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A challenge in neuroimaging is acquiring frame sequences at high temporal resolution from the largest possible number of pixels. Measuring 1%-10% fluorescence changes normally requires 12-bit or higher bit depth, constraining the frame size allowing imaging in the kHz range. We resolved Ca 2+ or membrane potential signals from cell populations or single neurons in brain slices by acquiring fluorescence at 8-bit depth and by binning pixels offline, achieving unprecedented frame sizes at kHz rates. In hippocampal slices stained with the Ca 2+ indicator Fluo-4 AM, we resolved transients at 2 kHz from large frames. Along the apical dendrite of a layer-5 pyramidal neuron, we measured Ca 2+ signals associated with a back-propagating action potential at 10 kHz. Finally, in the axon initial segment of the same cell type, we recorded an action potential at 40 kHz by voltage-sensitive dye imaging. This approach unlocks the potential for a range of imaging measurements., (© 2025 The Author(s). Journal of Biophotonics published by Wiley‐VCH GmbH.)

Although survival rates for patients with newly diagnosed multiple myeloma (NDMM) have improved over recent decades, multiple myeloma (MM) remains without a cure for most. There is increasing consensus that achievement of deep remissions, especially minimal residual disease negativity (MRD -), in frontline treatment is crucial and translates into improved survival. The standard of care (SOC) for NDMM consists at minimum of a triplet regimen of therapies, with or without an autologous stem cell transplant, or a doublet regimen for certain ineligible, particularly frail patients who may have specific limitations. Recently, anti-CD38 monoclonal antibodies (mAbs), such as daratumumab (Dara) or isatuximab (Isa), have been integrated into frontline SOC regimens. Seeking to further deepen and prolong responses, several clinical trials have commenced investigating the addition of anti-CD38 mAbs to carfilzomib, lenalidomide, and dexamethasone (KRd). These quadruplet regimens (Isa/Dara-KRd) are being evaluated in the context of evolving treatment considerations for the heterogeneous population of patients with NDMM. In clinical trials, the addition of Isa/Dara to KRd achieved high rates of deep responses and MRD - . Favorable outcomes were observed in patients with NDMM independent of age, transplant eligibility, and cytogenetic risk, while these treatments did not result in unexpected or emergent safety risks. The efficacy observed with intensified, yet well-tolerated therapy may offer further development of risk- and response-adapted therapy for individualized patient needs. This review summarizes the clinical outcomes of quadruplet-based therapy with Isa/Dara-KRd in NDMM., Competing Interests: Declarations. Ethics Approval: N/A. Consent: N/A Competing Interests: L.J.C. received research funding from Amgen, BMS, Caribou, Genentech, and Janssen; and honoraria from Adaptive Biotechnologies, Amgen, BMS, Janssen, and Pfizer. F.G. reports consulting fees from Amgen, BMS, Oncopeptides, Pfizer, and Roche; honoraria from AbbVie, Amgen, BMS, Janssen, Sanofi, and Takeda; and data safety monitoring or advisory board participation from AbbVie, Amgen, BMS, Janssen, Oncopeptides, Pfizer, Roche, Sanofi, and Takeda. O.L. acknowledges funding from Amgen, Celgene, FDA, Glenmark, IMF, Janssen, Karyopharm Therapeutics, LLS, MMRF, Myeloma Solutions Fund, NCI/NIH, Paula and Rodger Riney Foundation, Perelman Family Foundation, Rising Tide Foundation, Seattle Genetics, Takeda, and Tow Foundation; honoraria for scientific talks/participation in advisory boards for AbbVie, Adaptive, Amgen, Binding Site, BMS, Celgene, GSK, Janssen, Juno, and Pfizer; and serving on Independent Data Monitoring Committees (IDMCs) for international randomized trials by Janssen, Merck, Novartis, and Takeda. M-V.M. reports consulting fees from Amgen, GSK, Janssen, Seagen, and Takeda; honoraria and data safety monitoring or advisory board participation from AbbVie, Amgen, Celgene, GSK, Janssen, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, and Takeda. P.M. reports advisory board participation and honoraria from AbbVie, Amgen, BMS, Celgene, Janssen, Pfizer, Sanofi, and Takeda. C.T. received honoraria from and served in a consulting or advisory role for AbbVie, Amgen, Celgene, Janssen, and Takeda; and had travel, accommodations or other expenses paid or reimbursed by AbbVie, Amgen, Janssen, and Takeda. F.E., I.M., and R.N. are employees of Amgen. K.W. has served in a consulting or advisory role for Adaptive Biotechnologies, Amgen, BMS, Celgene, GSK, Janssen-Cilag, Karyopharm Therapeutics, Oncopeptides, Roche, Sanofi, and Takeda; received travel, accommodations, and/or expenses from Amgen, BMS, Celgene, GSK, Janssen-Cilag, and Takeda; honoraria from AbbVie, Adaptive Biotechnologies, Amgen, BMS, Celgene, GSK, Janssen-Cilag, Karyopharm Therapeutics, Novartis, Oncopeptides, Pfizer, Roche/Genentech, Sanofi, and Takeda; and research funding from Amgen, BMS, Celgene, GSK, Janssen-Cilag, and Sanofi., (© 2025. The Author(s).)

Most transplant-ineligible patients present with multiple myeloma (MM) refractory to lenalidomide and/or anti-CD38 monoclonal antibody at first relapse and represent a difficult-to-treat population. The Intergroupe Francophone du Myélome phase 2 study iberdomide, ixazomib and dexamethasone (I2D) evaluated the oral triplet iberdomide, ixazomib and dexamethasone in MM patients aged ≥70 years at first relapse (NCT04998786). Seventy patients were enrolled to receive iberdomide (1.6 mg on day 1-21), ixazomib (3 mg on day 1, 8, 15) and dexamethasone (20 mg on day 1, 8, 15, 22 on cycle 1-2 and 10 mg on day 1, 8, 15, 22 on cycle 3-6) (28-day cycle) until disease progression. Median age was 76; 50% patients were frail according to the International Myeloma Working Group frailty score; 74% and 37% were refractory to lenalidomide and daratumumab respectively. With a median follow-up of 14 months, the overall response rate was 64%, including 36% very good partial response or better. The 12-month progression-free survival, duration of response and overall survival were 52%, 76% and 86% respectively. The most common (46%) grade 3-4 toxicity was neutropenia. Non-haematological adverse events were mostly grade 1 or 2. Overall, I2D demonstrated a favourable risk-benefit profile in elderly MM patients at first relapse, including in patients with lenalidomide and daratumumab refractory disease., (© 2025 British Society for Haematology and John Wiley & Sons Ltd.)

The backbone of induction therapy in acute myeloid leukaemia (AML) is to use an anthracycline in combination with cytarabine. Despite recent advances in AML therapy, this treatment remains the standard, and it has been largely unchanged for decades. There are few curative options for patients unfit for this treatment. The anti-protozoal agent emetine improves efficacy of anthracycline treatment towards AML in vitro and in vivo but the effect is more potent when emetine is administered 30 minutes after anthracyclines. To delay the onset of protein synthesis inhibition we produced a novel inactive emetine prodrug and co-encapsulated this with the anthracycline daunorubicin (DNR) in liposomes. Nanoencapsulation protects the prodrug from degradation in the blood and ensure simultaneous delivery of both drugs to cancer cells. The prodrug concept will delay the onset of action of emetine relative to DNR. In AML cells, the combination of DNR and the emetine-prodrug in liposomes increased cytotoxicity compared to liposomes with DNR and native emetine. Liposomes loaded with the emetine prodrug did not show increased toxicity towards non-cancerous cell lines and zebrafish larvae. In patients, a liposomal formulation such as that presented herein could allow for a reduced DNR dose without compromising efficacy, thereby reducing toxic side effects and enabling improved therapy for patients not fit for current treatment options., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Lars Herfindal reports financial support was provided by Childhood Cancer Association. Edvin Tang Gundersen reports financial support was provided by Western Norway Regional Health Authority. Ingeborg N Reiten reports financial support was provided by Research Council of Norway. Francois-Xavier Legrand reports financial support was provided by National Centre for Scientific Research. David Chapron reports financial support was provided by National Centre for Scientific Research. If there are other authors, they 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.)

MXenes stand out from other 2D materials because they combine very good electrical conductivity with hydrophilicity, allowing cost-effective processing as thin films. Therefore, there is a high fundamental interest in unraveling the electronic transport mechanisms at stake in multilayers of the most conducting MXene, Ti 3 C 2 T x . Although weak localization (WL) has been proposed as the dominating low-temperature (LT) transport mechanism in Ti 3 C 2 T x thin films, there have been few attempts to model it quantitatively. In this work, the role of important structural parameters - thickness, interflake coupling, defects - on the dimensionality of the LT transport mechanisms in spin-coated Ti 3 C 2 T x thin films is investigated through LT and magnetic field dependent resistivity measurements. A dimensional crossover from 2D to 3D WL is clearly evidenced when the film thickness exceeds the dephasing length l ϕ , estimated here in the 50-100 nm range. 2D WL can be restored by weakening the coupling between adjacent flakes, the intrinsic thickness of which is lower than l ϕ , hence acting as parallel 2D conductors. Alternatively, l ϕ can be reduced down to the 10 nm range by defects. These results clearly emphasize the ability of WL quantitative study to give deep insights in the physics of electron transport in MXene thin films., (© 2024 Wiley‐VCH GmbH.)

Early intervention of smoldering multiple myeloma (SMM) may delay progression to multiple myeloma. Here, we present the final analysis of the phase 2 CENTAURUS study (NCT02316106). In total, 123 patients with intermediate/high-risk SMM were randomized to intravenous daratumumab 16 mg/kg following a Long intense (n = 41), Intermediate (n = 41), or Short intense (n = 41) dosing schedule. At a combined median follow-up of 85.2 months, in the Long intense, Intermediate, and Short intense arms complete response or better rates were 4.9%, 9.8%, and 0%; overall response rates were 58.5%, 53.7%, and 37.5%; progressive disease/death rates were 0.096, 0.102, and 0.109 (P <0.0001 for all arms); and median progression-free survival was not reached, 84.4, and 74.1 months, respectively. Median overall survival was not reached in any arm. Thirty-six patients in the Long intense or Intermediate arms continued daratumumab in an optional extension phase after completing 20 cycles of per protocol treatment. Median (range) duration of study treatment was 44.0 (1.0-91.6), 35.2 (1.9-90.6), and 1.6 (0.1-1.9) months in the Long intense, Intermediate, and Short intense arms, respectively. No new safety signals were observed. With extended follow-up (median, ~7 years), these data highlight the tolerability of daratumumab and support ongoing trials investigating daratumumab as an early intervention for SMM. ClinicalTrials.gov Identifier: NCT02316106., (Copyright © 2024 American Society of Hematology.)

