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Elranatamab efficacy in the single-arm, registrational MagnetisMM-3 trial (NCT04649359) was compared with that of physician's choice of treatment (PCT) for triple-class refractory multiple myeloma. MagnestisMM-3 eligibility criteria were applied to two USA-based oncology electronic health record databases, COTA and Flatiron Health (FH), to identify cohorts for this study (NCT05932290). Applied statistical techniques accounted for cohort imbalances. MagnetisMM-3 (BCMA-naive; n = 123) outcomes were compared with those from COTA (n = 239) and FH (n = 152). Elranatamab was associated with a significantly higher objective response rate (risk ratios, 1.88–2.25), significantly longer progression-free survival (hazard ratios [HRs], 0.37–0.57), and, across most analyses, significantly longer overall survival (HRs, 0.46–0.66) versus PCT. BCMA-naive patients who were treated with elranatamab exhibited significantly better outcomes than patients treated in real-world clinical practice. Elranatamab is a new medicine for the treatment of people with multiple myeloma. In the ongoing clinical trial MagnetisMM-3, most people had fewer myeloma cells when treated with elranatamab. However, MagnetisMM-3 only looks at the effects of elranatamab without comparing it to other myeloma treatments. Therefore, a new study was designed to compare the effectiveness of elranatamab in the MagnetisMM-3 study with other treatments used in real-world clinical practice (not in a clinical trial). Data from people in MagnetisMM-3 was compared with data from two US databases (COTA and Flatiron Health) containing health records of patients treated for multiple myeloma in real-life clinical practice. The same criteria used to select patients for the MagnetisMM-3 trial (123 people) were used to identify people with similar characteristics in COTA (239 people) and Flatiron Health (152 people). More people treated with elranatamab had fewer myeloma cells in their bodies after treatment than people who received their doctor's choice of treatment in clinical practice. In fact, six out of ten people treated with elranatamab had fewer myeloma cells versus about three in ten people from each real-world database. People treated with elranatamab versus physician's choice of treatment lived longer without their disease getting worse and lived longer overall. In conclusion, this study found that more people treated with elranatamab responded to treatment and lived longer than similar people from the COTA and Flatiron Health databases who were given treatments available in a real-world clinical setting. Clinical Trial Registration: NCT05932290 (ClinicalTrials.gov) Executive summary Elranatamab is a BCMAxCD3 bispecific antibody under investigation for the treatment of relapsed or refractory multiple myeloma in the single-arm, registrational phase II MagnetisMM-3 trial (NCT04649359) of elranatamab. Although favorable clinical outcomes have been observed in patients treated with elranatamab in MagnetisMM-3, it can be difficult to compare these clinical results with those of other available therapies due to the single-arm design. The aim of this study (NCT05932290) was to contextualize efficacy data from patients naive to BCMA-directed therapy who received elranatamab in the MagnetisMM-3 trial with data from similar patients from two USA-based oncology electronic health record databases, COTA and Flatiron Health, as external real-world control arms. Trial inclusion and exclusion criteria were applied to each real-world database to obtain comparable patient populations. Statistical techniques (e.g., inverse probability of treatment weighting) were used to account for imbalances across cohorts on key confounding variables, including age, sex, cytogenetic risk, number of prior lines of therapy, Eastern Cooperative Oncology Group performance status, time since initial multiple myeloma diagnosis, penta-drug refractory status and International Staging System disease stage. Ultimately, outcomes of 123 patients from MagnetisMM-3 Cohort A (BCMA naive) were compared with those of 239 and 152 similar patients from the COTA and Flatiron Health databases, respectively. Elranatamab was associated with a significantly higher objective response rate, longer progression-free survival and generally longer overall survival compared with real-world treatments. Among BCMA-naive patients, those treated with elranatamab exhibited improved clinical outcomes compared with patients who received treatments used in real-world clinical practice. [ABSTRACT FROM AUTHOR]

For patients with triple-class exposed/refractory multiple myeloma (TCE/RMM), where effective treatments options are limited, B-cell maturation antigen and CD3-directed bispecific antibodies offer a promising new approach. Teclistamab gained conditional approval in Europe and accelerated Food and Drug Administration (FDA) approval based on the MajesTEC-1 trial (NCT03145181). Elranatamab, approved by the FDA demonstrated its safety and efficacy in the MagnetisMM-3 trial (NCT04649359). Given the absence of head-to-head trials, an unanchored matching-adjusted indirect comparison (MAIC) was conducted to assess their relative efficacy. Key baseline characteristics were adjusted to be comparable between the two trials. In the MAIC, elranatamab demonstrated significantly better objective response rate and progression-free survival (PFS) than teclistamab, and numerically better complete response, duration of response, and overall survival (OS). These results suggest that elranatamab is an efficacious option for treating patients with TCE/R MM. [ABSTRACT FROM AUTHOR]

