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Maaike VJ Braham,1 Anil K Deshantri,2,3 Monique C Minnema,4 F Cumhur Öner,1 Raymond M Schiffelers,2 Marcel HAM Fens,2,5 Jacqueline Alblas1 1Department of Orthopaedics, University Medical Center Utrecht, Utrecht, the Netherlands; 2Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, the Netherlands; 3Department of Pharmacology, Sun Pharma Advanced Research Company Limited, Vadodara, Gujarat, India; 4Department of Hematology, University Medical Center Utrecht Cancer Center, Utrecht, the Netherlands; 5Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands Purpose: Liposomal drug delivery can improve the therapeutic index of treatments for multiple myeloma. However, an appropriate 3D model for the in vitro evaluation of liposomal drug delivery is lacking. In this study, we applied a previously developed 3D bone marrow (BM) myeloma model to examine liposomal drug therapy. Material and methods: Liposomes of different sizes (~75–200 nm) were tested in a 3D BM myeloma model, based on multipotent mesenchymal stromal cells, endothelial progenitor cells, and myeloma cells cocultured in hydrogel. The behavior and efficacy of liposomal drug therapy was investigated, evaluating the feasibility of testing liposomal drug delivery in 3D in vitro. Intracellular uptake of untargeted and integrin α4β1 (very late antigen-4) targeted liposomes was compared in myeloma and supporting cells, as well as the effectivity of free and liposome-encapsulated chemotherapy (bortezomib, doxorubicin). Either cocultured myeloma cell lines or primary CD138+ myeloma cells received the treatments. Results: Liposomes (~75–110 nm) passively diffused throughout the heterogeneously porous (~80–850 nm) 3D hydrogel model after insertion. Cellular uptake of liposomes was observed and was increased by targeting very late antigen-4. Liposomal bortezomib and doxorubicin showed increased cytotoxic effects toward myeloma cells compared with the free drugs, using either a cell line or primary myeloma cells. Cytotoxicity toward supporting BM cells was reduced using liposomes. Conclusion: The 3D model allows the study of liposome-encapsulated molecules on multiple myeloma and supporting BM cells, looking at cellular targeting, and general efficacy of the given therapy. The advantages of liposomal drug delivery were demonstrated in a primary myeloma model, enabling the study of patient-to-patient responses to potential drugs and treatment regimes. Keywords: liposomes, targeted delivery, tumor microenvironment, drug sensitivity and resistance testing, multiple myeloma

Background and Purpose: Complement factor C2 is a potential therapeutic target in immune-mediated neuropathies. However, literature suggests that classical complement pathway activation may proceed to C3 in the absence of C2, a so-called "C2 bypass." Here, we evaluated a C2 bypass mechanism during complement activation by pathogenic human IgM from patients with immune-mediated neuropathies., Methods: IgM autoantibodies from 51 patients with multifocal motor neuropathy (MMN) or anti-myelin-associated glycoprotein (MAG) neuropathy (AMN) were used to activate complement in ex vivo disease models. C2 bypass was evaluated using C2-depleted (C2D) serum and a therapeutic anti-C2 antibody., Results: In two different disease models of MMN, IgM anti-GM1 and IgM anti-GM2 autoantibodies from MMN patients were bound to induced pluripotent stem cell-derived motor neurons and Schwann cells, respectively, and fixed C3 upon incubation with fresh serum. C3 fixation was inhibited by anti-C2 and did not occur with C2D serum. Similarly, in an AMN model, IgM anti-MAG antibodies were incubated with fresh serum fixed C3, which in all cases was abrogated in the absence of C2 or in the presence of anti-C2., Conclusions: In ex vivo disease models of MMN and AMN, complement activation by IgM autoantibodies from 51 patients was in all cases dependent on C2 and was inhibited by an antihuman C2 antibody. No evidence of a C2 bypass mechanism was found., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Despite recent metastatic colorectal cancer (mCRC) therapeutic innovations a comprehensive synthesis of patient outcome and risk-benefit assessment of phase 1/2 trials is missing. The aim of this meta-analysis is to assess efficacy, safety, and trends over time for phase 1 and 2 mCRC trials by examining clinical benefit rate (CBR), overall response rate (ORR), grade 3 or higher adverse events (AE), and discontinuation due to AE., Methods: The PRISMA guidelines were followed. We searched PubMed and Embase for publications of phase 1/2 trials between 2010-2021. Trials reporting on new therapies for treatment-refractory mCRC were included., Results: The search strategy yielded 4175 unique reports, of which 258 publications were eligible. These publications report data of 277 unique treatment arms. Overall ORR was 6 %, CBR was 27 % in phase 1 and 36 % in phase 2 trials. CBR increased from 23 % in 2010-2012 to 42 % in 2019-2021. Compared to 2010-2012, trials in 2019-2021 more often tested immunomodulators (4 % vs 23 %), included molecularly preselected populations (4 % vs 38 %) and younger patients (median age<60 44 % vs 66 %). Grade 3 + AE occurred in 35 % of patients, most frequently in trials investigating targeted treatments., Conclusions: Treatment efficacy in phase 1/2 trials is modest but improved from 2010 to 2021. This improvement is accompanied by a shift towards testing in a younger, fitter, and more strictly molecularly preselected population, as well as an increased focus on targeted and immunotherapies., Competing Interests: Declaration of Competing Interest The authors declare no known conflict of interests. The following interests may be considered as potential competing interests. J.M.L.R. grants/contracts: BMS, Pierre Fabre, Servier, Cleara Biotech, HUB organoids; Board Membership: Foundation Hubrecht Organoid Biobank. M.K. grants/contracts: Bayer, BMS, Merck-Serono, Pierre Fabre, Servier, Roche, Sanofi, Personal Genome Diagnostics. M.C.M. grants/contracts: BeiGene; Consulting fees: Janssen-Cilag, GSK, CDR-life; Speakers bureaus: Janssen-Cilag, BMS, WebMD global. All grants were unrelated to the study and paid to individual’s institutions., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Marginal Zone Lymphoma (MZL) and Waldenström's Macroglobulinemia (WM) are indolent lymphomas that both arise from post germinal center lymphocytes. Both can secrete a monoclonal protein but high levels are mostly only seen in WM. The MYD88 L256P somatic mutation that is present in an estimated 95% of patients with WM has helped greatly in differentiating the two lymphomas. Several large clinical studies with new drugs have been performed that have provided new treatment options for both MZL and WM patients. In this short review we will discuss the recent literature published and provide some recommendations., (© 2023 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 CAR T-cell therapy approved in the USA and European Union (EU) for adults with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL; aged ≥26 years in EU). Here, outcomes for patients with R/R B-ALL aged ≥26 years in ZUMA-3 treated with brexu-cel were compared with historical standard-of-care (SOC) therapy. After median follow-up of 26.8 months, the overall complete remission (CR) rate among patients treated with brexu-cel in Phase 2 ( N  = 43) was 72% and median overall survival (OS) was 25.4 months (95% CI, 15.9-NE). Median OS was improved in Phase 2 patients versus matched historical SOC-treated patients. Compared with aggregate historical trial data, Phase 1 and 2 patients had improved OS versus blinatumomab, inotuzumab, and chemotherapy in a matching-adjusted indirect comparison (MAIC) study. These data demonstrate clinical benefit of brexu-cel relative to SOC in patients ≥26 years with R/R B-ALL.

