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Background: Monoclonal insulin autoimmune syndrome (IAS) is a very rare disease characterized by severe attacks of hypoglycemia caused by circulating anti-insulin antibodies produced by a B-cell clone, usually clonal plasma cells., Method: We present 2 female Norwegian patients with monoclonal IAS. The anti-insulin antibodies were quantified by immune precipitation and characterized using a 3-step manual in-house assay. Both patients received plasma cell directed therapy., Result: The first patient received plasma cell directed therapy for a time-limited period and achieved a sustained clinical remission without detectable anti-insulin antibodies. The second patient receives continuous plasma cell directed therapy and is in clinical remission with low values of detectable anti-insulin antibodies., Conclusion: Plasma cell directed therapy was effective and safe in our 2 cases of monoclonal IAS. We recommend considering plasma cell directed therapy for these patients., Competing Interests: Disclosure Frida Bugge Askeland has received consulting fees from Janssen, Sanofi and Amgen, honoraria/payment from Janssen and Sanofi and participated in advisory boards for Janssen and Sanofi. Hege M. Frøen has no conflict of interest Nils Bolstad has no conflict of interest Per Medbøe Thorsby has received consulting fees from Antidoping Norway. Fredrik Schjesvold has received grants from Targovax, consulting fees from GSK, BMS, Oncopeptides, XNK Therapeutics, Takeda, Janssen, Sanofi and Galapagos, honoraria/payment from Amgen, BMS, Takeda, Sanofi, Menarini, AbbVie, Janssen, Oncopeptides and GSK and participated in advisory boards for AbbVie, Janssen, Regeneron and Sanofi. Anne Cathrine Parelius Wammer has received consulting fees from Novo Nordisk, honoraria/payment from Novo Nordisk, Sanofi and Buehringer and participated in advisory boards for Novo Nordisk. Ivar Følling has no conflict of interest. Geir E. Tjønnfjord has no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.) more...

T-cell redirecting therapy (TCRT), specifically chimeric antigen receptor T-cell therapy (CAR T-cells) and bispecific T-cell engagers (TCEs) represent a remarkable advance in the treatment of multiple myeloma (MM). There are several products available around the world and several more in development targeting primarily B-cell maturation antigen (BCMA) and G protein-coupled receptor class C group 5 member D (GRPC5D). The relatively rapid availability of multiple immunotherapies brings the necessity to understand how a certain agent may affect the safety and efficacy of a subsequent immunotherapy so MM physicians and patients can aim at optimal sequential use of these therapies. The International Myeloma Working Group conveyed panel of experts to review patient and disease-related factors affecting efficacy and safety of immunotherapy, summarize existing information on sequencing therapy and provide a series of core recommendations., Competing Interests: Competing interests: LJC: Honoraria (Amgen, Bristol-Myers-Squibb, AbbVie, Pfizer, Johnson & Johnson, Adaptive Biotechnologies, Sanofi, Genentech/Roche), Research Funding (Amgen, Bristol-Myers-Squibb, Johnson & Johnson, AbbVie, Caribou, Gracell, Genentech/Roche); RB: Honoraria (Bristol-Myers-Squibb, Pfizer, Adaptive Biotechnologies, Caribou, Genentech/Roche, GSK, Karyopharm, Legend Biotech, Johnson & Johnson, SparkCures), Research Funding (AbbVie, Bristol-Myers-Squibb, Johnson & Johnson, Novartis, Pack Health, Prothena, Sanofi); HM: Honoraria (Bristol-Myers-Squibb, Pfizer, GSK, Karyopharm, AbbVie) Research Funding (Pfizer); SB: Honoraria (AbbVie, Adaptive Biotechnologies, Bristol-Myers-Squibb, Johnson & Johnson, MJH Lifesciences); BD: Honoraria (Sanofi, Johnson & Johnson, Canopy, COTA, Bristol-Myers-Squibb) Research Funding (Amgen, GSK); CN: Honoraria (Johnson & Johnson); JR: Honoraria (Janssen, Bristol-Myers-Squibb, Pfizer, Karyopharm, Sanofi, Takeda, Genentech, AbbVie, Regeneron, Forus, Menarini, Adaptive Biotechnologies); KW:Honoraria (Abbvie, Amgen, Adaptive Biotech, Astra Zeneca, Beigene, BMS, Celgene, Janssen, GSK, Karyopharm, Menarini, Novartis, Oncopeptides, Pfizer, Roche, Sanofi, Stemline, Takeda) Research Funding (Amgen, BMS/Celgene, Janssen, Sanofi; GSK, Abbvie) Consultancy (Abbvie, Amgen, Adaptive Biotech, Beigene, BMS, Celgene, Janssen, GSK, Karyopharm, Menarini, Novartis, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, Takeda); MJF: Honoraria (Kite/Gilead, CMS, Novartis, Janssen, Legend, Cytoagents, SITC); JCY: Honoraria (Janssen, Sanofi, Bristol-Myers-Squibb, Regeneron, GSK, Pfizer, Menarini); NWCJvdD: Honoraria (Janssen, Amgen, Celgene, Novartis, Cellectis, Bristol-Myers-Squibb/Celgene, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Pfizer, AbbVie, Servier) Research Funding (Janssen, Amgen, Bristol-Myers-Squibb/Celgene, Novartis, Cellectis); NB: Honoraria (AbbVie, Amgen, Bristol-Myers-Squibb, Forus, Genentech, GlaxoSmithKline, Janssen, Pfizer, Sanofi, Takeda) Research Funding (Pfizer); RP: Honoraria (GSK, Pfizer, Janssen, Bristol-Myers-Squibb, Abbvie, Roche) Research Funding (GSK, Pfizer); W-JC: Honoraria (AbbVie, Amgen, Pfizer, Sanofi, Regeneron, GSK, Novartis) Research Funding (Bristol-Myers-Squibb, Janssen, Novartis); PJH: Advisory Board without honoraria (Antengene, Gilead, iTeos Therapeutics, GSK, Janssen, Pfizer), Research Funding: Novartis; GK: Honoraria (Janssen, Bristol-Myers-Squibb, Sanofi, Kite, Arcellx, Pfizer, Kedrion, Cellectar); PK: Research Funding (Takeda Pharmaceuticals, Celgene, Sanofi, AbbVie, Karyopharm Therapeutics, Sorrento Therapeutics, Ichnos Sciences, Amgen); FS: Honoraria (AbbVie, GSK, Celgene, Takeda, Janssen, Oncopeptides, Sanofi, Bristol-Myers-Squibb, Novartis, SkyliteDX, Pfizer, Daiki-Sankyo,); JB: Honoraria (AstraZeneca, Bristol-Myers-Squibb, Caribou Biosciences, Galapagos, Janssen, K36 Therapeutics, Kite Pharma, Legend Biotech, Pfizer, Regeneron, Roche, Sanofi, Sebia, Takeda) Research Funding (2 Seventy Bio, Abbvie, Amgen, Bristol-Myers-Squibb, C4 Therapeutics, Caribou Biosciences, CARsgen, Cartesian Therapeutics, Celularity, CRISPR Therapeutics, Fate Therapeutics, Genentech, GSK, Ichnos Sciences, Incyte, Janssen, Juno Therapeutics, K36 Therapeutics. Karyopharm, Lilly, Novartis, Poseida, Roche, Takeda); HE: Honoraria (Bristol-Myers-Squibb, Celgene, Janssen, Amgen, Takeda, Sanofi, GSK, Novartis, Roche), Research Funding (BMS/Celgene, Janssen, Sanofi; GSK, Amgen) Consultancy (Amgen, BMS, Celgene, Janssen, GSK, Novartis, Roche, Sanofi, Takeda); ADC: Honoraria (GSK; Bristol-Myers-Squibb, Janssen, AbbVie, Pfizer, iTeos, Ichnos, Arcellx, Legend; Genentech/Roche, Novartis, AstraZeneca, Kite); Research Funding (GSK, Genentech, Janssen, BMS); Patent (Novartis); JM: Honoraria (Amgen, Sanofi, Bristol-Myers-Squibb, Janssen, Takeda); YL: Honoraria (Janssen, Sanofi, NexImmune, Caribou, Bristol-Myers-Squibb, Pfizer, Regeneron, Genentech; Sanofi, Regeneron) Research Funding (Janssen, Bristol-Myers-Squibb); TGM: Honoraria (GSK, Sanofi, Amgen, Janssen); AC: Honoraria (AbbVie, Adaptive biotechnologies, Amgen, Angengene, Bristol-Myers-Squibb, Forus, Genentech/Roche, GSK, Janssen, Karyopharm, Millenium/Takeda, Sanofi). The remaining authors declare no conflict of interest. The work presented in this manuscript did not receive any financial or material support., (© 2025. The Author(s).) more...

