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Multiple myeloma (MM) and its precursor states, smoldering myeloma (SM) and monoclonal gammopathy of undetermined significance (MGUS) are associated with increased incidence of thrombosis, however the cause of this is unknown. Lenalidomide treatment of MM substantially improves patient survival, although significantly increases thrombotic risk by an unknown mechanism. This pilot study aimed to establish the impact of MM and its treatment with Lenalidomide on platelet function. We analyzed platelet function in MGUS, SM and MM compared to healthy controls. We report an increase in platelet reactivity in MGUS, SM, and MM where increases in fibrinogen binding, P-selectin exposure, altered receptor expression, elevated levels of aggregation and enhanced sensitivity to agonist stimulation were observed. We also demonstrate an increase in patient platelet reactivity post Lenalidomide treatment compared to pre-treatment. We show Lenalidomide treatment of platelets ex vivo increased reactivity that was associated with formation of larger thrombi at arterial shear rates but not venous shear rates. This study demonstrates a clear increase in platelet reactivity and prothrombotic potential in patients with MGUS, SM and MM which is elevated further upon treatment with Lenalidomide. Our observations suggest that more detailed studies are warranted to determine mechanisms of thrombotic complications to enable the development of new preventative strategies that specifically target platelets. [ABSTRACT FROM AUTHOR]

Objectives: Daratumumab is the first anti-CD38 monoclonal antibody (Mab) used to treat myeloma in the newly diagnosed setting and in the relapsed setting. Isatuximab, another Mab targeting a specific epitope on the CD38 receptor, was recently approved in the UK in combination with pomalidomide and dexamethasone (IsaPomDex) to treat myeloma patients who received three prior lines of therapy. However, there is a lack of understanding of whether using a prior anti-CD38 Mab (e.g. daratumumab) can affect the efficacy of another Mab (e.g. isatuximab), when the latter is used to treat a subsequent relapse. Methods: We performed a UK-wide outcomes study of IsaPomDex in the real-world. In this case series, we report a detailed descriptive analysis of the characteristics and clinical outcomes of five IsaPomDex patients in UK routine practice (Patients I to V), with a prior exposure to daratumumab. Results: Age range was 51–77 years with two patients >70 and three patients <70 years. The cytogenetic risk was standard in two patients, high in two patients and not known in one patient. Prior daratumumab regimen were monotherapy (dara-mono) in one patient (II), and daratumumab with bortezomib and dexamethasone (DVd) in four patients. Responses to prior daratumumab were: very good partial response (VGPR) in two patients (I and III), minor response-stable disease (MR-SD) in one patient (II), and progressive disease (PD) in two patients (IV and V). Median (range) number of IsaPomDex cycles received was 2 (1–4). Outcomes of IsaPomDex were PD in three patients (II, IV and V) and a response in two patients. Response categories were: MR-SD in patient I and PR in patient III. Discussion: Despite the limitations of our case series, we described the first UK real-world report of IsaPomDex outcomes in myeloma patients with a prior exposure to daratumumab. Conclusion: Large prospective studies are required to further evaluate myeloma outcomes in this setting. [ABSTRACT FROM AUTHOR]

Insights into the mechanisms of protein homeostasis and proteasomal degradation have led to new strategies of redirecting the ubiquitin–proteasome system (UPS) to reduce or eliminate proteins or survival factors key to malignant pathobiology, multiple myeloma (MM) in particular. These strategies have enabled researchers to target proteins that were previously considered difficult to modulate by pharmacological means. This review provides a brief overview of UPS biology, particularly the role of the CRL4CRBN E3 ubiquitin ligase complex, and summarizes current strategies for co-opting the UPS, including CELMoD compounds, SNIPERs, PROTACs, and degronimids. A detailed discussion is provided on lead CELMoD compounds iberdomide and mezigdomide, which are currently being evaluated in clinical trials in patients with MM. Since a high proportion of patients develop drug resistance, it is vital to have novel therapeutic agents for treating relapsed patients with MM more effectively. It is encouraging that the expanding pathophysiological insight into cellular signaling pathways in MM increasingly translates into the development of novel therapeutic agents such as targeted protein degraders. This holds promise for improving outcomes in MM and beyond. [ABSTRACT FROM AUTHOR]

