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Purpose of Review: B-cell maturation antigen (BCMA)-directed T-cell immunotherapies, such as chimeric antigen receptor T-cells (CAR T-cells) and bispecific antibodies (BsAbs) have markedly improved the survival of triple-class refractory multiple myeloma (MM). However, the majority of patients still develops disease progression, underlining the need for new agents for these patients., Recent Findings: Novel T-cell redirecting BsAbs targeting alternative tumor-associated antigens have shown great promise in heavily pretreated MM, including patients previously exposed to BCMA-directed therapies. This includes the G-protein-coupled receptor class 5 member D (GPRC5D)-targeting BsAbs talquetamab and forimtamig, as well as the Fc receptor-homolog 5 (FcRH5)-targeting BsAb cevostamab. Toxicity associated with these BsAbs includes cytokine-release syndrome, cytopenias, and infections. In addition, GPRC5D-targeting BsAbs are associated with specific 'on target/off tumor' toxicities including rash, nail disorders, and dysgeusia. Trispecifc antibodies targeting two different MM-associated antigens to prevent antigen escape are in early clinical development, as well as trispecific antibodies (TsAbs) that provide an additional co-stimulatory signal to T-cells to prevent their exhaustion., Summary: Various T-cell redirecting BsAbs are in advanced stages of clinical development with promising activity and a manageable toxicity profile. Ongoing studies are evaluating combination strategies, fixed-duration treatment, and use of BsAbs in earlier lines of therapy. TsAbs hold great promise for the future., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: The success of B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T cells illustrates the potential of this novel therapy for multiple myeloma. Nonetheless, broadening CAR T-cell therapy beyond BCMA requires inventive strategies as there are only a few multiple myeloma- or plasma cell-specific target antigens. We investigated the feasibility of achieving multiple myeloma specificity by dual-split CD38/CD138 CAR targeting, whereby the stimulatory and costimulatory signals for T-cell activation are split into two separate stimulatory (sCAR) and costimulatory CARs (cCAR)., Experimental Design: Using various combinations of CD38 and CD138 sCARs and cCARs with different affinities, we generated several dual-split CAR T cells and analyzed them for multiple myeloma-specific effector functions in vitro. The best-functioning CAR T cells were tested in vivo in a murine xenograft model., Results: We found optimal designs of both CD38sCAR/CD138cCAR and CD138sCAR/CD38cCAR combinations, that effectively lysed multiple myeloma cells but spared single CD38- or CD138-positive healthy hematopoietic cells. While the CD38sCAR/CD138cCAR T cells achieved multiple myeloma-specific activity solely due to the low affinity of the CD38sCARs, the multiple myeloma-specific cytotoxicity, cytokine release, and proliferation of CD138sCAR/CD38cCAR T cells were established through a true combinatorial stimulatory and costimulatory effect. The most optimal combination comprised a low-affinity CD138sCAR combined with a high-affinity CD38cCAR. These CD138sCAR/CD38cCAR T cells also showed dual-antigen specific anti-multiple myeloma effects in vivo. Importantly, they were also effective against multiple myeloma cells from daratumumab pretreated patients with decreased CD38 expression levels., Conclusions: We demonstrate the possibility to specifically target multiple myeloma cells, even after CD38 targeted therapy, with carefully-designed dual-split CARs directed against CD38 and CD138., (©2023 American Association for Cancer Research.)

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

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

Competing Interests: FHS: Grants or contracts from Celgene, Janssen, Oncopeptides, Sanofi, GSK Targovax. Payments or honoraria for lectures/presentations/speakers bureus/article writing or educational events: Amgen, BMS, Takeda, Abbvie, Janssen, Novartis, SkyliteDX, Oncopeptides, Sanofi, Pfizer, Daiki-Sankyo, GSK. Participation on a Data Safety Monitoring Board or Advisory Board: Abbvie, GSK, Celgene, Takeda, Janssen, Oncopeptides, Sanofi, BMS. MH: Royalties of payments for lectures: Janssen, BMS, Pfizer. EvdS: Royalties for lectures Janssen. PFY: Royalties of payments for lectures/article preparations/etc: Janssen and Amgen: participation in a company sponsored speakers’ bureau. UHM: Employment/Consultation: Advisory boards: Amgen, Sanofi, Pfizer. Royalties of payments for lectures/article preparations/etc: Lecture honoraria: Amgen, Janssen, BMS, Sanofi, GSK. NWCJvdD: Research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis and BMS, and serves in advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Takeda, Roche, Novartis, Bayer, Adaptive, and Servier. PS: Consulting or Advisory Role: Celgene, Janssen, Amgen, Karyopharm Therapeutics, CARsgen Therapeutics, Pfizer. Research Funding: Janssen, Amgen, BMS/Celgene. NA: Research grant, honorarium and advisory board, Takeda. SZ: Consulting or Advisory Role: Janssen-Cilag, Takeda, Celgene/Bristol Myers Squibb, Sanofi, Oncopeptides (no personal funding). Research Funding: Janssen, Takeda. All the other authors have no conflicts of interest to disclose.

We used a modified Delphi approach to establish areas of consensus and nonconsensus regarding the utility of determining measurable residual disease (MRD) to assess multiple myeloma (MM) treatment response, which may inform disease management and design of future clinical trials. This modified Delphi study incorporated 2 iterative rounds of surveys to evaluate the opinions of an expert panel of 61 practicing hematological oncologists from across 14 countries in Europe concerning the use of MRD testing in MM management. Survey 1 assessed experts' opinions on MRD testing in different clinical situations and associated challenges. Survey 2 focused on the lack of consensus areas identified in survey 1. Consensus to an individual question was defined a priori as 75% agreement or disagreement by the panel. From the 2 rounds of surveys, the experts reached consensus agreement that MRD testing should be performed in newly diagnosed or relapsed patients who achieved complete response (CR) or better after transplantation. In transplant-ineligible patients, experts recommended MRD testing in those who are ≤70 years old and in CR. If a patient was previously positive on positron-emission tomography and computed tomography (PET/CT), both MRD and PET/CT should be assessed at CR. MRD testing should be performed ≤6 months after transplantation and every 6-12 months in continuously treated patients in CR. There was no consensus on making treatment decisions based on MRD status. MRD testing is an important component of clinical management in MM. Additional data will further clarify the role of MRD in guiding treatment decisions., Competing Interests: KR: Has served as an advisor for and received honoraria from Janssen, Adaptive Biotechnologies, Amgen, Takeda, Abbvie, Oncopeptides, Celgene – Bristol Myers Squibb, Pfizer, and GSK. Has received grant funding from Janssen, Amgen, Takeda, GSK and Celgene – Bristol Myers Squibb. HA-L: Has served as an advisor for and received honoraria from Amgen, Bristol Myers Squibb, Celgene, Janssen, Sanofi, GSK, Takeda, and Adaptive Biotechnologies. CHB: Has served as an advisor for and received honoraria from Amgen, Bristol Myers Squibb, Takeda, Sanofi, GSK, and Adaptive Biotechnologies. MD: Has served as an advisor for and received honoraria from Amgen, Celgene – Bristol Myers Squibb, GSK, Janssen, Sanofi, and Takeda. FG: Has served as an advisor for Janssen, Amgen, Celgene – Bristol Myers Squibb, Adaptive Biotechnologies, Roche, Abbvie, GSK, Takeda, Bluebird Bio, Oncopeptides, Pfizer, and Sanofi. Has received honoraria from Janssen, Amgen, Celgene – Bristol Myers Squibb, GSK, Takeda, and Sanofi. SM: Has served as an advisor for Abbvie, Adaptive Biotechnologies, Amgen, Celgene – Bristol Myers Squibb, GSK, Janssen, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, and Takeda. JM-L: Has served as an advisor for and received honoraria from Amgen, Bristol Myers Squibb, Celgene, Janssen, Sanofi, GSK, Incyte, Roche, Pfizer, Novartis and Adaptive Biotechnologies. MVM: Has served as an advisor for and received honoraria from Janssen, Celgene – Bristol Myers Squibb, Takeda, Amgen, Adaptive Biotechnologies, Oncopeptides, Sanofi, Roche, Regeneron, and Pfizer. MM: Has received honoraria from Amgen, Astellas, Bristol Myers Squibb, Celgene, Gilead, Janssen, Jazz, Takeda, Novartis, Pfizer, Sanofi, and Adaptive Biotechnologies. Has received research funding from Celgene, Janssen, Jazz, and Sanofi. NWCJvdD: Has served as an advisor for Janssen Pharmaceuticals, Amgen, Adaptive Biotechnologies, Celgene, Bristol Myers Squibb, Novartis, Roche, Takeda, Bayer, and Servier. Has received grant funding from Janssen Pharmaceuticals, Amgen, Celgene, Cellectis, and Bristol Myers Squibb. KW: Has served as an advisor for Amgen, Adaptive Biotechnologies, Bristol Myers Squibb, Celgene, GSK, Janssen, Karyopharm, Oncopeptides, Sanofi, and Takeda. Has received honoraria from Amgen, Adaptive Biotechnologies, Bristol Myers Squibb, Celgene, GSK, Janssen, Karyopharm, Oncopeptides, Sanofi, Takeda, and Roche. Has received grant funding from Amgen, Janssen, Celgene, and Sanofi (to the institution)., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Background: The outcome of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients is heterogeneous, partly depending on frailty level. The aim of this study was to prospectively investigate the efficacy and safety of Ixazomib-Daratumumab-low-dose dexamethasone (Ixa-Dara-dex) in NDMM intermediate-fit patients., Methods: In this phase II multicenter HOVON-143 study, IMWG Frailty index based intermediate-fit patients, were treated with 9 induction cycles of Ixa-Dara-dex, followed by maintenance with ID for a maximum of 2 years. The primary endpoint was overall response rate on induction treatment. Patients were included from October 2017 until May 2019. Trial Registration Number: NTR6297., Findings: Sixty-five patients were included. Induction therapy resulted in an overall response rate of 71%. Early mortality was 1.5%. At a median follow-up of 41.0 months, median progression-free survival (PFS) was 18.2 months and 3-year overall survival 83%. Discontinuation of therapy occurred in 77% of patients, 49% due to progression, 9% due to toxicity, 8% due to incompliance, 3% due to sudden death and 8% due to other reasons. Dose modifications of ixazomib were required frequently (37% and 53% of patients during induction and maintenance, respectively), mainly due to, often low grade, polyneuropathy. During maintenance 23% of patients received daratumumab alone. Global quality of life (QoL) improved significantly and was clinically relevant, which persisted during maintenance treatment., Interpretation: Ixazomib-Daratumumab-low-dose dexamethasone as first line treatment in intermediate-fit NDMM patients is safe and improves global QoL. However, efficacy was limited, partly explained by ixazomib-induced toxicity, hampering long term tolerability of this 3-drug regimen. This highlights the need for more efficacious and tolerable regimens improving the outcome in vulnerable intermediate-fit patients., Funding: Janssen Pharmaceuticals, Takeda Pharmaceutical Company Limited., Competing Interests: Claudia Stege. Speaker's Bureau: Sanofi, Celgene/Bristol Myers Squibb, Takeda. Consulting or Advisory Role: Sanofi, Janssen. Marie-Christiane Vekemans. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, Janssen, Takeda, Bristol Myers Squibb/Celgene. Consulting or Advisory Role: Amgen, Celgene-Bristol Myers Squibb, Janssen, Takeda, Sanofi, Pfizer, GlaxoSmithKline, Menarini. Ka-Lung Wu. Consulting or Advisory Role: Pfizer, Janssen, Bristol Myers Squibb. Niels W. C. J. van de Donk. Consulting or Advisory Role: Janssen, Celgene, Bristol Myers Squibb, Novartis, Amgen, Servier, Takeda, Bayer, Roche, Pfizer, Abbvie, Adaptive. Research Funding: Janssen, Celgene, Amgen, Novartis, Bristol Myers Squibb, Cellectis. Gert Jan Timmers. Participation on an Advisory Board: Novartis. Travel, Accommodations, Expenses: Novartis, Janssen. Ellen van der Spek. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Janssen. Pieter Sonneveld. Participation on a Data Safety Monitoring Board or Advisory Board: Celgene, Janssen, Amgen, Bristol Myers Squibb, Karyopharm Therapeutics, Pfizer. Research Funding: Janssen, Amgen, Bristol Myeres Squibb/Celgene, Karyopharm Therapeutics, Pfizer. Inger S. Nijhof. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Janssen, Celgene/Bristol Myers Squibb, Sanofi. Mark-David Levin. Support for attending meetings and/or travel: Janssen, Takeda. Paula F. Ypma. Payment or honoraria for presentations: Janssen. Support for attending meetings and/or travel: Janssen. Sonja Zweegman. Consulting or Advisory Role: Janssen-Cilag, Takeda, Celgene/Bristol Myers Squibb, Sanofi, Oncopeptides (no personal funding). Research Funding: Janssen, Takeda. No other potential conflicts of interest were reported., (© 2023 The Author(s).)