Background: In the CONPET study, multiple myeloma patients with abnormal 18FDG positron emission/computed tomography scan after upfront autologous stem cell transplantation were treated with four cycles of carfilzomib-lenalidomide-dexamethasone (KRd). Side effect registrations show that carfilzomib might cause dyspnea, cough, respiratory tract infections, and heart failure. The aims were to investigate patient-reported shortness of breath and dyspnea during KRd consolidation., Methods: To assess shortness of breath, patients completed the Functional Assessment of Cancer Therapy-Pulmonary Symptom Index (FACT-PSI) and the EORTC QLQ-C30 to assess dyspnea. Shortness of breath was defined as decrease in FACT-PSI score or starting/increasing diuretic drugs. Mixed effect logistic regression was used for the effect analysis. Linear mixed model and clinical relevance were used to investigate dyspnea., Results: A total of 50 patients were included, median age 62 years (interquartile range 54-67). 17% reported shortness of breath at Day 15 Cycles 1-4 versus 11% at Day 1 Cycles 2-4, Cycle 4 Day 29, and 1 month posttreatment (p-value 0.048). Compared with baseline, patients reported significant, and clinically relevant worsening in dyspnea during consolidation., Conclusion: Our study confirmed earlier findings of carfilzomib causing shortness of breath during KRd administration and revealed dyspnea during consolidation compared to baseline., Trial Registration: Clinicaltrials.gov: NCT03314636, EudraCT: 2017-000586-72., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.) more...

Background: Adding anti-CD38 monoclonal antibodies to standard therapies can improve outcomes in patients with multiple myeloma. Long-term treatment with corticosteroids increases the risk of infection. We aimed to evaluate the safety and activity of isatuximab, weekly bortezomib, lenalidomide, and limited dexamethasone in patients with newly diagnosed multiple myeloma ineligible for autologous haematopoietic stem-cell transplantation (HSCT)., Methods: REST is an academic, multicentre, single-arm, phase 2 trial of adults with newly diagnosed multiple myeloma and measurable disease as defined by International Myeloma Working Group criteria, ineligible for high-dose melphalan and autologous HSCT, Eastern Cooperative Oncology Group performance status of 0-3 (with 3 only allowed if related to myeloma). In 28-day cycles, patients received isatuximab (10 mg/kg intravenously on days 1, 8, 15, and 22 of cycle 1, and days 1 and 15 of cycles 2-18), bortezomib (1·3 mg/m 2 subcutaneously on days 1, 8, and 15 of cycles 1-8), and lenalidomide (25 mg orally on days 1-21, until progressive disease). Dexamethasone was given 20 mg orally on days 1, 8, 15 and 22, limited to the two first cycles only. The primary endpoint was measurable residual disease (MRD)-negative complete response, assessed by next-generation flow cytometry (sensitivity 1·0 × 10 -5 ), during or after 18 cycles of study treatment. MRD was tested in all patients who had at least complete response before cycle 19 and in all patients who had at least very good partial response at cycle 19. All patients enrolled initiated treatment and were included in the analyses. This trial is registered with ClinicalTrials.gov (NCT04939844); the primary endpoint is reported in this Article, and follow-up is ongoing., Findings: Between June 30, 2021 and Jan 19, 2023, we assessed for eligibility and recruited 51 patients (27 [53%] females and 24 [47%] males), with a median age of 77 years (IQR 73·5-80). 39 participants completed 18 cycles of treatment on protocol, of whom two had discontinued treatment but not protocol. At a median follow-up of 27·0 months (IQR 23·0-33·7), MRD-negative complete response was observed in 19 (37% [95% CI 25·3-51·0]) patients, with a median treatment duration of 22 months (IQR 15·2-28·8; range 1·4-35·1). Disease progression or death had occurred in 18 (35%) of 51 patients, and eight (16%) patients had died. During the first 18 cycles of study treatment, the most common adverse events of grade 3 or 4 were neutropenia (28 [55%] patients), infections (21 [41%] patients), and thrombocytopenia (11 [22%] patients). 48 serious adverse events of grade 3 or higher were reported in 27 (53%) patients. A total of 14 (27%) patients discontinued treatment before cycle 19, most commonly because of progressive disease (eight [16%]) and adverse events (four [8%]). Two deaths (one due to pneumonia and one due to sepsis) were assessed as possibly related to study treatment., Interpretation: Isatuximab, weekly bortezomib, and lenalidomide with limited dexamethasone was active and safe as initial therapy for older patients with multiple myeloma ineligible for autologous HSCT. A modified quadruplet regimen in which dexamethasone is omitted after two cycles can be used in this patient population., Funding: Sanofi., Competing Interests: Declaration of interests FBA has received consulting fees from J&J and Sanofi; has received honoraria or payments from J&J and Sanofi; and has participated on advisory boards for J&J and Sanofi. EHa has received honoraria or payments from J&J and participated in advisory boards for Sanofi. TSS has received consulting fees from BMS, GSK, Menarini Group, and Sanofi; has received honoraria or payments from Takeda, Amgen, J&J, AbbVie, and Pfizer; and has participated on advisory boards for BMS, J&J, Sanofi, and GSK. AK is a member of the advisory committee in the Danish Medicines Agency. EHe has received consulting fees from J&J; has received honoraria or payments from Pfizer; has participated on advisory boards for Sanofil; and is the president of the Danish Myeloma Study Group (academic group). FS has received grants from Targovax; has received consulting fees from GSK, BMS, Oncopeptides, XNK Therapeutics, Takeda, J&J, Sanofi, and Galapagos; has received honoraria/payment from Amgen, BMS, Takeda, Sanofi, Menarini, AbbVie, J&J, Oncopeptides and GSK; has participated on advisory boards for AbbVie, J&J, Regeneron, and Sanofi; and is the president of the Nordic Myeloma Study Group (academic group). All other authors declare no competing interests., (Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.) more...

