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Multiple Myeloma (MM) remains a challenging hematological malignancy despite significant advancements made during the past 2 decades. Outcomes have improved by incorporating immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies into treatment algorithms that include high dose chemotherapy and autologous hematopoietic stem cell transplantation. However, many patients may eventually relapse despite these innovations. Newer therapies targeting B-Cell Maturation Antigen (BCMA) offer promise for patients with relapsed or refractory disease. BCMA-targeted therapies carry notable side effects, necessitating vigilant monitoring and proactive infection prevention measures. They can also induce considerable immunosuppression, attributed to lower levels of immunoglobulins and increased susceptibility to infections. There is still a need for alternative treatment options with different mechanisms of action that can be easily administered and have a better safety profile. In addition, pomalidomide only overcomes lenalidomide refractoriness in a subset of patients. This review aims to explore 2 next-generation cereblon E3 ligase modulators (CELMoDs), Mezigdomide (CC92480), and Iberdomide (CC-220). We will discuss the biological aspects of these agents, including their mechanisms of action, efficacy, and toxicity profile, and provide a comprehensive review of current literature. Special attention will be paid to ongoing and future clinical trials that provide insights into the potential of these novel therapies in the management of MM., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The Glasgow prognostic score (GPS) and CAR-HEMATOTOX (CAR-HT) score identify multiple myeloma (MM) patients at high risk for immune-mediated toxicity and early mortality with cellular immunotherapy. However, their association with outcomes in patients receiving T-cell redirecting bispecific antibodies (bsAb) is unclear. This multi-centre retrospective study examines the association of baseline GPS and CAR-HT scores with outcomes in 126 MM patients treated with bsAb. Overall, 19% were identified as GPS high risk but did not experience increased toxicity or mortality. Conversely, high-risk CAR-HT patients had a higher incidence of infections and inferior survival, suggesting a need for aggressive infection mitigation strategies., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

(Charcot-Marie-Tooth disease (CMT) is a genetic disorder affecting peripheral nerves. The human induced pluripotent stem cell (iPSC) line JUCTCi018-A was created using dermal fibroblasts from a Charcot-Marie-Tooth disease type 2EE (CMT2EE) patient with a homozygous missense mutation in the MPV17 gene (c. 122G > A, p.Arg41Gln). These fibroblasts were reprogrammed using Sendai viruses that encoded OCT4, SOX2, KLF4, and c-MYC reprogramming factors. The iPSCs demonstrated normal morphology and karyotype, expressed pluripotency markers, and the ability to differentiate into the three germ layers. This iPSC line is valuable for investigating the mechanisms underlying CMT2EE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Waldenstrom's macroglobulinemia (WM) or lymphoplasmacytic lymphoma is a B-cell malignancy characterized by lymphoplasmacytic cells in the bone marrow that secrete high amounts of immunoglobulin (Ig) M. The large pentameric structure of IgM leads to a variety of unique complications in WM, such as hyperviscosity syndrome, cryoglobulinemia and sensory neuropathy. Furthermore, malignant cells can infiltrate the central nervous system and lead to a variety of neurological complications, also known as Bing Neel Syndrome. Because of the unique pathophysiology of WM and these complications, their diagnostic work up and treatment regimens vary greatly. Given the rarity of the disease and their complications, there are little to no randomized controlled trials regarding treatments of these complications and, therefore, suggested treatment regimens are usually based on observational studies. In this case series, we will present three cases of WM, each with their own unique complication, and discuss the pathophysiology along with current and future treatment options for each of the complications presented., Competing Interests: No statements or declarations to be made, there are no financial or non-financial interests. Figures made in Microsoft Word and obtained from patient charts