Background: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease., Methods: In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival., Results: A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%)., Conclusions: A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.)., (Copyright © 2023 Massachusetts Medical Society.)

T-cell-engaging bispecific antibodies (BsAbs) simultaneously bind to antigens on tumour cells and CD3 subunits on T cells. This simultaneous binding results in the recruitment of T cells to the tumour, followed by T-cell activation and degranulation, and tumour cell elimination. T-cell-engaging BsAbs have shown substantial activity in several haematological malignancies by targeting CD19 in acute lymphoblastic leukaemia, CD20 in B-cell non-Hodgkin lymphoma, and BCMA and GPRC5D in multiple myeloma. Progress with solid tumours has been slower, in part due to the paucity of therapeutic targets with a tumour-specific expression profile, which is needed to limit on-target off-tumour side-effects. Nevertheless, BsAb-mediated recognition of a peptide fragment of gp100 presented by HLA-A2:01 molecules has shown marked activity in patients with unresectable or metastatic uveal melanoma. Cytokine release syndrome is the most frequent toxicity associated with BsAb treatment and is caused by activated T cells secreting proinflammatory cytokines. Understanding of resistance mechanisms has resulted in the development of new T cell-redirecting formats and novel combination strategies, which are expected to further improve depth and duration of response., Competing Interests: Declaration of interests SZ has received research funding from Celgene, Takeda, and Janssen, all paid to their institution; and serves on advisory boards for Janssen, Takeda, Bristol Myers Squibb, Oncopeptides, and Sanofi, all paid to their institution. NWCJvdD has received research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis, and Bristol Myers Squibb, all paid to their institution; and serves on advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, Bristol Myers Squibb, Takeda, Roche, Novartis, and Adaptive, all paid to their institution., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Here, the International Myeloma Working Group (IMWG) updates its clinical practice recommendations for the management of multiple myeloma-related renal impairment on the basis of data published until Dec 31, 2022. All patients with multiple myeloma and renal impairment should have serum creatinine, estimated glomerular filtration rate, and free light chains (FLCs) measurements together with 24-h urine total protein, electrophoresis, and immunofixation. If non-selective proteinuria (mainly albuminuria) or involved serum FLCs value less than 500 mg/L is detected, then a renal biopsy is needed. The IMWG criteria for the definition of renal response should be used. Supportive care and high-dose dexamethasone are required for all patients with myeloma-induced renal impairment. Mechanical approaches do not increase overall survival. Bortezomib-based regimens are the cornerstone of the management of patients with multiple myeloma and renal impairment at diagnosis. New quadruplet and triplet combinations, including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, improve renal and survival outcomes in both newly diagnosed patients and those with relapsed or refractory disease. Conjugated antibodies, chimeric antigen receptor T-cells, and T-cell engagers are well tolerated and effective in patients with moderate renal impairment., Competing Interests: Declaration of interests MAD has received honoraria from AbbVie, Amgen, Bristol Myers Squibb (BMS), GSK, Janssen, Karyopharm Therapeutics, Pharmacyclics, Pfizer, Sanofi, and Takeda Pharmaceuticals. FB holds consulting roles for Janssen, AstraZeneca, Attralus, and Prothena; and is part of the speakers’ bureau for GSK, Janssen, and Sanofi. NL has received institutional research support for clinical trials from Omeros and holds stocks in AbbVie. JM holds consulting roles for Amgen, BMS, Janssen, Karyopharm Therapeutics, Sanofi, and Takeda Pharmaceuticals. SJH holds consulting roles for and has received honoraria from AbbVie, Amgen, BMS-Celgene, GSK, HaemaLogiX, Janssen, Novartis, Roche-Genetec, Takeda Pharmaceuticals, Sanofi, EUSA Pharma, and Terumo; and research funding from Amgen, BMS-Celgene, GSK, HaemaLogiX, Janssen, and Roche-Genetec. EK has received honoraria and research funding from Amgen, Janssen, GSK, and Pfizer. LG has received honoraria from BMS-Celgene, Janssen, Takeda Pharmaceuticals, Sanofi, and GSK. AG has received honoraria from Janssen, Amgen, and Sanofi. NWCJvdD has received research support from Janssen, Amgen, Celgene, Novartis, Cellectis, and BMS, all paid to their institution; and serves in advisory boards for Janssen, Amgen, Celgene, BMS, Takeda Pharmaceuticals, Roche, Novartis, and Adaptive Biotechnologies. KCW has received honoraria from AbbVie, Amgen, Adaptive Biotechnologies, AstraZeneca, BMS-Celgene, BeiGene, GSK, Janssen, Karyopharm Therapeutics, Novartis, Oncopeptides, Pfizer, Roche, Sanofi, Stemline Therapeutics, and Takeda Pharmaceuticals; and research support (paid to their institution) from AbbVie, Amgen, BMS-Celgene, GSK, Janssen, and Sanofi. AZB has received research grants from Janssen, BMS, GSK, and Celgene. MB serves in advisory boards for Janssen, Takeda Pharmaceuticals, Sanofi, Menarini, and Pfizer; and is part of the speakers’ bureau for Janssen, Takeda Pharmaceuticals, and Sanofi. JH has received honoraria for serving in advisory boards from Amgen, Angitia, Axxess Network, GSK, Janssen, and Sanofi; honoraria for talks from Amgen, BeiGene, Beijing Medical Award Foundation, Curio Science, Janssen, and Target Oncology; and is part of the Data Safety Monitoring Committee for Janssen. MM has received honoraria from Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, GSK, Janssen, Jazz Pharmaceuticals, Novartis, Pfizer, Sanofi, Stemline Therapeutics, and Takeda Pharmaceuticals; and research funding from Janssen and Sanofi. PJH is a member of advisory boards (without honorarium) for Antengene, Gilead Science, Janssen, and Pfizer. M-VM has received honoraria derived from lectures and participation in advisory boards from Janssen, BMS-Celgene, Takeda Pharmaceuticals, Amgen, GSK, AbbVie, Pfizer, Regeneron Pharmaceuticals, Roche, Sanofi, and Oncopeptides. PR holds consulting roles for Oncopeptides, BMS-Celgene, Karyopharm Therapeutics, Sanofi, GSK, AstraZeneca, Takeda Pharmaceuticals, and Janssen; and has received research grants from Oncopeptides, BMS-Celgene, Karyopharm Therapeutics, and Takeda. JB has received honoraria for lectures from Janssen, Amgen, BMS-Celgene, and Sanofi. PM has received honoraria from and serves in advisory boards for Janssen, Celgene, Amgen, Takeda Pharmaceuticals, Sanofi, AbbVie, and GSK. JS-M serves in advisory boards and provides consulting services, on behalf of their institution, for AbbVie, Amgen, BMS, Celgene, GSK, HaemaLogiX, Janssen-Cilag, Karyopharm Therapeutics, MSD, Novartis, Pfizer, Takeda Pharmaceuticals, Regeneron Pharmaceuticals, Roche, Sanofi, and SecuraBio. SVR is a member of the board of directors for the International Myeloma Foundation and has received royalties for creating content from UpToDate. HL has received honoraria from Celgene, Janssen-Cilag, Takeda Pharmaceuticals, Amgen, BMS, Sanofi, AbbVie, Pfizer, and Seagen; and research support from Amgen and Sanofi. ET has received honoraria from Amgen, AstraZeneca, BMS, EUSA Pharma, GSK, Integris Pharma, Janssen, Pfizer, Sanofi, and Takeda Pharmaceuticals; research support (paid to their institution) from Amgen, GSK, Janssen, Sanofi, and Takeda Pharmaceuticals; and travel grants from Amgen, EUSA Pharma, and Takeda Pharmaceuticals. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: HexaBody®-CD38 (GEN3014) is a hexamerization-enhanced human IgG1 that binds CD38 with high affinity. The E430G mutation in its Fc domain facilitates the natural process of antibody hexamer formation upon binding to the cell surface, resulting in increased binding of C1q and potentiated complement-dependent cytotoxicity (CDC)., Methods: Co-crystallization studies were performed to identify the binding interface of HexaBody-CD38 and CD38. HexaBody-CD38-induced CDC, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), trogocytosis, and apoptosis were assessed using flow cytometry assays using tumour cell lines, and MM patient samples (CDC). CD38 enzymatic activity was measured using fluorescence spectroscopy. Anti-tumour activity of HexaBody-CD38 was assessed in patient-derived xenograft mouse models in vivo., Findings: HexaBody-CD38 binds a unique epitope on CD38 and induced potent CDC in multiple myeloma (MM), acute myeloid leukaemia (AML), and B-cell non-Hodgkin lymphoma (B-NHL) cells. Anti-tumour activity was confirmed in patient-derived xenograft models in vivo. Sensitivity to HexaBody-CD38 correlated with CD38 expression level and was inversely correlated with expression of complement regulatory proteins. Compared to daratumumab, HexaBody-CD38 showed enhanced CDC in cell lines with lower levels of CD38 expression, without increasing lysis of healthy leukocytes. More effective CDC was also confirmed in primary MM cells. Furthermore, HexaBody-CD38 efficiently induced ADCC, ADCP, trogocytosis, and apoptosis after Fc-crosslinking. Moreover, HexaBody-CD38 strongly inhibited CD38 cyclase activity, which is hypothesized to relieve immune suppression in the tumour microenvironment., Interpretation: Based on these preclinical studies, a clinical trial was initiated to assess the clinical safety of HexaBody-CD38 in patients with MM., Funding: Genmab., Competing Interests: Declaration of interests IH, KS, MJ, BdG, WtH, SvD, PB, JvdB, SB, GA, BvK, DV, RH, TA, DS, AS, and EB are (former) employees of Genmab and own Genmab warrants and/or stock. BdG, GA, TA, and DS are co-inventors on patents related to the data described in the manuscript. NvdD received research funding from Janssen Pharmaceuticals, Amgen, Celgene, Novartis, Cellectis, and BMS, and served as a consultant or advisor to Janssen, Amgen, Celgene, BMS, Takeda, Roche, Novartis, Bayer, Adaptive, and Servier. TM has received research support from Janssen Pharmaceuticals, Genmab, Takeda, Onkimmune, and Gilead. KF declares no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, demonstrated an overall response rate of 63.0% in 165 heavily pretreated patients with relapsed or refractory multiple myeloma in the phase 1/2 MajesTEC-1 study. Cytokine release syndrome (CRS), a known manifestation of T-cell redirection, was observed in 119 of 165 patients (72.1%)., Methods: Patients received once-weekly teclistamab 1.5 mg/kg subcutaneously after two step-up doses (0.06 and 0.3 mg/kg). CRS was graded according to American Society for Transplantation and Cellular Therapy criteria and managed according to the study protocol, including use of tocilizumab and/or steroids., Results: Most cases of CRS occurred during the step-up dosing schedule of teclistamab and were grade 1 (50.3% of patients) or grade 2 (21.2% of patients); a single case of grade 3 CRS was reported in a patient with concurrent grade 3 pneumonia. All CRS cases resolved and none led to treatment discontinuation. Overall, 33.3% of patients had >1 CRS event; CRS recurrence was reduced when tocilizumab was administered for the first CRS event compared with when it was not (20.0% vs. 62.2%, respectively). Baseline characteristics such as tumor burden and cytokine levels did not appear to predict CRS incidence or severity., Conclusions: Findings of this study support the need for preemptive planning and prompt management of CRS in patients treated with T-cell-engaging bispecific antibodies. Intervention with tocilizumab for CRS appears to decrease the likelihood of patients experiencing subsequent CRS events without compromising response to teclistamab., Plain Language Summary: Cytokine release syndrome (CRS), observed in 72.1% of patients treated with teclistamab in the MajesTEC-1 study, was mostly grade 1 or 2 and manageable, without requiring treatment discontinuation. Most CRS occurred during the step-up schedule, requiring vigilance during treatment initiation. Ensure fever is resolved and patients have no signs of infection before initiating the teclistamab step-up schedule or administering the next teclistamab dose, to avoid exacerbating CRS. Tocilizumab reduced the risk of subsequent CRS in patients receiving it for their first CRS event (20.0% vs. 62.2% in those not receiving it), without affecting response to teclistamab. No baseline characteristics, including tumor burden or cytokine levels, appeared to clearly predict for CRS occurrence or severity., (© 2023 Janssen Pharmaceuticals. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