For patients with triple-class exposed/refractory multiple myeloma (TCE/R MM), prognosis is poor and effective treatment options are limited. Elranatamab is a novel B-cell maturation antigen (BCMA)- and CD3-directed bispecific antibody which was approved by the US Food and Drug Administration in August 2023 and demonstrated safety and efficacy in patients with TCE/R MM in the phase 2, single-arm MagnetisMM-3 trial (NCT04649359). To compare the effectiveness of elranatamab vs physician's choice of treatment (PCT) in the absence of head-to-head comparative data, a matching-adjusted indirect comparison (MAIC) was conducted. Individual patient data from MagnetisMM-3 (Cohort A [BCMA-naïve] N = 123, 14.7 months of follow-up) were reweighted to match published summary data from two real-world studies of PCT in patients with TCE/R MM (LocoMMotion and MAMMOTH) using a propensity score-type logistic regression. Unanchored MAIC analyses were conducted according to National Institute for Health and Care Excellence (NICE) Decision Support Unit (DSU) 18 guidance. Compared with PCT in LocoMMotion, elranatamab was associated with a significantly higher objective response rate (ORR rate difference: 37.52; 95% CI 26.20–48.83; odds ratio: 4.85; 95% CI 2.85–8.23) and complete or stringent complete response rate (≥CR rate difference: 42.29; 95% CI 31.84–52.74; odds ratio: 184.01; 95% CI 24.66–1372.86), longer progression-free survival (PFS HR 0.32; 95% CI 0.20–0.49), and overall survival (OS HR 0.62; 95% CI 0.40–0.94). Compared with PCT in MAMMOTH, elranatamab was associated with significantly higher ORR (rate difference: 28.14; 95% CI 16.77–39.52; odds ratio: 3.24; 95% CI 1.98–5.32) and ≥ CR (rate difference: 26.22; 95% CI 16.40–36.05; odds ratio: 5.48; 95% CI 2.88–10.44), as well as longer PFS (HR 0.25; 95% CI 0.17–0.37) and OS (HR 0.49; 95% CI 0.33–0.71). Sensitivity analysis results were consistent with the base case. In the MAIC, elranatamab was consistently associated with improved rates and depth of response and significantly longer PFS and OS versus PCT in LocoMMotion and MAMMOTH. [ABSTRACT FROM AUTHOR]

Simple Summary: Whilst multiple myeloma (MM) remains incurable, two clinical priorities are to prolong remission and reduce complications, of which fragility fractures are a major source of morbidity. To this end, there is the need to develop biomarkers that can accurately track tumour burden and bone loss to guide treatment decisions. Here, we conducted a pilot feasibility study exploring the value of novel serum bone turnover and plasma cell burden markers and Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) when added to standard clinical assessment in patients with MM, monoclonal gammopathy of undetermined significance (MGUS) and smouldering MM (SMM). We show serum DKK1 and BCMA as possible correlates of tumour burden, and that serum sclerostin may correlate with bone mineral density. Furthermore, we validate DW-MRI in longitudinal assessment of tumour volume. Our study highlights emerging serum and radiological biomarkers for assessment of tumour burden and bone loss, which require further study in larger cohorts to validate these findings and understand their clinical utility. Novel biomarkers for tumour burden and bone disease are required to guide clinical management of plasma cell dyscrasias. Recently, bone turnover markers (BTMs) and Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) have been explored, although their role in the prospective assessment of multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) is unclear. Here, we conducted a pilot observational cohort feasibility study combining serum BTMs and DW-MRI in addition to standard clinical assessment. Fifty-five patients were recruited (14 MGUS, 15 smouldering MM, 14 new MM and 12 relapsed MM) and had DW-MRI and serum biomarkers (P1NP, CTX-1, ALP, DKK1, sclerostin, RANKL:OPG and BCMA) measured at baseline and 6-month follow-up. Serum sclerostin positively correlated with bone mineral density (r = 0.40−0.54). At baseline, serum BCMA correlated with serum paraprotein (r = 0.42) and serum DKK1 correlated with serum free light chains (r = 0.67); the longitudinal change in both biomarkers differed between International Myeloma Working Group (IMWG)-defined responders and non-responders. Myeloma Response Assessment and Diagnosis System (MY-RADS) scoring of serial DW-MRI correlated with conventional IMWG response criteria for measuring longitudinal changes in tumour burden. Overall, our pilot study suggests candidate radiological and serum biomarkers of tumour burden and bone loss in MM/MGUS, which warrant further exploration in larger cohorts to validate the findings and to better understand their clinical utility. [ABSTRACT FROM AUTHOR]

The article discusses clinical management and diagnosis of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) that manifest with osteoporosis and fragility fractures. Topics explored include the increasing prevalence of osteoporosis and fractures in the elderly, the standardized incidence ratio of osteoporotic fracture in patients with MGUS, and the screening guidelines for myeloma bone disease and MGUS.