Background: Daratumumab, an anti-CD38 monoclonal antibody, has been approved for the treatment of multiple myeloma. Data are needed regarding the use of daratumumab for high-risk smoldering multiple myeloma, a precursor disease of active multiple myeloma for which no treatments have been approved., Methods: In this phase 3 trial, we randomly assigned patients with high-risk smoldering multiple myeloma to receive either subcutaneous daratumumab monotherapy or active monitoring. Treatment was continued for 39 cycles, for 36 months, or until confirmation of disease progression, whichever occurred first. The primary end point was progression-free survival; progression to active multiple myeloma was assessed by an independent review committee in accordance with International Myeloma Working Group diagnostic criteria., Results: Among the 390 enrolled patients, 194 were assigned to the daratumumab group and 196 to the active-monitoring group. With a median follow-up of 65.2 months, the risk of disease progression or death was 51% lower with daratumumab than with active monitoring (hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.67; P<0.001). Progression-free survival at 5 years was 63.1% with daratumumab and 40.8% with active monitoring. A total of 15 patients (7.7%) in the daratumumab group and 26 patients (13.3%) in the active-monitoring group died (hazard ratio, 0.52; 95% CI, 0.27 to 0.98). Overall survival at 5 years was 93.0% with daratumumab and 86.9% with active monitoring. The most common grade 3 or 4 adverse event was hypertension, which occurred in 5.7% and 4.6% of the patients in the daratumumab group and the active-monitoring group, respectively. Adverse events led to treatment discontinuation in 5.7% of the patients in the daratumumab group, and no new safety concerns were identified., Conclusions: Among patients with high-risk smoldering multiple myeloma, subcutaneous daratumumab monotherapy was associated with a significantly lower risk of progression to active multiple myeloma or death and with higher overall survival than active monitoring. No unexpected safety concerns were identified. (Funded by Janssen Research and Development; AQUILA ClinicalTrials.gov number, NCT03301220.)., (Copyright © 2024 Massachusetts Medical Society.)

Abstract: Outcomes are poor in triple-class-exposed (TCE) relapsed and refractory multiple myeloma (R/RMM). In the phase 3 KarMMa-3 trial, patients with TCE R/RMM and 2 to 4 prior regimens were randomized 2:1 to idecabtagene vicleucel (ide-cel) or standard regimens (SRs). An interim analysis (IA) demonstrated significantly longer median progression-free survival (PFS; primary end point; 13.3 vs 4.4 months; P < .0001) and higher overall response rate (ORR) with ide-cel vs SRs. At final PFS analysis (median follow-up, 30.9 months), ide-cel further improved median PFS vs SRs (13.8 vs 4.4 months; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.38-0.63). PFS benefit with ide-cel vs SRs was observed regardless of number of prior lines of therapy, with greatest benefit after 2 prior lines (16.2 vs 4.8 months, respectively). ORR benefit was maintained with ide-cel vs SRs (71% vs 42%; complete response, 44% vs 5%). Patient-centric design allowed crossover from SRs (56%) to ide-cel upon progressive disease, confounding overall survival (OS) interpretation. At IA of OS, median was 41.4 (95% CI, 30.9 to not reached [NR]) vs 37.9 (95% CI, 23.4 to NR) months with ide-cel and SRs, respectively (HR, 1.01; 95% CI, 0.73-1.40); median OS in both arms was longer than historical data (9-22 months). Two prespecified analyses adjusting for crossover showed OS favoring ide-cel. This trial highlighted the importance of individualized bridging therapy to ensure adequate disease control during ide-cel manufacturing. Ide-cel improved patient-reported outcomes vs SRs. No new safety signals were reported. These results demonstrate the continued favorable benefit-risk profile of ide-cel in early-line and TCE R/RMM. This trial was registered at www.ClinicalTrials.gov as #NCT03651128., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Abstract: Teclistamab is a B-cell maturation antigen (BCMA)-directed bispecific antibody approved for the treatment of patients with triple-class exposed relapsed/refractory multiple myeloma (R/RMM). In the phase 1/2 MajesTEC-1 study, a cohort of patients who had prior BCMA-targeted therapy (antibody-drug conjugate [ADC] or chimeric antigen receptor T-cell [CAR-T] therapy) was enrolled to explore teclistamab in patients previously exposed to anti-BCMA treatment. At a median follow-up of 28.0 months (range, 0.7-31.1), 40 patients with prior BCMA-targeted therapy had received subcutaneous 1.5 mg/kg weekly teclistamab. The median prior lines of treatment was 6 (range, 3-14). Prior anti-BCMA therapy included ADC (n = 29), CAR-T (n = 15), or both (n = 4). The overall response rate was 52.5%; 47.5% of patients achieved very good partial response or better, and 30.0% achieved complete response or better. The median duration of response was 14.8 months, the median progression-free survival was 4.5 months, and the median overall survival was 15.5 months. The most common treatment-emergent adverse events (TEAEs) were neutropenia, infections, cytokine release syndrome, and anemia; cytopenias and infections were the most common grade ≥3 TEAEs. Infections occurred in 28 patients (70.0%; maximum grade 3/4, n = 13 [32.5%]; grade 5, n = 4 [10%]). Before starting teclistamab, baseline BCMA expression and immune characteristics were unaffected by prior anti-BCMA treatment. The MajesTEC-1 trial cohort C results demonstrate favorable efficacy and safety of teclistamab in patients with heavily pretreated R/RMM and prior anti-BCMA treatment. This trial was registered at www.ClinicalTrials.gov as #NCT03145181 and #NCT04557098., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Treatment of relapsed/refractory multiple myeloma (RRMM) is challenging as patients exhaust all available therapies and the disease becomes refractory to standard drug classes. Here we report the final results of LocoMMotion, the first prospective study of real-world clinical practice (RWCP) in triple-class exposed (TCE) patients with RRMM, with a median follow-up of 26.4 months (range, 0.1-35.0). Patients (N  =  248) had received median 4 prior LOT (range, 2-13) at enrollment. 91 unique regimens were used in index LOT. Overall response rate was 31.9% (95% CI, 26.1-38.0), median progression-free survival (PFS) was 4.6 months (95% CI, 3.9-5.6) and median overall survival was 13.8 months (95% CI, 10.8-17.0). 152 patients (61.3%) had subsequent LOTs with 134 unique regimens, of which 78 were used in first subsequent LOT. Median PFS2 (from start of study through first subsequent LOT) was 10.8 months (95% CI, 8.4-13.0). 158 patients died on study, 67.7% due to progressive disease. Additional subgroup analyses and long-term safety summaries are reported. The high number of RWCP treatment regimens utilized and poor clinical outcomes confirm a lack of standardized treatment for TCE patients with RRMM, highlighting the need for new treatments with novel mechanisms., Competing Interests: Competing interests: M-VM has received honoraria from or served on the board of directors/advisory committees for AbbVie, Adaptive Biotechnologies, Amgen, BMS/Celgene, GSK, Janssen, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, Seagen, and Takeda. KW has served as a consultant and received honoraria from Adaptive Biotechnologies, Karyopharm, and Takeda; has received honoraria from Roche; and has received honoraria and served as a member on boards of directors and/or advisory committees for Amgen, BMS, Celgene, GSK, Janssen, Oncopeptides, and Sanofi. VDS has served on an advisory board or speakers’ bureaus and received honoraria from AbbVie, Alexion, AOP Health, argenx, BMS, GSK, Grifols, Leo Pharma, Novartis, Novo Nordisk, Sanofi, SOBI, and Takeda. HG has served as a consultant for Amgen, Novartis, and Takeda; has served as a consultant and received honoraria, grants, and/or provision of investigational medicinal product and research funding from Amgen, BMS, Celgene, Chugai, Janssen, and Sanofi; has received research funding from Incyte, Molecular Partners, MSD, Mundipharma, and Novartis; and has received other grants from Dietmer Hopp Foundation. MD has received honoraria from Amgen, BMS, GSK, and Janssen; and has served on the speakers’ bureau for Janssen. MM has received honoraria from Adaptive Biotech, Amgen, Astellas, BMS, Gilead, Novartis, Pfizer, and Takeda; and has received honoraria/research funding from Celgene and Sanofi. JL-H has no relationships to disclose. DD is an employee/consultant/honoraria/member of board of directors/advisory committees for Janssen Cilag; and a member of the board of directors/advisory committees/received research funding from Celgene. EA has no relationships to disclose. LV has served on the advisory board of BMS, Janssen, and Takeda. AP has received honoraria from or has served in a consulting/advisory role for AbbVie, Amgen, BMS, Janssen, Pfizer, Sanofi, and Takeda. RB has received honoraria/research funding from Allogene, BMS, Gilead, Janssen, and Servier. NWCJvdD has received research funding from AbbVie, Amgen, BMS, Celgene, Cellectis, Janssen Pharmaceuticals, and Novartis; and has served in a consulting/advisory role for Adaptive, Amgen, Bayer, BMS, Celgene, Janssen, Novartis, Pfizer, Roche, Sanofi, Servier, and Takeda. EMO has received honoraria from or has served in a consulting/advisory role for AbbVie, Amgen, BMS, GSK, Janssen, Karyopharm, Menarini, Oncopeptides, Pfizer, Sanofi, and Takeda. TR is a former Janssen employee. JMS is a Janssen employee. SK is a Janssen employee. IH is a Janssen employee. VS is a Janssen employee. LM is a Janssen employee. JB is a Janssen employee. OCF is an employee of Legend Biotech USA Inc. HE has received research funding or honoraria and has served in a consulting/advisory role for Amgen, BMS/Celgene, GSK, Janssen, and Sanofi. PM has received honoraria and/or served on advisory boards for AbbVie, Amgen, Celgene, Janssen, Sanofi, and Takeda., (© 2024. The Author(s).)

Electronic wastes are a valuable resource due to their critical and precious metal content. To include these wastes in recycling or recovery chains, it is necessary to precisely determine their metal content. Because analysing the whole sample of a batch of electronic waste is not practical, different preparation and sampling or subsampling steps are necessary. Sampling induces an error in the composition of the final sample compared to that of the initial batch, which finally leads to uncertainty in the final metal content measurement as compared to the "actual" batch metal content. The aim was to characterize the uncertainty in metal content of a batch of 372 kg of WPCB. Thirty-nine metals were analysed and thirty-two were considered: base, precious, rare-earths and critical metals. An empirical method (i.e. replicated measurement tests) was thus applied, based on statistical calculations according to Eurachem Guidelines. Uncertainty arising during the 3 different stages of the preparation process (primary, secondly and tertiary sampling steps) was calculated. For the analysed given weight (0.5 g), the shredding efficiency, which directly affects metal particle size distribution, was found to be the most important factor influencing the uncertainty. Uncertainties in base metal content, which is often concentrated in the coarsest particles, arose mainly from the last preparation step (tertiary sampling). Conversely, precious metals and rare-earths were finely ground during the 3 preparation steps, which led to low uncertainties, despite their low concentration in the waste (<337 mg/t for precious and < 35 mg/t for rare-earths)., 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. Published by Elsevier Ltd.)