T-cell engaging bispecific antibodies (BsAbs) have substantial activity in heavily pretreated patients with multiple myeloma (MM). The overall response rate obtained with B-cell maturation antigen (BCMA)-targeting BsAbs is approximately 60%-70%, including a high proportion of patients achieving very good partial response or complete response. Comparable efficacy is seen with BsAbs targeting GPRC5D or FcRH5. Cytokine release syndrome is frequently observed with BsAb treatment, but mostly during the step-up doses and the first full dose. Early intervention with IL-6 receptor blocking antibodies (e.g., tocilizumab) prevents escalation to severe manifestations. Infections are also common during treatment and related to the extent of exposure to immune suppressive anti-MM agents, as well as development of hypogammaglobulinemia due to elimination of normal plasma cells, and probably because of T-cell exhaustion resulting from continuous BsAb-mediated T-cell activation. Adequate monitoring for infections and institution of infectious prophylaxis are essential. Patients treated with GPRC5D-targteing BsAbs often develop skin and nail disorders and loss of taste, which is likely related to GPRC5D expression in cells that produce hard keratin. Currently ongoing studies are aiming at further improving these results by evaluating BsAbs in combination with other drugs, such as immunomodulatory agents and anti-CD38 antibodies, as well as the application of BsAbs in earlier lines of therapy, including patients with newly diagnosed disease. We expect that the outcomes of patients with MM will further improve by the introduction of this novel type of T-cell immunotherapy., Competing Interests: C.O.N. has no conflict of interest. N.W.C.J.v.d.D. has received research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis, and BMS and serves in advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Takeda, Roche, Novartis, Bayer, Adaptive, and Servier, (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

In the post-pandemic COVID-19 period, human activities have returned to normal and COVID-19 cases are usually mild. However, patients with multiple myeloma (MM) present an increased risk for breakthrough infections and severe COVID-19 outcomes, including hospitalization and death. The European Myeloma Network has provided an expert consensus to guide patient management in this era. Vaccination with variant-specific booster vaccines, such as the bivalent vaccine for the ancestral Wuhan strain and the Omicron BA.4/5 strains, is essential as novel strains emerge and become dominant in the community. Boosters should be administered every 6-12 months after the last vaccine shot or documented COVID-19 infection (hybrid immunity). Booster shots seem to overcome the negative effect of anti-CD38 monoclonal antibodies on humoral responses; however, anti-BCMA treatment remains an adverse predictive factor for humoral immune response. Evaluation of the immune response after vaccination may identify a particularly vulnerable subset of patients who may need additional boosters, prophylactic therapies and prevention measures. Pre-exposure prophylaxis with tixagevimab/cilgavimab is not effective against the new dominant variants and thus is no longer recommended. Oral antivirals (nirmatrelvir/ritonavir and molnupiravir) and remdesivir are effective against Omicron subvariants BA.2.12.1, BA.4, BA.5, BQ.1.1 and/or XBB.1.5 and should be administered in MM patients at the time of a positive COVID-19 test or within 5 days post symptoms onset. Convalescent plasma seems to have low value in the post-pandemic era. Prevention measures during SARS-CoV-2 outbreaks, including mask wearing and avoiding crowded places, seem prudent to continue for MM patients., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Given the significance of the immune system and the important role of therapies within the context of the immune system in plasma cell disorders, the International Myeloma Society annual workshop convened a session dedicated to this topic. A panel of experts covered various aspects of immune reconstitution and vaccination. The top oral presentations were highlighted and discussed. This is a report of the proceedings., Competing Interests: Disclosure E.T. has received honoraria from Amgen, Astra/Zeneca, Bristol Myers Squibb, Eusa Pharma, GSK, Integris Pharma, Janssen, Pfizer, Sanofi and Takeda; research grants from Amgen, GSK, Janssen, Sanofi and Takeda and travel grants from Amgen, Eusa Pharma and Takeda. P.N. has received speaker's bureau honoraria from BMS, Janssen, Sanofi and Pfizer and is a consultant/advisory board member for Janssen, Sanofi, and Pfizer. N.W.C.J.v.d.D. has received research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis and BMS, and serves in advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Takeda, Roche, Novartis, and Adaptive, all paid to institution. M.D. has received research support from Janssen Pharmaceuticals; has received honoraria for lectures from GlaxoSmithKline, Sanofi, and Janssen; has served on advisory boards for GlaxoSmithKline, Sanofi, and Bristol Myers Squibb. S.P. has served on advisory boards for Grail and Genentech; has received research support from Amgen Inc. and Celgene/BMS Corporation. H.L. has received honoraria for advisory boards or lectures from Celgene, Janssen-Cilag, Takeda, Amgen, BMS, Sanofi, Abbvie, Pfizer, Seattle Genetics; has received research support from Amgen, and Sanofi. D.E.A. has received research support from Celgene, Pharmacyclics, and Kite Pharma; has served as consultant for Parexel, Kite Pharma, Takeda, Sanofi, Kowa, and Janssen; has served on advisory boards for Celgene, Juno, Partners TX, Karyopharm, Bristol Myers Squibb, Aviv MedTech Ltd., Takeda, Legend Bio Tech, Chugai, Kite Pharma, and Caribou Biosciences. M.V.D. has served on advisory boards for Janssen, Sanofi, BMS, Lava Therapeutics. N.S.R. declares consultancy and advisory boards for Pfizer, BMS, Janssen, Sanofi, Abbvie, Regeneron, Amgen, Caribou, Immuneel; has received research funding from Pfizer and 2Seventybio., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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

Introduction: Patients with triple-class-exposed relapsed/refractory multiple myeloma (TCE-RRMM) have a poor prognosis and limited treatment options. Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, was studied in patients with TCE-RRMM in the single-arm MajesTEC-1 study. To assess the relative effectiveness of teclistamab versus real-world physician's choice of therapy (RWPC), adjusted comparisons were performed using individual patient data from MajesTEC-1 and LocoMMotion, a prospective study of patients with TCE-RRMM., Methods: An external control arm for MajesTEC-1 was created from patients in LocoMMotion (n = 248; clinical cut-off: November 2, 2021) and compared with treated patients (n = 165) from MajesTEC-1 (teclistamab 1.5 mg/kg weekly; clinical cut-off: March 16, 2022). Inverse probability weighting was used to adjust for imbalances in baseline covariates. For binary endpoints [overall response rate (ORR), very good partial response or better (≥ VGPR) rate, complete response or better (≥ CR)], relative effect of teclistamab versus RWPC was estimated with an odds ratio and relative response rate and 95% confidence interval (CI), derived from weighted logistic regression. Weighted Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% CIs for time-to-event endpoints [duration of response (DOR), progression-free survival (PFS), and overall survival (OS)]., Results: After weighting, baseline characteristics were balanced across cohorts. In adjusted comparisons, teclistamab-treated patients were 2.3-fold, 5.2-fold and 148.3-fold, more likely to reach ORR [response-rate ratio (RR) = 2.31, 95% CI 1.77-2.85, p < 0.0001], ≥ VGPR (RR = 5.19, 95% CI 3.26-7.12, p < 0.0001) and ≥ CR (RR = 148.25, 95% CI 20.63-1065.40, p < 0.0001), respectively, versus patients receiving RWPC. Following adjustment, DOR (HR 0.32, 95% CI 0.19-0.54, p < 0.0001) and PFS (HR 0.48, 95% CI 0.35-0.65, p < 0.0001) were significantly longer with teclistamab versus RWPC. OS was numerically better with teclistamab versus RWPC [HR 0.77 (0.55-1.09), p = 0.1419]., Conclusion: Teclistamab demonstrated improved effectiveness versus RWPC, highlighting its clinical benefit as a novel and effective treatment for patients with TCE-RRMM., Trial Registration: Majest TEC-1, ClinicalTrials.gov NCT04557098; LocoMMotion, ClinicalTrials.gov NCT04035226., (© 2023. The Author(s).)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology , to patients seen in their own clinical practice. Careful evaluation of peripheral blood for the presence of circulating plasma cells by morphologic assessment or by flow cytometric analysis is an essential component of the diagnostic workup in all patients with newly diagnosed multiple myeloma (MM) to timely differentiate between MM and primary plasma cell leukemia (pPCL), which is the most aggressive plasma cell dyscrasia. The improvement in survival over time is more modest in pPCL, compared with what has been achieved in MM. pPCL is currently defined by the presence of ≥ 5% circulating plasma cells. However, this cutoff is now challenged by new data, from three large cohorts of patients with newly diagnosed MM, showing that a threshold of 2% circulating tumor cells (CTCs) by flow cytometry can be used to identify a subset of patients with ultra-high-risk MM with comparable prognosis as patients with pPCL. These patients may benefit from more intensified first-line therapies, or from enrollment into specific clinical trials, designed for ultra-high-risk MM and pPCL. Apart from differentiating MM from pPCL, the quantification of CTCs is also useful for risk stratification in MM. The detection of CTCs above a threshold of 0.01%-0.07% (much lower than the threshold to define pPCL) appears to be an independent predictor of poor clinical outcomes in newly diagnosed MM. Additional studies, including transplant-ineligible patients or with incorporation of novel immunotherapies, are needed to identify a definitive prognostic CTC cutoff. The next step will be the incorporation of CTC detection into existing staging systems to improve risk stratification and treatment personalization.

