressed during or after their most recent treatment and had an Eastern Cooperative Oncology Group performance status of 0 to 2.

Exploring the role of cyclin D1 in the pathogenesis of multiple myeloma beyond cell cycle regulation.

Cyclins D could be a unifying event in multiple myeloma (MM), even though MM is not typically considered a proliferative disease. In this study, we hypothesized that cyclins D might have additional roles in the pathogenesis of MM beyond cell cycle control. We showed that overexpression of CCND1 and CCND2 in MM cell lines lacking these proteins revealed a mutually exclusive expression pattern, with both cyclins D localized in the cytoplasm and no impact on proliferation.

Microbiota Shape Metabolic and Immune Determinants of CAR-T Therapy and Correlate with Outcomes in Myeloma.

Unlabelled: Multiple myeloma remains incurable despite advances in immunotherapies like chimeric antigen receptor (CAR) T-cell therapy. This study investigates the role of metabolites and gut microbiota in clinical outcomes in patients treated with the humanized B-cell maturation antigen (BCMA)-directed CAR-T therapy ARI0002h. Stool metabolites, particularly succinate, were associated with CAR T-cell phenotypes and persistence in patients.

Talquetamab improves patient-reported symptoms and health-related quality of life in relapsed or refractory multiple myeloma: Results from the phase 1/2 MonumenTAL-1 study.

Background: Talquetamab is the first approved G protein-coupled receptor family C group 5 member D-targeting bispecific antibody for the treatment of triple-class exposed relapsed/refractory multiple myeloma (RRMM) on the basis of results from the phase 1/2 MonumenTAL-1 study (ClinicalTrials.gov identifiers NCT03399799 and NCT04634552). This study describes patient-reported outcomes (PROs) among patients who received talquetamab in MonumenTAL-1.

EHA-EMN Evidence-Based Guidelines for diagnosis, treatment and follow-up of patients with multiple myeloma.

Since the publication in 2021 of the European Hematology Association (EHA) Clinical Practice Guidelines for the treatment of patients with smouldering multiple myeloma (SMM) and multiple myeloma (MM), developed in collaboration with the European Society for Medical Oncology, a novel international staging system (R2-ISS) has been developed, several prognostic factors are entering clinical practice (such as minimal residual disease, circulating plasma cells and monoclonal protein assessed by mass spectrometry) and, at the time of writing, 14 novel regimens have been approved by the EMA and/or the FDA for the treatment of patients with MM. A multidisciplinary group of experts from the EHA and European Myeloma Network, based in various institutions mostly located in Europe, have updated the previous guidelines and produced algorithms for everyday clinical practice that incorporate levels of evidence and grades of recommendation based on the aforementioned new data. In these Evidence-Based Guidelines, we provide key treatment recommendations for both patients with newly diagnosed MM and those with relapsed and/or refractory MM, including guidance for the use of established drugs as well as contemporary immunotherapies.

Optimising T-cell immunotherapy in patients with multiple myeloma: practical considerations from the European Myeloma Network.

Novel T-cell immunotherapies (chimeric antigen receptor [CAR] T cells and T-cell redirecting bispecific antibodies) are changing the treatment landscape of relapsed or refractory multiple myeloma. In this Review, the European Myeloma Network provides recommendations to optimise both safety and efficacy of T-cell immunotherapy. In patients who are eligible for both CAR T-cell therapy and bispecific antibodies, we recommend using CAR T-cell therapy first due to the high response rate and durable progression-free survival, accompanied by improved quality of life.

High-dose busulfan-melphalan vs melphalan and reinforced VRD for newly diagnosed multiple myeloma: a phase 3 GEM trial.

In retrospective studies, autologous stem cell transplantation (ASCT) conditioning with intravenous busulfan and melphalan (BUMEL) led to longer progression-free survival (PFS) than melphalan alone (MEL200). We compared BUMEL vs. MEL200 outcomes in newly diagnosed multiple myeloma (NDMM) patients receiving intensified bortezomib, lenalidomide and dexamethasone (VRD) induction and consolidation therapy.

Isatuximab Subcutaneous by On-Body Injector Versus Isatuximab Intravenous Plus Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Phase III IRAKLIA Study.