Multiple myeloma is characterized by malignant cells which produce high amounts of monoclonal immunoglobulin. Myeloma cells are, therefore, dependent on effective protein degradation. Proteasomal protein degradation is targeted by proteasome inhibitors in routine care. Autophagic protein degradation is currently not targeted in myeloma treatment. This Phase I trial showed that the combination of the proteasome inhibitor carfilzomib and the autophagy inhibitor hydroxychloroquine was well tolerated in patients with relapsed/refractory multiple myeloma. Adverse events were mostly Grades 1 and 2. An overall response rate of 44% indicates a meaningful clinical efficacy of this combination. Trial Registration : The study was registered at clinicaltrials.gov # NCT04163107., Competing Interests: Tobias S. Slørdahl has received honoraria from Takeda, Celgene, Amgen, Janssen, AbbVie, Pfizer; consultancy for Bristol Myers Squibb, GSK, Pfizer, Menarini Group, Sanofi; advisory board consultancy: Bristol Myers Squibb, Sanofi, Amgen, Celgene, GSK, Janssen. Frida Bugge Askeland has received consulting fees from Janssen, Sanofi, and Amgen, honoraria/payment from Janssen and Sanofi, participated in advisory boards for Janssen and Sanofi, and received research support from Sanofi. Fredrik Schjesvold has received grants from Targovax, consulting fees from GSK, BMS, Oncopeptides, XNK Therapeutics, Takeda, Janssen, Sanofi, and Galapagos, honoraria/payment from Amgen, BMS, Takeda, Sanofi, Menarini, AbbVie, Janssen, Oncopeptides, and GSK, and participated in advisory boards for AbbVie, Janssen, Regeneron, and Sanofi. The other authors declare no conflicts of interest., (© 2025 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.) more...

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

Multiple myeloma (MM) is a hematological cancer marked by plasma cell accumulation in the bone marrow. Despite treatment advancements, MM remains incurable in most patients. MM-associated immune dysregulation fosters disease progression, prompting research into immunotherapy to combat the disease. An area of immunotherapy investigation is the design of myeloma vaccine therapy to reverse tumor-associated immune suppression and elicit tumor-specific immune responses to effectively target MM cells. This article reviews vaccine immunotherapy for MM, categorizing findings by antigen type and delivery method. Antigens include idiotype (Id), tumor-associated (TAA), tumor-specific (TSA), and whole tumor lysate. Myeloma vaccination has so far shown limited clinical efficacy. However, further studies are essential to optimize various aspects, including antigen and patient selection, vaccine timing and sequencing, and rational combinations with emerging MM treatments., Competing Interests: HN: Honoraria: Janssen, BMS and Sanofi. FS: Honoraria: Amgen, BMS, Takeda, Abbvie, Janssen, Novartis, SkyliteDX, Oncopeptides, Sanofi, Schain, Pfizer, Daiki-Sankyo; Consultancy: GSK, Celgene, Takeda, Janssen, Oncopeptides, Sanofi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2024 Abdollahi, Norseth and Schjesvold.) more...

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

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

Multiple myeloma remains an incurable disease, despite the development of numerous drug classes and combinations that have contributed to improved overall survival. Immunotherapies directed against cancer cell-surface antigens, such as chimeric antigen receptor (CAR) T-cell therapy and T-cell-redirecting bispecific antibodies, have recently received regulatory approvals and shown unprecedented efficacy. However, these immunotherapies have unique mechanisms of action and toxicities that are different to previous treatments for myeloma, so experiences from clinical trials and early access programmes are essential for providing specific recommendations for management of patients, especially as these agents become available across many parts of the world. Here, we provide expert consensus clinical practice guidelines for the use of bispecific antibodies for the treatment of myeloma. The International Myeloma Working Group is also involved in the collection of prospective real-time data of patients treated with such immunotherapies, with the aim of learning continuously and adapting clinical practices to optimise the management of patients receiving immunotherapies., Competing Interests: Declaration of interests PR-O reports personal fees derived from consulting or advisory board roles from Celgene-BMS, Janssen, Roche, AbbVie, Pfizer, GSK, Sanofi, and H3Biomedicine; steering committee membership from Celgene-BMS, Regeneron, and Janssen; speaker's bureau fess from Janssen, Celgene-BMS, GSK, Sanofi, and AbbVie; and a travel grant from Pfizer. SU reports grants and personal fees from AbbVie, Amgen, BMS, EdoPharma, Genentech, Gilead, GSK, Merck, Sanofi, and Seagen; speakers’ bureau fees, consulting and advisory board participation, and steering committee membership from Janssen; participation on advisory boards from Karyopharm Therapeutics, Oncopeptides, Secura Bio, SkylineDx, and Takeda; and grants from Moderna, TeneoBio, and Pharmacyclics, outside the submitted work. ADC reports personal fees and participation on advisory boards from GSK; personal fees from Bristol Myers Squibb, Janssen, AbbVie, Pfizer, iTeos, Ichnos, Arcellx, and Legend; personal fees and participation on advisory boards from Genentech/Roche; participation on advisory boards from Novartis, outside the submitted work; and has a patent licensed for Novartis. NWCJvdD reports personal fees from Janssen Pharmaceuticals, Amgen, Celgene, Novartis, Cellectis, Bristol Myers Squibb/Celgene, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Pfizer, AbbVie, and Servier, outside the submitted work. JGP-L reports personal fees from Janssen and GSK, outside the submitted work. MVM reports personal fees from Janssen, Celgene/Bristol Myers Squibb, Novartis, GSK, Sanofi, Amgen, Pfizer, AbbVie, and Regeneron, outside the submitted work. HE reports personal fees and research support from Bristol Myers Squibb/Celgene, Janssen, Sanofi, and GSK; and personal fees from Amgen, Takeda, and Novartis; outside the submitted work. MM reports personal fees from Janssen, Bristol Myers Squibb, WebMD global, GSK, and CDR-Life; and research funding from Siemens and BeiGene; outside the submitted work. BAD reports advisory board participation and consulting fees from COTA and Janssen; personal fees from Multiple Myeloma Research Foundation; honoraria for CME-related activities from Plexus Communications; research funding from Amgen and GSK; and involvement as an independent reviewer of a clinical trial for BMS; outside the submitted work. NP reports research funding and accomodation expenses from Amgen, Bristol Myers Squibb, Janssen, Takeda, and The Binding Site; research funding from Sanofi, and personal fees from Pfizer, outside the submitted work. PJH reports personal fees from Antengene, Gilead, iTeos Therapeutics, Janssen, Novartis, and Pfizer, outside the submitted work. W-JC reports personal fees from AbbVie, Amgen, Pfizer, Sanofi, Regeneron, GSK, and Novartis; and grants and personal fees from Bristol Myers Squibb, Janssen, and Novartis, outside the submitted work. GG reports personal fees from and is a shareholder of XNK Therapeutics Sweden, and personal fees from Fujimoto Pharmaceutical corporation, outside the submitted work. FS reports personal fees from AbbVie, GSK, Celgene, Takeda, Janssen, Oncopeptides, Sanofi, BMS, Novartis, SkyliteDX, Pfizer, and Daiki-Sankyo, outside the submitted work. JCY reports personal fees from Janssen, Sanofi, BMS, Regeneron, GSK, Pfizer, Menarini, outside the submitted work. EZ reports personal fees from Janssen, Bristol Myers Squibb, Amgen, and Takeda, outside the submitted work. RP reports personal fees and travel support from GSK and Janssen; and personal fees from Pfizer, AbbVie, Bristol Myers Squibb, and Sanofi, outside the submitted work. CN reports personal fees and participation on advisory boards from Janssen; personal fees from Bristol Myers Squibb, Sanofi, GSK, Pfizer, AstraZeneca, and DKSH; and personal fees and participation on advisory boards from Amgen, outside the submitted work. YL reports grants and personal fees from Janssen; personal fees from Sanofi, NexImmune, Caribou, Bristol Myers Squibb, Regeneron, and Genentech; and personal fees and participation on data safety monitoring boards from Pfizer, outside the submitted work. AC reports personal fees from AbbVie, Adaptive, Amgen, Antengene, Bristol Myers Squibb, Forus, Genetech/Roche, GSK, Janssen, Karyopharm, Millenium/Takeda, and Sanofi/Genzyme, outside the submitted work. JM reports personal fees from Amgen, Sanofi, Bristol Myers Squibb, Janssen, and Takeda, outside the submitted work. MC reports personal fees from Janssen, Celgene/Bristol Myers Squibb, GSK, Sanofi, Amgen, Menarini-Stemline, AbbVie, and Pfizer, outside the submitted work. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.) more...