Background and Objectives: Polyneuropathy associated with an immunoglobulin M (IgM) monoclonal gammopathy is characterized by slowly progressive, predominantly distal sensorimotor deficits, sensory ataxia, and electrophysiologic features of demyelination. IgM antibodies against myelin-associated glycoprotein (MAG) are present in serum from most patients. Nerve damage most likely results from the concerted action of binding of anti-MAG antibodies to nerves, followed by complement activation. The interaction of anti-MAG antibodies with complement activation and their relation to clinical characteristics have not been studied in detail. We studied the correlation among anti-MAG antibody titers, complement activation, and IgM-associated polyneuropathy disease severity., Methods: We used serum samples from 101 patients with IgM-associated polyneuropathy to assess IgM anti-MAG titers by ELISA and antibody-mediated complement deposition using both an ELISA-based system and a cell-based system of primate peripheral nerve slides. We studied correlations of complement activation with anti-MAG ELISA titers and clinical characteristics., Results: IgM anti-MAG titers varied from negative to strongly positive. Complement deposition in the ELISA-based system correlated significantly with anti-MAG antibody titer (Spearman rho 0.80; p < 0.0001) despite large variability between serum samples with comparable anti-MAG titers. This variability was even larger in the cell-based assay, which also showed complement deposition in IgM anti-MAG negative patients, indicating the presence of autoantibodies directed against epitopes other than MAG in a subset of patients with IgM-associated polyneuropathy. Clinical characteristics did not correlate with anti-MAG titers or complement activation., Discussion: Anti-MAG antibody titers correlate with the level of complement activation in both ELISA and cell-based systems. However, clinical characteristics of IgM-associated polyneuropathy do not or only weakly correlate with titers or the level of complement deposition. The lack of clear correlations between complement activation and clinical characteristics does, at this stage, not support the use of complement inhibitors in the treatment of IgM-associated polyneuropathy.

Historically, dose selection of anticancer drugs has mainly been based on establishing the maximum tolerated dose in phase 1 clinical trials with a traditional 3 plus 3 design. In the era of targeted therapies and immune-modulating agents, this approach does not necessarily lead to selection of the most favourable dose. This strategy can introduce potentially avoidable toxicity or inconvenience for patients. Multiple changes in drug development could lead to more rational dose selection, such as use of better predictive preclinical models, adaptive and randomised trial design, evaluation of multiple dose levels in late-phase development, assessment of target activity and saturation, and early biomarker use for efficacy and safety evaluation. In this Review, we evaluate the rationale and validation of dose selection in each phase of drug development for anticancer drugs approved by the European Medicines Agency and US Food and Drug Administration from Jan 1, 2020, to June 30, 2023, and give recommendations for dose optimisation to improve safety and patient convenience. In our evaluation, we classified 20 (65%) of the 31 recently registered anticancer agents as potential candidates for dose optimisation, which could be achieved either by reducing the dose (n=10 [32%]) or adjusting the dosage regimen (n=10 [32%]). Dose selection seemed to be adequately justified for nine (29%) of the drugs, whereas the reviewed data were inconclusive for formulating a recommendation on dose optimisation for two (6%) of the drugs., Competing Interests: Declaration of interests NPvE has received research grants from Astellas and Ipsen. NM received consultancy fees from Janssen-Cilag, Bayer, Astellas Pharma, AstraZeneca, Pfizer, and Merck Sharp and Dohme, and research funding (all paid to the institution) from Janssen-Cilag, Astellas Pharma, AstraZeneca/Merck, and Bristol Myers Squibb Foundation. KB received consultancy fees (all paid to the institution) from Merck Sharp and Dohme and Pierre Fabre. HG's institution has received research grants or compensation for patients in studies from Bayer, Boehringer Ingelheim, Deciphera, AmmaxBio, Abbisko, Springworks, Amgen, Pfizer, Novartis, and Servier. GSS received research support (all paid to the institution) from Agendia, AstraZeneca, Merck Sharp and Dohme, Novartis, Roche, and Seagen, and serves on advisory boards for Biovica and Seagen. AJdL reports financial interests and institutional research grants from Bristol Myers Squibb, Merck Sharp and Dohme, Boehringer Ingelheim, and AstraZeneca; and non-financial interests from Merck Serono and Roche. NWCJvdD has received research support (all paid to the institution) from Janssen Pharmaceuticals, Amgen, Celgene, Novartis, Cellectis, and Bristol Myers Squibb; and serves on advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, Bristol Myers Squibb, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Pfizer, AbbVie, and Servier. JJWMJ has received research support (all paid to the institution) from Novartis and Bristol Myers Squibb; serves as president for Apps for Care and Science, a non-profit foundation supported by AbbVie, Alexion, Amgen, Astellas, AstraZeneca, Bristol Myers Squibb, Daiichi-Sankyo, Janssen-Cilag, Novartis, Olympus, Incyte, Sanofi Genzyme, Servier, Jazz, and Takeda; and has received honoraria (all paid to the institution) from AbbVie, Novartis, Pfizer, and Incyte. MCM has received research support (all paid to the institution) from Beigene, consultancy fees (all paid to the institution) from Janssen-Cilag, CDR-life, BMC, and GlaxoSmithKline; fees for speakers bureau (all paid to the institution) from Siemens and Janssen-Cilag; and hospitality from Janssen-Cilag. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The HOVON 104 studied bortezomib-dexamethasone induction therapy and autologous stem cell transplantation in 50 patients, of whom 35 received an autologous stem cell transplantation (ASCT). We demonstrate a 5-year overall survival (OS) of 73% and progression-free survival (PFS) of 52% for all 50 patients with a median follow-up of 61.3 months. For the 35 transplanted patients, calculated from the date of ASCT, the 5-year OS and PFS were 91% and 68%, respectively. After ASCT, the rate of organ response improved over time but stabilized around 3 years. A complete cardiac response was seen in around 60% of patients and remained stable from 2 years onward. Reaching complete renal response was slower over time and achieved by 61% of the renal-affected patients at 5 years. We confirm the excellent outcomes after ASCT and demonstrate a 60% complete organ response with longer follow-up., Competing Interests: MCM Research Funding: Beigene Consultancy: Janssen Cilag, BMS, GSK, CDR‐life, Speakers Bureau: Siemens, Janssen Cilag, all paid to the institution, UH Speakers Bureau: Janssen Cilag, Pfizer, Alnylam, Akcea, Prothena, Astra Zeneca, Hospitality: Janssen, Prothena, Pfizer. Advisory Boards: Pfizer, Prothena, Janssen, Alexion. MJK Honoraria: BMS/Celgene, Kite/Gilead, Novartis, Roche; Consulting or Advisory Role: BMS/Celgene, Kite/Gilead, Miltenyi, Biotech, Novartis, Takeda, Adicet Bio and Miltenyi Biomedicine; Research Funding: Kite/Gilead, all paid to the institution. SZ Research funding: Janssen Cilag, Advisory board: Janssen Cilag, BMS, Sanofi, Oncopeptides, Amgen, all paid to the institution. AB Advisory board: Janssen Pharmaceuticals, Amgen, Celgene, BMS, Takeda. PS Research funding: Janssen Pharmaceuticals, Amgen, Celgene, Karyopharm. Advisory board: Janssen Pharmaceuticals, Pfizer, BMS. SOS Research support: Janssen, Prothena, Sanofi, Neurimmune Advisory boards: Janssen, Telix and Prothena Honoraria: AstraZeneca, Alexion, Sobi, Janssen, Takeda, Pfizer, Prothena. KN, PFY, SC, LT, KLW, GMJB, and HK declare no conflict of interest., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, was approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL) based on the results from pivotal Cohorts 1+2 of ZUMA-1 (NCT02348216). ZUMA-1 was expanded to investigate safety management strategies aimed at reducing the incidence and severity of cytokine release syndrome (CRS) and neurologic events (NEs). Prospective safety expansion Cohort 5 evaluated the impact of debulking therapy, including rituximab-containing immunochemotherapy regimens and radiotherapy, in axi-cel-treated patients; the CRS and NE management strategy paralleled those in Cohorts 1+2. Among the 50 patients in Cohort 5 who received axi-cel, 40% received ≥3 prior lines of chemotherapy, and 40% had disease that progressed while on the most recent chemotherapy. Forty-eight patients (96%) received debulking therapy, 14 (28%) radiotherapy only, and 34 (71%) systemic immunochemotherapy. Median decrease in tumor burden (per sum of product of diameters of target lesions) relative to screening was 17.4% with R-ICE/R-GDP, 4.3% with other debulking chemotherapies, and 6.3% with radiotherapy only. All patients were followed for ≥8 months. CRS was reported in 43 patients (86%), with 1 patient (2%) experiencing grade ≥3. NEs were reported in 28 patients (56%), with 6 (12%) experiencing grade ≥3. Cytopenias were the most frequent grade ≥3 adverse event (AE); 19 (38%) and 18 (36%) treated patients had any and grade ≥3 prolonged thrombocytopenia, respectively, and 25 (50%) and 24 (48%) patients had any and grade ≥3 prolonged neutropenia, respectively. Overall, patients who received debulking chemotherapy had higher incidences of serious treatment-emergent AEs than those who received radiotherapy only. At the 24-month analysis, objective response rate was 72%, and complete response rate was 56%. Median duration of response, progression-free survival, and overall survival were 25.8, 3.1, and 20.6 months, respectively. These results from exploratory Cohort 5 demonstrate the feasibility of debulking prior to axi-cel, and together with current real-world evidence, suggest that debulking regimens may help minimize the frequency and severity of CRS and NEs in patients with R/R LBCL. The incidence of other AEs observed in Cohort 5 suggest the risk/benefit profile was not improved via the debulking regimens studied here., Competing Interests: TvM: honoraria from Kite, a Gilead Company, Gilead Sciences, Celgene/Bristol Myers Squibb; consulting/advisory role for Janssen, Lilly, and Kite; and research funding from Celgene/Bristol Myers Squibb, Siemens, and Genentech. JK: honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Gilead Sciences, Incyte, Janssen, Karyopharm, Merck, Novartis, Pfizer, Roche, and Seattle Genetics; consulting/advisory role for AbbVie, Antengene, Bristol Myers Squibb, Gilead Sciences, Karyopharm, Medison Ventures, Merck, Roche, and Seattle Genetics; research funding from AstraZeneca, Merck, and Roche; and other relationship with DSMB, Karyopharm, and Chair of Scientific Advisory Board Lymphoma Canada. KWS: honoraria from Amgen, Bristol Myers Squibb, Janssen, and Kite, a Gilead Company. CT: consulting or advisory role for Amgen, Bristol Myers Squibb, Incyte, Kite, a Gilead Company, Novartis, Roche, and Takeda; research funding from Roche; and travel, accommodations, and expenses from Bristol Myers Squibb, Incyte, Kite, Novartis, Roche, and Takeda. MCM: consulting or advisory role for Bristol Myers Squibb, CDR-life, GSK, and Janssen-Cilag (institution); speaker’s bureau participation for WebMD (institution); and research funding from BeiGene (institution). EF: consulting or advisory role for Novartis; speakers’ bureau participation for Alexion, Astellas, Gilead Sciences, GSK, Novartis, and Sanofi; and travel support from Alexion, Gilead Sciences, MSD, and Novartis. SDG: honoraria from and consulting/advisory role for AbbVie, Gilead Sciences, and Janssen. MJK: honoraria from and consulting/advisory role for Adicet Bio, Celgene/Bristol Myers Squibb, Kite, a Gilead Company, Miltenyi Biotec, Novartis, and Roche; research funding from Kite (all to institution); and travel support from Kite, Miltenyi Biotec, Novartis, and Roche. PGNJM: no relevant financial relationships to disclose. MW: honoraria from AstraZeneca, Bristol Myers Squibb, Merck, Novartis, and Pfizer; consulting/advisory role for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genmab, Kite, a Gilead Company, Merck, Novartis, and Pfizer; and travel support from AstraZeneca, Bristol Myers Squibb, and Novartis. YZ: employment with Kite, a Gilead Company; and stock or other ownership in Gilead Sciences. AX: Stock or other ownership in Amgen, Biogen, and Kite, a Gilead Company. JNW: employment with and research funding from Kite, a Gilead Company, and stock or other ownership in Gilead. JN: employment with and stock or other ownership in Kite, a Gilead Company. RRS: employment with and stock or other ownership in Kite, a Gilead Company; and patents, royalties, and other intellectual property from Atara and Kite. CS: employment with Kite, a Gilead Company; and stock or other ownership in Gilead Sciences. FN: employment with Kite, a Gilead Company; and stock or other ownership in Gilead Sciences. JJK: employment with and stock or other ownership in Kite, a Gilead Company. MST: consulting/advisory role for AstraZeneca, Bristol Myers Squibb, Genmab, Kite, a Gilead Company, and Roche; research funding from Kite, Regeneron, Roche, and Takeda; and travel support from Janssen and Kite., (AJCR Copyright © 2024.)