B-cell maturation antigen (BCMA)-targeting therapies, including bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs), are promising treatments for multiple myeloma (MM), but disease may progress after their use. CARTITUDE-2 is a phase 2, multicohort study evaluating the safety and efficacy of cilta-cel, an anti-BCMA chimeric antigen receptor T therapy, in various myeloma patient populations. Patients in cohort C progressed despite treatment with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and noncellular anti-BCMA immunotherapy. A single cilta-cel infusion was given after lymphodepletion. The primary end point was minimal residual disease (MRD) negativity at 10-5. Overall, 20 patients were treated (13 ADC exposed; 7 BsAb exposed; 1 in the ADC group also had prior BsAb exposure). Sixteen (80%) were refractory to prior anti-BCMA therapy. At a median follow-up of 11.3 months (range, 0.6-16.0), 7 of 20 (35%) patients were MRD negative (7 of 10 [70.0%] in the MRD-evaluable subset). Overall response rate (95% confidence interval [CI]) was 60.0% (36.1-80.9). Median duration of response and progression-free survival (95% CI) were 11.5 (7.9-not estimable) and 9.1 (1.5-not estimable) months, respectively. The most common adverse events were hematologic. Cytokine release syndrome occurred in 12 (60%) patients (all grade 1-2); 4 had immune effector cell-associated neurotoxicity syndrome (2 had grade 3-4); none had parkinsonism. Seven (35%) patients died (3 of progressive disease, 4 of adverse events [1 treatment related, 3 unrelated]). Cilta-cel induced favorable responses in patients with relapsed/refractory MM and prior exposure to anti-BCMA treatment who had exhausted other therapies. This trial was registered at www.clinicaltrials.gov as NCT04133636., (© 2023 by The American Society of Hematology.)

Background: Iberdomide is a novel cereblon E3 ligase modulator with enhanced tumouricidal and immune-stimulatory effects compared with immunomodulatory drugs. In preclinical myeloma models, iberdomide has shown synergy with dexamethasone, proteasome inhibitors, and CD38 monoclonal antibodies. We aimed to evaluate the safety and clinical activity of iberdomide plus dexamethasone in patients with heavily pretreated relapsed or refractory multiple myeloma., Methods: We conducted a multicohort, open-label, phase 1/2 trial (CC-220-MM-001) at 42 treatment centres in Europe, Canada, and the USA. Patients aged 18 years or older with multiple myeloma who had received at least two previous lines of therapy, including lenalidomide or pomalidomide and a proteasome inhibitor, were enrolled into the dose-escalation cohort. Patients received escalating doses of oral iberdomide (0·3-1·6 mg on days 1-21 of each 28-day cycle) plus oral dexamethasone (40 mg [20 mg if age >75 years] once per week). A dose-expansion cohort at the recommended phase 2 dose was planned for patients who had received at least three previous lines of therapy and had triple-class refractory disease (refractory to immunomodulatory drugs, proteasome inhibitors, and CD38 antibodies). Treatment continued until progressive disease or unacceptable toxicity. The primary outcomes were the recommended phase 2 dose (in the dose-escalation cohort, phase 1) and overall response rate (defined as complete response or partial response; in the dose-expansion cohort, phase 2) in the full analysis set. This trial is ongoing and is registered with ClinicalTrials.gov, NCT02773030., Findings: Between Dec 5, 2016, and Dec 16, 2020, 460 patients were assessed for eligibility across all cohorts and 197 were enrolled and treated with iberdomide plus dexamethasone (90 patients in the dose-escalation cohort and 107 in the dose-expansion cohort). In the dose-escalation cohort, 47 (52%) patients were female and 43 (48%) were male, 70 (78%) were White, and the median number of previous lines of therapy was 5 (IQR 4-8). In the dose-expansion cohort, 47 (44%) were female and 60 (56%) were male, 84 (79%) were White, and the median number of previous lines of therapy was 6 (IQR 5-8). At data cutoff (June 2, 2021), median follow-up was 5·8 months (IQR 3·0-13·7) in the dose-escalation cohort and 7·7 months (5·3-11·4) in the dose-expansion cohort. Two dose-limiting toxicities (both infections, at 1·2 mg and 1·3 mg) were observed in the dose-escalation cohort, and 1·6 mg was selected as the recommended phase 2 dose. In the dose-escalation cohort, the overall response rate was 32% (95% CI 23-43; 29 of 90 patients) across all doses, and the maximum tolerated dose was not reached. In the dose-expansion cohort, the overall response rate was 26% (95% CI 18-36; 28 of 107 patients). The most common grade 3 or worse adverse events were neutropenia (48 [45%] of 107 patients), anaemia (30 [28%]), infection (29 [27%]), and thrombocytopenia (23 [22%]). Serious adverse events occurred in 57 (53%) patients. There was one (1%) treatment-related death (sepsis) and five (5%) patients discontinued iberdomide due to adverse events., Interpretation: Iberdomide plus dexamethasone was generally safe and showed meaningful clinical activity in heavily pretreated patients with multiple myeloma, including in disease that was refractory to immunomodulatory drugs. These data suggest that further evaluation of iberdomide plus dexamethasone or other standard antimyeloma therapies is warranted., Funding: Bristol Myers Squibb., Competing Interests: Declaration of interests SL reports consulting fees from AbbVie, Bristol Myers Squibb, GlaxoSmithKline, Janssen Pharmaceuticals, and Takeda; institution grants or contracts from Bristol Myers Squibb, Janssen, and Takeda; membership on an entity's Board of Directors or advisory committees for TG Therapeutics; and stock ownership in TG Therapeutics. RP reports honoraria and travel grants from Bristol Myers Squibb. CH reports honoraria from AbbVie, Amgen, Bristol Myers Squibb, Cilag, Janssen Pharmaceuticals, Sanofi, and Takeda. SJ reports consulting fees from Bristol Myers Squibb, Elsevier, Janssen Pharmaceuticals, Karyopharm Therapeutics, Legend Biotech, Sanofi, and Takeda. AO reports honoraria and consulting fees from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen Pharmaceuticals, and Sanofi. PGR reports institution grants or contracts from Bristol Myers Squibb, Karyopharm Therapeutics, Oncopeptides, and Takeda; consulting fees from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Karyopharm Therapeutics, Oncopeptides, Protocol Intelligence, Regeneron, Secura Bio, Sanofi, and Takeda. KW reports institution grants or contracts from Amgen, Bristol Myers Squibb, Celgene, Janssen Pharmaceuticals, GlaxoSmithKline, and Sanofi; honoraria and consulting fees from AbbVie, Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, GlaxoSmithKline, Karyopharm Therapeutics, Novartis, Oncopeptides, Pfizer, Roche, Sanofi, and Takeda; and membership of an advisory board for German Society for Hematology and Medical Oncology and Stiftung Immunonkologie. MCM reports honoraria from Alnylam Pharmaceuticals, Bristol Myers Squibb, Cilag, Gilead Sciences, Janssen Pharmaceuticals, and Medscape; travel grants from Celgene, a Bristol Myers Squibb Company; and membership on an entity's Board of Directors or advisory committees for Bristol Myers Squibb. AZB reports research support from GlaxoSmithKline. SK reports honoraria, research support, and consulting fees from Bristol Myers Squibb. EAS reports institution grants or contracts from AbbVie and Bristol Myers Squibb; consulting fees from AbbVie, Amgen, Bristol Myers Squibb, and GlaxoSmithKline; and membership on an entity's Board of Directors or advisory committees for Amgen. YC, TVN, AA, and TP are employees of Bristol Myers Squibb and have stock ownership in Bristol Myers Squibb. MA is an employee of Bristol Myers Squibb, has stock ownership in Bristol Myers Squibb, and has received travel grants from Bristol Myers Squibb. MC is an employee of Bristol Myers Squibb. NWCJvdD reports institution grants or contracts from Amgen, Cellectis, and Janssen Pharmaceuticals; and membership on an entity's Board of Directors or advisory committees for Adaptive Biotechnologies, Amgen, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis, Roche Sanofi, and Takeda. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Patients with newly diagnosed multiple myeloma (NDMM) show heterogeneous outcomes, and approximately 60% of them are at intermediate-risk according to the Revised International Staging system (R-ISS), the standard-of-care risk stratification model. Moreover, chromosome 1q gain/amplification (1q+) recently proved to be a poor prognostic factor. In this study, we revised the R-ISS by analyzing the additive value of each single risk feature, including 1q+., Patients and Methods: The European Myeloma Network, within the HARMONY project, collected individual data from 10,843 patients with NDMM enrolled in 16 clinical trials. An additive scoring system on the basis of top features predicting progression-free survival (PFS) and overall survival (OS) was developed and validated., Results: In the training set (N = 7,072), at a median follow-up of 75 months, ISS, del(17p), lactate dehydrogenase, t(4;14), and 1q+ had the highest impact on PFS and OS. These variables were all simultaneously present in 2,226 patients. A value was assigned to each risk feature according to their OS impact (ISS-III 1.5, ISS-II 1, del(17p) 1, high lactate dehydrogenase 1, and 1q+ 0.5 points). Patients were stratified into four risk groups according to the total additive score: low (Second Revision of the International Staging System [R2-ISS]-I, 19.2%, 0 points), low-intermediate (II, 30.8%, 0.5-1 points), intermediate-high (III, 41.2%, 1.5-2.5 points), high (IV, 8.8%, 3-5 points). Median OS was not reached versus 109.2 versus 68.5 versus 37.9 months, and median PFS was 68 versus 45.5 versus 30.2 versus 19.9 months, respectively. The score was validated in an independent validation set (N = 3,771, of whom 1,214 were with complete data to calculate R2-ISS) maintaining its prognostic value., Conclusion: The R2-ISS is a simple prognostic staging system allowing a better stratification of patients with intermediate-risk NDMM. The additive nature of this score fosters its future implementation with new prognostic variables.

Purpose: Primary plasma cell leukemia (pPCL) is an aggressive subtype of multiple myeloma, which is distinguished from newly diagnosed multiple myeloma (NDMM) on the basis of the presence of ≥ 20% circulating tumor cells (CTCs). A molecular marker for pPCL is currently lacking, which could help identify NDMM patients with high-risk PCL-like disease, despite not having been recognized as such clinically., Methods: A transcriptomic classifier for PCL-like disease was bioinformatically constructed and validated by leveraging information on baseline CTC levels, tumor burden, and tumor transcriptomics from 154 patients with NDMM included in the Cassiopeia or HO143 trials and 29 patients with pPCL from the EMN12/HO129 trial. Its prognostic value was assessed in an independent cohort of 2,139 patients with NDMM from the HOVON-65/GMMG-HD4, HOVON-87/NMSG-18, EMN02/HO95, MRC-IX, Total Therapy 2, Total Therapy 3, and MMRF CoMMpass studies., Results: High CTC levels were associated with the expression of 1,700 genes, independent of tumor burden (false discovery rate < 0.05). Of these, 54 genes were selected by leave-one-out cross-validation to construct a transcriptomic classifier representing PCL-like disease. This not only demonstrated a sensitivity of 93% to identify pPCL in the validation cohort but also classified 10% of NDMM tumors as PCL-like. PCL-like MM transcriptionally and cytogenetically resembled pPCL, but presented with significantly lower CTC levels and tumor burden. Multivariate analyses in NDMM confirmed the significant prognostic value of PCL-like status in the context of Revised International Staging System stage, age, and treatment, regarding both progression-free (hazard ratio, 1.64; 95% CI, 1.30 to 2.07) and overall survival (hazard ratio, 1.89; 95% CI, 1.42 to 2.50)., Conclusion: pPCL was identified on the basis of a specific tumor transcriptome, which was also present in patients with high-risk NDMM, despite not being clinically leukemic. Incorporating PCL-like status into current risk models in NDMM may improve prognostic accuracy.