Introduction: A proportion of patients with multiple myeloma (MM) are older and/or have comorbidities, requiring dose adjustments. Data from OPTIMISMM (NCT01734928) supported the use of pomalidomide, bortezomib, and dexamethasone (PVd) for treating relapsed/refractory MM. This subanalysis of OPTIMISMM assessed outcome by frailty and/or bortezomib dose adjustment., Methods: Patient frailty (nonfrail vs. frail) was classified using age, Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status. Data from patients requiring a bortezomib dose reduction, interruption, and/or withdrawal during PVd treatment were assessed., Results: Among 559 patients, 93 of 281 (33.1%) and 93 of 278 (33.5%) patients who received PVd and bortezomib and dexamethasone (Vd), respectively, were frail. Overall response rate (ORR) and median progression-free survival (PFS) were higher in nonfrail vs. frail with PVd treatment (ORR, 82.8% vs. 79.6%; PFS, 14.7 vs. 9.7 months); significantly higher than with Vd regardless of frailty. Grade ≥ 3 treatment-emergent adverse events (TEAEs) were higher with PVd vs. Vd, regardless of frailty. Discontinuations of PVd were lower in nonfrail vs. frail patients (19.2% vs. 30.1%); the median duration of treatment was similar (DoT; 8.8 vs. 8.9 months, respectively). Patients who received PVd with a bortezomib dose adjustment (n = 240) had a longer median DoT (9.3 vs. 4.5 months) and PFS (12.1 vs. 8.4 months) vs. those without., Conclusion: Frail patients treated with PVd demonstrated a higher ORR and a longer PFS and DoT vs. Vd, despite a higher frequency of grade ≥ 3 TEAEs leading to pomalidomide, bortezomib, and/or dexamethasone discontinuation. Therefore, PVd treatment may improve patient outcomes, regardless of frailty., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.) more...

Scarce data exist on double maintenance in transplant-eligible high-risk (HR) newly diagnosed multiple myeloma (NDMM) patients. This prospective phase 2 study enrolled 120 transplant-eligible NDMM patients. The treatment consisted of four cycles of ixazomib-lenalidomide-dexamethasone (IRD) induction plus autologous stem cell transplantation followed by IRD consolidation and cytogenetic risk-based maintenance therapy with lenalidomide + ixazomib (IR) for HR patients and lenalidomide (R) alone for NHR patients. The main endpoint of the study was undetectable minimal residual disease (MRD) with sensitivity of <10 -5 by flow cytometry at any time, and other endpoints were progression-free survival (PFS) and overall survival (OS). We present the preplanned analysis after the last patient has been two years on maintenance. At any time during protocol treatment, 28% (34/120) had MRD < 10 -5 at least once. At two years on maintenance, 66% of the patients in the HR group and 76% in the NHR group were progression-free ( p = 0.395) and 36% (43/120) were CR or better, of which 42% (18/43) had undetectable flow MRD <10 -5 . Altogether 95% of the patients with sustained MRD <10 -5 , 82% of the patients who turned MRD-positive, and 61% of those with positive MRD had no disease progression at two years on maintenance ( p < 0.001). To conclude, prolonged maintenance with all-oral ixazomib plus lenalidomide might improve PFS in HR patients. more...