The International Staging System for multiple myeloma recently underwent a second revision (R2-ISS) to include gain/amplification of 1q21 and account for the additive prognostic significance of multiple high-risk features. The phase 3 ICARIA-MM (isatuximab-pomalidomide-dexamethasone vs. pomalidomide-dexamethasone) and IKEMA (isatuximab-carfilzomib-dexamethasone vs. carfilzomib-dexamethasone) studies provide large datasets for retrospectively validating the prognostic value of the R2-ISS in relapsed/refractory multiple myeloma. Of 609 pooled patients, 68 (11.2%) were reclassified as R2-ISS stage I, 136 (22.3%) as R2-ISS stage II, 204 (33.5%) as R2-ISS stage III, 55 (9.0%) as stage IV, and 146 (24.0%) "Not classified". Median progression-free survival was shorter among those reclassified as R2-ISS stage II (HR 1.52, 95% CI 0.979-2.358), stage III (HR 2.59, 95% CI 1.709-3.923), and stage IV (HR 3.51, 95% CI 2.124-5.784) versus stage I. Adding isatuximab led to longer progression-free survival versus doublet therapy (adjusted HR 0.544 [95% CI 0.436-0.680]), with a consistent treatment effect observed across all R2-ISS stages. This is the first study to validate the R2-ISS with novel agents, including anti-CD38 monoclonal antibodies, and to show that R2-ISS, as a prognostic scoring system, can be applied to patients with relapsed/refractory multiple myeloma., Competing Interests: Competing interests: PGR reports research funding from Celgene/BMS, Karyopharm, Oncopeptides, and Takeda; and participation on advisory boards for AstraZeneca, Celgene/BMS, GSK, Karyopharm, Oncopeptides, Regeneron, and Sanofi. AP reports honoraria from AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Pfizer, Sanofi, and Takeda; research funding from Takeda; and support for attending meetings and/or travel from Amgen and Janssen. JM reports consulting fees from Amgen, BMS, Janssen, Karyopharm, Sanofi, and Takeda. TM reports research funding from Sanofi. MB reports honoraria from Janssen, Sanofi, and Takeda; and participation on a data safety monitoring board or advisory board for Amgen, Menarini, Sanofi, and Takeda. IS reports honoraria from Amgen, BMS, GSK, Janssen, Karyopharm, Sanofi, and Takeda; and participation on a data safety monitoring board or advisory board for Amgen, BMS, GSK, Janssen, Karyopharm, Sanofi, and Takeda. MC reports honoraria from BMS, Janssen, and Sanofi; and support for attending meetings and/or travel from Janssen and Sanofi. MD reports honoraria from GSK, Janssen, and Sanofi; and participation on a data safety monitoring board or advisory board for BMS, GSK, and Sanofi. PS reports research funding/honoraria from Amgen, Janssen, Karyopharm, Pfizer, and Sanofi. KB, TF, KT, CT, SM, RZ, ZK, and HvdV are employees of Sanofi and may hold stock and/or stock options. PM reports participation on a data safety monitoring board or advisory board for AbbVie, Amgen, Celgene, Janssen, Sanofi, and Takeda., (© 2024. The Author(s).)

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Competing Interests: Enrique M. Ocio received honoraria from Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, Oncopeptides, Pfizer, Regeneron, Sanofi, and Takeda; disclosed consulting/advisory role for AbbVie, Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, Menarini/Stemline Therapeutics, Oncopeptides, Pfizer, Sanofi, and Takeda, and participation in speakers' bureau for Janssen; received travel/accommodation expenses from Bristol Myers Squibb, GlaxoSmithKline, Janssen, and Lilly. Aurore Perrot: received honoraria from AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Pfizer, Sanofi, and Takeda; research funding from Takeda; and support for attending meetings and/or travel from Amgen, Janssen. Philippe Moreau: disclosed honoraria and consulting/advisory role for AbbVie, Amgen, Celgene, Janssen, Oncopeptides, Roche, and Sanofi. Maria‐Victoria Mateos: received honoraria from AbbVie, Adaptive, Amgen, Bluebird bio, Celgene, GSK, Janssen, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, Sea‐Gen, and Takeda, and is on the Editorial Board of HemaSphere. Sara Bringhen: received honoraria from Amgen, BMS/Celgene, and Janssen, and consulting fees from BMS/Celgene, Janssen, and Takeda; disclosed participation on a data safety monitoring board or advisory board for Amgen, Celgene, GSK, Janssen, Karyopharm, and Sanofi. Joaquín Martínez‐López received honoraria and consulting fees from BMS/Celgene, Incyte, Janssen, Novartis, Roche, and Sanofi; travel and accommodation support from BMS, Janssen, Novartis, Roche, and Sanofi. Lionel Karlin: received honoraria from AbbVie, Amgen, Celgene, Janssen, Sanofi, and Takeda; disclosed advisory role for Amgen, Celgene, GSK, Janssen, and Takeda. Song‐Yau Wang: disclosed no conflicts. Corina Oprea, Yi Li, and Ercem Kodas are employed by Sanofi and may hold stock and/or stock options in the company. Jesus San‐Miguel: received honoraria and consulting fees from Amgen, BMS/Celgene, GSK, Janssen, Karyopharma, Sanofi, and Takeda.

Background: Bortezomib, lenalidomide, and dexamethasone (VRd) is a preferred first-line treatment option for patients with newly diagnosed multiple myeloma. Whether the addition of the anti-CD38 monoclonal antibody isatuximab to the VRd regimen would reduce the risk of disease progression or death among patients ineligible to undergo transplantation is unclear., Methods: In an international, open-label, phase 3 trial, we randomly assigned, in a 3:2 ratio, patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation to receive either isatuximab plus VRd or VRd alone. The primary efficacy end point was progression-free survival. Key secondary end points included a complete response or better and minimal residual disease (MRD)-negative status in patients with a complete response., Results: A total of 446 patients underwent randomization. At a median follow-up of 59.7 months, the estimated progression-free survival at 60 months was 63.2% in the isatuximab-VRd group, as compared with 45.2% in the VRd group (hazard ratio for disease progression or death, 0.60; 98.5% confidence interval, 0.41 to 0.88; P<0.001). The percentage of patients with a complete response or better was significantly higher in the isatuximab-VRd group than in the VRd group (74.7% vs. 64.1%, P = 0.01), as was the percentage of patients with MRD-negative status and a complete response (55.5% vs. 40.9%, P = 0.003). No new safety signals were observed with the isatuximab-VRd regimen. The incidence of serious adverse events during treatment and the incidence of adverse events leading to discontinuation were similar in the two groups., Conclusions: Isatuximab-VRd was more effective than VRd as initial therapy in patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation. (Funded by Sanofi and a Cancer Center Support Grant; IMROZ ClinicalTrials.gov number, NCT03319667.)., (Copyright © 2024 Massachusetts Medical Society.)

In multiple myeloma, as in B-cell malignancies, mono- and especially bi-allelic TP53 gene inactivation is a high-risk factor for treatment resistance, and there are currently no therapies specifically targeting p53 deficiency. In this study, we evaluated if the loss of cell cycle control in p53-deficient myeloma cells would confer a metabolically actionable vulnerability. We show that CTP synthase 1 ( CTPS1 ), which encodes a CTP synthesis rate-limiting enzyme essential for DNA and RNA synthesis in lymphoid cells, is overexpressed in samples from myeloma patients displaying a high proliferation rate (high MKI67 expression) or a low p53 score (synonymous with TP53 deletion and/or mutation). This overexpression of CTPS1 was associated with reduced survival in two cohorts. Using scRNA-seq analysis in 24 patient samples, we further demonstrate that myeloma cells in the S or G2/M phase display high CTPS1 expression. Pharmacological inhibition of CTPS1 by STP-B induced cell cycle arrest in early S phase in isogenic NCI-H929 or XG7 TP53 +/+ , TP53 -/- , and TP53 R175H/R175H cells and in a TP53 -/R123STOP patient sample. The functional annotation of transcriptional changes in 10 STP-B-treated myeloma cell lines revealed a decrease in protein translation and confirmed the blockade of cells into the S phase. The pharmacological inhibition of ATR, which governs the intrinsic S/G2 checkpoint, in STP-B-induced S-phase arrested cells synergistically induced cell death in TP53 +/+ , TP53 -/- , and TP53 R175H/R175H isogenic cell lines (Bliss score >15). This combination induced replicative stress and caspase-mediated cell death and was highly effective in resistant/refractory patient samples with TP53 deletion and/or mutation and in TP53 -/- NCI-H929 xenografted NOD-scid IL2Rgamma mice. Our in vitro, ex vivo, and in vivo data provide the rationale for combined CTPS1 and ATR inhibition for the treatment of p53-deficient patients., Competing Interests: Hélène Asnagli, Andrew Parker, and Philip Beer are employees of Step Pharma. The remaining authors declare no conflict of interest., (© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

Despite recent advances in immunotherapies targeting single tumor-associated antigens, patients with multiple myeloma eventually relapse. ISB 2001 is a CD3 + T cell engager (TCE) co-targeting BCMA and CD38 designed to improve cytotoxicity against multiple myeloma. Targeting of two tumor-associated antigens by a single TCE resulted in superior cytotoxic potency across a variable range of BCMA and CD38 tumor expression profiles mimicking natural tumor heterogeneity, improved resistance to competing soluble factors and exhibited superior cytotoxic potency on patient-derived samples and in mouse models. Despite the broad expression of CD38 across human tissues, ISB 2001 demonstrated a reduced T cell activation profile in the absence of tumor cells when compared to TCEs targeting CD38 only. To determine an optimal first-in-human dose for the ongoing clinical trial ( NCT05862012 ), we developed an innovative quantitative systems pharmacology model leveraging preclinical data, using a minimum pharmacologically active dose approach, therefore reducing patient exposure to subefficacious doses of therapies., (© 2024. The Author(s).)

Objective: This study aimed to develop and implement a program-wide active learning framework to guide active learning and assessment efforts in an entry-to-practice competency-based Doctor of Pharmacy program., Methods: The development of the framework involved 3 stages: creation of a framework aligned with the program's guiding principles, provision of training and support to faculty and students, and evaluation of the students' and academic staff satisfaction using an online survey over 2 academic years (2022-2023). Data from this survey were analyzed descriptively., Results: An active learning framework that was aligned with the program's guiding principles while allowing flexibility for individual teaching styles was developed. It consisted of 4 stages: preclass preparation, in-class work, prelaboratory preparation, and in-laboratory activities (emphasizing knowledge acquisition and competency development). Academic staff surveys reported higher satisfaction of staff in year 2 than year 3 of the program, with indications of further training on specific modalities. Students' satisfaction improved from year 2 to 3, particularly, in areas related to class objectives, learning environment, and feedback., Conclusion: The transformation of a curriculum that includes the evolution of the teaching and learning strategy is a complex, long-term project that deserves continuing attention. Having frameworks in place helps the management, instructors, and students to understand the global direction, stay focused, and support the implementation of competency-based education and student-centered learning., 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 American Association of Colleges of Pharmacy. Published by Elsevier Inc. All rights reserved.)