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening., Competing Interests: Declaration of interests M.G. Best, R.J.A.N., and T.W. are inventors on relevant patent applications (PCT/NL2011/050518 and PCT/NL2018/050110). R.J.A.N. and T.W. are shareholders of Illumina, Inc. M.H. is chief formulation officer at Nurish.Me, Inc., and Camelina Sun LLC and has equity in those companies (whose business activities are unrelated to the present work). D.M.P. and D.K.L. are shareholders of ExBiome BV., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Teclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma., Methods: In this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better)., Results: Among 165 patients who received teclistamab, 77.6% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell-associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2)., Conclusions: Teclistamab resulted in a high rate of deep and durable response in patients with triple-class-exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2. (Funded by Janssen Research and Development; MajesTEC-1 ClinicalTrials.gov numbers, NCT03145181 and NCT04557098.)., (Copyright © 2022 Massachusetts Medical Society.)

T-cell redirecting bispecific antibodies hold high promise for treatment of B-cell malignancies. B-cell maturation antigen (BCMA) exhibits high expression on normal and malignant mature B cells including plasma cells, which can be enhanced by inhibition of γ-secretase. BCMA is considered a validated target in multiple myeloma but whether mature B-cell lymphomas can be targeted by the BCMAxCD3 T-cell redirector teclistamab is currently unknown. BCMA expression on B-cell non-Hodgkin lymphoma and primary chronic lymphocytic leukemia (CLL) cells was assessed by flow cytometry and/or IHC. To assess teclistamab efficacy, cells were treated with teclistamab in presence of effector cells with/without γ-secretase inhibition. BCMA could be detected on all tested mature B-cell malignancy cell lines, while expression levels varied per tumor type. γ-secretase inhibition universally increased BCMA surface expression. These data were corroborated in primary samples from patients with Waldenstrom's macroglobulinemia, CLL, and diffuse large B-cell lymphoma. Functional studies with the B-cell lymphoma cell lines revealed teclistamab-mediated T-cell activation, proliferation, and cytotoxicity. This was independent of the level of BCMA expression, but generally lower in mature B-cell malignancies compared with multiple myeloma. Despite low BCMA levels, healthy donor T cells and CLL-derived T cells induced lysis of (autologous) CLL cells upon addition of teclistamab. These data show that BCMA is expressed on various B-cell malignancies and that lymphoma cell lines and primary CLL can be targeted using teclistamab. Further studies to understand the determinants of response to teclistamab are required to identify which other diseases might be suitable for teclistamab targeting., Significance: Besides reported BCMA expression on multiple myeloma, we demonstrate BCMA can be detected and enhanced using γ-secretase inhibition on cell lines and primary material of various B-cell malignancies. Furthermore, using CLL we demonstrate that low BCMA-expressing tumors can be targeted efficiently using the BCMAxCD3 DuoBody teclistamab., Competing Interests: N.W.C.J. van de Donk reports grants and other from Janssen Pharmaceuticals during the conduct of the study; grants and other from Amgen, Celgene/BMS, Novartis, Cellectis; other from Takeda, Roche, Bayer, Adaptive, and Servier outside the submitted work. H.C. Adams reports other from Janssen R&D outside the submitted work; in addition, H.C. Adams has a patent to PRD4087 issued. E. Eldering reports other from Janssen during the conduct of the study; grants from Janssen outside the submitted work. R. Verona reports other from Janssen R&D during the conduct of the study; other from Janssen R&D outside the submitted work; in addition, R. Verona has a patent to 63/194,470 pending. A.P. Kater reports grants from Janssen during the conduct of the study; grants and other from Abbvie, Genentech, AstraZeneca, BMS, and other from LAVA outside the submitted work; in addition, A.P. Kater has a patent to BCMA-bispecific for lymphoma pending. No other disclosures were reported., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Despite treatment advances, patients with multiple myeloma (MM) often progress through standard drug classes including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (mAbs). LocoMMotion (ClinicalTrials.gov identifier: NCT04035226) is the first prospective study of real-life standard of care (SOC) in triple-class exposed (received at least a PI, IMiD, and anti-CD38 mAb) patients with relapsed/refractory MM (RRMM). Patients (N = 248; ECOG performance status of 0-1, ≥3 prior lines of therapy or double refractory to a PI and IMiD) were treated with median 4.0 (range, 1-20) cycles of SOC therapy. Overall response rate was 29.8% (95% CI: 24.2-36.0). Median progression-free survival (PFS) and median overall survival (OS) were 4.6 (95% CI: 3.9-5.6) and 12.4 months (95% CI: 10.3-NE). Treatment-emergent adverse events (TEAEs) were reported in 83.5% of patients (52.8% grade 3/4). Altogether, 107 deaths occurred, due to progressive disease (n = 74), TEAEs (n = 19), and other reasons (n = 14). The 92 varied regimens utilized demonstrate a lack of clear SOC for heavily pretreated, triple-class exposed patients with RRMM in real-world practice and result in poor outcomes. This supports a need for new treatments with novel mechanisms of action., (© 2022. The Author(s).)

Competing Interests: The authors declare no conflict of interest.

Chimeric antigen receptor (CAR) T-cell therapies are highly effective for multiple myeloma (MM) but their impressive efficacy is associated with treatment-related neurotoxicities in some patients. In CARTITUDE-1, 5% of patients with MM reported movement and neurocognitive treatment-emergent adverse events (MNTs) with ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen-targeted CAR T-cell therapy. We assessed the associated factors for MNTs in CARTITUDE-1. Based on common features, patients who experienced MNTs were characterized by the presence of a combination of at least two variables: high tumor burden, grade ≥2 cytokine release syndrome (CRS) or any grade immune effector cell-associated neurotoxicity syndrome (ICANS) after cilta-cel infusion, and high CAR T-cell expansion/persistence. Strategies were implemented across the cilta-cel development program to monitor and manage patients with MNTs, including enhanced bridging therapy to reduce baseline tumor burden, early aggressive treatment of CRS and ICANS, handwriting assessments for early symptom detection, and extended monitoring/reporting time for neurotoxicity beyond 100 days post-infusion. After successful implementation of these strategies, the incidence of MNTs was reduced from 5% to <1% across the cilta-cel program, supporting its favorable benefit-risk profile for treatment of MM., (© 2022. The Author(s).)

We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) using data from 4 phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD negativity rates and reduced the risk of disease progression or death by approximately half vs standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response or better (≥CR) with MRD-negative status and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10-5 sensitivity threshold). Patient-level data were pooled from all 4 studies and for patients with TIE NDMM and patients with RRMM who received ≤2 prior lines of therapy (≤2 PL). PFS was evaluated by response and MRD status. Median follow-up (months) was 54.8 for POLLUX, 50.2 for CASTOR, 40.1 for ALCYONE, and 36.4 for MAIA. Patients who achieved ≥CR and MRD negativity had improved PFS vs those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P < .0001; TIE NDMM and RRMM ≤2 PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that ≥CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching ≥CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support ≥CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.clinicaltrials.gov as #NCT02076009, #NCT02136134, #NCT02195479, and #NCT02252172., (© 2022 by The American Society of Hematology.)

There is a strong biological rationale for the augmentation of allogeneic natural killer (NK) cell therapies with a chimeric antigen receptor (CAR) to enhance acute myeloid leukemia (AML) targeting. CD38 is an established immunotherapeutic target in multiple myeloma and under investigation as a target antigen in AML. CD38 expression on NK cells and its further induction during ex vivo NK cell expansion represents a barrier to the development of a CD38 CAR-NK cell therapy. We set out to develop a CD38 CAR-NK cell therapy for AML, first by using an NK cell line which has low baseline CD38 expression and subsequently healthy donor expanded NK cells. To overcome anticipated fratricide due to NK cell CD38 expression when using primary expanded NK cells, we applied CRISPR/Cas9 genome editing to disrupt the CD38 gene during expansion achieving a mean knockdown efficiency of 84%. The resulting CD38 KD expanded NK cells, after expression of an affinity optimized CD38 CAR, showed reduced NK cell fratricide and an enhanced ability to target primary AML blasts. Furthermore, the cytotoxic potential of CD38 CAR-NK cells was augmented by pre-treatment of the AML cells with all-trans retinoic acid which drove enhanced CD38 expression offering a rational combination therapy. These findings support the further investigation of CD38 KD - CD38 CAR-NK cells as a viable immunotherapeutic approach to the treatment of AML.

Despite the high remission rates achieved using T cells bearing a chimeric antigen receptor (CAR) against hematogical malignancies, there is still a considerable proportion of patients who eventually experience tumor relapse. Clinical studies have established that mechanisms of treatment failure include the down-regulation of target antigen expression and the limited persistence of effective CAR T cells. We hypothesized that dual targeting mediated by a CAR and a chimeric costimulatory receptor (CCR) could simultaneously enhance T cell cytotoxicity and improve durability. Concomitant high-affinity engagement of a CD38-binding CCR enhanced the cytotoxicity of BCMA-CAR and CD19-CAR T cells by increasing their functional binding avidity. In comparison to second-generation BCMA-CAR or CD19-CAR T cells, double-targeted CAR + CD38-CCR T cells exhibited increased sensitivity to recognize and lyse tumor variants of multiple myeloma and acute lymphoblastic leukemia with low antigen density in vitro. In addition, complimentary costimulation by 4-1BB and CD28 endodomains provided by the CAR and CCR combination conferred increased cytokine secretion and expansion and improved persistence in vivo. The cumulatively improved properties of CAR + CCR T cells enabled the in vivo eradication of antigen-low tumor clones, which were otherwise resistant to treatment with conventional CAR T cells. Therefore, multiplexing targeting and costimulation through the combination of a CAR and a CCR is a powerful strategy to improve the clinical outcomes of CAR T cells by enhancing cytotoxic efficacy and persistence, thus preventing relapses of tumor clones with low target antigen density.

Identification of risk factors for early mortality (EM) in multiple myeloma (MM) patients may contribute to different therapeutic approaches in patients at risk for EM. This population-based study aimed to assess trends in EM and risk factors for EM among MM patients diagnosed in the Netherlands. All MM patients, newly diagnosed between 1989 and 2018, were identified in the Netherlands Cancer Registry. Patients were categorized into three calendar periods (1989-1998, 1999-2008, 2009-2018) and into five age groups (≤65, 66-70, 71-75, 76-80, >80 years). EM was defined as death by any cause ≤180 days post-diagnosis. We included 28,328 MM patients (median age 70 years; 55% males). EM decreased from 22% for patients diagnosed in 1989-1998 to 13% for patients diagnosed in 2009-2018 (P < 0.01) and this decrease was observed among all age groups. Exact causes of death could not be elucidated. Besides patient's age, we found that features related to a more aggressive disease presentation, and patient characteristics reflecting patients' physical condition were predictive of EM. In summary, EM decreased from 1999 onwards. Nevertheless, EM remains high, especially for patients aged >70 years. Therefore, novel strategies should be explored to improve the outcome of patients at risk for EM., (© 2021. The Author(s).)