Although mesenchymal stem cells (MSCs) are extensively applied in the regenerative field, the majority of MSCs die after a few weeks of transplantation. Therefore, hypoxia pre-conditioning is a crucial step in increasing the MSCs' tolerance to physiological conditions. Meanwhile, induced pluripotent stem cell-derived MSCs (iMSCs) were proposed as a possible alternative to MSCs, and recently, the interest is growing in applying iMSCs in the regenerative field. This study examined the effect of hypoxia pre-conditioning on the proliferation, viability, and differentiation of iMSCs. Both iMSCs and MSCs were subjected to two rounds of severe short-term hypoxia (1 % O 2 for 24h). After that, iMSCs and MSCs were characterized by testing their surface markers' expression, proliferation, viability, oxidative stress, and differentiation potential. Our findings revealed that hypoxia did not have a consistent effect among all the analyzed lines: the severe short-term hypoxia (1 % O 2 ) reduced iMSCs proliferation, cell viability, and MMP while showing a benign effect on surface markers expression, colony formation, ROS accumulation, and osteogenic and adipogenic differentiation. Though hypoxia adversely affected iMSCs' proliferation, this does not necessarily mean that hypoxia is harmful to iMSCs; on the contrary, our results suggest that short-term hypoxia might have a beneficial long-term effect on the proliferation of iMSCs. Thus, the effect of hypoxia on proliferation, viability, and differentiation should also be tested after a long recovery period from iMSCs. Our next step will be to test the effect of hypoxia for a longer period besides uncovering the changes in the expression profile of hypoxic iMSCs., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

In our study of 246 newly diagnosed individuals with MGUS or SMM (115 MGUS, 131 SMM), we found that 19% reported anxiety, with no significant difference between the MGUS and SMM groups (22% vs. 17%). Those with a history of psychiatric disorders or belonging to certain racial groups were more likely to experience anxiety. Initial coping responses included religious coping, denial, frustration, irritability, and seeking social support. Given anxiety's detrimental effects, our findings emphasize the importance of incorporating psychosocial assessments to optimize care for MGUS and SMM patients., Competing Interests: The authors declare no relevant conflict of interest.

Background: Smoldering multiple myeloma (SMM), an asymptomatic precursor of multiple myeloma (MM), carries a variable risk of progression to MM. There is little consensus on the efficacy or optimal timing of treatment in SMM. We systematically reviewed the landscape of all clinical trials in SMM. We compared the efficacy of treatment regimens studied in SMM to results from these regimens when used in newly diagnosed multiple myeloma (NDMM), to determine whether the data suggest deeper responses in SMM versus NDMM., Methods: All prospective interventional clinical trials for SMM, including published studies, meeting abstracts, and unpublished trials listed on ClinicalTrials.gov up to April 1, 2023, were identified. Trial-related variables were captured, including treatment strategy and efficacy results. Relevant clinical endpoints were defined as overall survival (OS) and quality of life., Results: Among 45 SMM trials identified, 38 (84.4%) assessed active myeloma drugs, while 7 (15.6%) studied bone-modifying agents alone. Of 18 randomized trials in SMM, only one (5.6%) had a primary endpoint of OS; the most common primary endpoint was progression-free survival (n = 7, 38.9%). Among 32 SMM trials with available results, 9 (28.1%) met their prespecified primary endpoint, of which 5 were single-arm studies. Six treatment regimens were tested in both SMM and NDMM; 5 regimens yielded a lower rate of very good partial response rate or better (≥VGPR) in SMM compared to the corresponding NDMM trial (32% vs 63%, 43% vs 53%, 40% vs 63%, 86% vs 89%, 92% vs 95%, and 94% vs 87%, respectively)., Conclusion: In this systematic review of all prospective interventional clinical trials in SMM, we found significant variability in trial design, including randomization status, primary endpoints, and types of intervention used. Despite the statistical limitations, comparison of treatment regimens revealed no compelling evidence that the treatment is more effective when introduced early in SMM compared to NDMM., (© The Author(s) 2024. Published by Oxford University Press.)