Background: Isatuximab is an anti-CD38 monoclonal antibody approved for the treatment of relapsed or refractory multiple myeloma. Previous analyses of the IKEMA trial showed prolonged progression-free survival in patients with this disease who received isatuximab in combination with carfilzomib-dexamethasone as compared with those who received carfilzomib-dexamethasone alone. Herein, we report the analysis of overall survival from the IKEMA trial., Methods: This prospective, randomised, open-label, active-controlled, phase 3 study included patients with relapsed or refractory multiple myeloma aged 18 years or older, who had received one to three previous lines of treatment from 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were randomly allocated (3:2) to treatment with either isatuximab plus carfilzomib-dexamethasone (isatuximab group) or carfilzomib-dexamethasone (control group). In the isatuximab group, patients received intravenous isatuximab (10 mg/kg on days 1, 8, 15, and 22 of the first 28-day cycle, and days 1 and 15 of subsequent 28-day cycles). In both treatment groups, intravenous carfilzomib (20 mg/m 2 on days 1 and 2 of the first cycle; and 56 mg/m 2 on days 8, 9, 15, and 16 of the first cycle, and days 1, 2, 8, 9, 15, and 16 of subsequent cycles) and intravenous or oral dexamethasone (20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23) were administered. The primary endpoint of the trial was progression-free survival, which was reported previously. Treatment continued until progression, unacceptable toxicity, or patient request to discontine. The overall survival analysis reported here was planned to be conducted 3 years after the primary progression-free survival analysis in the intention-to-treat population. Additional analyses were conducted on the secondary endpoints of time to next treatment and second-progression-free survival. Reported p values are non-inferential due to hierarchical testing. This trial is registered with ClinicalTrials.gov (NCT03275285)., Findings: Between Nov 15, 2017, and March 21, 2019, 302 patients were enrolled and randomly allocated: 179 (59%) to the isatuximab group and 123 (41%) to the control group. 169 (56%) patients were male, 133 (44%) were female, 214 (71%) were White, 50 (17%) were Asian, nine (3%) were Black or African American, and three (1%) were multiracial. At data cutoff for this overall survival analysis (Feb 7, 2023), 79 (44%) overall survival events in the isatuximab group and 59 (48%) in the control group had occurred (median follow-up 56·61 months [IQR 54·90-58·02]). Median overall survival (in months) was not reached (NR; 95% CI 52·17-NR) in the isatuximab group and was 50·60 months (38·93-NR) in the control group (hazard ratio [HR] 0·855 [95% CI 0·608-1·202], nominal one-sided p=0·18). Survival probability at 48 months was 59·7% (95% CI 52·0-66·7) in the isatuximab group and 52·2% (95% CI 42·7-60·8) in the control group (based on Kaplan-Meier analysis). Improvements in time to next treatment (HR 0·583 [95% CI 0·429-0·792], nominal one-sided p=0·0002) and second-progression-free survival (0·663 [0·491-0·895], nominal one-sided p=0·0035) were observed in the isatuximab group. The most common treatment-emergent adverse events were infusion reactions (82 [46%] patients in the isatuximab group and four [3%] in the control group) and upper respiratory tract infections (71 [40%] and 34 [28%], respectively). Discontinuations due to treatment-emergent adverse events were similar between treatment groups (24 [14%] in the isatuximab group and 22 [18%] in the control group), despite an additional 30 weeks of exposure in the isatuximab group. 12 (7%) patients in the isatuximab group and six (5%) patients in the control group had a treatment-related adverse event with a fatal outcome during study treatment., Interpretation: At the time of the current analysis, a difference in overall survival could not be detected between the treatment groups, and no new safety signals were observed. Collectively, the evidence suggests that isatuximab plus carfilzomib-dexamethasone is a key treatment for patients with relapsed or refractory multiple myeloma., Funding: Sanofi., Competing Interests: Declaration of interests KY declares research support from BMS, Janssen, and Sanofi; honoraria from Amgen, Sanofi, and Takeda; and advisory roles for Janssen and Sanofi. TM declares research support from Sanofi. M-AD declares honoraria from Amgen, BeiGene, BMS, Janssen, Sanofi, and Takeda. JM declares consulting for Amgen, BMS, GSK, Janssen, Karyopharm, Sanofi, and Takeda. MC declares honoraria from BMS, Janssen, and Sanofi; and advisory roles for Janssen and Sanofi. RH declares research support from Amgen, BMS, Celgene, Janssen, Novartis, and Takeda; consulting for AbbVie, Amgen, BMS, Celgene, Janssen, Novartis, PharmaMar, and Takeda; honoraria from Amgen, BMS, Celgene, Janssen, PharmaMar, Takeda; and advisory roles for Amgen, BMS, GSK, Janssen, Oncopeptides, Sanofi, Takeda. IS declares research support from and consulting for Amgen, BMS, Celgene, Janssen-Cilag, Novartis, PharmMar, Sanofi, and Takeda. RB declares research support from AbbVie, Acerta Pharma, Alexion, Amgen, Bayer, BeiGene, BMS, Boehringer Ingelheim, Celgene, CSL Behring, Daiichi Sankyo, Janssen-Cilag, MorphoSys, Pfizer, Pharmaxis, Portola, Rigel Pharmaceuticals, Roche, Sanofi, Takeda, and Technoclone; honoraria from Bayer, BMS, Cardinal Health, Janssen-Cilag, and Roche; and advisory roles for Janssen-Cilag, Pharmaxis, and Roche. KK declares consulting for LG Chemistry; and advisory roles for Amgen, GSK, and Janssen. AO declares honoraria from Amgen, BMS/Celgene, GSK, and Sanofi. YK declares honoraria from Amgen, GSK, and Janssen. KS declares honoraria from AbbVie, Amgen, BMS, Janssen, Novartis, ONO, Sanofi, and Takeda; consulting for Amgen, BMS, and Takeda; and research funding from BMS. FC, SM, and M-LR are employees of Sanofi and may hold stock or stock options. PM declares advisory roles for AbbVie, Amgen, Celgene, GSK, Janssen, and Sanofi. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

This study investigated community empowerment as a means of addressing food insecurity amongst underserved neighborhoods by increasing available and affordable food choices through Clementine Collective stands in Staten Island, New York (Richmond County), one of the 5 Boroughs of New York City. Given the growing complexity of food insecurity, inclusive and equitable action must be taken that incorporates the voices, perspectives and needs of those most impacted. Through methods of community engagement and empowerment, the Clementine Collective collaborates with local community residents to introduce sustainable solutions that address food insecurity. A survey (N = 132) was administered to customers of a Clementine Collective stand, located in Staten Island, that assessed customers' food habits and attitudes towards their food environment and solutions. The stand was placed in a local meat market grocery store. Descriptive statistics suggested that residents recognized gaps in their food environment and were empowered to advocate for solutions. Engaging residents from their food environment to advocate for local solutions, such as at community bodegas, or small grocery stores, may be an effective method of addressing food insecurity., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Homology search is a central step of DNA double-strand break (DSB) repair by homologous recombination (HR). How it operates in cells remains elusive. We developed a Hi-C-based methodology to map single-stranded DNA (ssDNA) contacts genome-wide in S. cerevisiae, which revealed two main homology search phases. Initial search conducted by short Rad51-ssDNA nucleoprotein filaments (NPFs) is confined in cis by cohesin-mediated chromatin loop folding. Progressive growth of stiff NPFs enables exploration of distant genomic sites. Long-range resection drives this transition from local to genome-wide search by increasing the probability of assembling extensive NPFs. DSB end-tethering promotes coordinated search by opposite NPFs. Finally, an autonomous genetic element on chromosome III engages the NPF, which stimulates homology search in its vicinity. This work reveals the mechanism of the progressive expansion of homology search that is orchestrated by chromatin organizers, long-range resection, end-tethering, and specialized genetic elements and that exploits the stiff NPF structure conferred by Rad51 oligomerization., Competing Interests: Declaration of interests A patent, “A METHOD FOR IDENTIFYING GENOMIC INTERACTIONS,” that covers aspects of the ssHi-C methodology has been submitted on September 11, 2023 by the Centre National de la Recherche Scientifique under PCT application number PCT/FR2023/051384, with A.D. and A.P. as listed inventors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Idecabtagene vicleucel (ide-cel), a chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen (BCMA), received early access program (EAP) authorization in France in April 2021 for relapsed/refractory multiple myeloma (RRMM). We conducted a real-world registry-based multicentre observational study in 11 French hospitals to evaluate ide-cel outcomes. Data from 176 RRMM patients who underwent apheresis between June 2021 and November 2022 were collected from the French national DESCAR-T registry. Of these, 159 patients (90%) received ide-cel. Cytokine release syndrome occurred in 90% with 2% grade ≥3, and neurotoxicity occurred in 12% with 3% grade ≥3. Over the first 6 months, the best overall response and ≥complete response rates were 88% and 47% respectively. The median progression-free survival (PFS) from the ide-cel infusion was 12.5 months, the median overall survival (OS) was 20.8 months and the estimated OS rate at 12 months was 73.3%. Patients with extra-medullary disease (EMD) had impaired PFS (6.2 months vs. 14.8 months). On multivariable analysis, EMD and previous exposure to BCMA-targeted immunoconjugate or T-cell-redirecting GPRC5D bispecific antibody were associated with inferior PFS. Our study supports ide-cel's feasibility, safety and efficacy in real-life settings, emphasizing the importance of screening for EMD and considering prior treatments to optimize patient selection., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Therapeutic strategies for patients with newly diagnosed multiple myeloma (NDMM) have considerably improved during the last 10 years. The IFM2014-03 trial proposed an all-oral triplet induction/consolidation regimen in transplant-eligible NDMM patients, followed by lenalidomide maintenance. Induction consisted of three 21-day cycles of ixazomib, lenalidomide and dexamethasone (IRd), before high-dose Melphalan with transplant followed by eight 28-day cycles of IRd consolidation before 13 cycles of lenalidomide maintenance. Forty-six patients were enrolled and received at least one dose of therapy, and 39 entered the maintenance phase. The primary end-point was stringent complete response after consolidation, and was achieved in nine patients (20.9%, 90% CI 11.4-33.7; p = 0.998). Ten patients (24.4%) had an undetectable minimal residual disease. The overall response rate was 95.7%. The 3-year progression-free survival was 66.3%. No unexpected toxicities were recorded, and only eight patients suspended from any study drug. Of note, 21 (45.7%) patients reported peripheral neuropathy (PN) (grades 1-2 with no serious adverse events). IRd induction and consolidation with transplant before lenalidomide maintenance shows lower response rates compared to other triplet therapies. It could be an alternative for patients who require an all-oral regimen and/or with pre-existent PN, especially if quadruplet regimens including anti-CD38 antibody are not available., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