Purpose: To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial., Patients and Methods: The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS)., Results: Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively ( P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without ( P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease-negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable., Conclusion: Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone., Competing Interests: Pieter SonneveldConsulting or Advisory Role: Celgene, Janssen, Amgen, Karyopharm Therapeutics, CARsgen TherapeuticsResearch Funding: Janssen, Amgen, Skyline Diagnostics Meletios A. DimopoulosHonoraria: Amgen, Takeda, Janssen-Cilag, Bristol Myers Squibb, BeigeneConsulting or Advisory Role: Amgen, Janssen-Cilag, Takeda, Bristol Myers Squibb, Beigene Meral BeksacConsulting or Advisory Role: Amgen, Janssen, Sanofi, Oncopeptides, TakedaTravel, Accommodations, Expenses: Amgen, Janssen, Takeda, Sanofi Meral BeksacConsulting or Advisory Role: Celgene, Janssen-Cilag, Amgen, Takeda, Sanofi Pasteur, OncopeptidesSpeakers' Bureau: Amgen, Celgene, Janssen-Cilag, Sanofi Pasteur Heinz LudwigConsulting or Advisory Role: Amgen, Janssen-Cilag, Sanofi, Seattle GeneticsSpeakers' Bureau: Celgene, Bristol Myers Squibb, Janssen-Cilag, Amgen, TakedaResearch Funding: Takeda, Amgen Sonja ZweegmanConsulting or Advisory Role: Janssen-Cilag, Takeda, Celgene, Sanofi, OncopeptidesResearch Funding: Janssen-Cilag, Takeda, CelgeneTravel, Accommodations, Expenses: Janssen-Cilag, Takeda, Celgene Elena ZamagniHonoraria: Janssen-Cilag, Celgene, Amgen, Bristol Myers Squibb, Takeda, GlaxoSmithKline, Oncopeptides, SanofiConsulting or Advisory Role: Celgene, Janssen-Cilag, Amgen, SanofiTravel, Accommodations, Expenses: Janssen-Cilag, Celgene, Amgen Ruth WesterHonoraria: Sanofi Roman HajekConsulting or Advisory Role: Takeda, Amgen, Celgene, AbbVie, BMS, PharmaMar, Janssen-Cilag, NovartisSpeakers' Bureau: Takeda, AmgenResearch Funding: Novartis, BMS, Amgen, Celgene, Takeda Lucia PantaniHonoraria: Celgene, Janssen, Takeda, Amgen Francesca GayHonoraria: Amgen, Bristol Myers Squibb, Celgene, Takeda, AbbVie, Janssen, GlaxoSmithKlineConsulting or Advisory Role: AbbVie, Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Oncopeptides, Roche, Takeda, Janssen, Bluebird bio Stefania OlivaHonoraria: Amgen, Celgene/Bristol Myers Squibb, JanssenConsulting or Advisory Role: Adaptive Biotechnologies, Janssen, Amgen, Takeda Vincent van de VeldenResearch Funding: BD Biosciences, Pfizer, Janssen, Novartis/Navigate, Agilent/DAKOPatents, Royalties, Other Intellectual Property: Patent EuroFlow MRD antibody tubes. No financial relationship KaLung WuConsulting or Advisory Role: Janssen Oncology Gerard BosEmployment: CiMaasLeadership: CiMaasStock and Other Ownership Interests: CIMaasHonoraria: CiMaas Mark-David LevinHonoraria: AbbVie, Celgene, Janssen, TakedaTravel, Accommodations, Expenses: Takeda, Janssen Annemiek BroijlHonoraria: Amgen, Sanofi, Celgene, Bristol Myers Squibb/Celgene, JanssenTravel, Accommodations, Expenses: Bristol Myers Squibb/Celgene Monique MinnemaConsulting or Advisory Role: Janssen-Cilag, Alnylam, Gilead SciencesSpeakers' Bureau: Celgene/Bristol Myers SquibbTravel, Accommodations, Expenses: Celgene Anders WaageHonoraria: Janssen OncologySpeakers' Bureau: Janssen Oncology Cecilie BlimarkHonoraria: Bristol Myers Squibb/Celgene, Janssen, Takeda, AmgenConsulting or Advisory Role: Adaptive Biotechnologies, Janssen, GlaxoSmithKline Niels W. C. J. van de DonkConsulting or Advisory Role: Janssen, Celgene, Bristol Myers Squibb, Novartis, Amgen, Servier, Takeda, BayerSpeakers' Bureau: Janssen Research & Development, Celgene, Amgen, Bristol Myers SquibbResearch Funding: Janssen, Celgene, Amgen, Novartis, Bristol Myers Squibb, Cellectis Massimo OffidaniHonoraria: BMS, Janssen, CelgeneConsulting or Advisory Role: Janssen Giuseppe A. PalumboConsulting or Advisory Role: Novartis, Janssen Oncology, AOP Orphan Pharmaceuticals, AbbVie, AstraZeneca, Celgene/Bristol Myers SquibbSpeakers' Bureau: Novartis, Celgene/Bristol Myers Squibb, AbbVieTravel, Accommodations, Expenses: Takeda, Novartis Andrew SpencerHonoraria: Janssen-Cilag, BMSConsulting or Advisory Role: Janssen-Cilag, BMSSpeakers' Bureau: Janssen-CilagResearch Funding: Janssen-Cilag Mario BoccadoroHonoraria: Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, AbbVieConsulting or Advisory Role: Janssen, GlaxoSmithKlineResearch Funding: Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, Mundipharma Michele CavoHonoraria: Janssen, Bristol Myers Squibb, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm Therapeutics, Adaptive BiotechnologiesConsulting or Advisory Role: Janssen, Bristol Myers Squibb, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm Therapeutics, Adaptive BiotechnologiesSpeakers' Bureau: Janssen, CelgeneNo other potential conflicts of interest were reported.

Multiple myeloma (MM) patients eventually develop multi-drug-resistant disease with poor survival. Hence, the development of novel treatment strategies is of great importance. Recently, different classes of immunotherapeutic agents have shown great promise in heavily pre-treated MM, including T cell-redirecting bispecific antibodies (BsAbs). These BsAbs simultaneously interact with CD3 on effector T cells and a tumor-associated antigen on MM cells, resulting in redirection of T cells to MM cells. This leads to the formation of an immunologic synapse, the release of granzymes/perforins, and subsequent tumor cell lysis. Several ongoing phase 1 studies show substantial activity and a favorable toxicity profile with BCMA-, GPRC5D-, or FcRH5-targeting BsAbs in heavily pre-treated MM patients. Resistance mechanisms against BsAbs include tumor-related features, T cell characteristics, and impact of components of the immunosuppressive tumor microenvironment. Various clinical trials are currently evaluating combination therapy with a BsAb and another agent, such as a CD38-targeting antibody or an immunomodulatory drug (e.g., pomalidomide), to further improve response depth and duration. Additionally, the combination of two BsAbs, simultaneously targeting two different antigens to prevent antigen escape, is being explored in clinical studies. The evaluation of BsAbs in earlier lines of therapy, including newly diagnosed MM, is warranted, based on the efficacy of BsAbs in advanced MM.