In recent years, the therapeutic landscape for hematological malignancies has markedly advanced, particularly since the inaugural approval of autologous chimeric antigen receptor T cell (CAR-T) therapy in 2017 for relapsed/refractory acute lymphoblastic leukemia (ALL). Autologous CAR-T therapy involves the genetic modification of a patient's T cells to specifically identify and attack cancer cells, while bispecific antibodies (BsAbs) function by binding to both cancer cells and immune cells simultaneously, thereby triggering an immune response against the tumor. The subsequent approval of various CAR-T therapies and BsAbs have revolutionized the treatment of multiple hematological malignancies, highlighting high response rates and a subset of patients achieving prolonged disease control. This review explores the mechanisms underlying autologous CAR-T therapies and BsAbs, focusing on their clinical application in multiple myeloma, ALL, and non-Hodgkin lymphoma. We provide comprehensive insights into their individual efficacy, limitations concerning broad application, and the potential of combination therapies. These upcoming strategies aim to propel the field forward, paving the way for safer and more effective therapeutic interventions in hematological malignancies., Competing Interests: Declaration of interests S.A.H. reports receiving consulting fees from Jansen, Pfizer, Sanofi, and Galapagos, and research funding from the International Myeloma Society and Alexion. H.E.H. has equity in Allovir and Marker Therapeutics, has served on advisory boards for Tessa Therapeutics, March Biosciences, GSK, Kiadis, and Fresh Wind Biotechnologies, and received research support from Tessa Therapeutics and Kuur Therapeutics. M.K.B. has equity in Allovir, Marker Therapeutics, March Biosciences, and Tessa Therapeutics, has served on advisory boards for Walking Fish Therapeutics, CellGenix GmbH, Marker Therapeutics, Tessa Therapeutics, Abintus, Allogene, Bellicum Pharmaceuticals, Bluebird Bio, Athenex, Memgen, Turnstone Biologics, Coya Therapeutics, TScan Therapeutics, Onkimmune, Poseida Therapeutics, Allovir, Triumvira, MEMGEN, Adaptimmune, and AstraZeneca, and received research support from Tessa Therapeutics. M.S. was a scientific consultant for Tessa Therapeutics and received research support from Tessa Therapeutics and AstraZeneca. Disclosure of outside interests for CAGT investigators: BCM (https://www.bcm.edu/academic-centers/cell-and-gene-therapy/research/disclosure-of-outside-interests)., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

In 2020, the FDA's Oncology Center of Excellence, in collaboration with the American Association for Cancer Research, launched a novel educational partnership known as the FDA-AACR Oncology Educational Fellowship. This year-long program is aimed for hematology/oncology fellows, scientists, and early-career investigators, offering an in-depth exploration of the regulatory review process by blending didactic learning with practical cases discussing oncology drug approvals. The fellowship has been met with enthusiastic feedback, with participants lauding its role in demystifying the regulatory landscape and enhancing their professional careers. This article reflects on the experiences of four alumni, showcasing the program's transformative impact across diverse oncology career paths in government, academia, and industry., (©2024 American Association for Cancer Research.)

Talquetamab is an approved therapy for relapsed multiple myeloma. This study examined dysgeusia and weight loss occurrences, alongside investigating symptom reversibility post-treatment cessation. Dysgeusia was prevalent, persisting in 15% of patients. On average, patients lost 6% of their weight during treatment, with weight loss persisting in about half of the patients post-discontinuation. Weight loss and dysgeusia are important adverse events to consider while on talquetamab treatment. Extending dose intervals can potentially prevent such adverse events and should be studied in future prospective clinical trials., Competing Interests: Samer Al Hadidi reports receiving honoraria from Jansen, Sanofi, and Pfizer., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Context.—: In 2022, 2 distinct guidelines for the diagnosis of myeloid neoplasms became available: the 5th edition of the World Health Organization guideline (WHO2022) solely and the International Consensus Classification (ICC). Despite major overlap, there are important differences that can have important implications., Objective.—: To explore the current opinions and diagnostic practices of hemato-oncologists and hematopathologists across the United States., Design.—: An online anonymous survey was created using REDCap, and a secure link was shared via email to fellowship program leaderships and via posts on social media., Results.—: A total of 310 responses were obtained. Only 33 of 309 respondents (10.7%) reported using solely the 2016 World Health Organization guideline to make diagnoses, whereas 167 of 309 (54%) supplemented it with other guidelines. The rest were either not sure (17; 5.5%), used WHO2022 solely (46; 14.9%), or used ICC solely (6; 1.9%). The choice of guideline was not related to region (P = .15), practice setting (P = .86), or hospital size (P = .22). More than 90% reported it is a source of confusion in clinical diagnosis, management, trial design, and other areas., Conclusions.—: Overall, our study found that having 2 distinct guidelines could be a source of confusion for physicians and calls for a unified diagnostic language., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