This study uncovers a regulatory interplay between WRINKLED1 (WRI1), a master transcription factor for glycolysis and lipid biosynthesis, and Translocator Protein (TSPO) expression in Arabidopsis thaliana seeds. We identified potential WRI1-responsive elements upstream of AtTSPO through bioinformatics, suggesting WRI1's involvement in regulating TSPO expression. Our analyses showed a significant reduction in AtTSPO levels in wri1 mutant seeds compared to wild type, establishing a functional link between WRI1 and TSPO. This connection extends to the coordination of seed development and lipid metabolism, with both WRI1 and AtTSPO levels decreasing post-imbibition, indicating their roles in seed physiology. Further investigations into TSPO's impact on fatty acid synthesis revealed that TSPO misexpression alters WRI1's post-translational modifications and significantly enhances seed oil content. Additionally, we noted a decrease in key reserve proteins, including 12 S globulin and oleosin 1, in seeds with TSPO misexpression, suggesting a novel energy storage strategy in these lines. Our findings reveal a sophisticated network involving WRI1 and AtTSPO, highlighting their crucial contributions to seed development, lipid metabolism, and the modulation of energy storage mechanisms in Arabidopsis., (Copyright © 2024 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Abstract: Teclistamab, an off-the-shelf B-cell maturation antigen (BCMA) × CD3 bispecific antibody that mediates T-cell activation and subsequent lysis of BCMA-expressing myeloma cells, is approved for the treatment of patients with relapsed/refractory multiple myeloma (R/RMM). As a T-cell redirection therapy, clinical outcomes with teclistamab may be influenced by patient immune fitness and tumor antigen expression. We correlated tumor characteristics and baseline immune profiles with clinical response and disease burden in patients with R/RMM from the pivotal phase 1/2 MajesTEC-1 study, focusing on patients treated with 1.5 mg/kg of teclistamab (N = 165). Peripheral blood samples were collected at screening, and bone marrow samples were collected at screening and cycle 3. Better clinical outcomes to teclistamab correlated with higher baseline total T-cell counts in the periphery. In addition, responders (partial response or better) had a lower proportion of immunosuppressive regulatory T cells (Tregs), T cells expressing coinhibitory receptors (CD38, PD-1, and PD-1/TIM-3), and soluble BCMA and a T-cell profile suggestive of a more cytolytic potential, compared with nonresponders. Neither frequency of baseline bone marrow BCMA expression nor BCMA-receptor density was associated with clinical response to teclistamab. Improved progression-free survival was observed in patients with a lower frequency of T cells expressing exhaustion markers and immunosuppressive Tregs. Overall, response to teclistamab was associated with baseline immune fitness; nonresponders had immune profiles suggestive of immune suppression and T-cell dysfunction. These findings illustrate the importance of the contribution of the immune landscape to T-cell redirection therapy response. This trial was registered at www.ClinicalTrials.gov as #NCT03145181/NCT04557098., (© 2024 American Society of Hematology. Published by Elsevier Inc. 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: CASSIOPEIA part 1 demonstrated superior depth of response and prolonged progression-free survival with daratumumab in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) alone as an induction and consolidation regimen in transplant-eligible patients newly diagnosed with myeloma. In CASSIOPEIA part 2, daratumumab maintenance significantly improved progression-free survival and increased minimal residual disease (MRD)-negativity rates versus observation. Here, we report long-term study outcomes of CASSIOPEIA., Methods: CASSIOPEIA was a two-part, open-label, phase 3 trial of patients done at 111 European academic and community-based centres. Eligible patients were aged 18-65 years with transplant-eligible newly diagnosed myeloma and an Eastern Cooperative Oncology Group performance status of 0-2. In part 1, patients were randomly assigned (1:1) to pre-transplant induction and post-transplant consolidation with D-VTd or VTd. Patients who completed consolidation and had a partial response or better were re-randomised (1:1) to intravenous daratumumab maintenance (16 mg/kg every 8 weeks) or observation for 2 years or less. An interactive web-based system was used for both randomisations, and randomisation was balanced using permuted blocks of four. Stratification factors for the first randomisation (induction and consolidation phase) were site affiliation, International Staging System disease stage, and cytogenetic risk status. Stratification factors for the second randomisation (maintenance phase) were induction treatment and depth of response in the induction and consolidation phase. The primary endpoint for the induction and consolidation phase was the proportion of patients who achieved a stringent complete response after consolidation; results for this endpoint remain unchanged from those reported previously. The primary endpoint for the maintenance phase was progression-free survival from second randomisation. Efficacy evaluations in the induction and consolidation phase were done on the intention-to-treat population, which included all patients who underwent first randomisation, and efficacy analyses in the maintenance phase were done in the maintenance-specific intention-to-treat population, which included all patients who were randomly assigned at the second randomisation. This analysis represents the final data cutoff at the end of the study. The trial is registered with ClinicalTrials.gov, NCT02541383., Findings: Between Sept 22, 2015 and Aug 1, 2017, 1085 patients were randomly assigned to D-VTd (n=543) or VTd (n=542); between May 30, 2016 and June 18, 2018, 886 were re-randomised to daratumumab maintenance (n=442) or observation (n=444). At the clinical cutoff date, Sept 1, 2023, median follow-up was 80·1 months (IQR 75·7-85·6) from first randomisation and 70·6 months (66·4-76·1) from second randomisation. Progression-free survival from second randomisation was significantly longer in the daratumumab maintenance group than the observation-alone group (median not reached [95% CI 79·9-not estimable (NE)] vs 45·8 months [41·8-49·6]; HR 0·49 [95% CI 0·40-0·59]; p<0·0001); benefit was observed with D-VTd with daratumumab maintenance versus D-VTd with observation (median not reached [74·6-NE] vs 72·1 months [52·8-NE]; 0·76 [0·58-1·00]; p=0·048) and VTd with daratumumab maintenance versus VTd with observation (median not reached [66·9-NE] vs 32·7 months [27·2-38·7]; 0·34 [0·26-0·44]; p<0·0001)., Interpretation: The long-term follow-up results of CASSIOPEIA show that including daratumumab in both the induction and consolidation phase and the maintenance phase led to superior progression-free survival outcomes. Our results confirm D-VTd induction and consolidation as a standard of care, and support the option of subsequent daratumumab monotherapy maintenance, for transplant-eligible patients with newly diagnosed multiple myeloma., Funding: Intergroupe Francophone du Myélome, Dutch-Belgian Cooperative Trial Group for Hematology Oncology, and Janssen Research & Development., Competing Interests: Declaration of interests PM served on advisory boards for and received honoraria from Janssen, Bristol Myers Squibb, Amgen, Takeda, AbbVie, Sanofi, and Pfizer. CH received honoraria from Janssen, Bristol Myers Squibb, Amgen, AbbVie, and Pfizer. AP served in a consulting or advisory role for Bristol Myers Squibb, Janssen, and Pfizer; and received research funding from Bristol Myers Squibb, Sanofi, and Takeda. BA received research funding (paid to institution) from Bristol Myers Squibb; received honoraria from Janssen, Bristol Myers Squibb, Sanofi, and GSK; received travel funding from Janssen, Bristol Myers Squibb, and Sanofi; and served on an advisory board for Janssen, Bristol Myers Squibb, and Takeda. KB has a direct financial relationship with Janssen, Bristol Myers Squibb, Amgen, Sanofi, and Pfizer. SZ received research support from Janssen and Takeda; and served on advisory boards for Janssen, Bristol Myers Squibb, Sanofi, Oncopeptides, Amgen, and Takeda. MD received honoraria from and served in a consulting or advisory role for Amgen, Bristol Myers Squibb, Janssen, Sanofi, and Stemline; and received research funding from Janssen. CS received consulting fees or honoraria from Takeda, Bristol Myers Squibb, Janssen, Amgen, Sanofi, and Pfizer. MMo received honoraria from Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Celgene, Janssen, Takeda, Novartis, and Sanofi; and received research funding from Celgene, Janssen, and Sanofi. LK received honoraria from, served on advisory boards for, or received travel funding from AbbVie, Amgen, Janssen, Celgene/Bristol Myers Squibb, Pfizer, Sanofi, and Takeda. MMa received honoraria from and served in a consulting or advisory role for Janssen, Bristol Myers Squibb/Celgene, Sanofi, and Takeda; received research funding from Janssen and Takeda; and received travel, accommodations, or expenses from Janssen and Sanofi. FO-P served on boards for Janssen, Sanofi, and Pfizer. MR served on an advisory board for Janssen and Pfizer; received research funding from Bristol Myers Squibb, Janssen, and Sanofi; gave lectures for Amgen, Bristol Myers Squibb, Janssen, and Takeda; and had travel, accommodations, or other expenses paid or reimbursed by Amgen, Bristol Myers Squibb, GSK, Janssen, Pfizer, Sanofi, and Takeda. JMSdC served on an advisory board and received honoraria from Janssen, Sanofi, GSK, and AbbVie; and received accommodations from Pfizer and Amgen. NWCJvdD received research support from Janssen, Amgen, Celgene, Novartis, Cellectis, and Bristol Myers Squibb; and serves on advisory boards for Janssen, Amgen, Celgene, Bristol Myers Squibb, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Merck, Pfizer, AbbVie, and Servier (all paid to institution). AB served on advisory boards for Janssen, Sanofi, Amgen, and Bristol Myers Squibb. CT served on an advisory board for and received honoraria from Janssen. NM served on an advisory board for Janssen. M-CV received travel support from Janssen and Sanofi. M-DL received travel expenses from Janssen. WH is an employee of Cytel and is a contractor for Johnson & Johnson. JW, CdB, MR, VV, RC, and JV are employees of Janssen and hold stock in Johnson & Johnson. AT is an employee of Janssen. JC served on advisory boards for Sanofi and Bristol Myers Squibb; served as a consultant for Janssen, Sanofi, Bristol Myers Squibb, Pfizer, and Adaptive; received research support from Sanofi and Bristol Myers Squibb; and received travel support from Janssen, Sanofi, Bristol Myers Squibb, and Pfizer. PS served on an advisory board for Amgen, Bristol Myers Squibb, Celgene, Janssen, Karyopharm, and Pfizer; and received research funding from Amgen, Bristol Myers Squibb, Celgene, Janssen, and Karyopharm. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Chimeric antigen receptor (CAR) T-cell therapy has shown promise in patients with late-line refractory multiple myeloma, with response rates ranging from 73 to 98%. To date, three products have been approved: Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), which are approved by the US Food and Drug Administration, the European Medicines Agency, Health Canada (ide-cel only), and Brazil ANVISA (cilta-cel only); and equecabtagene autoleucel (eque-cel), which was approved by the Chinese National Medical Products Administration. CAR T-cell therapy is different from previous anti-myeloma therapeutics with unique toxic effects that require distinct mitigation strategies. Thus, a panel of experts from the International Myeloma Working Group was assembled to provide guidance for clinical use of CAR T-cell therapy in myeloma. This consensus opinion is from experts in the field of haematopoietic cell transplantation, cell therapy, and multiple myeloma therapeutics., Competing Interests: Declaration of interests YL received consultancy fees from Janssen, Sanofi, NexImmune, Caribou, Bristol Myers Squibb (BMS), Pfizer, Regeneron, and Genentech; research fees from Janssen and BMS; serves on advisory boards for Janssen, Sanofi, BMS, Regeneron, and Genentech; serves on scientific advisory boards for NexImmune and Caribou; and serves on the data safety monitor board for Pfizer. LQ received consultancy fees from Beigene, Xi'an, Janssen, Pfizer, Sanofi, and AstraZeneca; and is on the speaker board for Beigene, Xi'an, Janssen, Pfizer, Sanofi, AstraZeneca, and Roche. SU receives consultancy fees from AbbVie, Amgen, BMS, EdoPharma, Genentech, Gilead, GlaxoSmithKline (GSK), Janssen, Karyopharm Therapeutics, Merck, Oncopeptides, Sanofi, Seagen, Secura Bio, SkylineDx, and Takeda; and received research funding from AbbVie, Amgen, Array Biopharma, BMS, EdoPharma, Genentech, Gilead, GSK, Janssen, Merck, Moderna, Pharmacyclics, Seagen, Sanofi, SkylineDx, Takeda, and TeneoBio. CWJ received honoraria from AbbVie, Amgen, BMS, Pfizer, Sanofi, Regeneron, GSK, and Janssen; and research funding from Novartis, Janssen, and BMS Celgene. LC received research grants from Amgen, Janssen, BMS, Genentech, Caribou, and AbbVie; and honoraria from Amgen, Janssen, AbbVie, Pfizer, Sanofi, and Adaptive Biotechnologies. BD received advisory board and consulting fees from Janssen and COTA; research fees from GSK and Amgen; honoraria from the Multiple Myeloma Research Foundation and Plexus Communications; and is an independent reviewer for BMS. HE has an advisory role for and received consulting fees from BMS Celgene, Janssen, Amgen, GSK, and Sanofi; and received research funding from BMS Celgene, Janssen, Amgen, GSK, and Sanofi. CFdL received institutional grants from BMS, Janssen, and Amgen; honoraria from Amgen, Jassen, BMS, GSK, and Sanofi; support for attending meetings or travel from Janssen, BMS, GSK, and Amgen; is on data safety monitoring or advisory boards for Janssen, BMS, Amgen, Pfizer, and Sanofi; and received funding from the Spanish Institute of Health, the Asociación Española Contra el Cancer (AECC), the “La Caixa” Foundation, and AGAUR. RH received grants from Janssen, Amgen, Celgene, BMS, Novartis, and Takeda; consulting fees from Janssen, Amgen, Celgene, BMS, Novartis, Takeda, AbbVie, PharmaMar, Oncopeptides, Sanofi, and GSK; and honoraria from Janssen, Amgen, Celgene, BMS, PharmaMar, and Takeda. PJH serves on advisory boards (honoraria not accepted) for Antengene, Gilead, iTeos Therapeutics, Janssen, Novartis, and Pfizer. EK received honoraria from Janssen, Pfizer, GSK, and Prothena; and research support to the institution from GSK, Janssen, and Pfizer. JM-L received consultancy fees from Janssen, BMS, Sanofi, GSK, Novartis, Menarini, Incity, Roche, Gilead, Pfizer, and Karyopharm; and research funding from BMS, Janssen, Incity, Amgen, and Pfizer. M-VM received honoraria for serving on advisory boards and received fees for lectures from Janssen, BMS Celgene, Novartis, GSK, Sanofi, Amgen, Pfizer, AbbVie, and Regeneron. JM received consultancy fees from Amgen, BMS, Janssen, Sanofi, and Takeda; and research funding from BMS Clinical Trial. PM serves on advisory boards and received honoraria from Janssen and BMS Celgene. CN received consultancy fees from Janssen, BMS, Sanofi, GSK, Pfizer, Amgen, AstraZeneca, and DKSH; and research funding from Janssen and Amgen. AN serves on advisory boards and received honoraria from Adaptive Biotechnologies, Amgen, BMS, Cellectar Biosciences, GSK, Janssen, K36 therapeutics, ONK therapeutics, Pfizer, Sanofi, and Takeda; received research grants from Aduro Biotech, Amgen, Arch Oncology, BMS, Cellectis, Genentech, GSK, Janssen, Karyopharm, Kite Pharma, Merck, Pfizer, and Takeda; and received grants for investigator initiated studies from Amgen, GSK, Janssen, Merck, and Takeda. FS received consultancy fees from AbbVie, GSK, Celgene, Takeda, Janssen, Oncopeptides, Sanofi, and BMS; honoraria from Amgen, BMS, Takeda, AbbVie, Janssen, Novartis, SkyliteDX, Oncopeptides, Sanofi, Pfizer, Daiki-Sankyo, and GSK; and research grants from Celgene, Janssen, Oncopeptides, Sanofi, GSK, and Targovax. SS received research grants from Magenta Therapeutics, BMS, Allogene, Jansse, Novartis, AbbVie, Sanofi, Oncopeptides, Takeda, Kite, and Regeneron; and consultancy fees from Magenta Therapeutics, BMS, Janssen, AbbVie, Sanofi, Oncopeptides, Takeda, Kite, and Regeneron. NWCJvdD received research grants from Janssen, Amgen, Celgene, Novartis, Cellectis, and BMS; and serves on advisory boards for Janssen, Amgen, Celgene, BMS, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Pfizer, AbbVie, and Servier (all paid to institution). KW received research grants from AbbVie, Amgen, BMS Celgene, Janssen, GSK, Sanofi, and Takeda; honoraria from AbbVie, Amgen, Adaptive Biotech, Astra Zeneca, BMS Celgene, BeiGene, Janssen, GSK, Karyopharm, Novartis, Oncopeptides, Pfizer, Roche Pharma, Sanofi, Stemline, Takeda, and Menarini; and consulting fees from AbbVie, Amgen, Adaptive Biotech, BMS Celgene, BeiGene, Janssen, GSK, Karyopharm, Oncopeptides, Pfizer, Roche Pharma, Sanofi, Takeda, and Menarini. SZ serves on advisory boards for Janssen, BMS, Takeda, Sanofi, Oncopeptides, and Amgen (no personal fees). PRO received honoraria for consulting or advisory board from BMS Celgene, Janssen, Roche, AbbVie, Pfizer, GSK, Sanofi, H3Biomedicine; travel grants from Pfizer; serves on steering committees for BMS Celgene, Regeneron, and Janssen; and is on the speakers bureau for Janssen, BMS Celgene, GSK, Sanofi, and AbbVie. LDA received consulting fees and serves on advisory boards for Janssen, Celgene, BMS, Amgen, GSK, AbbVie, Beigene, Cellectar, Sanofi, and Prothena. SK received consultancy fees from Oncopeptides, AbbVie, Celgene, Janssen, Takeda, Adaptive, KITE, and MedImmune AstraZeneca; and research grants from AbbVie, Celgene, Janssen, Takeda, Adaptive, KITE, MedImmune AstraZeneca, Merck, Novartis, Roche, and Sanofi. TM received research funding from Sanofi. All other authors declare no competing interests. IMWG are listed in the appendix (pp 9–21)., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