This article endeavors to navigate the clinical journey of bispecific antibodies (BsAbs), from elucidating common toxicities and management strategies to examining novel agents and broadening access in community health care. These drugs, commonly through T-cell activation, result in shared adverse events such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Variations in target antigens and designs, however, might introduce unique toxicities for different BsAbs, warranting specific management approaches. Recent US Food and Drug Administration approvals of BsAbs targeting CD3 + T cells linked to CD20 for non-Hodgkin lymphoma and to B-cell maturation antigen or GPRC5D for multiple myeloma have transformed the treatment landscape for hematologic malignancies. Emerging new agents promise further enhancement and safety, exploring novel antigen targets, innovative structures such as trispecific antibodies, and the engagement of diverse immune cells. Simultaneously, the expansion of BsAbs into community practices is underway, demanding a multifaceted strategy that encompasses educational initiatives, operational adaptations, and collaborative frameworks. This ensures comprehensive treatment access, allowing every patient, irrespective of geographical or socioeconomic status, to benefit from these advancements in cancer therapy.

Objectives: To report healthcare resource utilization (HCRU) and safety outcomes in systemic light chain (AL) amyloidosis from the EMN23 study., Materials and Methods: The retrospective, observational, multinational EMN23 study included 4,480 patients initiating first-line treatment for AL amyloidosis in 2004-2018 and assessed, among other objectives, HCRU and safety outcomes. HCRU included hospitalizations, examinations, and dialysis; safety included serious adverse events (SAEs) and adverse events of special interest (AESIs). Data were descriptively analyzed by select prognostic factors (e.g., cardiac staging by Mayo2004/European) for 2004-2010 and 2011-2018. A cost-of-illness analysis was conducted for the UK and Spain., Results: HCRU/safety and dialysis data were extracted for 674 and 774 patients, respectively. Of patients with assessed cardiac stage (2004-2010: 159; 2011-2018: 387), 67.9% and 61.0% had ≥ 1 hospitalization, 56.0% and 51.4% had ≥ 1 SAE, and 31.4% and 28.9% had ≥ 1 AESI across all cardiac stages in 2004-2010 and 2011-2018, respectively. The per-patient-per-year length of hospitalization increased with disease severity (cardiac stage). Of patients with dialysis data (2004-2010: 176; 2011-2018: 453), 23.9% and 14.8% had ≥ 1 dialysis session across all cardiac stages in 2004-2010 and 2011-2018, respectively. The annual cost-of-illness was estimated at €40,961,066 and €31,904,386 for the UK and Spain, respectively; dialysis accounted for ∼28% (UK) and ∼35% (Spain) of the total AL amyloidosis costs., Conclusions: EMN23 showed that the burden of AL amyloidosis is substantial, highlighting the need for early disease diagnosis and effective treatments targeting the underlying pathology., Competing Interests: Disclosure Arnaud Jaccard, honoraria from Servier, Amgen, Abbvie, and Pfizer; participating in advisory committees for Janssen; research funding from Sanofi and Janssen; Frank Bridoux, lecture fees from Janssen, Astra Zeneca, GSK, and Novartis; consultancy for Janssen, Attralus and Astra Zeneca; Wilfried Roeloffzen, honoraria/advisory board from Janssen, MSD, Amgen, and Sanofi; Monique C. Minnema, honoraria from BMS; consultancy for Janssen-Cilag, GSK, CDR life and Gilead; speaker's bureau for Medscape. Research support from Beigene; Rui Bergantim, honoraria/advisory board from Janssen, BMS, Amgen, Takeda and Pfizer; research funding from BMS and Amgen; Roman Hájek, consultancy/advisory relationship with Janssen, Amgen, Celgene, Abbvie, BMS, Novartis, PharmaMar, and Takeda; honoraria from Janssen, Amgen, Celgene, BMS, PharmaMar, and Takeda; research funding from Janssen, Amgen, Celgene, BMS, Novartis, and Takeda; Cristina João, scientific advisory for Takeda, BMS, Janssen, GSK, and Amgen, Abbvie, Pfizer; M. Teresa Cibeira, honoraria for lectures/advisory board for Janssen, Amgen, Akcea, and Sanofi; Giovanni Palladini; participating in advisory boards for Alexion, Argobio, Janssen, and Protego; honoraria from Alexion, Argobio, Janssen, Protego, The Binding Site, Pfizer, Prothena, Sebia, and Siemens; research funding from Gate bioscience and The Binding Site; Stefan Schönland, research support from Janssen, Prothena, and Sanofi; participating in advisory boards for Janssen, Telix, and Prothena; honoraria from Janssen, Takeda, Pfizer, and Prothena; travel and congress participation grants from Janssen, Prothena, Celgene, Binding Site, and Jazz; Paolo Milani, speaker honoraria from Janssen and Pfizer; participating in advisory board for Janssen; Meletios A. Dimopoulos, honoraria from participation in advisory boards from Abbvie, Amgen, Bristol Myers Squibb, Beigene Inc, GSK, Janssen, Karyopharm, Pfizer, Regeneron, Sanofi and Takeda; Ute Hegenbart, travel grants from Janssen, Prothena, and Pfizer; participating in advisory boards for Pfizer, Janssen, and Prothena; honoraria from Janssen, Pfizer, Alnylam, and Akcea; research funding from Janssen and Prothena; Blanca Gros, current employment with Janssen; Aisha Asra, current employment with Janssen; Valeria Magarotto, current employment with Janssen; Giorgos Cheliotis, current employment with Health Data Specialists; Giorgos Psarros, current employment with Health Data Specialists; Pieter Sonneveld, research support from Janssen, BMS, Sanofi, and Amgen, all for EMN trials; participating in advisory boards for Janssen, BMS, Sanofi, Amgen, Cargen, and Pfizer; Ashutosh Wechalekar, honoraria/advisory board from Janssen, Alexion, Attralus, Celgene/BMS, Takeda, and GSK; Efstathios Kastritis, honoraria/advisory board from Genesis Pharma, Janssen, GSK, and Pfizer; research support from Amgen, Janssen, and Pfizer., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: The phase 3 ASPEN trial (NCT03053440) compared Bruton tyrosine kinase inhibitors (BTKis), zanubrutinib and ibrutinib, in patients with Waldenström macroglobulinemia (WM). Post-hoc biomarker analysis was performed using next-generation sequencing on pretreatment bone marrow samples from 98 patients treated with zanubrutinib and 92 patients treated with ibrutinib with mutated (MUT) MYD88 and 20 patients with wild-type (WT) MYD88 treated with zanubrutinib. Of 329 mutations in 52 genes, mutations in CXCR4 (25.7%), TP53 (24.8%), ARID1A (15.7%), and TERT (9.0%) were most common. TP53MUT, ARID1AMUT, and TERTMUT were associated with higher rates of CXCR4MUT (P < .05). Patients with CXCR4MUT (frameshift or nonsense [NS] mutations) had lower very good partial response (VGPR) and complete response rates (CR; 17.0% vs 37.2%, P = .020) and longer time to response (11.1 vs 8.4 months) than patients with CXCR4WT treated with BTKis. CXCR4NS was associated with inferior progression-free survival (PFS; hazard ratio [HR], 3.39; P = .017) in patients treated with ibrutinib but not in those treated with zanubrutinib (HR, 0.67; P = .598), but VGPR + CR rates were similar between treatment groups (14.3% vs 15.4%). Compared with ibrutinib, patients with CXCR4NS treated with zanubrutinib had a favorable major response rate (MRR; 85.7% vs 53.8%; P = .09) and PFS (HR, 0.30; P = .093). In patients with TP53MUT, significantly lower MRRs were observed for patients treated with ibrutinib (63.6% vs 85.7%; P = .04) but not for those treated with zanubrutinib (80.8% vs 81.9%; P = .978). In TP53MUT, compared with ibrutinib, patients treated with zanubrutinib had higher VGPR and CR (34.6% vs 13.6%; P < .05), numerically improved MRR (80.8% vs 63.6%; P = .11), and longer PFS (not reached vs 44.2 months; HR, 0.66; P = .37). Collectively, patients with WM with CXCR4MUT or TP53MUT had worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes., (© 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.)

Background: Studies on the efficacy of rituximab in primary CNS lymphoma (PCNSL) reported conflicting results. Our international randomized phase 3 study showed that the addition of rituximab to high-dose methotrexate, BCNU, teniposide, and prednisolone (MBVP) in PCNSL was not efficacious in the short term. Here we present long-term results after a median follow-up of 82.3 months., Methods: One hundred and ninety-nine eligible newly diagnosed, nonimmunocompromised patients with PCNSL aged 18-70 years with WHO performance status 0-3 was randomized between treatment with MBVP chemotherapy with or without rituximab, followed by high-dose cytarabine consolidation in responding patients, and reduced-dose WBRT in patients aged ≤ 60 years. Event-free survival was the primary endpoint. Overall survival rate, neurocognitive functioning (NCF), and health-related quality of life (HRQoL) were additionally assessed, with the IPCG test battery, EORTC QLQ-C30 and QLQ-BN20 questionnaires, respectively., Results: For event-free survival, the hazard ratio was 0.85, 95% CI 0.61-1.18, P = .33. Overall survival rate at 5 years for MBVP and R-MBVP was 49% (39-59) and 53% (43-63) respectively. In total, 64 patients died in the MBVP arm and 55 in the R-MBVP arm, of which 69% were due to PCNSL. At the group level, all domains of NCF and HRQoL improved to a clinically relevant extent after treatment initiation, and remained stable thereafter up to 60 months of follow-up, except for motor speed which deteriorated between 24 and 60 months. Although fatigue improved initially, high levels persisted in the long term., Conclusions: Long-term follow-up confirms the lack of added value of rituximab in addition to MBVP and HD-cytarabine for PCNSL., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

ZUMA-1 safety management cohort 6 investigated the impact of prophylactic corticosteroids and earlier corticosteroids and/or tocilizumab on the incidence and severity of cytokine release syndrome (CRS) and neurologic events (NEs) following axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL). Prior analyses of cohort 6 with limited follow-up demonstrated no Grade ≥3 CRS, a low rate of NEs, and high response rates, without negatively impacting axi-cel pharmacokinetics. Herein, long-term outcomes of cohort 6 (N = 40) are reported (median follow-up, 26.9 months). Since the 1-year analysis (Oluwole, et al. Blood. 2022;138[suppl 1]:2832), no new CRS was reported. Two new NEs occurred in two patients (Grade 2 dementia unrelated to axi-cel; Grade 5 axi-cel-related leukoencephalopathy). Six new infections and eight deaths (five progressive disease; one leukoencephalopathy; two COVID-19) occurred. Objective and complete response rates remained at 95% and 80%, respectively. Median duration of response and progression-free survival were reached at 25.9 and 26.8 months, respectively. Median overall survival has not yet been reached. Eighteen patients (45%) remained in ongoing response at data cutoff. With ≥2 years of follow-up, prophylactic corticosteroids and earlier corticosteroids and/or tocilizumab continued to demonstrate CRS improvement without compromising efficacy outcomes, which remained high and durable., (© 2024. The Author(s).)