Introduction: Achieving diversity and equity in healthcare, especially within academic and clinical spheres, poses significant challenges. This study aims to evaluate gender representation, geographical diversity among authors, and disclosure of conflicts of interest (COIs) in educational materials published by the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH)., Materials and Methods: We conducted a comprehensive cross-sectional analysis covering all volumes of ASCO and ASH educational chapters from 2012 to 2022 and 2000 to 2022, respectively. Author data were extracted from the official websites of ASCO and ASH educational books, focusing on names, affiliations, countries of practice, COIs, and publication titles/subjects., Results: Analysis of 2796 articles revealed significant trends in gender representation. Women comprised 44 % of first authors and 38 % of last authors in ASCO educational books, and 39 % of first authors and 39% of last authors in ASH educational books. Notably, there was a marked increase in female first and last authors over time across both ASCO and ASH publications (p < 0.001). Geographical diversity showed disparities, with the majority of authors affiliated with US institutions (72 % of first and last authors). International authors were less represented, with Canada, the UK, and Italy prominent among articles featuring international women authors. A substantial portion of analyzed articles disclosed COIs, mainly research funding, honoraria, and travel expenses., Discussion: Our findings suggest a notable rise in female authorship, potentially reflecting efforts by ASH and ASCO to promote diversity. International authorship remained stable, while COIs were prevalent, primarily involving research funding. Addressing the need for greater international engagement and improving COI reporting quality are crucial to promote inclusivity and transparency in academic publications., Competing Interests: Declaration of Competing Interest SAH reports receiving honoraria from Pfizer, Jansen and Sanofi., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: The prognosis of multiple myeloma (MM) continues to improve. Recent progress in therapies, using immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies, has greatly improved patients' outcomes. Despite these advancements, relapses still happen often, and patients can become resistant to the usual treatments. Newer treatments, such as chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies (BsAbs) targeting B-cell maturation antigen (BCMA), have resulted in excellent outcomes in patients with limited treatment options. G protein - coupled receptor, class C group 5 member D (GPRC5D) is considered a very promising target with early results from clinical trials showing high response rates in patients with relapsed or refractory multiple myeloma., Areas Covered: This review covers the efficacy and safety of CAR-T and BsAbs targeting GPRC5D in MM, focusing on talquetamab - the inaugural FDA-approved BsAb targeting GPRC5D. Talquetamab has exhibited promising response rates alongside a distinctive side effect profile. Additionally, ongoing trials examining talquetamab in combination with agents like daratumumab and teclistamab are discussed., Expert Opinion: We offer insights into the potential utilization of various GPRC5D-based therapies in the treatment paradigm for MM, either independently or in combination with established therapies.

Talquetamab recently received approval for relapsed refractory multiple myeloma. However, there is currently no available data on how patients perform with BCMA based agents after progression on talquetamab. Herein, we present the outcome of 10 patients who received BCMA based therapies following talquetamab. The median follow-up was 9.5 months (range: 6-24 months). The median progression free survival was 5.5 months (range: 1-10 months). Patients had varying grades of cytokine release syndrome and Immune effector cell-associated neurotoxicity syndrome. Our results suggest that treatment with talquetamab followed by BCMA based therapies is feasible and can be considered as clinically indicated., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Autologous stem cell transplantation (ASCT) has been a mainstay in myeloma treatment for over three decades, but patient prognosis post-ASCT varies significantly. In a retrospective study of 5259 patients with multiple myeloma (MM) at the University of Arkansas for Medical Sciences undergoing ASCT with a median 57-month follow-up, we divided the dataset into training (70%) and validation (30%) subsets. Employing univariable and multivariable Cox analyses, we systematically assessed 29 clinical variables, identifying crucial adverse prognostic factors, such as extended duration between MM diagnosis and ASCT, elevated serum ferritin, and reduced transferrin levels. These factors could enhance existing prognostic models. Additionally, we pinpointed significant poor prognosis markers like high serum calcium and low platelet counts, though they are applicable to a smaller patient population. Utilizing seven easily accessible high-risk variables, we devised a four-stage system (ATM4S) with primary stage borders determined through K-adaptive partitioning. This staging system underwent validation in both the training dataset and an independent cohort of 514 ASCT-treated MM patients from the University of Iowa. We also explored cytogenetic risk factors within this staging system, emphasizing its potential clinical utility for refining prognostic assessments and guiding personalized treatment approaches.