TOURMALINE-MM1, the only blinded randomized study in patients with relapsed and/or refractory multiple myeloma (RRMM; ≥1 prior therapy) in the last 10 years, investigated ixazomib + lenalidomide + dexamethasone (IRd) versus lenalidomide + dexamethasone (Rd). Final overall survival (OS) data were based on a median follow-up of 85 months. In RRMM trials where patients have had 1-3 relapses after initial treatment, a high proportion receive subsequent therapy. Application of salvage therapies in blinded trials and newer modes of therapy can increasingly complicate the interpretation of OS. This analysis explores the impact of subsequent therapies on OS outcomes in TOURMALINE-MM1. The inverse probability of censoring weights (IPCW) method, marginal structural model (MSM), and rank-preserving structural failure time model (RPSFTM) were utilized to adjust for confounding on OS, introduced by subsequent therapies. Analyses were conducted for the intent-totreat (ITT) population and ≥2 prior lines subgroup. Unadjusted hazard ratio (HR) for IRd versus Rd was 0.94 (95% confidence interval [CI]: 0.78-1.13) in the ITT population. After adjusting for the impact of subsequent therapies by the RPSFTM method, estimated HR for IRd versus Rd in the ITT population was 0.89 (95% CI: 0.74-1.07). Adjusting with IPCW and MSM methods also showed an improvement in HR, favoring IRd. IRd may be particularly beneficial in patients with ≥2 prior lines of therapy (IPCW and MSM HR=0.52, 95% CI: 0.30-0.88; RPSFTM HR=0.68, 95% CI: 0.51-0.91). These analyses highlight the growing challenge of demonstrating OS benefit in MM patients and the importance of assessing confounding introduced by subsequent therapies when interpreting OS.

Objectives: To analyze the impact of prior therapies on outcomes with selinexor, bortezomib, and dexamethasone (SVd) versus bortezomib and dexamethasone (Vd) in 402 patients with relapsed/refractory multiple myeloma (RRMM) in the phase 3 BOSTON trial., Methods: Post hoc analysis of progression-free survival (PFS), overall survival (OS), and safety for lenalidomide-refractory, proteasome inhibitor (PI)-naïve, bortezomib-naïve, and one prior line of therapy (1LOT) patient subgroups., Results: At a median follow-up of over 28 months, clinically meaningful improvements in PFS were noted across all groups with SVd. The median SVd PFS was longer in all subgroups (lenalidomide-refractory: 10.2 vs. 7.1 months, PI-naïve: 29.5 vs. 9.7; bortezomib-naïve: 29.5 vs. 9.7; 1LOT: 21.0 vs. 10.7; p < .05). The lenalidomide-refractory subgroup had longer OS with SVd (26.7 vs. 18.6 months; HR 0.53; p = .015). In all subgroups, overall response and ≥very good partial response rates were higher with SVd. The manageable safety profile of SVd was similar to the overall patient population., Conclusions: With over 2 years of follow-up, these clinically meaningful outcomes further support the use of SVd in patients who are lenalidomide-refractory, PI-naïve, bortezomib-naïve, or who received 1LOT (including a monoclonal antibody) and underscore the observed synergy between selinexor and bortezomib., (© 2024 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

CD38-targeting immunotherapy is approved in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM) that are transplant ineligible (TI) and is considered the best standard of care (SOC). To improve current SOC, we evaluated the added value of weekly bortezomib (V) to isatuximab plus lenalidomide and dexamethasone (IsaRd versus Isa-VRd). This Intergroupe Francophone of Myeloma phase 3 study randomized 270 patients with NDMM that were TI, aged 65-79 years, to IsaRd versus Isa-VRd arms. The primary endpoint was a minimal residual disease (MRD) negativity rate at 10 -5 by next-generation sequencing at 18 months from randomization. Key secondary endpoints included response rates, MRD assessment rates, survival and safety. The 18-month MRD negativity rates at 10 -5 were reported in 35 patients (26%, 95% confidence interval (CI) 19-34) in IsaRd versus 71 (53%, 95% CI 44-61) in Isa-VRd (odds ratio for MRD negativity 3.16, 95% CI 1.89-5.28, P < 0.0001). The MRD benefit was consistent across subgroups at 10 -5 and 10 -6 , and was already observed at month 12. The proportion of patients with complete response or better at 18 months was higher with Isa-VRd (58% versus 33%; P < 0.0001), as was the proportion of MRD negativity and complete response or better (37% versus 17%; P = 0.0003). At a median follow-up of 23.5 months, no difference was observed for survival times (immature data). The addition of weekly bortezomib did not significantly affect the relative dose intensity of IsaRd. Isa-VRd significantly increased MRD endpoints, including the 18-month negativity rate at 10 -5 , the primary endpoint, compared with IsaRd. This study proposes Isa-VRd as a new SOC for patients with NDMM that are TI. ClinicalTrials.gov identifier: NCT04751877 ., (© 2024. The Author(s).)