Purpose: To report the results of the multicenter, open-label IRAKLIA trial (ClinicalTrials.gov identifier: NCT05405166) of isatuximab subcutaneous (SC) versus intravenous (IV), plus pomalidomide and dexamethasone, in relapsed/refractory multiple myeloma (MM), to our knowledge, the first phase III MM trial using an on-body injector (OBI).

Methods: Patients with ≥1 prior line of therapy were randomly assigned 1:1 to Isa OBI (1,400 mg) or IV (10 mg/kg) once weekly in cycle (C)1 and then every 2 weeks, plus pomalidomide (4 mg once daily, day [D]1-21) and dexamethasone (40 mg once weekly [age ≥75: 20 mg]) and treated until progression, unacceptable toxicity, or patient request.

Beyond maximum grade: tolerability of immunotherapies, cellular therapies, and targeted agents in haematological malignancies.

The increasing use of immunotherapeutic approaches, cellular therapies, and targeted agents is rapidly and profoundly changing the treatment paradigms of haematological malignancies. These novel therapies are increasingly incorporated into earlier lines of treatment. Some are administered for a fixed duration, often with curative intent, whereas others are administered chronically for disease control.

Ultrasensitive detection of circulating multiple myeloma cells by next-generation flow after immunomagnetic enrichment.

The continuous improvement in progression-free survival (PFS) of patients with multiple myeloma (MM) raises interest in evaluating peripheral residual disease (PRD) toward more frequent readouts of tumor kinetics while preserving quality of life. We present BloodFlow, a new method combining immunomagnetic enrichment of CD138+ circulating plasma cells in peripheral blood (PB) with next-generation flow (NGF), for the detection of PRD below the 2 × 10-6 NGF threshold. BloodFlow detected PRD in 55 of 644 PB samples (8.

Impact of the Addition of Daratumumab to the Frontline Treatment of Patients with Immunoglobulin Light-Chain Amyloidosis: A Single-Centre Experience.

: Daratumumab-based regimens represent the gold-standard therapy for newly diagnosed AL amyloidosis patients. However, there are few studies about the efficacy of this treatment in real life. : This study included 99 patients: 27 (27.

Outcomes of Patients With Extramedullary Disease in Triple-Class Exposed Relapsed/Refractory Multiple Myeloma From the Pooled LocoMMotion and MoMMent Studies.

Background: Patients with relapsed/refractory multiple myeloma (RRMM) who develop extramedullary disease (EMD) generally have a poor prognosis, highlighting the urgent need for new therapies. We report effectiveness outcomes and safety in patients with and without EMD from the pooled analysis of LocoMMotion and MoMMent.

Methods: LocoMMotion and MoMMent-1 are prospective, noninterventional, consecutive studies assessing the evolving standard of care from 20192022 in patients with triple-class exposed RRMM.

High-risk features of early relapse in newly-diagnosed multiple myeloma: The impact of cytogenetics and response to initial therapy.

Patients with newly-diagnosed multiple myeloma (MM) who experience early relapse (ER) have dismal overall survival (OS). Their prospective identification, either before or soon after treatment initiation, is paramount to use alternative approaches and prevent ER. In this study, we investigated the frequency and disease characteristics of ER during the first 18 months after treatment initiation (ER18), in a series of 1215 newly-diagnosed MM patients enrolled in four PETHEMA/GEM clinical trials for the transplant-eligible and transplant-ineligible populations.

Dynamics of Mutant Hematopoietic Progenitor Cells Are Not Associated with Clinical Outcomes in Multiple Myeloma.

SPMs that develop in patients with multiple myeloma have a deleterious impact on survival. Patients with CH may be at risk of developing SPMs, which could potentially be avoided through individualized treatment. However, our results suggest that screening for CH at diagnosis has limited utility.

Bortezomib, melphalan, and prednisone with or without daratumumab in transplant-ineligible patients with newly diagnosed multiple myeloma (ALCYONE): final analysis of an open-label, randomised, multicentre, phase 3 trial.

Background: In the phase 3 ALCYONE study, the addition of daratumumab to bortezomib, melphalan, and prednisone (D-VMP) significantly improved outcomes in transplant-ineligible patients with newly diagnosed multiple myeloma. Here, we present results from the final analysis of ALCYONE.

Methods: ALCYONE was an international, multicentre, randomised, open-label, active-controlled, phase 3 trial in adults aged 18 years or older with newly diagnosed multiple myeloma who were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or presence of substantial comorbidities, and had an Eastern Cooperative Oncology Group performance status of 0-2.