A man in his 60s, known with multiple sclerosis, presented with seizures and paresis of the left arm and leg. Brain imaging showed a white matter lesion, right parietal, which was progressive over the last 6 years and not typical for multiple sclerosis. Brain biopsy showed a B-cell infiltrate with IgA lambda monotypic plasma cell differentiation and amyloid deposits, typed as lambda immunoglobulin light chain (AL). Bone marrow biopsy and PET/CT ruled out a systemic lymphoma. Extended history taking, blood and urine testing (including cardiac biomarkers) identified no evidence of systemic amyloidosis-induced organ dysfunction.Primary cerebral AL amyloidoma is a very rare entity where optimal treatment is difficult to assess. The patient was treated with locally applied volumetric modulated arc radiotherapy, 24 Gy, divided in 12 fractions. Afterwards, the paresis of the left arm partially resolved, and the function of the left leg improved. Seizures did not occur anymore., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patients with newly diagnosed high-risk Burkitt lymphoma are treated with high-intensity immune-chemotherapy regimens such as R-CODOX-M/R-IVAC or with lower-intensity regimens such as DA-EPOCH-R. The aim of this study was to make a formal comparison between these regimens., Methods: This multicentre, phase 3, open-label, randomised study was done in 26 clinical centres in the Netherlands, Belgium, and Switzerland. Eligible patients were aged 18-75 years with newly diagnosed high-risk Burkitt lymphoma without CNS involvement. Patients were randomly assigned to two cycles of R-CODOX-M/R-IVAC (R-CODOX-M: rituximab 375 mg/m 2 on day 1 and 9, cyclophosphamide 800 mg/m 2 on day 1, cyclophosphamide 200 mg/m 2 on days 2-5, vincristine 1·5 mg/m 2 on days 1 and 8, doxorubicin 40 mg/m 2 on day 1, and methotrexate 3000 mg/m 2 on day 10; R-IVAC: rituximab 375 mg/m 2 on days 3 and 7, iphosphamide 1500 mg/m 2 on days 1-5, etoposide 60 mg/m 2 on days 1-5, and cytarabin 2000 mg/m 2 on day 1 and 2) or six cycles of DA-EPOCH-R (dose-adjusted etoposide 50-124 mg/m 2 on days 1-4, prednisolone 120 mg/m 2 on days 1-5, vincristine 0·4 mg/m 2 on days 1-4, dose-adjusted cyclophosphamide 480-1866 mg/m 2 on day 5, dose-adjusted doxorubicin 10-24·8 mg/m 2 on days 1-4, rituximab 375 mg/m 2 on days 1 and 5). Patients older than 65 years received a dose modified R-CODOX-M/R-IVAC. All drugs were intravenous except for prednisolone, which was oral. Patients also received four intrathecal CNS administrations with cytarabin (70 mg) and four with methotrexate (15 mg). Patients were stratified by centre, leukemic disease, and HIV-positivity. The primary endpoint was progression-fee survival. All analyses were done by modified intention-to-treat, excluding randomly assigned patients who were subsequently found to have CNS involvement or diagnosis other than Burkitt lymphoma at study entry. This study is registered with the European Clinical Trial Register, EudraCT2013-004394-27., Findings: Due to a slow accrual, the study was closed prematurely on Nov 15, 2021. Between Aug 4, 2014, and Sept 17, 2021, 89 patients were enrolled and randomly assigned to receive R-CODOX-M/R-IVAC (n=46) or DA-EPOCH-R (n=43). Five patients were excluded after random assignment (three in the R-CODOX-M/R-IVAC group [one diagnosis other than Burkitt lymphoma at study entry according to local pathology and two CNS involvement] and two in the DA-EPOCH-R group [one diagnosis other than Burkitt lymphoma at study entry according to local pathology and one CNS involvement]. 84 remaining patients were included in the modified intention-to-treat analysis. 73 (87%) of 84 patients were male, 76 (90%) presented with stage III or IV disease, and nine (11%) had HIV-positive Burkitt lymphoma. Median patient age was 52 years (IQR 37-64). With a median follow-up of 28·5 months (IQR 13·2-43·7), 2-year progression-free survival was 76% (95% CI 60-86%) in the R-CODOX-M/R-IVAC group and 70% (54-82%) in the DA-EPOCH-R group (hazard ratio 1·42, 95% CI 0·63-3·18; p=0·40). There were two deaths in the R-CODOX-M/R-IVAC group (one infection [treatment related] and one due to disease progression [not treatment related]) and one death in the DA-EPOCH-R group (COVID-19 infection [treatment related]). In the R-CODOX-M/R-IVAC group, four patients went off-protocol because of toxic effects, versus none in the DA-EPOCH-R group. Patients treated with R-CODOX-M/R-IVAC had more infectious adverse events (24 [56%] of 43 patients had at least one grade 3-5 infection vs 14 [34%] of 41 patients in the DA-EPOCH-R group)., Interpretation: The trial stopped early, but the available data suggest that while DA-EPOCH-R did not result in superior progression-free survival compared with R-CODOX-M/R-IVAC, it was associated with fewer toxic effects and need for supportive care. DA-EPOCH-R appears to be an additional valid therapeutic option for patients with high-risk Burkitt lymphoma without CNS involvement., Funding: The Dutch Cancer Society and the Schumacher-Kramer Foundation., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Response to daratumumab in patients with relapsed/refractory multiple myeloma is heterogeneous, and a reliable biomarker of response is lacking. We aimed to develop a method that identifies response to daratumumab therapy. Patient-derived MM cells were collected before start of daratumumab treatment and were cultured in a hydrogel-based culture system. The extent of antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in vitro was associated with both clinical response and progression-free survival in corresponding patients. Together, our results demonstrate that in vitro sensitivity to daratumumab therapy in a hydrogel culture with primary MM cells might be used to identify patients most likely to benefit from treatment., Competing Interests: M.C.M received honoraria paid to institution by Jansen Cilag, BMS, Gilead, Medscape, GSK, and Alnylam. M.J. received research funding by Novartis. V.P. received royalty payments related to venetoclax. The other authors declare no potential conflict of interest., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

The phase III ASPEN study demonstrated the comparable efficacy and improved safety of zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia (WM). Here, we report long-term follow-up outcomes from ASPEN. The primary end point was the sum of very good partial response (VGPR) + complete response (CR) rates; secondary and exploratory end points were also reported. Cohort 1 comprised 201 patients (myeloid differentiation primary response 88-mutant WM: 102 receiving zanubrutinib; 99 receiving ibrutinib); cohort 2 comprised 28 patients (myeloid differentiation primary response 88 wild-type WM: 28 zanubrutinib; 26 efficacy evaluable). At 44.4-month median follow-up, VGPR + CR rates were 36.3% with zanubrutinib versus 25.3% with ibrutinib in cohort 1 and 30.8% with one CR in cohort 2. In patients with CXC motif chemokine receptor 4 mutation, VGPR + CR rates were 21.2% with zanubrutinib versus 10.0% with ibrutinib (cohort 1). Median progression-free survival and overall survival were not reached. Any-grade adverse events (AEs) of diarrhea (34.7% v 22.8%), muscle spasms (28.6% v 11.9%), hypertension (25.5% v 14.9%), atrial fibrillation/flutter (23.5% v 7.9%), and pneumonia (18.4% v 5.0%) were more common with ibrutinib versus zanubrutinib; neutropenia (20.4% v 34.7%) was less common with ibrutinib versus zanubrutinib (cohort 1). Zanubrutinib was associated with lower risk of AE-related treatment discontinuation. Overall, these findings confirm the long-term response quality and tolerability associated with zanubrutinib.