The objective of our study was to report real-world data on the safety and efficacy of standard-of-care teclistamab in patients with relapsed/refractory multiple myeloma (MM). This is a multi-institutional retrospective cohort study and included all consecutive patients that received at least one dose of teclistamab up until August 2023. One hundred and ten patients were included, of whom, 86% had triple-class refractory disease, 76% penta-refractory disease, and 35% had prior exposure to B-cell maturation antigen (BCMA)-targeting therapies. The overall response rate (ORR) in our cohort was 62%, with a ≥ very good partial remission (VGPR) rate of 51%. The ORR in patients with and without prior BCMA-targeted therapies was 54% vs 67%, respectively (p = 0.23). At a median follow-up of 3.5 months (range, 0.39-10.92), the estimated 3 month and 6 month progression free survival (PFS) was 57% (95% CI, 48%, 68%) and 52% (95% CI, 42%, 64%) respectively. The incidence of cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) was 56% and 11% respectively, with grade ≥3 CRS and ICANS noted in 3.5% and 4.6% of patients respectively. 78 unique infections were diagnosed in 44 patients, with the incidence of all-grade and grade ≥3 infections being 40% vs 26% respectively. Primary prophylaxis with intravenous immunoglobulin (IVIG) was associated with a significantly lower infection risk on multivariate analysis (Hazard ratio [HR] 0.33; 95% CI 0.17, 0.64; p = 0.001)., (© 2024. The Author(s).)

The treatment of multiple myeloma has evolved significantly over the past few decades with the development of novel therapeutics. The introduction of proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and high-dose chemotherapy followed by hematopoietic stem cell transplantation has led to improved response rates and survival outcomes. The use of bispecific antibodies and chimeric antigen receptor T-cell therapy is currently under study, and early results are showing promise. Although outcomes for patients with MM have improved with the development of new treatments, there remains a subset of patients with high-risk disease who have a particularly poor prognosis. Therefore, it is critical that future clinical trials focus on developing new therapies specifically for high-risk multiple myeloma. Here we review the literature and provide guidance on treating patients with multiple myeloma for practicing oncologists., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Subjective minimizing language in oncology conferences may undermine patient-centered care and hinder comprehensive treatment strategies. Subjective terms like "safe," "tolerable," and "well-tolerated" can vary in interpretation among individuals, making it difficult to compare results across trials and potentially downplaying significant risks and limitations associated with treatments., Methods: This study evaluates subjective minimizing language in major oncology conferences and its use in adverse event reporting. We conducted a search of three electronic databases, ASCO, ASH, and ESMO, for published abstracts from January 1, 2019, to December 31, 2021. This study included prospective cohort studies or clinical trials in humans that used safety terms like "safe," "well-tolerated," "tolerable," "no new safety signal," or "no new safety concern" in the abstract text., Results: Out of 34,975 reviewed records, 5299 (15.2%) abstracts used subjective minimizing language terms. The analysis included 2797 (52.8%) abstracts meeting the inclusion criteria. The majority of studies were Phase 1 trials (45.5%), followed by Phase 2 (29.6%) and Phase 3 trials (7.4%). Solid tumors accounted for the most common disease category (56.5%), followed by malignant hematology following (37.1%). Subjective minimizing terms like "safe" (69.2%), "well-tolerated" (53.2%), "tolerable" (25.6%), and "no new safety signal/concerns" (10%) were used frequently. Of the abstracts using subjective minimizing language (n = 2797), 81.9% reported data on any grade adverse events (AEs). Grade I/II AEs were reported in 62.6% of abstracts, Grade III/IV AEs in 78%, and Grade V AEs (death related to AEs) in 8.8%. Discontinuation due to AEs occurred in 11.4% (SD 9.5%) of studies using subjective minimizing language terms., Conclusions: Frequent use of subjective minimizing language in major oncology conferences' abstracts may obscure interpretation of study results and the safety of novel treatments. Researchers and clinicians should provide precise and standardized information to avoid overstatement of benefits and understand the true impact of interventions on patients' safety and well-being., Competing Interests: Declaration of Competing Interest A.A., M.A., M.A.A., A.R.,O.O, G.R.M, A.H.K, A.M.G and R.C. reported no conflict of interest. ERSC receives research funding from Arnold Ventures. S.A. reported receiving honoraria from Janssen and Sanofi., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