Background: Decisions regarding maintenance therapy in patients with multiple myeloma should be based on both treatment efficacy and health-related quality of life (HRQL) consequences. In the CARFI trial, patients with first relapse of multiple myeloma underwent salvage autologous stem cell transplantation (salvage ASCT) before randomization to carfilzomib-dexamethasone maintenance therapy (Kd) or observation. The primary clinical endpoint was time to progression, which was extended by 8 months by Kd. The aim of this paper is to present the all HRQL endpoints of the CARFI trial including the HRQL effect of Kd maintenance therapy relative to observation. The primary HRQL endpoint was assessed by EORTC QLQ-C30 Summary score (QLQ-C30-sum) at 8 months follow-up. A key secondary HRQL endpoint was quality-adjusted progression-free-survival (QAPFS)., Methods: HRQL was assessed with EORTC QLQ-C30, EORTC QLQ-MY20 and FACT/GOG-Ntx at randomization and every second month during follow-up. HRQL data were analyzed with linear mixed effect models until 8 months follow-up. QAPFS per individual was calculated by multiplying progression-free survival (PFS) by two quality-adjustment metrics, the QLQ-C30-sum and EORTC Quality of Life Utility Measure-Core 10 dimensions (QLU-C10D). The QAPFS per treatment group was estimated with the Kaplan-Meier method. P < 0.05 was used for statistical significance, and a between-group minimal important difference of 10 points was interpreted as clinically relevant for the QLQ-C30-sum., Results: 168 patients were randomized. HRQL questionnaire compliance was 93%. For the QLQ-C30-sum, the difference of 4.62 points (95% confidence interval (CI) -8.9: -0.4, p = 0.032) was not clinically relevant. PFS was 19.3 months for the Kd maintenance group and 16.8 months for the observation group; difference = 2.5 months (95% CI 0.5; 4.5). QAPFS based on the QLQ-C30-sum for the Kd maintenance group was 18.0 months (95% CI 16.4; 19.6) and for the observation group 15.0 months (95% CI 13.5; 16.5); difference = 3.0 months (95% CI 0.8-5.3). QAPFS based on the QLU-C10D for the Kd maintenance group was 17.5 months (95% CI 15.9; 19.2) and 14.0 months (95% CI 12.4; 15.5) for the observation group; difference = 3.5 months (95% CI 1.1-5.9)., Conclusions: Kd maintenance therapy after salvage ASCT did not adversely affect overall HRQL, but adjustment for HRQL reduced the PFS compared to unadjusted PFS. PFS of maintenance therapy should be quality-adjusted to balance the benefits and HRQL impact., (© 2024. The Author(s).) more...

Background: Daratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed., Methods: In this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)-negative status., Results: At a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P = 0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group., Conclusions: The addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma. (Funded by the European Myeloma Network in collaboration with Janssen Research and Development; PERSEUS ClinicalTrials.gov number, NCT03710603; EudraCT number, 2018-002992-16.)., (Copyright © 2023 Massachusetts Medical Society.) more...

What Is This Summary About?: This summary describes the first analysis of the PERSEUS study, which looked at adults with multiple myeloma that had never been treated before, also called newly diagnosed multiple myeloma. Multiple myeloma is a type of cancer in the blood, specifically in plasma cells within the soft, spongy tissue in the center of most bones, called the bone marrow. Researchers wanted to see if adding daratumumab (D) to a standard treatment of three other medicines called VRd, which stands for bortezomib (V), lenalidomide (R), and dexamethasone (d), could stop the multiple myeloma from getting worse and help participants live longer without multiple myeloma.Half of the participants were assigned to the treatment plan with daratumumab; they received D-VRd during initial treatment phases (induction and consolidation), followed by daratumumab as well as lenalidomide (D-R) in the maintenance phase. The other half of participants received treatment without daratumumab; they received VRd induction and consolidation followed by lenalidomide alone (R) maintenance. In addition, all participants were able to receive an autologous stem cell transplant, a procedure used to further help reduce multiple myeloma., What Were the Results?: At the time of this analysis of PERSEUS, about 4 years after participants started the study, participants who received D-VRd treatment followed by D-R maintenance had a better response to treatment (as measured by specific markers of multiple myeloma) and were more likely to be alive and free from their multiple myeloma getting worse in comparison to participants who received VRd followed by R maintenance. Side effects (unwanted or undesirable effects of treatment) in both treatment groups were in line with the known side effects of daratumumab and VRd., What Do the Results Mean?: The results of the PERSEUS study showed that including daratumumab in D-VRd induction/consolidation and D-R maintenance was better for treating multiple myeloma than the current standard VRd treatment followed by R maintenance alone in adults with a new diagnosis of multiple myeloma who were also able to receive an autologous stem cell transplant. Of importance, there were no unexpected side effects in either group. Clinical Trial Registration: NCT02874742 (GRIFFIN) (ClinicalTrials.gov). more...

18 F-Fluorodeoxyglucose positron emission tomography/computed tomography (PET) positivity after first-line treatment with autologous stem cell transplantation (ASCT) in multiple myeloma is strongly correlated with reduced progression-free and overall survival. However, PET-positive patients who achieve PET negativity after treatment seem to have comparable outcomes to patients who were PET negative at diagnosis. Hence, giving PET-positive patients additional treatment may improve their outcome. In this phase II study, we screened first-line patients with very good partial response (VGPR) or better after ASCT with PET. PET-positive patients received four 28-day cycles of carfilzomib-lenalidomide-dexamethasone (KRd). Flow cytometry-based minimal residual disease (MRD) analysis was performed before and after treatment for correlation with PET. Overall, 159 patients were screened with PET. A total of 53 patients (33%) were PET positive and 57% of PET-positive patients were MRD negative, demonstrating that these response assessments are complementary. KRd consolidation converted 33% of PET-positive patients into PET negativity. MRD-negative patients were more likely to convert than MRD-positive patients. In summary, PET after ASCT detected residual disease in a substantial proportion of patients in VGPR or better, even in patients who were MRD negative, and KRd consolidation treatment changed PET status in 33% of patients., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.) more...

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.) more...

Overall outcomes for multiple myeloma have improved due to the availability of new therapies, but patients with relapsed/refractory multiple myeloma harbouring certain factors continue to pose a therapeutic challenge. These challenging features include high-risk cytogenetics, renal impairment, patient characteristics such as age and frailty, and extramedullary disease. Prior refractory status and number of prior lines add further complexity to the treatment of these patients. While newer regimens are available and have suggested efficacy in these patient populations through subgroup analyses, differences in trial definitions and cut-offs make meaningful comparisons difficult. This review aims to examine the available clinical trial data for patients with high-risk cytogenetics, renal impairment, age and frailty and extramedullary disease., Competing Interests: M‐SR: honoraria – BMS, Janssen; advisory role – Amgen, BMS, Janssen, Novartis, Sanofi, Takeda; consultant – Amgen, BMS, Janssen, Novartis, Sanofi, Takeda; research support – BMS, Janssen, Novartis, Sanofi. EZ: honoraria – Amgen, BMS, GSK, Janssen, Pfizer, Roche, Sanofi, Takeda; advisory role – Amgen, BMS, GSK, Janssen, Pfizer, Roche, Sanofi, Takeda. SM: advisory role – AbbVie, Adaptive Biotechnology, Amgen, Celgene/BMS, GlaxoSmithKline, Janssen, Novartis, Oncopeptide, Regeneron, Roche, Sanofi, Takeda; research support – AbbVie, Adaptive Biotechnology, Amgen, Celgene/BMS, GlaxoSmithKline, Janssen, Novartis, Oncopeptide, Regeneron, Roche, Sanofi, Takeda. PR‐O:  honoraria – Amgen, BMS, GSK, Janssen, Regeneron, Sanofi, Takeda; advisory role – Abbvie, BMS, GSK, Janssen, Kite Pharma, Oncopeptides, Pfizer, Sanofi, Takeda; consultant – Celgene‐BMS, GSK, Pfizer. FS: honoraria – Abbvie, Amgen, BMS, Daiichi‐Sankyo, GSK, Janssen, Novartis, Oncopeptides, Pfizer, Sanofi, SkyliteDX, Takeda; advisory role – Abbvie, Celgene, GSK, Janssen, Oncopeptides, Sanofi, Takeda; research support – Celgene, GSK, Janssen, Oncopeptides, Sanofi, Targovax. AB: honoraria – Amgen, BMS, Janssen, Sanofi, Takeda; advisory role – Amgen, BMS, Janssen, Sanofi, Takeda., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.) more...