Background: Primary plasma cell leukaemia is a rare and aggressive plasma cell disorder with a poor prognosis. The aim of the EMN12/HOVON-129 study was to improve the outcomes of patients with primary plasma cell leukaemia by incorporating carfilzomib and lenalidomide in induction, consolidation, and maintenance therapy., Methods: The EMN12/HOVON-129 study is a non-randomised, phase 2, multicentre study conducted at 19 academic centres and hospitals in seven European countries (Belgium, Czech Republic, Denmark, Italy, Norway, The Netherlands, and the UK) for previously untreated patients with primary plasma cell leukaemia aged 18 years or older. Inclusion criteria were newly diagnosed primary plasma cell leukaemia (defined as >2 ×10 9 cells per L circulating monoclonal plasma cells or plasmacytosis >20% of the differential white cell count) and WHO performance status 0-3. Patients aged 18-65 years (younger patients) and 66 years or older (older patients) were treated in age-specific cohorts and were analysed separately. Younger patients were treated with four 28-day cycles of carfilzomib (36 mg/m 2 intravenously on days 1, 2, 8, 9, 15, and 16), lenalidomide (25 mg orally on days 1-21), and dexamethasone (20 mg orally on days 1, 2, 8, 9, 15, 16, 22, and 23). Carfilzomib-lenalidomide-dexamethasone (KRd) induction was followed by double autologous haematopoietic stem-cell transplantation (HSCT), four cycles of KRd consolidation, and then maintenance with carfilzomib (27 mg/m 2 intravenously on days 1, 2, 15, and 16 for the first 12 28-day cycles, and then 56 mg/m 2 on days 1 and 15 in all subsequent cycles) and lenalidomide (10 mg orally on days 1-21) until progression. Patients who were eligible for allogeneic HSCT, could also receive a single autologous HSCT followed by reduced-intensity conditioning allogeneic HSCT and then carfilzomib-lenalidomide maintenance. Older patients received eight cycles of KRd induction followed by maintenance therapy with carfilzomib and lenalidomide until progression. The primary endpoint was progression-free survival. The primary analysis population was the intention-to-treat population, irrespective of the actual treatment received. Data from all participants who received any study drug were included in the safety analyses. The trial was registered at www.trialregister.nl (until June 2022) and https://trialsearch.who.int/ as NTR5350; recruitment is complete and this is the final analysis., Findings: Between Oct 23, 2015, and Aug 5, 2021, 61 patients were enrolled and received KRd induction treatment (36 patients aged 18-65 years [20 (56%) were male and 16 (44%) female], and 25 aged ≥66 years [12 (48%) were male and 13 (52%) female]). With a median follow-up of 43·5 months (IQR 27·7-67·8), the median progression-free survival was 15·5 months (95% CI 9·4-38·4) for younger patients. For older patients, median follow-up was 32·0 months (IQR 24·7-34·6), and median progression-free survival was 13·8 months (95% CI 9·2-35·5). Adverse events were most frequently observed directly after treatment initiation, with infections (two of 36 (6%) younger patients and eight of 25 (32%) older patients) and respiratory events (two of 36 [6%] younger patients and four of 25 [16%] older patients) being the most common grade 3 or greater events during the first four KRd cycles. Treatment-related serious adverse events were reported in 26 (72%) of 36 younger patients and in 19 (76%) of 25 older patients, with infections being the most common. Treatment-related deaths were reported in none of the younger patients and three (12%) of the older patients (two infections and one unknown cause of death)., Interpretation: Carfilzomib and lenalidomide-based therapy provides improved progression-free survival compared with previously published data. However, results remain inferior in primary plasma cell leukaemia compared with multiple myeloma, highlighting the need for new studies incorporating novel immunotherapies., Funding: Dutch Cancer Society, Celgene (a BMS company), and AMGEN., Competing Interests: Declaration of interests NWCJvdD reports research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis and BMS, and advisory board role with Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Takeda, Roche, Novartis, Bayer, Pfizer, Abbvie, Adaptive, and Servier, all paid to employer. MCM reports research support from Beigene; consultancy or advisory roles with Janssen, GSK, and CDR-life; honoraria from BMS, Pfizer, Janssen, and Medscape; and data safety monitoring board role for BMS, all paid to employer. BvdH reports honoraria for data safety monitoring board membership from the Intergroupe Francophone du Myélome. FS reports research support from Celgene, Janssen, Oncopeptides, Sanofi, GSK, and Targovax; honoraria from Amgen, BMS, Takeda, Abbvie, Janssen, Novartis, SkyliteDX, Oncopeptides, Sanofi, Pfizer, Daiki-Sankyo, and GSK; and participated on a data safety monitoring board or advisory board for Abbvie, GSK, Celgene, Takeda, Janssen, Oncopeptides, Sanofi, and BMS. KLW has served in advisory boards for Janssen and Pfizer. AB received honoraria and served in advisory boards from BMS, Janssen, Amgen, and Sanofi. WWHR reports honoraria from Amgen and SANOFI, all paid to employer; support for travel from Takeda and Abbvie; and advisory board participations for BMS/Celgene, and Janssen, all paid to employer. VHJvdV reports a Laboratory Services Agreement with BD Biosciences, Cytognos, and Agilent, all paid to employer. TL has received research grants from Takeda, AMGEN, and Janssen, honoraria from AMGEN, Janssen, BMS, and Pfizer; traveling support from Pfizer and Janssen; and equipment from Takeda and Pfizer. MO has received honoraria and served in advisory board for AbbVie, Amgen, BMS, GSK, Janssen, Sanofi, and Takeda. PT has received honoraria from Janssen, BMS/Celgene, GlaxoSmithKline, Takeda, Amgen, Sanofi, Pfizer, and AbbVie and support for traveling from Janssen, BMS/Celgene, Sanofi, and AMGEN. KM has received honoraria from GSK, Janssen, Pfizer, and Sanofi; support for traveling from Sanofi; and participates on an advisory board for Pfizer. JC has received research funding from Janssen, honoraria from AMGEN and Janssen, and support for travel from GILEAD. SZ has received research funding from Takeda and Janssen and serves in advisory boards for Janssen, Takeda, and BMS, all paid to institution. RH has received research funding from Janssen, AMGEN, Celgene/BMS, Novartis, and Takeda, all paid to employer; consulting fees from Janssen, AMGEN, Celgene, Abbvie, BMS, Novartis, Pharmamar, and Takeda; honoraria from Janssen, AMGEN, Celgene, BMS, Pharmamar, and Takeda; support for attending meetings from AMGEN, Celgene, Takeda, and Janssen; and has participated on advisory boards from BMS, Takeda, AMGEN, Oncopeptides, Sanofi, Janssen, and GSK. RB reports educational grant from BMS/Celgene. AJV reports honoraria from BMS. MB reports research funding from Sanofi, Celgene, Amgen, Janssen, Novartis, BMS, and Mundipharma; honoraria from Sanofi, Celgene, Amgen, Janssen, Novartis, BMS, and Abbvie; and advisory board role for Janssen. FG reports honoraria from Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, AbbVie, GlaxoSmithKline, data safety monitoring board or advisory board participation for Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, AbbVie, GlaxoSmithKline, Roche, Adaptive Biotechnologies, Oncopeptides, bluebird bio, and Pfizer. PS reports advisory board roles with Amgen, BMS, Celgene, Janssen, Karyopharm, and Pfizer and research funding from Amgen, BMS, Celgene, Janssen, Karyopharm, and Pfizer. PM reports honoraria from or Advisory Board role with AMGEN and BMS. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