There is a paucity of granular data on infection risk with B-cell maturation antigen (BMCA) and GPRC5D bispecific antibodies (bsAb) in relapsed/refractory multiple myeloma (RRMM). The aim of our multi-institutional study was to characterize the incidence, etiologies, and risk factors of infections from the start of therapy to the last follow-up or 90 days after study exit. A total of 66 patients received BCMA bsAb monotherapy, 15 GPRC5D bsAb monotherapy, and 15 GPRC5D bsAb combination therapy with daratumumab and/or pomalidomide. While the infection rate per 100 days was 0.57 for BCMA bsAb, it was 0.62 for GPRC5D bsAb combination and 0.13 for GPRC5D bsAb monotherapy; P=0.05. The proportion of infections that were grade ≥3 was higher in the BCMA bsAb group compared to the GPRC5D groups (58% vs. 36%; P=0.04). Grade 5 events were observed in 8% (n=8) of the patients, all treated with BCMA bsAb. The 9 month cumulative incidence of any grade of infection was similar in the BCMA and GPRC5D-combination groups (57% and 62%) and significantly higher than in the GPRC5D-mono group (16%); P=0.012. The cumulative incidence of grade ≥3 infections was highest in the BCMA group reaching 54% at 18 months; P=0.06. Multivariate analysis showed that BCMA bsAb therapy or GPRC5D combination therapy, history of previous infections, baseline lymphopenia, and baseline hypogammaglobulinemia were significantly associated with a higher risk of grade ≥3 infections. Our results indicate that BCMA bsAb and GPRC5D-combination therapies in RRMM are associated with higher cumulative incidence of infection and grade ≥3 infection compared to GPRC5D bsAb mono.

Approximately 90% of patients with multiple myeloma experience significant pain from osseous involvement during their lifetime. Untreated osseous involvement results in vertebral compression fractures, leading to negative consequences for quality of life. Vertebral augmentation procedures, including percutaneous vertebroplasty and kyphoplasty, offer better and faster pain control and likely lower morbidity compared with non-operative interventions. Our review provides an up-to-date summary of the indications, contraindications, timing, outcomes, and potential complications of vertebral augmentation procedures to guide practicing oncologists in effectively managing bone disease in patients with multiple myeloma., Competing Interests: None