T-cell redirecting bispecific antibodies (BsAbs) and chimeric antigen receptor T cells (CAR T cells) have revolutionised multiple myeloma therapy, but adverse events such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, hypogammaglobulinaemia, and infections are common. This Policy Review presents a consensus from the European Myeloma Network on the prevention and management of these adverse events. Recommended measures include premedication, frequent assessing for symptoms and severity of cytokine release syndrome, step-up dosing for several BsAbs and some CAR T-cell therapies; corticosteroids; and tocilizumab in the case of cytokine release syndrome. Other anti-IL-6 drugs, high-dose corticosteroids, and anakinra might be considered in refractory cases. ICANS often arises concomitantly with cytokine release syndrome. Glucocorticosteroids in increasing doses are recommended if needed, as well as anakinra if the response is inadequate, and anticonvulsants if convulsions occur. Preventive measures against infections include antiviral and antibacterial drugs and administration of immunoglobulins. Treatment of infections and other complications is also addressed., Competing Interests: Declaration of interests HL reports honoraria for lectures and for advisory boards from Celgene-BMS, Janssen-Cilag, Takeda, Amgen, Sanofi, AbbVie, and Pfizer; and research funding from Amgen and Sanofi. ET reports grants from Amgen, Janssen, GSK, Takeda, and Sanofi; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Amgen, ASTRA, BMS, GSK, Integris, Pfizer, Sanofi, and Takeda; support for attending meetings or travel from Amgen, Takeda, and Eusa Pharma; and participation on a data safety monitoring board or advisory board from BMS, GSK, Sanofi, Takeda, Eusa Pharma, Janssen, ASTRA, and Amgen. NvdD reports research support from Janssen, Amgen, Celgene, Novartis, Cellectis, and BMS; and participation on a data safety monitoring board or advisory board from Janssen, Amgen, Celgene, BMS, Takeda, Roche, Novartis, and Adaptive. M-VM reports honoraria derived from lectures and participation in advisory boards from Janssen, BMS-Celgene, Takeda, Amgen, GSK, AbbVie, Pfizer, Regeneron, Roche, Sanofi, and Oncopeptides. PMo reports honoraria for advisory boards and symposia from Celgene, Janssen, Pfizer, and Abbvie; and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Janssen, Celgene, Takeda, Amgen, AbbVie, Sanofi, and GSK. M-AD reports participation in advisory boards for Amgen, Takeda, BMS, Janssen, Beigene, and Sanofi. MD reports grants from Janssen and BMS; consulting fees from Amgen, BMS, Janssen, Sanofi, Stemline, and Takeda; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from BMS and Janssen; and participation on a data safety monitoring board or advisory board for BMS and Takeda. PR-O reports honoraria for lectures from BMS, Janssen, Sanofi, GSK, Amgen, Regeneron, and Takeda; and participation in advisory boards for BMS, Janssen, Sanofi, Kite Pharma, AbbVie, Oncopeptides, Takeda, Pfizer, and GSK. JS-M reports consulting fees from Takeda, Janssen, Celgene, BMS, Amgen, Sanofi, and GSK; honoraria from Takeda, Janssen, Celgene, Amgen, BMS, Sanofi, and GSK; and participation in scientific advisory boards for Takeda, Janssen, Celgene, Novartis, Amgen, BMS, Sanofi, GSK Roche, and Regeneron. KY reports consulting fees from Sanofi, and Janssen; speaker bureaus from Sanofi, Amgen, Takeda, and Pfizer; honoraria from Sanofi, Janssen, Amgen, Takeda, and Pfizer; and research funding from Sanofi, Janssen, Amgen, Takeda, and BMS. FG reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Janssen, Amgen, Sanofi, BMS, Takeda, GSK, Roche, and AbbVie; and participation on a data safety monitoring board or advisory board from Janssen, Amgen, Sanofi, BMS, Takeda, GSK, Roche, AbbVie, Oncopeptides, Pfizer, and Adaptive. HE reports consulting fees, payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events; and support for attending meetings or travel from Janssen, BMS–Celgene, Amgen, GSK, Sanofi, Takeda, and Novartis. RM reports consulting fees from Janssen, Takeda, and Sanofi; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Janssen, Celgene, Takeda, Amgen; and participation on an advisory board for Janssen, Celgene, Takeda, BMS, and Amgen. JC reports grants from Janssen; consulting fees from Janssen and Sanofi; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Amgen; support for attending meetings or travel from Gilead; and a patent planned, issued, or pending: 20175032.0: anti-CD38 single-domain antibodies in disease monitoring and treatment. ME reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Janssen, BMS, Takeda, Amgen, GSK, and Sanofi; and support for attending meetings or travel from Janssen, BMS, Takeda, and Amgen. GC reports research funding from Takeda and BMS; consulting fees from Takeda, BMS, AbbVie, Roche, Pfizer, Janssen, Karyopharm, and Amgen; and speaker bureau for Janssen, Takeda, AbbVie, and Amgen. KW reports honoraria and participation on advisory boards from AbbVie, Adaptive, Amgen, Bristol Myers Squibb, Celgene, Janssen, GSK, Karyopharm, Novartis, Oncopeptides, Pfizer, Roche Pharma, Takeda, and Sanofi; and reports research funding from Amgen, Celgene, Janssen, and Sanofi. AB reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from BMS, Sanofi, Janssen, and Amgen. MBe reports participation on advisory boards for Amgen, Bristol-Myers Squibb, Janssen, Sanofi, Takeda, and Oncopeptides. JB reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Janssen, Takeda, and Amgen; payment for expert testimony from Janssen and Amgen; support for attending meetings or travel from Janssen and Takeda; and a leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, in the Serbian Myeloma Group and the Balkan Myeloma Study Group. FS reports grants or contracts from Celgene, Janssen, Oncopeptides, Sanofi, GSK, and Targovax; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Amgen, BMS, Takeda, AbbVie, Janssen, Novartis, SkyliteDX, Oncopeptides, Sanofi, Pfizer, Daiki-Sankyo, and GSK; and participation on a data safety monitoring board or advisory board for AbbVie, GSK, Celgene, Takeda, Janssen, Oncopeptides, Sanofi, and BMS. MC reports consulting fees from Glaxo Smith Kline, Janssen, Sanofi, Roche, Amgen, Takeda, AbbVie, Bristol Myers Squibb, Celgene, and Pfizer; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Janssen, Sanofi, and Bristol Myers Squibb; and participation on a data safety monitoring board or advisory board from Glaxo Smith Kline, Janssen, Sanofi, Roche, Amgen, Takeda, AbbVie, Bristol Myers Squibb, Celgene, and Pfizer. RH reports grants or contracts paid to institution from Janssen, Amgen, Celgene, BMS, Novartis, and Takeda; consulting fees from Janssen, Amgen, Celgene, AbbVie, BMS, Novartis, PharmaMar, and Takeda; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Janssen, Amgen, Celgene, BMS, PharmaMar, and Takeda; support for attending meetings or travel from Amgen, Celgene, Takeda, and Janssen; and participation in a data safety monitoring board or advisory board for BMS, Takeda, Amgen, Oncopeptides, Sanofi, Janssen, and GSK. CT reports consulting fees from AbbVie, Janssen, and Pfizer; payment for lectures from Janssen and BMS; support for attending meetings or travel from Janssen; and participation in advisory boards for Janssen, Pfizer, and BMS. MBo reports honoraria from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, and AbbVie; participation in an advisory board for Janssen and GSK; and research funding from Sanofi, Celgene, Amgen, Janssen, Novartis, BMS, and Mundipharma. PS reports participation in an advisory board for and research funding from Amgen, BMS, Celgene, Janssen, Karyopharm, and Pfizer. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.) more...