The therapeutic management of patients with multiple myeloma (MM) is complex. Despite substantial advances, MM remains incurable, and management involves cycles of treatment response, disease relapse, and further therapy. Currently, evidence to support the therapeutic decision is limited. Thus, the EMMY longitudinal, real-world study was designed to annually assess therapeutic management of MM in France to provide evidence to support physicians. During an annual prespecified 3-month recruitment period, eligible patients will be identified from their medical records. Adults aged ≥18 years diagnosed with symptomatic MM and requiring systemic treatment will be eligible. The primary objective, the evolution of MM therapeutic management, will be described, as well as the impact on the following outcomes: time-to-next treatment (TTNT), progression-free survival (PFS), and overall survival (OS). The study plans to recruit 5000 patients over 6 years: 700 to 900 patients annually. EMMY is a unique opportunity to collect real-world data to describe the evolving MM therapeutic landscape and record outcomes in France. These data will provide annual snapshots of various aspects of MM management. This knowledge will provide physicians with real-life, evidence-based data for therapeutic decision-making and ultimately improve treatment for MM patients., Competing Interests: Olivier Decaux declares receiving honoraria from Bristol Myers Squib (BMS), Gilead, GlaxoSmithKline (GSK), Janssen, Roche, Sanofi, and Takeda. Karim Belhadj-Merzoug received honoraria, research funding, and traveling expenses from Amgen, BMS, Janssen, Pfizer, Sanofi, and Takeda. Margaret Macro received honoraria and research funding from Amgen, BMS, GSK, Janssen, Sanofi, and Takeda.  Laurent Frenzel received consulting fees and research funding from BioMarin, CSL Behring, Pfizer, Sobi, and Roche. Aurore Perrot received honoraria from AbbVie, Adaptive, Amgen, BMS, Janssen, Pfizer, Sanofi, and Takeda. Philippe Moreau received honoraria and payment for advisory boards from AbbVie, Amgen, BMS-Celgene, Janssen, Pfizer, Sanofi, and Takeda. Xavier Leleu received consultancy fees from AbbVie, Amgen, BMS, Gilead, GSK, Harpoon Therapeutic, iTeos therapeutics, Janssen, Merck, Novartis, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, and Takeda. Mohamad Mohty received honoraria, consultancy fees, and research funding from Amgen, BMS, Gilead, GSK, Janssen, Jazz Pharmaceuticals, Novartis, Pfizer, Sanofi, Stemline Therapeutics, and Takeda. Lionel Karlin received honoraria, payment for advisory boards, as well as logistical and financial assistance for attending conferences from AbbVie, Amgen, BMS-Celgene, GSK, Janssen, Pfizer, Sanofi, Stemline Therapeutics, and Takeda. Cécile Sonntag is a member of the board of directors or on the advisory committee of BMS, Janssen, Sanofi, and Takeda. Laurent Vincent declares being a board member for BMS and Takeda. He also declares that he is receiving honoraria from Janssen and Pfizer. Cyrille Hulin received honoraria from AbbVie, Amgen, BMS, Janssen, Pfizer, and Sanofi. The other authors have no competing interests to declare.

Background: Dynamic contrast-enhanced-MRI (DCE-MRI) is able to study bone marrow angiogenesis in patients with multiple myeloma (MM) and asymptomatic precursor diseases but its role in the management of MM has not yet been established. The aims of this prospective study was to compare DCE-MRI-based parameters between all monoclonal plasma cell disease stages in order to find out discriminatory parameters and to seek correlations with other diffusion-weighted MRI and positron emission tomography (PET)-based biomarkers in a hybrid simultaneous whole-body-2-[18F]fluorodeoxyglucose (FDG)-PET/MRI (WB-2-[18F]FDG-PET/MRI) imaging approach., Methods: Patients with newly diagnosed Monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) or symptomatic MM according to international myeloma working group and underwent WB-2-[18F]FDG-PET/MRI imaging including bone marrow DCE sequences at the Nantes University Hospital were prospectively enrolled in this study before receiving treatment., Results: One hundred and sixty-seven patients (N = 167, mean age: 64 years ± 11 [Standard deviation], 66 males) were considered for the analysis. DCE-MRI-based Peak Enhancement Intensity (PEI), Time to PEI (TPEI) and their maximum intensity time ratio (MITR: PEI/TPEI) values were significantly different between the different monoclonal plasma cell disease stages, PEI values increasing and TPEI values decreasing progressively along the spectrum of plasma cell disorders, from MGUS stage to symptomatic multiple myeloma. PEI values were significantly higher in patients with diffuse bone marrow involvement (either in PET or in MRI images) than in those without diffuse bone marrow involvement, unlike TPEI values. PEI and TPEI values were not significantly different between patients with or without focal bone lesions., Conclusion: Different DCE-MRI-based parameters (PEI, TPEI, MITR) could significantly differentiate all monoclonal plasma cell disease stages and complemented conventional MRI and PET-based biomarkers., (© 2024. The Author(s).)

A series of 3,5-disubtituted pyridin-2(1 H )-ones was synthesized. As part of a structure-activity relationship study performed in this series, structural modifications were based on 3-(indol-4-yl)-5-(pyridin-4-ylamino)pyridin-2(1 H )-one B, which exhibited a potent anti-allodynic effect in a rat model of inflammatory pain. In this study, new compounds were assessed for their ability to inhibit cutaneous mechanical allodynia in rats by using the capsaicin pain model. Compound 36, a 2-methoxypyridine derivative, yielded the most promising outcome, demonstrating an enhanced analgesic effect., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

The global diversity of fungi has been estimated between 2 to 11 million species, of which only about 155 000 have been named. Most fungi are invisible to the unaided eye, but they represent a major component of biodiversity on our planet, and play essential ecological roles, supporting life as we know it. Although approximately 20 000 fungal genera are presently recognised, the ecology of most remains undetermined. Despite all this diversity, the mycological community actively researches some fungal genera more commonly than others. This poses an interesting question: why have some fungal genera impacted mycology and related fields more than others? To address this issue, we conducted a bibliometric analysis to identify the top 100 most cited fungal genera. A thorough database search of the Web of Science, Google Scholar, and PubMed was performed to establish which genera are most cited. The most cited 10 genera are Saccharomyces , Candida , Aspergillus , Fusarium , Penicillium , Trichoderma , Botrytis , Pichia , Cryptococcus and Alternaria . Case studies are presented for the 100 most cited genera with general background, notes on their ecology and economic significance and important research advances. This paper provides a historic overview of scientific research of these genera and the prospect for further research. Citation: Bhunjun CS, Chen YJ, Phukhamsakda C, Boekhout T, Groenewald JZ, McKenzie EHC, Francisco EC, Frisvad JC, Groenewald M, Hurdeal VG, Luangsa-ard J, Perrone G, Visagie CM, Bai FY, Błaszkowski J, Braun U, de Souza FA, de Queiroz MB, Dutta AK, Gonkhom D, Goto BT, Guarnaccia V, Hagen F, Houbraken J, Lachance MA, Li JJ, Luo KY, Magurno F, Mongkolsamrit S, Robert V, Roy N, Tibpromma S, Wanasinghe DN, Wang DQ, Wei DP, Zhao CL, Aiphuk W, Ajayi-Oyetunde O, Arantes TD, Araujo JC, Begerow D, Bakhshi M, Barbosa RN, Behrens FH, Bensch K, Bezerra JDP, Bilański P, Bradley CA, Bubner B, Burgess TI, Buyck B, Čadež N, Cai L, Calaça FJS, Campbell LJ, Chaverri P, Chen YY, Chethana KWT, Coetzee B, Costa MM, Chen Q, Custódio FA, Dai YC, Damm U, de Azevedo Santiago ALCM, De Miccolis Angelini RM, Dijksterhuis J, Dissanayake AJ, Doilom M, Dong W, Alvarez-Duarte E, Fischer M, Gajanayake AJ, Gené J, Gomdola D, Gomes AAM, Hausner G, He MQ, Hou L, Iturrieta-González I, Jami F, Jankowiak R, Jayawardena RS, Kandemir H, Kiss L, Kobmoo N, Kowalski T, Landi L, Lin CG, Liu JK, Liu XB, Loizides M, Luangharn T, Maharachchikumbura SSN, Makhathini Mkhwanazi GJ, Manawasinghe IS, Marin-Felix Y, McTaggart AR, Moreau PA, Morozova OV, Mostert L, Osiewacz HD, Pem D, Phookamsak R, Pollastro S, Pordel A, Poyntner C, Phillips AJL, Phonemany M, Promputtha I, Rathnayaka AR, Rodrigues AM, Romanazzi G, Rothmann L, Salgado-Salazar C, Sandoval-Denis M, Saupe SJ, Scholler M, Scott P, Shivas RG, Silar P, Souza-Motta CM, Silva-Filho AGS, Spies CFJ, Stchigel AM, Sterflinger K, Summerbell RC, Svetasheva TY, Takamatsu S, Theelen B, Theodoro RC, Thines M, Thongklang N, Torres R, Turchetti B, van den Brule T, Wang XW, Wartchow F, Welti S, Wijesinghe SN, Wu F, Xu R, Yang ZL, Yilmaz N, Yurkov A, Zhao L, Zhao RL, Zhou N, Hyde KD, Crous PW (2024). What are the 100 most cited fungal genera? Studies in Mycology 108 : 1-411. doi: 10.3114/sim.2024.108.01., Competing Interests: The authors declare that there is no conflict of interest., (© 2024 Westerdijk Fungal Biodiversity Institute.)

The primary and prespecified updated analyses of ICARIA-MM (clinicaltrial gov. Identifier: NCT02990338) demonstrated improved progression-free survival (PFS) and a benefit in overall survival (OS) was reported with the addition of isatuximab, an anti-CD38 monoclonal antibody, to pomalidomide-dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma. Here, we report the final OS analysis. This multicenter, randomized, open-label, phase III study included patients who had received and failed ≥2 previous therapies, including lenalidomide and a proteasome inhibitor. Between January 10, 2017, and February 2, 2018, 307 patients were randomized (1:1) to isatuximab-pomalidomide-dexamethasone (Isa-Pd; N=154) or Pd (N=153), stratified based on age (<75 vs. ≥75 years) and number of previous lines of therapy (2-3 vs. >3). At data cutoff for the final OS analysis after 220 OS events (January 27, 2022), median follow-up duration was 52.4 months. Median OS was 24.6 months (95% confidence interval [CI]: 20.3-31.3) with Isa-Pd and 17.7 months (95% CI: 14.4- 26.2) with Pd (hazard ratio=0.78; 95% CI: 0.59-1.02; 1-sided P=0.0319). Despite subsequent daratumumab use in the Pd group and its potential benefit on PFS in the first subsequent therapy line, median PFS2 was significantly longer with Isa-Pd versus Pd (17.5 vs. 12.9 months; log-rank 1-sided P=0.0091). In this analysis, Isa-Pd continued to be efficacious and well tolerated after follow-up of approximately 52 months, contributing to a clinically meaningful, 6.9-month improvement in median OS in patients with relapsed/refractory multiple myeloma.

Abstract: Bispecific T-cell engagers (TCEs) are revolutionizing patient care in multiple myeloma (MM). These monoclonal antibodies, that redirect T cells against cancer cells, are now approved for the treatment of triple-class exposed relapsed/refractory MM (RRMM). They are currently tested in earlier lines of the disease, including in first line. Yet, primary resistance occurs in about one-third of patients with RRMM, and most responders eventually develop acquired resistance. Understanding the mechanisms of resistance to bispecific TCE is thus essential to improve immunotherapies in MM. Here, we review recent studies investigating the clinical and molecular determinants of resistance to bispecific TCE. Resistance can arise from tumor-intrinsic or tumor-extrinsic mechanisms. Tumor-intrinsic resistance involves various alterations leading to the loss of the target antigen, such as chromosome deletions, point mutations, or epigenetic silencing. Loss of major histocompatibility complex (MHC) class I, preventing MHC class I: T-cell receptor (TCR) costimulatory signaling, was also reported. Tumor-extrinsic resistance involves abundant exhausted T-cell clones and several factors generating an immunosuppressive microenvironment. Importantly, some resistance mechanisms impair response to 1 TCE while preserving the efficacy of others. We next discuss the clinical implications of these findings. Monitoring the status of target antigens in tumor cells and their immune environment will be key to select the most appropriate TCE for each patient and to design combination and sequencing strategies for immunotherapy in MM., (© 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.)

Competing Interests: Declaration of Competing Interest In addition to his academic work, PM works as a consultant (University of Ottawa) on competency-based education. FC works as a consultant in the private sector on competency-based education of employees. She worked for more than a decade as a consultant for Université de Montréal. ASK has no competing interests.