What Is This Summary About?: This plain language summary describes the results of a phase 1 research study (or clinical trial) called MonumenTAL-1 published in the New England Journal of Medicine in December 2022. A phase 1 study is an early clinical trial where researchers evaluate how safe a medicine is at different doses in a small number of people. In the MonumenTAL-1 study, researchers looked at a new medicine under development called talquetamab, for people living with multiple myeloma (a type of blood cancer) who did not respond (refractory), stopped responding (relapsed), or who had difficulty dealing with their previous treatments., How Was the Study Conducted?: The phase 1 MonumenTAL-1 study was performed in 2 parts. Safety was the main focus of Part 1 in which side effects, and how serious they were, were assessed. The results of Part 1 were used to identify doses of talquetamab that were well tolerated, without a need to stop treatment or reduce the doses, for further study in Part 2. Part 2 of the study examined how well talquetamab worked to decrease signs of the cancer and what side effects, and their severity, people experienced at the doses identified in Part 1., What Were the Results?: In Part 1 of the study, researchers identified 2 doses of talquetamab for further study: 405 micrograms for every kilogram of body weight (μg/kg) given weekly and 800 μg/kg every other week. All participants experienced at least one side effect of treatment at these 2 doses. Less than half of participants (43% at 405 μg/kg weekly dose and 34% at the 800 μg/kg every other week dose) experienced serious side effects which are those side effects that led to hospitalization, death, or permanent or life-threatening damage). The most common side effects at both doses were a condition known as cytokine release syndrome (CRS); changes in blood cell levels (where different types of cells in the blood were measured); changes in skin such as itching, dry skin, eczema, ulcers or shedding; changes in nails such as discoloration or ridging (lines or dents); and changes in sense of taste such as food tasting sour or metallic. CRS is caused by the overactivation of the immune system (the body's natural defense system) and can result in fever, feeling sick (nausea), being tired (fatigue), low blood pressure, low blood oxygen levels and body aches. Most cases of CRS, as well as most other side effects, were mild or moderate. Most common serious events were CRS, fever and bone pain. Most people had fewer signs of the cancer after taking talquetamab, and the response was similar between the 2 doses. The median duration of response at the 2 identified doses was 8-10 months., What Do the Results Mean?: Most of the side effects people experienced when taking talquetamab were mild or moderate. Most people who took talquetamab responded to the treatment even though they hadn't responded or stopped responding to previous multiple myeloma treatments or stopped taking those treatments because they were unable to tolerate them. These results demonstrate the potential of talquetamab as a treatment option in people who have used up other available therapy options. The 2 doses of talquetamab identified here are being examined in a larger group of participants to further test for safety and to test how well people respond.

Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder characterized by the presence of a predominant monoclonal antibody (i.e., M-protein) in serum, without clinical symptoms. Here we present a case study in which we detect MGUS by liquid-chromatography coupled with mass spectrometry (LC-MS) profiling of IgG1 in human serum. We detected a Fab-glycosylated M-protein and determined the full heavy and light chain sequences by bottom-up proteomics techniques using multiple proteases, further validated by top-down LC-MS. Moreover, the composition and location of the Fab-glycan could be determined in CDR1 of the heavy chain. The outlined approach adds to an expanding mass spectrometry-based toolkit to characterize monoclonal gammopathies such as MGUS and multiple myeloma, with fine molecular detail. The ability to detect monoclonal gammopathies and determine M-protein sequences straight from blood samples by mass spectrometry provides new opportunities to understand the molecular mechanisms of such diseases.

The real-world results of chimeric antigen receptor T-cell (CAR-T) therapy for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) substantially differ across countries. In the Netherlands, the CAR-T tumorboard facilitates a unique nationwide infrastructure for referral, eligibility assessment and data collection. The aim of this study was to evaluate real-world outcomes of axicabtagene ciloleucel (axi-cel) in the Dutch population, including the thus-far underreported effects on health-related quality of life (HR-QoL). All patients with R/R LBCL after ≥2 lines of systemic therapy referred for axi-cel treatment between May 2020-May 2022 were included (N = 250). Of the 160 apheresed patients, 145 patients received an axi-cel infusion. The main reason for ineligibility was rapidly progressive disease. The outcomes are better or at least comparable to other studies (best overall response rate: 84% (complete response: 66%); 12-month progression-free-survival rate and overall survival rate: 48% and 62%, respectively). The 12-month NRM was 5%, mainly caused by infections. Clinically meaningful improvement in several HR-QoL domains was observed from Month 9 onwards. Expert-directed patient selection can support effective and sustainable application of CAR-T treatment. Matched comparisons between cohorts will help to understand the differences in outcomes across countries and select best practices. Despite the favorable results, for a considerable proportion of patients with R/R LBCL there still is an unmet medical need.