Background: CASSIOPEIA part 1 showed superior depth of response and significantly improved progression-free survival with daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) as induction and consolidation in patients with autologous stem-cell transplant (ASCT)-eligible newly diagnosed multiple myeloma. In part 2, we compared daratumumab maintenance versus observation only., Methods: CASSIOPEIA is a two-part, open-label, randomised, phase 3 trial of patients aged 18-65 years with newly diagnosed multiple myeloma and Eastern Cooperative Oncology Group performance status 0-2, done in 111 European academic and community practice centres. In part 1, patients were randomly assigned (1:1) to induction and consolidation with D-VTd or VTd. Patients still on study who had a partial response or better were randomly assigned (1:1) by an interactive web-response system to daratumumab 16 mg/kg intravenously every 8 weeks (a reduced frequency compared with standard daratumumab long-term dosing) or observation only for up to 2 years. Stratification factors were induction treatment and depth of response in part 1. The part 2 primary endpoint was progression-free survival from second randomisation. This preplanned interim analysis of progression-free survival was done after 281 events and shall be considered the primary analysis of progression-free survival. Sponsor personnel and designees who were involved in the analysis were masked to treatment group until the independent data monitoring committee recommended that the preplanned interim analysis be considered the main analysis of progression-free survival in part 2. Otherwise, treatment assignments were unmasked. The interaction between induction and consolidation and maintenance was tested at a two-sided significance level of 0·05 by a stratified Cox regression model that included the interaction term between maintenance treatment and induction and consolidation treatment. Efficacy analyses were done in the maintenance-specific intention-to-treat population, which comprised all patients who underwent second randomisation. Safety was analysed in all patients in the daratumumab group who received at least one dose and all patients randomly assigned to observation only. This trial is registered with ClinicalTrials.gov, NCT02541383. Long-term follow-up is ongoing and the trial is closed to new participants., Findings: Between May 30, 2016, and June 18, 2018, 886 patients (458 [84%] of 543 in the D-VTd group and 428 [79%] of 542 in the VTd group) were randomly assigned to daratumumab maintenance (n=442) or observation only (n=444). At a median follow-up of 35·4 months (IQR 30·2-39·9) from second randomisation, median progression-free survival was not reached (95% CI not evaluable [NE]-NE) with daratumumab versus 46·7 months (40·0-NE) with observation only (hazard ratio 0·53, 95% CI 0·42-0·68, p<0·0001). A prespecified analysis of progression-free survival results showed a significant interaction between maintenance and induction and consolidation therapy (p<0·0001). The most common grade 3 or 4 adverse events were lymphopenia (16 [4%] of 440 patients in the daratumumab group vs eight [2%] of 444 patients in the observation-only group), hypertension (13 [3%] vs seven [2%]), and neutropenia (nine [2%] vs ten [2%]). Serious adverse events occurred in 100 (23%) patients in the daratumumab group and 84 (19%) patients in the observation-only group. In the daratumumab group, two adverse events led to death (septic shock and natural killer-cell lymphoblastic lymphoma); both were related to treatment., Interpretation: Daratumumab maintenance every 8 weeks for 2 years significantly reduced the risk of disease progression or death compared with observation only. Longer follow-up and other ongoing studies will shed further light on the optimal daratumumab-containing post-ASCT maintenance treatment strategy., Funding: Janssen Research & Development, the Intergroupe Francophone du Myélome, and the Dutch-Belgian Cooperative Trial Group for Hematology Oncology., Competing Interests: Declaration of interests PM reports personal fees from Celgene, Amgen, Takeda, Janssen, and AbbVie, outside the submitted work. CH reports personal fees from Janssen, AbbVie, Amgen, and Celgene, outside the submitted work. AP reports personal fees from Celgene, Amgen, Janssen, Sanofi, and Takeda, outside the submitted work. BA reports grants from Amgen, Celgene, Sanofi, and Janssen, during the conduct of the study; personal fees from Amgen, Celgene/Bristol Myers Squibb, Sanofi, GlaxoSmithKline, Takeda, and Janssen, outside the submitted work; and advisory board participation from Amgen, Celgene/Bristol Myers Squibb, Sanofi, GlaxoSmithKline, and Janssen, outside the submitted work. KB reports grants from Celgene outside the submitted work; personal fees from Celgene, Janssen, Takeda, and Amgen, outside the submitted work; and non-financial support from Celgene, AbbVie, and Takeda, outside the submitted work. SZ reports grants from Celgene, Janssen, and Takeda, during the conduct of the study. MD reports grants from Celgene and Janssen during the conduct of the study; participation on an advisory board for Celgene, Takeda, Janssen, Sanofi, and Oncopeptides, outside the submitted work. TD reports grants from Celgene and Janssen, during the conduct of the study; and personal fees and advisory board participation from Celgene, Takeda, Janssen, and Amgen, outside of the submitted work. CD reports personal fees from Janssen, outside the submitted work. TF reports personal fees from Janssen, Bristol Myers Squibb, Takeda, Amgen, Roche, Karyopharm, Sanofi, and Oncopeptides, outside the submitted work. CS reports personal fees from Celgene, outside the submitted work. MMo reports grants from Stemline, BMS, Amgen, Jazz Pharmaceuticals, Novartis, Takeda, Janssen, GSK, Sanofi, and Celgene; non-financial support from Stemline, BMS, Amgen, Jazz Pharmaceuticals, Novartis, Takeda, Janssen, GSK, Sanofi, and Celgene; and personal fees from Stemline, BMS, Amgen, Jazz Pharmaceuticals, Novartis, Takeda, Janssen, GSK, Sanofi, and Celgene, outside the submitted work. LK reports personal fees from Amgen, Janssen, Celgene, Takeda, and AbbVie, outside the submitted work. XL reports personal fees from Janssen, outside the submitted work. MMa reports personal fees from and advisory board participation for Amgen, Celgene, Janssen, and Takeda, outside the submitted work. A-MS reports personal fees from Celgene outside the submitted work. NWCJvdD reports grants from Amgen, Bristol Myers Squibb, Celgene, Janssen, and Novartis, during the conduct of the study; and personal fees from Amgen, Bristol Myers Squibb, Celgene, Janssen, Novartis, Bayer, Roche, Servier, and Takeda, outside the submitted work. AB reports personal fees from Amgen, Celgene, Janssen, and Bristol Myers Squibb, outside the submitted work. CT reports personal fees from Janssen, outside the submitter work. MR reports grants from Janssen, during the conduct of the study; personal fees and travel support from Celgene, Amgen, Sanofi, Takeda, and Janssen, outside the submitted work. M-DL reports grants from AbbVie, Amgen, Janssen, Roche, and Takeda, during the conduct of the study; and personal fees and advisory board participation from AbbVie, Janssen, Roche, and Takeda, outside the submitted work. TA reports employment and equity ownership from Genmab. MK reports employment with Janssen. KZ reports employment with Janssen. CdB reports employment and equity ownership from Janssen. SV reports employment with Janssen. TK reports employment with Janssen. VV reports employment with Janssen. JV reports employment with Janssen. HA-L reports grants from Celgene and Janssen, during the conduct of the study; and personal fees from Celgene, Amgen, Bristol-Myers Squibb, Sanofi, and Janssen, outside the submitted work. PS reports personal fees from Celgene and Janssen, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Frail patients with newly diagnosed multiple myeloma have an inferior outcome, mainly because of a high discontinuation rate due to toxicity. We designed a phase II trial specifically for frail patients, evaluating the efficacy and tolerability of ixazomib-daratumumab-low-dose-dexamethasone (Ixa-Dara-dex)., Methods: Sixty-five patients, who were frail according to the International Myeloma Working Group frailty index, were treated with nine induction cycles Ixa-Dara-dex followed by maintenance with Ixa-Dara for a maximum of 2 years., Results: The overall response rate on induction therapy was 78%. After a median follow-up of 22.9 months, median progression-free survival (PFS) was 13.8 months and 12-month overall survival (OS) was 78%. Median PFS and 12-month OS were 21.6 months and 92% in patients who were frail based on age > 80 years alone, versus 13.8 months and 78%, and 10.1 months and 70% in patients who were frail based on additional frailty parameters either ≤ 80 or > 80 years of age, respectively. In 51% of patients, induction therapy had to be discontinued prematurely, of which 6% because of noncompliance to study treatment, 9% because of toxicity, and 9% because of death (8% within 2 months, of which 80% because of toxicity). Quality of life improved during induction treatment, being clinically meaningful already after three induction cycles., Conclusion: Ixa-Dara-dex lead to a high response rate and improved quality of life. However, treatment discontinuation because of toxicity and early mortality, negatively influencing PFS and OS, remains a concern in frail patients. The outcome was heterogeneous across frail subpopulations. This should be taken into account in the design and interpretation of future studies in frail patients, to pave the way for more precise treatment guidance., Competing Interests: Ellen van der SpekOther Relationship: Amgen Alain KentosConsulting or Advisory Role: Amgen, Sanofi, Janssen-Cilag Niels W. C. J. van de DonkConsulting or Advisory Role: Janssen, Celgene, Bristol Myers Squibb, Novartis, Amgen, Servier, Takeda, BayerSpeakers' Bureau: Janssen Research & Development, Celgene, Amgen, Bristol Myers SquibbResearch Funding: Janssen, Celgene, Amgen, Novartis, Bristol Myers Squibb, Cellectis Esther G. M. de WaalSpeakers' Bureau: CelgeneTravel, Accommodations, Expenses: Roche Marie-Christiane VekemansConsulting or Advisory Role: Amgen, Celgene, Bristol Myers Squibb, Janssen, TakedaTravel, Accommodations, Expenses: Amgen, Bristol Myers Squibb, Teva, Janssen Gert Jan TimmersConsulting or Advisory Role: Daiichi Sankyo Ned, Janssen-CilagSpeakers' Bureau: Novartis, ServierTravel, Accommodations, Expenses: Gilead Sciences Paul A. F. GeertsHonoraria: SanofiConsulting or Advisory Role: Janssen-Cilag Inger S. NijhofConsulting or Advisory Role: Janssen, Celgene/Bristol Myers Squibb Pieter SonneveldConsulting or Advisory Role: Celgene, Janssen, Amgen, Karyopharm Therapeutics, CARsgen TherapeuticsResearch Funding: Janssen, Amgen, Skyline Diagnostics Mark-David LevinHonoraria: AbbVie, Celgene, Janssen, TakedaTravel, Accommodations, Expenses: Takeda, Janssen Sonja ZweegmanConsulting or Advisory Role: Janssen-Cilag, Takeda, Celgene, Sanofi, OncopeptidesResearch Funding: Janssen-Cilag, Takeda, CelgeneTravel, Accommodations, Expenses: Janssen-Cilag, Takeda, CelgeneNo other potential conflicts of interest were reported.

Background: There is a need for novel therapies for relapsed or refractory multiple myeloma, and B-cell maturation antigen (BCMA) is a validated target. Teclistamab is a bispecific antibody that binds BCMA and CD3 to redirect T cells to multiple myeloma cells. The aim of the MajesTEC-1 study was to evaluate the safety, tolerability, and preliminary efficacy of teclistamab in patients with relapsed or refractory multiple myeloma., Methods: This open-label, single-arm, phase 1 study enrolled patients with multiple myeloma who were relapsed, refractory, or intolerant to established therapies. Teclistamab was administered intravenously (range 0·3-19·2 μg/kg [once every 2 weeks] or 19·2-720 μg/kg [once per week]) or subcutaneously (range 80-3000 μg/kg [once per week]) in different cohorts, with step-up dosing for 38·4 μg/kg or higher doses. The primary objectives were to identify the recommended phase 2 dose (part one) and characterise teclistamab safety and tolerability at the recommended phase 2 dose (part two). Safety was assessed in all patients treated with at least one dose of teclistamab. Efficacy was analysed in response-evaluable patients (ie, patients who received at least one dose of teclistamab and had at least one post-baseline response evaluation). This ongoing trial is registered with ClinicalTrials.gov, NCT03145181., Findings: Between June 8, 2017, and March 29, 2021, 219 patients were screened for study inclusion, and 157 patients (median six previous therapy lines) were enrolled and received at least one dose of teclistamab (intravenous n=84; subcutaneous n=73). 40 patients were administered the recommended phase 2 dose, identified as once per week subcutaneous administration of teclistamab at 1500 μg/kg, after 60 μg/kg and 300 μg/kg step-up doses (median follow-up 6·1 months, IQR 3·6-8·2). There were no dose-limiting toxicities at the recommended phase 2 dose in part one. In the 40 patients treated at the recommended phase 2 dose, the most common treatment-emergent adverse events were cytokine release syndrome in 28 (70%; all grade 1 or 2 events) and neutropenia in 26 (65%) patients (grade 3 or 4 in 16 [40%]). The overall response rate in response-evaluable patients treated at the recommended phase 2 dose (n=40) was 65% (95% CI 48-79); 58% achieved a very good partial response or better. At the recommended phase 2 dose, the median duration of response was not reached. 22 (85%) of 26 responders were alive and continuing treatment after 7·1 months' median follow-up (IQR 5·1-9·1). At the recommended phase 2 dose, teclistamab exposure was maintained above target exposure levels, and consistent T-cell activation was reported., Interpretation: Teclistamab is a novel treatment approach for relapsed or refractory multiple myeloma. At the recommended phase 2 dose, teclistamab showed promising efficacy, with durable responses that deepened over time, and was well tolerated, supporting further clinical development., Funding: Janssen Research & Development., Competing Interests: Declaration of interests SZU received grant support from Bristol Myers Squibb and Pharmacyclics; grant support and consulting fees from Amgen, Celgene, Sanofi, Seattle Genetics, Janssen, Takeda, SkylineDx, Merck, and GlaxoSmithKline; and consulting fees from AbbVie, Karyopharm, and Mundipharma. ALG received grant support from Novartis and CRISPR Therapeutics; grant support and consulting fees from Janssen and Tmunity Therapeutics; consulting fees from GlaxoSmithKline and Surface Oncology; and holds a pending patent (15/757,123) with royalties paid, and pending patents (16/768,260 and 16/746,459) licensed to Novartis. NWCJvdD received grant support and advisory board fees from Bristol Myers Squibb/Celgene, Janssen, Novartis, and Amgen; advisory board fees from Takeda, Servier, Bayer, Adaptive Biotechnologies, Roche, GlaxoSmithKline, and Sanofi; and grant support from Cellectis. JFS-M received consulting and advisory board fees from Amgen, Celgene, Takeda, Bristol Myers Squibb, Merck, Sharp & Dohme, Novartis, Sanofi, Janssen, Roche, AbbVie, GlaxoSmithKline, Karyopharm Therapeutics, and Secura Bio. AO received consulting fees from Amgen, Celgene, Sanofi, Janssen, and GlaxoSmithKline. LR received consulting fees from Amgen, Celgene, Sanofi, Janssen, and Takeda. AC received grant support and consulting fees from Amgen, Janssen, Celgene, Novartis Pharmaceuticals, Seattle Genetics, Millennium/Takeda; consulting fees from Bristol Myers Squibb, Karyopharm, Sanofi, Oncopeptides, Antengene, GlaxoSmithKline, Secura Bio, Shattuck Labs; and grant support from Pharmacyclics. MB received payment for speaker bureaus from Amgen, Bristol Myers Squibb, and Takeda; served as a consultant for Sanofi Genzyme; and received grant support from Janssen, MedImmune, Takeda, Prothena, Bristol Myers Squibb/Celgene, Cerecor, and Celularity. LK received consulting fees from Janssen-Cilag, Celgene, Amgen, Takeda, and GlaxoSmithKline. LP, RV, SG, TS, YE, JI, JDG, and AB are employed by Janssen. M-VM received consulting fees from Janssen-Cilag, GlaxoSmithKline, Celgene, Amgen, Regeneron, Pfizer, AbbVie, Takeda, Roche/Genentech, and Adaptive Biotechnologies. AK received consulting fees from Janssen Oncology, GlaxoSmithKline, Celgene, Adaptive Biotechnologies, Regeneron, Pfizer, Bristol-Myers Squib, Takeda, and Sutro Biopharma. HN and LB declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Chimeric antigen receptor (CAR) T cells (CAR-T) have dramatically changed the treatment landscape of B-cell malignancies, providing a potential cure for relapsed/refractory patients. Long-term responses in patients with acute lymphoblastic leukemia and non Hodgkin lymphomas have encouraged further development in myeloma. In particular, B-cell maturation antigen (BCMA)-targeted CAR-T have established very promising results in heavily pre-treated patients. Moreover, CAR-T targeting other antigens (i.e., SLAMF7 and CD44v6) are currently under investigation. However, none of these current autologous therapies have been approved, and despite high overall response rates across studies, main issues such as long-term outcome, toxicities, treatment resistance, and management of complications limit as yet their widespread use. Here, we critically review the most important pre-clinical and clinical findings, recent advances in CAR-T against myeloma, as well as discoveries in the biology of a still incurable disease, that, all together, will further improve safety and efficacy in relapsed/refractory patients, urgently in need of novel treatment options.