There are limited real world data on ixazomib, lenalidomide, and dexamethasone (IRd) in multiply relapsed myeloma. We analyzed outcomes of 116 patients who received IRd predominantly at second and subsequent relapse including those refractory to proteasome inhibitors (PIs). With a median follow up 16.3 months, the overall response rate was 66.9%; median progression-free survival (PFS) was 17.7 months with median overall survival (OS) not reached (NR). PFS and OS were significantly shorter in advanced disease (PFS; 12.6 vs. 21.2 months (p =.01), OS; 15.9 months vs. NR (p =.01) for ISS3 vs. ISS 1&2, respectively). PFS and OS were significantly shorter in clinical high risk (CHR) compared to standard risk (SR) patients (PFS; 9.3 months vs. NR (p =.001), OS; 11.5 months vs. NR (p <.001), respectively). There was a trend toward shorter PFS in PI-refractory patients 13.7 vs. 19.6 months for non-PI refractory (p =.2). The triplet combination was generally well tolerated. [ABSTRACT FROM AUTHOR]

Established treatments for transplant-ineligible (TNE) patients with newly diagnosed multiple myeloma (NDMM) include melphalan and prednisone (MP) combined with either bortezomib (VMP) or thalidomide (MPT), or lenalidomide plus low-dose dexamethasone (Rd). New treatments for TNE NDMM include Rd plus bortezomib (RVd) and daratumumab plus VMP (VMP + D), daratumumab plus lenalidomide and dexamethasone (D + Rd). Relative efficacy of these treatments was compared using a network meta-analysis. Eight trials identified by a systematic literature review were included in the primary analysis; hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were used. Rd was superior to other MP-based regimens for OS and PFS. There was strong evidence that, compared with Rd, both D + Rd and RVd improved PFS (HR 0.57; 95% credible interval (CrI) 0.43, 0.73 and HR 0.72; 95% CrI 0.56, 0.91, respectively). However, there was strong evidence only for RVd in respect to OS (HR 0.72; 95% CrI 0.52, 0.96). [ABSTRACT FROM AUTHOR]

Similarly, median PFS (Figure 1(B)) and TTNT (Figure 1(C)) were significantly shorter in the FDT cohort (9.0 vs. 25.7 months; I p i < 0.0001 and 16.7 vs. 42.2 months; I p i < 0.0001, respectively); after 5 years, more patients in the FDT cohort had progressed to second-line treatment (94% vs. 61%). Conversely, a study that evaluated patient preferences for multiple myeloma (MM) treatment attributes reported that achieving TFI after frontline therapy can sometimes drive patient preference for FDT [[11]]. The median frontline treatment duration of 4.6 months for patients in our real-world FDT cohort was substantially shorter than the 15.4 months for patients treated with MPT in the MM-020 trial [[3]]. [Extracted from the article]

Triclosan is a common antimicrobial agent that is found in significant levels in the aquatic environment and may elicit effects on aquatic organisms through unexpected modes of action. In this study, triclosan was quantified in fish from the Kaveri River, India, by using the gas chromatography and mass spectrometry technique and it was found in the range of 0.73–50 ng/g wet weight (ww). The mean bioaccumulation factor based on water (BAFw820) and sediment (BAFs2.12) in the Kaveri River showed that triclosan is accumulative in fish, and reflects its feeding behavior. The bioaccumulation indicates triclosan's persistence or prevalence throughout the river stretch. Human risk assessment through dietary intake demonstrated that the triclosan exposure is five orders of magnitude lower than the acceptable daily intake (50 μg/kg bw) and US EPA reference dose (300 μg/kg bw/day). This investigation is the first to report the bioaccumulation of triclosan in freshwater fish from India. Further, the results indicate that this fish acts as a biomarker of exposure for triclosan and thus shall be used to report triclosan pollution in the future. [ABSTRACT FROM AUTHOR]

Although myeloid sarcomas (MS) are frequently associated with acute myeloid leukaemia (AML), the occurrence of mediastinal MS is a much rarer event. The authors describe a distinct group of three AML patients with mediastinal MS and complex cytogenetics presenting at their centre over a 7-year period. Clinical features consistent with superior vena caval obstruction were noted at presentation in two of the three patients. Mediastinal mass was detected on routine chest radiography, and biopsies confirmed the diagnosis of MS. One patient relapsed after consolidation chemotherapy and died from progressive disease. Two patients underwent allogeneic haemopoietic stem cell transplant, but succumbed to transplant related complications. Review of mediastinal MS over the last 20 years shows that a significant proportion of patients have complex cytogenetic abnormalities and a poor long-term prognosis. Early and accurate diagnosis is essential and patients should be managed along the lines of high risk AML. [ABSTRACT FROM AUTHOR]