Background: Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the USA for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and in the European Union for patients ≥26 years with R/R B-ALL. After 2 years of follow-up in ZUMA-3, the overall complete remission (CR) rate (CR+CR with incomplete hematological recovery (CRi)) was 73%, and the median overall survival (OS) was 25.4 months in 78 Phase 1 and 2 patients with R/R B-ALL who received the pivotal dose of brexu-cel. Outcomes by prior therapies and subsequent allogeneic stem cell transplantation (alloSCT) are reported., Methods: Eligible adults had R/R B-ALL and received one infusion of brexu-cel (1×10⁶ CAR T cells/kg) following conditioning chemotherapy. The primary endpoint was the CR/CRi rate per central review. Post hoc subgroup analyses were exploratory with descriptive statistics provided., Results: Phase 1 and 2 patients (N=78) were included with median follow-up of 29.7 months (range, 20.7-58.3). High CR/CRi rates were observed across all prior therapy subgroups examined: 1 prior line of therapy (87%, n=15) and ≥2 prior lines (70%, n=63); prior blinatumomab (63%, n=38) and no prior blinatumomab (83%, n=40); prior inotuzumab (59%, n=17) and no prior inotuzumab (77%, n=61); and prior alloSCT (76%, n=29) and no prior alloSCT (71%, n=49). The frequency of Grade ≥3 cytokine release syndrome, neurological events, and treatment-related Grade 5 adverse events were largely similar among prior therapy subgroups.Median duration of remission (DOR) in responders with (n=14) and without (n=43) subsequent alloSCT was 44.2 (95% CI, 8.1 to not estimable (NE)) and 18.6 months (95% CI, 9.4 to NE); median OS was 47.0 months (95% CI, 10.2 to NE) and not reached (95% CI, 23.2 to NE), respectively. Median DOR and OS were not reached in responders without prior or subsequent alloSCT (n=22)., Conclusions: In ZUMA-3, adults with R/R B-ALL benefited from brexu-cel, regardless of prior therapies and subsequent alloSCT status, though survival appeared better in patients without certain prior therapies and in earlier lines of therapy. Additional studies are needed to determine the impact prior therapies and subsequent alloSCT have on outcomes of patients who receive brexu-cel., Competing Interests: Competing interests: BS reports honoraria from Acrotech Biopharma, BeiGene, Gilead Sciences, Janssen, Pharmacyclics, and Spectrum; consulting/advisory role for Adaptive Biotechnologies; Amgen; Celgene/BMS; Kite, a Gilead Company; Novartis; Pfizer; and Precision BioSciences; research funding from Gilead Sciences, Incyte, Jazz Pharmaceuticals, and Kite; and travel support from Celgene, Janssen, Kite, Novartis, Pfizer, Seattle Genetics, and Stemline Therapeutics. RC reports spouse employment with Seagen; stock or other ownership in Seagen; honoraria from Amgen, Autolus (board member), PeproMene Bio (board member), Pfizer, and Kite; consultancy/advisory role for Amgen and Jazz; and research funding from Pfizer, Merck, Amgen, Servier, Kite, and Vanda. JHP reports consulting/advisory role for AstraZeneca, Kite, and Novartis and research funding from Amgen, Genentech, and Juno. RH reports honoraria from ADC therapeutics, Bristol Myers Squibb, Celgene, Gilead Sciences, Janssen, Kite, MSD, Novartis, and Roche; and consulting/advisory role for Kite/Gilead. OOO reports consulting/advisory role for Pfizer, Kite, Gilead, AbbVie, Janssen, TG Therapeutics, ADC, Novartis, Epizyme, Curio Science, Nektar, and Syncopation; research funding from Kite, Pfizer, Daiichi Sankyo, and Allogene; and honoraria from Pfizer and Gilead. ACL reports consulting/advisory role for AbbVie, Bristol Myers Squibb, and Pfizer; research funding from Amgen, Amphivena, Astellas, Autolus, Jazz, Kadmon, Kite, and Pharmacyclics. NB reports honoraria from and consulting/advisory role for Gilead Sciences. TL reports consultancy/advisory role for Amgen and Servier. MRBi reports honoraria from Incyte, Bristol Myers Squibb, Sanofi, and ADC Therapeutics; consulting/advisory role for Novartis, Kite/Gilead, Bristol Myers Squibb, Sana Bio, and CRISPR Therapeutics; and speakers’ bureau participation for Incyte, Bristol Myers Squibb, Sanofi, and ADC Therapeutics. MST reports consulting/advisory role for Amgen, Celgene, Kite, Regeneron, and Roche and research funding from Amgen, Kite, MacroGenics, Regeneron, and Roche. DT reports consulting/advisory role for Bristol Myers Squibb, EUSA, Partner, and Takeda; and research funding from Bristol Myers Squibb. KMO reports consulting/advisory role for Beam Therapeutics. MLA reports consulting/advisory role for Kite and Syndax Pharmaceuticals, Inc. and research funding from Kite (institutional PI). YL reports consulting/advisory role for Kite/Gilead, Celgene/BMS, Juno/BMS, bluebird bio, Janssen, Legend Biotech, Gamida Cell, Novartis, Iovance, Takeda, Fosun Kite, and Pfizer and research funding from Kite/Gilead, Celgene/BMS, bluebird bio, Janssen, Legend Biotech, Merck, Takeda, and Boston Scientific. MRBa reports research funding from AbbVie, Ascentage, Kite, Kura, and Takeda. GJS reports honoraria and research funding from and speakers’ bureau participation for Kite. MS reports consulting/advisory role for Amgen, Celgene/BMS, Gilead Sciences, Janssen, and Novartis; speakers’ bureau participation for Celgene/BMS, Gilead Sciences, Janssen, and Novartis; research funding from Amgen, Gilead Sciences, Miltenyi Biotec, MorphoSys, Roche, and Seattle Genetics; and travel support from Takeda. MA reports stock or other ownership in CytoDyn; consulting/advisory role for Celgene; and speakers’ bureau participation for Celgene, Bristol Myers Squibb, AbbVie, and Kite. MCM reports consulting/advisory role for Gilead Sciences and Janssen-Cilag and speakers’ bureau participation for Janssen-Cilag and Medscape. WW reports consulting/advisory role for Genzyme and Sanofi and research funding from AbbVie, Acerta, Cyclacel, Genentech, Gilead Sciences, GSK, Janssen, Juno, Karyopharm, Loxo Oncology, miRagen, Novartis, Oncternal, Pharmacyclics, Sunesis, and Xencor. DJD reports consulting or advisory role for Agios, Amgen, Autolus, Blueprint Medicines, Forty Seven, Gilead Sciences, Incyte, Jazz, Novartis, Pfizer, Shire, and Takeda and research funding from AbbVie, Glycomimetics, Novartis, and Blueprint Medicines. PJS reports honoraria from and consulting or advisory role for MorphoSys and CRISPR Therapeutics and research funding from Amgen, Gamida Cell, Pfizer, Karyopharm, Gilead Sciences, Incyte, Seagen, and Cellectar. DJ reports research funding from Jazz Pharmaceuticals and Pfizer. DM has nothing to report. SA reports employment with and stock or other ownership in Kite. LZ reports employment with Kite and ownership of AbbVie RSU or stock in the past 2 years. reports employment with Kite; stock or other ownership in Gilead Sciences; and travel support from Kite and Gilead Sciences. RDK reports employment, stock, or other ownership in Kite. AG reports consulting/advisory role for Amgen, Atara, Bristol Myers Squibb, CRISPR Therapeutics, Kite, and Wugen Inc.; research funding from Amgen, Genentech, and Kite; and honoraria from Kite., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Bing-Neel syndrome is a rare manifestation of Waldenström macroglobulinemia (WM), which is caused by infiltration of the malignant lymphoplasmacytic cells in the central nervous system. Patients can present with a diverse range of neurologic symptoms, and differentiation with other comorbidities seen in WM, such as immunoglobulin M-related polyneuropathy, can be challenging. Both the rarity of this disorder and the heterogeneity of the clinical presentation often cause a significant diagnostic delay with the risk of permanent neurologic damage. This review summarizes current knowledge regarding diagnosis, treatment and prognosis of Bing-Neel syndrome., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: In an analysis of the primary outcome of this phase 3 trial, patients with early relapsed or refractory large B-cell lymphoma who received axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, as second-line treatment had significantly longer event-free survival than those who received standard care. Data were needed on longer-term outcomes., Methods: In this trial, we randomly assigned patients with early relapsed or refractory large B-cell lymphoma in a 1:1 ratio to receive either axi-cel or standard care (two to three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation in patients who had a response). The primary outcome was event-free survival, and key secondary outcomes were response and overall survival. Here, we report the results of the prespecified overall survival analysis at 5 years after the first patient underwent randomization., Results: A total of 359 patients underwent randomization to receive axi-cel (180 patients) or standard care (179 patients). At a median follow-up of 47.2 months, death had been reported in 82 patients in the axi-cel group and in 95 patients in the standard-care group. The median overall survival was not reached in the axi-cel group and was 31.1 months in the standard-care group; the estimated 4-year overall survival was 54.6% and 46.0%, respectively (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.54 to 0.98; P = 0.03 by stratified two-sided log-rank test). This increased survival with axi-cel was observed in the intention-to-treat population, which included 74% of patients with primary refractory disease and other high-risk features. The median investigator-assessed progression-free survival was 14.7 months in the axi-cel group and 3.7 months in the standard-care group, with estimated 4-year percentages of 41.8% and 24.4%, respectively (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). No new treatment-related deaths had occurred since the primary analysis of event-free survival., Conclusions: At a median follow-up of 47.2 months, axi-cel as second-line treatment for patients with early relapsed or refractory large B-cell lymphoma resulted in significantly longer overall survival than standard care. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.)., (Copyright © 2023 Massachusetts Medical Society.)

The CD38-targeting antibody daratumumab has marked activity in multiple myeloma (MM). Natural killer (NK) cells play an important role during daratumumab therapy by mediating antibody-dependent cellular cytotoxicity via their FcγRIII receptor (CD16), but they are also rapidly decreased following initiation of daratumumab treatment. We characterized the NK cell phenotype at baseline and during daratumumab monotherapy by flow cytometry and cytometry by time of flight to assess its impact on response and development of resistance (DARA-ATRA study; NCT02751255). At baseline, nonresponding patients had a significantly lower proportion of CD16 + and granzyme B + NK cells, and higher frequency of TIM-3 + and HLA-DR + NK cells, consistent with a more activated/exhausted phenotype. These NK cell characteristics were also predictive of inferior progression-free survival and overall survival. Upon initiation of daratumumab treatment, NK cells were rapidly depleted. Persisting NK cells exhibited an activated and exhausted phenotype with reduced expression of CD16 and granzyme B, and increased expression of TIM-3 and HLA-DR. We observed that addition of healthy donor-derived purified NK cells to BM samples from patients with either primary or acquired daratumumab-resistance improved daratumumab-mediated MM cell killing. In conclusion, NK cell dysfunction plays a role in primary and acquired daratumumab resistance. This study supports the clinical evaluation of daratumumab combined with adoptive transfer of NK cells., Competing Interests: MCM has a consultancy or advisory role for Gilead Sciences, BMS, Alnylam, Janssen Cilag, Takeda, and Servier; all paid to employer, hospitality from Celgene. MDL serves in advisory boards for Roche, Janssen and Abbvia. AB receives honoraria from Celgene, Janssen, Amgen, Takeda, and Sanofi. MJK has received research support from Kite/Gilead, and honoraria from Kite/Gilead, Novartis, BMS/Celgene, Takeda, Roche, and Miltenyi Biotec (all paid to institution). MK, TC, YA, RIV, TS, GV, DCS, LvS, and ER are employed by Janssen. PS has received honoraria from Amgen, BMS, Celgene, Janssen, Karyopharm, Takeda, and receives research funding from Amgen, Celgene, Janssen, Karyopharm, SkylineDx, Takeda. SZ has received research funding from Celgene, Takeda, Janssen, and serves in advisory boards for Janssen, Takeda, BMS, Oncopeptides and Sanofi, all paid to institution. TM has received research support from Janssen Pharmaceuticals, Takeda, Genmab, Novartis, and ONK Therapeutics. NWCJvdD has received research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis, and BMS, and serves in advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Takeda, Roche, Novartis, Bayer, Adaptive, and Servier. All the other authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)