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.) more...

B-cell maturation antigen (BCMA) is an ideal target in multiple myeloma (MM) due to highly specific expression in malignant plasma cells. BCMA-directed therapies including antibody drug conjugates, chimeric antigen receptor-T cells and bispecific antibodies (BsAbs) have shown high response rates in MM. WVT078 is an anti-BCMA× anti-CD3 BsAb that binds to BCMA with subnanomolar-affinity. It was selected based on potent T cell activation and anti-MM activity in preclinical models with favorable tolerability in cynomolgus monkey. In the ongoing first-in-human phase I dose-escalation study (NCT04123418), 33 patients received intravenous WVT078 once weekly at escalated dosing. At the active doses of 48-250 µg/kg tested to date (n = 26), the overall response rate (ORR) was 38.5% (90% CI: 22.6-56.4%) and the complete response rate (CRR, stringent complete response + complete response) was 11.5%, (90% CI: 3.2-27.2%). At the highest dose level tested, the ORR was 75% (3 of 4 patients). 26 (78.8%) patients reported at least one Grade ≥3 AE and 16 of these AEs were suspected to be drug related. 20 patients (60.6%) experienced cytokine release syndrome. WVT078 has an acceptable safety profile and shows preliminary evidence of clinical activity at doses tested to date., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.) more...

Tumor heterogeneity is an important driver of treatment failure in cancer since therapies often select for drug-tolerant or drug-resistant cellular subpopulations that drive tumor growth and recurrence. Profiling the drug-response heterogeneity of tumor samples using traditional genomic deconvolution methods has yielded limited results, due in part to the imperfect mapping between genomic variation and functional characteristics. Here, we leverage mechanistic population modeling to develop a statistical framework for profiling phenotypic heterogeneity from standard drug-screen data on bulk tumor samples. This method, called PhenoPop, reliably identifies tumor subpopulations exhibiting differential drug responses and estimates their drug sensitivities and frequencies within the bulk population. We apply PhenoPop to synthetically generated cell populations, mixed cell-line experiments, and multiple myeloma patient samples and demonstrate how it can provide individualized predictions of tumor growth under candidate therapies. This methodology can also be applied to deconvolution problems in a variety of biological settings beyond cancer drug response., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).) more...

Introduction: This phase 1 trial assessed the safety, pharmacokinetics, and preliminary antitumor activity of RO7297089, an anti-BCMA/CD16a bispecific antibody., Methods: RO7297089 was administered weekly by intravenous infusion to patients with relapsed/refractory multiple myeloma. The starting dose was 60 mg in this dose-escalation study utilizing a modified continual reassessment method with overdose control model., Results: Overall, 27 patients were treated at doses between 60 and 1850 mg. The maximally administered dose was 1850 mg due to excipients in the formulation that did not allow for higher doses to be used. The maximum tolerated dose was not reached. The most common adverse events irrespective of grade and relationship to the drug were anemia, infusion-related reaction, and thrombocytopenia. Most common treatment-related grade ≥ 3 toxicities were ALT/AST increase and reduced lymphocyte count. Pharmacokinetic studies suggested non-linear pharmacokinetics and target-mediated drug disposition, with a trend of approaching linear pharmacokinetics at doses of 1080 mg and higher. Partial response was observed in two patients (7%), minimal response in two patients (7%), and stable disease in 14 patients (52%)., Conclusions: RO7297089 was well tolerated at doses up to 1850 mg, and the efficacy data supported activity of RO7297089 in multiple myeloma. Combination with other agents may further enhance its potential as an innate immune cell engager in multiple myeloma., Trial Registration: ClinicalTrials.gov: NCT04434469; Registered June 16, 2020; https://www., Clinicaltrials: gov/ct2/show/NCT04434469 ., (© 2023. Genentech, Inc.) more...

Introduction: Mitogen-activated protein kinase pathway mutations are present in >50% of patients with relapsed/refractory (R/R) multiple myeloma (MM). MEK inhibitors show limited single-agent activity in R/R MM; combination with B-cell lymphoma-2 (BCL-2) and programmed death-ligand 1 inhibition may improve efficacy. This phase Ib/II trial (NCT03312530) evaluated safety and efficacy of cobimetinib (cobi) alone and in combination with venetoclax (ven) with/without atezolizumab (atezo) in patients with R/R MM., Patients and Methods: Forty-nine patients were randomized 1:2:2 to cobi 60 mg/day on days 1-21 (n = 6), cobi 40 mg/day on days 1-21 + ven 800 mg/day on days 1-28 with/without atezo 840 mg on days 1 and 15 of 28-day cycles (cobi-ven, n = 22; cobi-ven-atezo, n = 21). Safety run-in cohorts evaluated cobi-ven and cobi-ven-atezo dose levels., Results: Any-grade common adverse events (AEs) with cobi, cobi-ven, and cobi-ven-atezo, respectively, included diarrhea (33.3%, 81.8%, 90.5%) and nausea (16.7%, 50.0%, 66.7%); common grade ≥3 AEs included anemia (0%, 22.7%, 23.8%), neutropenia (0%, 13.6%, 38.1%), and thrombocytopenia (0%, 18.2%, 23.8%). The overall response rate for all-comers was 0% (cobi), 27.3% (cobi-ven), and 28.6% (cobi-ven-atezo), and 0%, 50.0%, and 100%, respectively, in patients with t(11;14)+. Biomarker analysis demonstrated non-t(11;14) patient selection with NRAS/KRAS/BRAF mutation or high BCL-2/BCL-2-L1 ratio (>52% of the study population) could enrich for responders to the cobi-ven combination., Conclusions: Cobi-ven and cobi-ven-atezo demonstrated manageable safety with moderate activity in all-comers, and higher activity in patients with t(11;14)+ MM, supporting a biomarker-driven approach for ven in MM., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.) more...