Once-weekly carfilzomib at 56 mg/m 2 plus immunomodulatory drugs and dexamethasone has shown efficacy and tolerability treating early relapsed/refractory multiple myeloma (RRMM). The phase 2 SELECT study (NCT04191616) evaluated efficacy/safety of weekly carfilzomib, pomalidomide, and dexamethasone (KPd) in early RRMM patients refractory to lenalidomide. All 52 treated patients were refractory to prior treatment, and 19 (37%) were triple-class refractory. Overall response rate (ORR; primary endpoint) was 58% (35% ≥ very good partial response, 6% ≥ complete response); median response duration was 20.3 months. Minimal residual disease negativity (10 -5 ) was achieved in 10% of patients. Median progression-free survival was 11.1 months; median overall survival was 18.8 months. Adverse events (AEs) were consistent with the known safety profile including grade ≥3 treatment-emergent AEs reported in 67% of patients. Although the primary endpoint of ORR was not met, KPd showed meaningful clinical benefits in lenalidomide-refractory RRMM patients, including those who were daratumumab-refractory and/or triple-class refractory.

Abstract: High-risk (HR) cytogenetics are associated with poor outcomes in newly diagnosed multiple myeloma (NDMM), and dedicated studies should address this difficult-to-treat population. The phase 2 study 2018-04 from the Intergroupe Francophone du Myelome evaluated feasibility of an intensive strategy with quadruplet induction and consolidation plus tandem transplant in HR transplant-eligible (TE) NDMM. HR cytogenetics were defined by presence of del(17p), t(4;14), and/or t(14;16). Treatment consisted of daratumumab-carfilzomib-lenalidomide-dexamethasone (D-KRd) induction, autologous stem cell transplantation (ASCT), D-KRd consolidation, second ASCT, and daratumumab-lenalidomide maintenance. The primary end point was feasibility. Fifty patients with previously untreated NDMM were included. Median age was 57. Del(17p), t(4;14), and t(14;16) were found in 40%, 52%, and 20% of patients, respectively. At data cutoff, the study met the primary end point with 36 patients completing second transplant. Twenty patients discontinued the study due to stem cell collection failure (n = 8), disease progression (n = 7), adverse event (n = 4), or consent withdrawal (n = 1). Grade 3 to 4 D-KRd induction/consolidation-related adverse events (>5% of patients) were neutropenia (39%), anemia (12%), thrombocytopenia (7%), and infection (6%). The overall response rate was 100% for patients completing second transplant, including 81% complete response. Premaintenance minimal residual disease (MRD) negativity rate (10-6) was 94%. After a median follow-up of 33 months, the 30-month progression-free survival (PFS) and overall survival were 80% and 91%, respectively. In conclusion, D-KRd with tandem transplant is feasible in patients with HR TE-NDMM and resulted in high response rates and PFS. This trial was registered at www.clinicaltrials.gov as #NCT03606577., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Human bone marrow permanently harbors high numbers of neutrophils, and a tumor-supportive bias of these cells could significantly impact bone marrow-confined malignancies. In individuals with multiple myeloma, the bone marrow is characterized by inflammatory stromal cells with the potential to influence neutrophils. We investigated myeloma-associated alterations in human marrow neutrophils and the impact of stromal inflammation on neutrophil function. Mature neutrophils in myeloma marrow are activated and tumor supportive and transcribe increased levels of IL1B and myeloma cell survival factor TNFSF13B (BAFF). Interactions with inflammatory stromal cells induce neutrophil activation, including BAFF secretion, in a STAT3-dependent manner, and once activated, neutrophils gain the ability to reciprocally induce stromal activation. After first-line myeloid-depleting antimyeloma treatment, human bone marrow retains residual stromal inflammation, and newly formed neutrophils are reactivated. Combined, we identify a neutrophil-stromal cell feed-forward loop driving tumor-supportive inflammation that persists after treatment and warrants novel strategies to target both stromal and immune microenvironments in multiple myeloma., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Pyrazole analogues of the staurosporine aglycone K252c, in which the lactam ring was replaced by a pyrazole moiety, were synthesized. In this series, one or the other nitrogen atoms of the indolocarbazole scaffold was substituted by aminoalkyl chains, aiming at improving protein kinase inhibition as well as cellular potency toward acute myeloid leukemia (AML) cell lines. Compound 19a, substituted at the N12-position by a 3-(methylamino)propyl group, showed high cellular activity in the low micromolar range toward three AML cell lines (MOLM-13, OCI-AML3 and MV4-11) with selectivity over non-cancerous cells (NRK, H9c2). 19a is also a highly potent inhibitor of the three Pim kinase isoforms, Pim-3 being the most inhibited with an IC 50 value in the nanomolar range. A selectivity screening toward a panel of 50 protein kinases showed that 19a also potently inhibited PRK2 and to a lower extent AMPK, MARK3, GSK3β and JAK3. Our results enhance the understanding of the structural characteristics of indolopyrazolocarbazoles essential for potent protein kinase inhibition with therapeutic potential against AML., 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. Published by Elsevier Masson SAS.)

Background: Despite advances in treatments for multiple myeloma (MM), most patients relapse and become refractory to standard drug classes including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 antibodies. The LocoMMotion study showed poor clinical outcomes in triple-class exposed patients with relapsed/refractory MM (RRMM) treated with real-world clinical practice (RWCP) therapy. Here, we report efficacy outcomes for Spanish patients receiving RWCP treatments in the LocoMMotion study compared with the full cohort., Patients and Methods: The prospective, noninterventional, multinational LocoMMotion study (NCT04035226) enrolled 248 patients who had received ≥ 3 prior lines of therapy (LOT), including a PI, an IMiD, and an anti-CD38 antibody, with disease progression during or after their last LOT. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS) and overall survival (OS)., Results: Spanish patients (n = 24) had received a median of 4 prior LOT (range, 2-7). At 29.2 months median follow-up, patients had received 14 different treatment regimens used in RWCP during the study. Efficacy outcomes were consistent between the Spanish cohort and overall study population. The ORR was 29.2% (95% CI, 12.6%-51.1%). Median PFS and OS were 4.6 months (95% CI, 1.2-6.3) and 11.6 months (95% CI, 6.4-24.5), respectively., Conclusion: Spanish patients from the LocoMMotion study demonstrated poor outcomes in response to RWCP treatments consistent with those of the overall study population, highlighting the need for access to new and effective therapies for patients with RRMM in Spain and globally., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Talquetamab, a bispecific antibody targeting GPRC5D × CD3, is approved for the treatment of patients with triple-class -exposed (TCE) relapsed/refractory multiple myeloma (RRMM) on the basis of the results from the phase I/II MonumenTAL-1 trial. The relative effectiveness of talquetamab vs. real-world physician's choice of therapy (RWPC) was assessed using adjusted comparisons., Methods: An external control arm for MonumenTAL-1 (subcutaneously administered talquetamab 0.4 mg/kg weekly [QW] and 0.8 mg/kg every other week [Q2W]) was created from two observational real-world studies: LocoMMotion and MoMMent. Imbalances in baseline covariates were adjusted using inverse probability weighting. The relative effectiveness of talquetamab vs. RWPC was estimated for overall response rate (ORR), ≥ very good partial response (VGPR), and ≥ complete response (CR); odds ratios and relative response ratios (RRs) were derived from weighted logistic regression. Hazard ratios (HRs) for duration of response (DOR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS) were estimated using a weighted Cox proportional hazards model., Results: After reweighting, baseline characteristics were balanced across cohorts. In adjusted comparisons, patients treated with talquetamab QW (n = 143) had significantly improved outcomes vs. RWPC; RRs were ORR 2.67, p < 0.0001; ≥ VGPR 4.70, p < 0.0001; ≥ CR 78.05, p = 0.0002; and HRs were PFS 0.52, p < 0.0001; TTNT 0.48, p < 0.0001; OS 0.36, p < 0.0001. Patients treated with talquetamab Q2W (n = 145) also had significantly improved outcomes vs. RWPC; RRs were ORR 2.62, p < 0.0001; ≥ VGPR 5.04, p < 0.0001; ≥ CR 101.14, p = 0.0002; and HRs were PFS 0.40, p < 0.0001; TTNT 0.39, p < 0.0001; OS 0.37, p < 0.0001., Conclusion: Effectiveness of talquetamab for both schedules was significantly better than RWPC for ORR, ≥ VGPR, ≥ CR, PFS, OS, and TTNT, highlighting its clinical benefit for patients with TCE RRMM., Trial Registration: MonumenTAL-1, ClinicalTrials.gov identifier NCT03399799/NCT04634552; LocoMMotion, ClinicalTrials.gov identifier NCT04035226; MoMMent, ClinicalTrials.gov identifier NCT05160584., (© 2024. The Author(s).)

Abstract: To establish a strict p53-dependent gene-expression profile, TP53-/- clones were derived from TP53+/+ and TP53-/mut t(4;14) human myeloma cell lines (HMCLs) using CRISPR/Cas9 technology. From the 17 dysregulated genes shared between the TP53-/- clones from TP53+/+ HMCLs, we established a functional p53 score, involving 13 genes specifically downregulated upon p53 silencing. This functional score segregated clones and myeloma cell lines as well as other cancer cell lines according to their TP53 status. The score efficiently identified samples from patients with myeloma with biallelic TP53 inactivation and was predictive of overall survival in Multiple Myeloma Research Foundation-coMMpass and CASSIOPEA cohorts. At the functional level, we showed that among the 13 genes, p53-regulated BAX expression correlated with and directly affected the MCL1 BH3 mimetic S63845 sensitivity of myeloma cells by decreasing MCL1-BAX complexes. However, resistance to S63845 was overcome by combining MCL1 and BCL2 BH3 mimetics, which displayed synergistic efficacy. The combination of BH3 mimetics was effective in 97% of patient samples with or without del17p. Nevertheless, single-cell RNA sequencing analysis showed that myeloma cells surviving the combination had lower p53 score, showing that myeloma cells with higher p53 score were more sensitive to BH3 mimetics. Taken together, we established a functional p53 score that identifies myeloma cells with biallelic TP53 invalidation, demonstrated that p53-regulated BAX is critical for optimal cell response to BH3 mimetics, and showed that MCL1 and BCL2 BH3 mimetics in combination may be of greater effectiveness for patients with biallelic TP53 invalidation, for whom there is still an unmet medical need., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Antibody engineering can tailor the design and activities of therapeutic antibodies for better efficiency or other advantageous clinical properties. Here we report the development of ISB 1442, a fully human bispecific antibody designed to re-establish synthetic immunity in CD38+ hematological malignancies. ISB 1442 consists of two anti-CD38 arms targeting two distinct epitopes that preferentially drive binding to tumor cells and enable avidity-induced blocking of proximal CD47 receptors on the same cell while preventing on-target off-tumor binding on healthy cells. The Fc portion of ISB 1442 is engineered to enhance complement dependent cytotoxicity, antibody dependent cell cytotoxicity and antibody dependent cell phagocytosis. ISB 1442 thus represents a CD47-BsAb combining biparatopic targeting of a tumor associated antigen with engineered enhancement of antibody effector function to overcome potential resistance mechanisms that hamper treatment of myeloma with monospecific anti-CD38 antibodies. ISB 1442 is currently in a Phase I clinical trial in relapsed refractory multiple myeloma., (© 2024. The Author(s).)