Indwelling central venous catheters (CVCs) are used in the management of hematologic patients. However, insertion and maintenance of CVCs are susceptible to complications. Study design and methods data concerning 388 consecutive catheterisations, performed in oncohematologic patients between April 2003 and December 2004, were prospectively collected. At insertion thrombocytopenia was present in 109 cases (28.1%) and neutropenia in 67 (17.3%). Hemorrhage after CVC insertion occurred in five thrombocytopenic patients (1.3%). The median duration of catheterisation was 18.8 days (range 1-89), longer in the 7-French CVCs utilised in leukemic patients (24.3 days) and shorter in 12-French CVCs (11 days), used for PBSC harvesting. Deep venous thrombosis was diagnosed in 13 cases (3.3%). Ninety-two catheterisations (12.6/1000 days-catheter) were complicated by infections: 19 local infections (4.8%) and 73 (18.8%) bacteraemias of which 45 (11.6%) were catheter-related, mainly due to Gram positive germs (32/45, 71.1%). The frequency of catheter-related bacteraemia was 7.2 events/1000 days-catheter. Thirteen CVCs were removed due to thrombosis, 15 due to infections, 20 due to malfunction, the remaining 333 at patients discharge. At univariate analysis high-dose chemotherapy (p = 0.013), 7-Fr lumen (p = 0.023), acute myeloid leukemia (AML) (p = 0.001), duration of neutropenia >10 days and length of catheterisation were significantly correlated to infection. Multivariate analysis confirmed the duration of catheterisation, AML and high-dose chemotherapy as risk factors. Even though hematological in-patients are at increased risk for bleeding and infections, non-tunnelled CVCs offer a safe venous access also in patients affected by severe thrombocytopenia and prolonged neutropenia. [ABSTRACT FROM AUTHOR]

Interactions between multiple myeloma (MM) and bone marrow (BM) are well documented to support tumour growth, yet the cellular mechanisms underlying pain in MM are poorly understood. We have used in vivo murine models of MM to show significant induction of nerve growth factor (NGF) by the tumour-bearing bone microenvironment, alongside other known pain-related characteristics such as spinal glial cell activation and reduced locomotion. NGF was not expressed by MM cells, yet bone stromal cells such as osteoblasts expressed and upregulated NGF when cultured with MM cells, or MM-related factors such as TNF-α. Adiponectin is a known MM-suppressive BM-derived factor, and we show that TNF-α-mediated NGF induction is suppressed by adiponectin-directed therapeutics such as AdipoRON and L-4F, as well as NF-κB signalling inhibitor BMS-345541. Our study reveals a further mechanism by which cellular interactions within the tumour-bone microenvironment contribute to disease, by promoting pain-related properties, and suggests a novel direction for analgesic development. [ABSTRACT FROM AUTHOR]

Abstract: We studied circulating (C)CD34+ cells by flow cytometry in 96 patients with myelodisplastic syndromes (MDS) at diagnosis, and in a subset of 35 cases during follow-up. CCD34+ counts were stratified within both International Prognostic Scoring System (IPSS) and World Health Organization (WHO) categories. Counts >10/μl were associated with poorer leukemia-free survival, a prognostic value for evolution independent from that of WHO, and a higher progression probability within intermediate-risk IPSS and WHO classes. When serial measurements were performed, counts >10/μl more frequently correlated to evolution. Separating newly diagnosed patients on the basis of 10/μl cut-off of circulating CD34+ cells retains prognostic utility, especially in intermediate-risk MDS. [Copyright &y& Elsevier]

Novel biomarkers for tumour burden and bone disease are required to guide clinical management of plasma cell dyscrasias. Recently, bone turnover markers (BTMs) and Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) have been explored, although their role in the prospective assessment of multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) is unclear. Here, we conducted a pilot observational cohort feasibility study combining serum BTMs and DW-MRI in addition to standard clinical assessment. Fifty-five patients were recruited (14 MGUS, 15 smouldering MM, 14 new MM and 12 relapsed MM) and had DW-MRI and serum biomarkers (P1NP, CTX-1, ALP, DKK1, sclerostin, RANKL:OPG and BCMA) measured at baseline and 6-month follow-up. Serum sclerostin positively correlated with bone mineral density ( r = 0.40-0.54). At baseline, serum BCMA correlated with serum paraprotein ( r = 0.42) and serum DKK1 correlated with serum free light chains ( r = 0.67); the longitudinal change in both biomarkers differed between International Myeloma Working Group (IMWG)-defined responders and non-responders. Myeloma Response Assessment and Diagnosis System (MY-RADS) scoring of serial DW-MRI correlated with conventional IMWG response criteria for measuring longitudinal changes in tumour burden. Overall, our pilot study suggests candidate radiological and serum biomarkers of tumour burden and bone loss in MM/MGUS, which warrant further exploration in larger cohorts to validate the findings and to better understand their clinical utility.