Purpose: The microenvironment of multiple myeloma (MM) can critically impair therapy outcome, including immunotherapies. In this context, we have earlier demonstrated that bone marrow mesenchymal stromal cells (BMMSC) protect MM cells against the lytic machinery of MM-reactive cytotoxic T cells (CTL) and daratumumab-redirected natural killer (NK) cells through the upregulation of antiapoptotic proteins Survivin and Mcl-1 in MM cells. Here, we investigated the significance of this mode of immune escape on T cells engineered to express chimeric antigen receptors (CAR T cells)., Experimental Design: We tested the cytolytic ability of a panel of 10 BCMA-, CD38-, and CD138-specific CAR T cells with different affinities against a model MM cell line and against patient-derived MM cells in the presence versus absence of BMMSCs., Results: Although BMMSCs hardly protected MM cells from lysis by high-affinity, strongly lytic BCMA- and CD38-CAR T cells, they significantly protected against lower affinity, moderately lytic BCMA-, CD38-, and CD138-specific CAR T cells in a cell-cell contact-dependent manner. Overall, there was a remarkable inverse correlation between the protective ability of BMMSCs and the lytic activity of all CAR T cells, which was dependent on CAR affinity and type of costimulation. Furthermore, BMMSC-mediated resistance against CAR T cells was effectively modulated by FL118, an inhibitor of antiapoptotic proteins Survivin, Mcl-1, and XIAP., Conclusions: These results extend our findings on the negative impact of the microenvironment against immunotherapies and suggest that outcome of CAR T cell or conventional CTL therapies could benefit from inhibition of antiapoptotic proteins upregulated in MM cells through BMMSC interactions., (©2021 American Association for Cancer Research.)

BCMA-specific CAR T-cells have substantial therapeutic potential in multiple myeloma (MM), but most patients eventually relapse. Determinants of response and mechanisms of resistance are most likely multifactorial and include MM-related factors, premanufacturing T-cell characteristics, CAR T-cell-related features, and several components of the immunosuppressive microenvironment. Efforts to improve the potency and safety of CAR T-cell therapy include optimizing CAR design, combinatorial approaches to enhance persistence and activity, treatment of less heavily pretreated patients, and dual-antigen targeting to prevent antigen escape. We expect that these rationally designed strategies will contribute to further improvement in the clinical outcome of MM patients.

Chimeric antigen receptors (CAR) are fusion proteins containing an antigen-recognition domain coupled to a T-cell activation domain (eg, CD3ζ [CD247]) and to a costimulatory domain (eg, CD28 or 4-1BB [TNFRSF9, also known as CD137]). The B-cell maturation antigen (BCMA; TNFRSF17) is an attractive target for CAR T-cell therapy because it is only expressed by normal and malignant plasma cells and by a subset of mature B cells. Several trials of anti-BCMA CAR T cells have shown high-quality responses, including minimal residual disease-negativity in patients with multiple myeloma who were heavily pretreated. Phase 3 trials are currently evaluating CAR T-cell therapy versus standard-of-care regimens in patients in earlier stages of the disease. Trials are also ongoing in newly diagnosed patients with high-risk cytogenetic profiles or with residual disease after transplantation. CAR T cells targeting other multiple myeloma antigens, such as CD19, CD38, CD138 (SYND1), and SLAMF7, are also being explored. Toxicities associated with CAR T cells include cytokine-release syndrome, different types of cytopenia, infections, and neurotoxicity. Although some subsets of patients have sustained responses for more than 1 year, most patients eventually relapse, which might be related to the loss of CAR T cells, loss of antigen expression on the tumour cell surface, or to an immunosuppressive microenvironment that impairs the activity of T cells. Efforts to improve the effectiveness of CAR T-cell therapy include optimising CAR design and adapting the manufacturing process to generate cell products enriched for specific subsets of T cells (eg, early memory cells). Other strategies explored in trials include dual-antigen targeting to prevent antigen escape and rational combination therapy to enhance persistence. Several approaches are also being developed to improve the safety of CAR T-cell therapy, such as the incorporation of a suicide gene safety system., Competing Interests: Declaration of interests NWCJvdD reports research support from Janssen Pharmaceuticals, Amgen, Celgene, Novartis, Cellectis, and Bristol-Myers Squibb; and being on the advisory boards for Janssen Pharmaceuticals, Amgen, Celgene, Bristol-Myers Squibb, Novartis, Roche, Takeda, GlaxoSmithKline, Sanofi, Bayer, and Servier Laboratories. SZU reports research funding from Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen Pharmaceuticals, Merck Sharp and Dohme, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, and Takeda; consulting fees from AbbVie, Amgen, Celgene, GlaxoSmithKline, Janssen Pharmaceuticals, Merck Sharp and Dohme, Mundipharma, Sanofi, Seattle Genetics, SkylineDx, and Takeda; and speaker's fees from Celgene, Janssen Pharmaceuticals, Sanofi, and Takeda. KY reports research support from Janssen Pharmaceuticals, Sanofi Genzyme Oncology, and Takeda Oncology; consultancy, honoraria, and travel support from Takeda Oncology, Janssen Pharmaceuticals, Sanofi Genzyme Oncology; consultancy and honoraria from Roche Pharmaceuticals; consultancy from Autolus; and honoraria from Amgen., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Intravenous daratumumab is approved for the treatment of multiple myeloma. In Part 1 of the PAVO study, a mix-and-deliver subcutaneous formulation of daratumumab with recombinant human hyaluronidase PH20 (rHuPH20) was well tolerated, with low rates of infusion-related reactions and similar efficacy to intravenous daratumumab. Part 2 of PAVO evaluated a concentrated, pre-mixed co-formulation of daratumumab and rHuPH20 (DARA SC). Patients with ≥2 prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug, received daratumumab (1800 mg) and rHuPH20 (30,000 U) in 15 mL subcutaneously over 3-5 minutes per the approved intravenous monotherapy dosing schedule. Primary endpoints were daratumumab trough concentration at the end of weekly dosing (just prior to the Cycle 3 Day 1 dose) and safety. Twenty-five patients were enrolled in PAVO Part 2. DARA SC achieved daratumumab trough concentrations similar to or greater than intravenous daratumumab 16 mg/kg. The adverse event profile of DARA SC was consistent with intravenous daratumumab, with no new safety concerns and a lower infusion-related reaction rate. At a median follow-up of 14.2 months, the overall response rate was 52%, median duration of response was 15.7 months, and median progression-free survival was 12.0 months. DARA SC 1800 mg was well tolerated in relapsed/refractory multiple myeloma, with a low infusion-related reaction rate and reduced administration time. Daratumumab serum concentrations following DARA SC were consistent with intravenous dosing, and deep and durable responses were observed. Based on these results, ongoing studies are investigating DARA SC in multiple myeloma and other conditions. (ClinicalTrials.gov identifier: 02519452).

Multiple functions of CD38 need exploring to expand clinical application of anti-CD38 antibodies in multiple myeloma (MM). We investigated membrane dynamics of MM cells and subsequent events when CD38 is targeted by therapeutic antibodies. Human MM cells (BF01) were co-cultured in vitro with therapeutic antibody (or control immunoglobulin G) and analysed using gene expression profiling. Microvesicles from antibody-exposed cells were analysed for differential gene and microRNA (miRNA) expression, and for phenotypic characterisation. Exposure of BF01 cells to anti-CD38 antibody resulted in CD38 membrane redistribution, upregulation of metabolism-related genes and downregulation of genes involved in cell cycle processes. Microvesicles derived from antibody-exposed cells showed increased CD73 and CD39 expression, presence of programmed death-ligand 1 and significant up-/down-modulation of miRNAs. Microvesicles accumulated around immunoglobulin Fc receptor-positive (FcR + ) cells. Upon internalisation, natural killer cells displayed significantly increased expression of genes related to activation and immune response, and downregulation of genes involved in the cell cycle. Cells may use microvesicles to transmit signals distally as part of a survival strategy. Microvesicles are equipped on their surface with enzymatic machinery leading to production of tolerogenic adenosine. Further, they are internalised in FcR + cells with significant functional modifications. These observations have relevance for improving anti-CD38 therapeutic antibodies through targeting this mechanism and its sequelae., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Diagnostic and treatment response criteria for the JAK2/CALR/MPL mutation-related myeloproliferative neoplasms (MPNs) are largely based on bone marrow (BM) biopsy results. However, these biopsies have several limitations, such as the risk of sampling error. Also, the prognostic impact of BM abnormalities is largely unclear. Although not currently used in clinical practice, imaging techniques might offer additional information. In this review, we investigated the value of BM, liver, and spleen imaging for diagnosis, prognostication, and response monitoring of the JAK2/CALR/MPL mutation-related MPNs (i.e. essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF))., Methods: A systematic literature search was performed via PubMed, Embase and the Cochrane Library up to 2020 March 26th. Of 5505 identified records, 55 publications met the eligibility criteria (i.e. containing original data on the imaging appearance of BM, spleen, or liver in adult ET, PV, or MF patients, published in a peer-reviewed journal, written in English)., Results: Many explorative studies described imaging features, sometimes with comparisons to clinical characteristics. Studies reporting measures of diagnostic accuracy included 1) splenic transient elastography to predict BM fibrosis grade in MF, 2) dynamic contrast-enhanced MRI to discern MF patients from ET patients and healthy controls, and 3) 18-fluorodeoxyglucose PET to detect residual disease after stem cell transplantation in MF. The diagnostic accuracies of radiography and 99m Tc-colloid scintigraphy were derived from several other articles. Except for the study on 18-fluorodeoxyglucose PET, we established substantial concerns regarding risk of bias and applicability across these studies, using the QUADAS-2 tool. Three publications described a correlation between imaging results and prognosis, of which one quantified the effect., Conclusions: Based on current data, MRI (T1-weighted/STIR, Dixon) seems especially promising for the evaluation of BM fat content - and indirectly cellularity/fibrosis - in MF, and possibly for estimating BM cellularity in ET/PV. 18-fluorodeoxyglucose and 18-fluorothymidine PET/CT might be useful for evaluating BM fibrosis, with good reported accuracy of the former for the diagnosis of residual disease. Further research on these and other techniques is warranted to determine their exact value. Future researchers should improve methodology and focus on evaluation of diagnostic accuracy and prognostic implications of results.