Introduction: Given the rapid increase in novel treatments for patients with multiple myeloma (MM), this patient preference study aimed to establish which treatment attributes matter most to MM patients and evaluate discrete choice experiment (DCE) and swing weighting (SW) as two elicitation methods for quantifying patients' preferences., Methods: A survey incorporating DCE and SW was disseminated among European MM patients. The survey included attributes and levels informed by a previous qualitative study with 24 MM patients. Latent class and mixed logit models were used to estimate the DCE attribute weights and descriptive analyses were performed to derive SW weights. MM patients and patient organisations provided extensive feedback during survey development., Results: 393 MM patients across 21 countries completed the survey ( M years since diagnosis =6; M previous therapies =3). Significant differences (p<.01) between participants' attribute weights were revealed depending on participants' prior therapy experience, and their experience with side-effects and symptoms. Multivariate analyses showed that participants across the three MM patient classes identified via the latent class model differed regarding their past number of therapies ( F =4.772, p =.009). Patients with the most treatments (class 1) and those with the least treatments (class 3) attached more value to life expectancy versus quality of life-related attributes such as pain, mobility and thinking problems. Conversely, patients with intermediary treatment experience (class 2) attached more value to quality of life-related attributes versus life expectancy. Participants highlighted the difficulty of trading-off between life expectancy and quality of life and between physical and mental health. Participants expressed a need for greater psychological support to cope with their symptoms, treatment side-effects, and uncertainties. With respect to patients' preferences for the DCE or SW questions, 42% had no preference, 32% preferred DCE, and 25% preferred SW., Conclusions: Quality of life-related attributes affecting MM patients' physical, mental and psychological health such as pain, mobility and thinking problems were considered very important to MM patients, next to life expectancy. This underscores a need to include such attributes in decision-making by healthcare stakeholders involved in MM drug development, evidence generation, evaluation, and clinical practice. This study highlights DCE as the preferred methodology for understanding relative attribute weights from a patient's perspective., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Janssens, Lang, Vallejo, Galinsky, Morgan, Plate, De Ronne, Verschueren, Schoefs, Vanhellemont, Delforge, Schjesvold, Cabezudo, Vandebroek, Stevens, Simoens and Huys.) more...

Purpose: [ 18 F]FDG PET/CT in multiple myeloma (MM) is currently the best technology to demonstrate patchy and extramedullary disease. However, [ 18ipt> F]FDG PET has some limitations, and imaging with alternative tracers should be explored. In this study, we aimed to evaluate the performance of [ 18 F]fluciclovine PET compared to [ 18 F]FDG PET in newly diagnosed MM patients., Procedures: Thirteen newly diagnosed transplant eligible MM patients were imaged both with [ 18 F]FDG PET/CT and [ 18 F]fluciclovine PET/CT within 1 week in a prospective study. The subjects were visually assessed positive or negative for disease. The number of lesions and the SUV max of selected lesions were measured for both tracers. Furthermore, tracer uptake ratios were obtained by dividing lesion SUV max by blood or bone marrow SUV max . Between-group differences and correlations were assessed with paired t-tests and Pearson tests. Bone marrow SUVs were compared to bone marrow plasma cell percentage in biopsy samples., Results: Nine subjects were assessed positively by [ 18 F]FDG PET (69%) and 12 positives by [ 18 F]fluciclovine PET (92%). All positive subjects had [ 18 F]fluciclovine scans that were qualitatively scored as easier to interpret visually than the [ 18 F]FDG scans. The number of lesions was also higher; seven of nine subjects with distinct hot spots on [ 18 F]fluciclovine PET had fewer or no visible lesions on [ 18 F]FDG PET. The mean lesion SUV max values were 8.2 and 3.8 for [ 18 F]fluciclovine and [ 18 F]FDG, respectively. The mean tumour to blood values were 6.4 and 2.0 for [ 18 F]fluciclovine and [ 18 F]FDG, and the mean ratios between tumour and bone marrow were 2.1 and 1.5 for [ 18 F]fluciclovine and [ 18 F]FDG. The lesion SUV max and ratios were significantly higher for [ 18 F]fluciclovine (all p < 0.01). Local [ 18 F]fluciclovine SUV max or SUV mean values in os ilium and the percentage of plasma cells in bone marrow biopsies were linearly correlated (p = 0.048). There were no significant correlations between [ 18 F]FDG SUVs and plasma cells (p = 0.82)., Conclusions: Based on this pilot study, [ 18 F]fluciclovine is a promising tracer for MM. The visual and semi-quantitative evaluations indicate that [ 18 F]fluciclovine PET/CT can out-perform [ 18 F]FDG PET/CT at diagnosis., (© 2022. The Author(s).) more...

CD38 is a transmembrane glycoprotein that functions both as a receptor and an ectoenzyme, playing key roles in the regulation of calcium signaling and migration of immune cells to tumor microenvironments. High expression on multiple myeloma (MM) cells and limited expression on normal cells makes CD38 an ideal target for the treatment of MM patients. Two monoclonal antibodies directed at CD38, isatuximab and daratumumab, are available for use in patients with relapsed and/or refractory MM (RRMM); daratumumab is also approved in newly diagnosed MM and light-chain amyloidosis. Clinical experience has shown that anti-CD38 antibody therapy is transforming treatment of MM owing to its anti-myeloma efficacy and manageable safety profile. Isatuximab and daratumumab possess similarities and differences in their mechanisms of action, likely imparted by their binding to distinct, non-overlapping epitopes on the CD38 molecule. In this review, we present the mechanistic properties of these two antibodies and outline available evidence on their abilities to induce adaptive immune responses and modulate the bone marrow niche in MM. Further, we discuss differences in regulatory labeling between these two agents and analyze recent key clinical trial results, including evidence in patients with underlying renal impairment and other poor prognostic factors. Finally, we describe the limited existing evidence for the use of isatuximab or daratumumab after disease progression on prior anti-CD38 mono- or combination therapy, highlighting the need for additional clinical evaluations to define optimal anti-CD38 antibody therapy selection and sequencing in RRMM., (© 2022. The Author(s).) more...