Abstract: The total therapy (TT) IIIB phase 2 study incorporated bortezomib into tandem melphalan-based hematopoietic stem cell transplantation with dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide for induction/consolidation and bortezomib, lenalidomide, and dexamethasone (VRD) for maintenance in patients with newly diagnosed multiple myeloma (MM). This updated analysis presents a 15.4-year median follow-up. Of 177 patients, 21% patients had gene expression profile (GEP)-defined high-risk MM. 15-year progression free survival (PFS) was 27.9%. Median PFS was better in GEP-defined low-risk patients at 7.8 years and in International Staging System stage 1 patients at 8.7 years. Overall, median OS was 9.1 years, and 15-year overall survival (OS) was 35.9%. GEP-defined low-risk patients' median OS was 11.2 years, and that of GEP-defined high-risk patients was 2.8 years. There was no difference in OS between TT IIIB and TT IIIA. This study includes the longest follow-up of patients treated with maintenance VRD reported to date. In patients with GEP-defined low-risk, nearly half and one-third of patients without ongoing treatment showed no signs of progression at 10 and 15 years, respectively. One-third of patients survived more than 15 years, but 3 years of VRD maintenance did not improve outcomes for patients with GEP-defined high-risk MM. The study was registered on www.clinicaltrials.gov as #NCT00572169., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF) and is recommended for patients with higher risk disease. However, there is a risk of early mortality, and optimal timing is unknown. JAK inhibitor (JAKi) therapy may offer durable improvement in symptoms, splenomegaly and quality of life. The aim of this multicentre, retrospective observational study was to compare outcomes of patients aged 70 years or below with MF in chronic phase who received upfront JAKi therapy vs. upfront HCT in dynamic international prognostic scoring system (DIPSS)-stratified categories. For the whole study cohort, median overall survival (OS) was longer for patients who received a JAKi vs. upfront HCT, 69 (95% CI 57-89) vs. 42 (95% CI 20-not reached, NR) months, respectively (p = 0.01). In patients with intermediate-2 and high-risk disease, median OS was 55 (95% CI 36-73) months with JAKi vs. 36 (95% CI 20-NR) months for HCT (p = 0.27). An upfront HCT strategy was associated with early mortality and difference in median OS was not observed in any risk group by 5 years of follow-up. Within the limitations of a retrospective observational study, we did not observe any benefit of a universal upfront HCT approach for higher-risk MF., (© 2023. The Author(s).)

Anti-multiple myeloma B cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapies represent a promising treatment strategy with high response rates in myeloma. However, durable cures following anti-BCMA CAR-T cell treatment of myeloma are rare. One potential reason is that a small subset of minimal residual myeloma cells seeds relapse. Residual myeloma cells following BCMA-CAR-T-mediated treatment show less-differentiated features and express stem-like genes, including CD24. CD24-positive myeloma cells represent a large fraction of residual myeloma cells after BCMA-CAR-T therapy. In this work, we develop CD24-CAR-T cells and test their ability to eliminate myeloma cells. We find that CD24-CAR-T cells block the CD24-Siglec-10 pathway, thereby enhancing macrophage phagocytic clearance of myeloma cells. Additionally, CD24-CAR-T cells polarize macrophages to a M1-like phenotype. A dual-targeted BCMA-CD24-CAR-T exhibits improved efficacy compared to monospecific BCMA-CAR-T-cell therapy. This work presents an immunotherapeutic approach that targets myeloma cells and promotes tumor cell clearance by macrophages., (© 2024. The Author(s).)

We have previously demonstrated that cystatin E/M (CST6), which is elevated in a subset of patients with multiple myeloma (MM) lacking osteolytic lesions (OLs), suppresses MM bone disease by blocking osteoclast differentiation and function. CST6 is a secreted type 2 cystatin, a cysteine protease inhibitor that regulates lysosomal cysteine proteases and the asparaginyl endopeptidase legumain. Here, we developed B cell maturation antigen (BCMA) CST6 chimeric antigen receptor T cells (CAR-T cells), which lysed MM cells and released CST6 proteins. Our in vitro studies show that these CAR-T cells suppressed the differentiation and formation of tartrate-resistant acid phosphatase-positive (TRAP+) osteoclasts. Using xenografted MM mice, bioluminescence images showed that both BCMA-CAR-T and BCMA-CST6-CAR-T cells inhibited MM growth to a similar extent. Reconstructed micro-computed tomography images revealed that BCMA-CST6-CAR-T cells, but not BCMA-CAR-T cells, prevented MM-induced bone damage and decreased osteoclast numbers. Our results provide a CAR-T strategy that targets tumor cells directly and delivers an inhibitor of bone resorption.