Thrombosis in multiple myeloma: mechanisms, risk assessment and management.

Multiple myeloma (MM) is associated with an increased risk of venous and arterial thrombosis. Pathophysiologic mechanisms include patient, disease and treatment related factors. Risk assessment models have been developed to determine whichpatients are at highest thrombotic risk and pursuant to this, risk adapted thrombosis prophylaxis has been suggested. Areas in which further basic and clinical research is imperative include the molecular and cellular mechanisms of thrombosis in myeloma, the inclusion of relevant biomarkers in risk assessment scores and controlled clinical trials of VTE prophylaxis and treatment using direct oral anticoagulants.

Real-world experience with belantamab mafodotin therapy for relapsed/refractory multiple myeloma: A multicentre retrospective study.

Belantamab mafodotin, an immuno-conjugate targeting B-cell maturation antigen, showed single-agent activity in phase 1 and 2 studies, and was recently approved for heavily pretreated relapsed/refractory multiple myeloma (RRMM) patients. Real-world data and long-term follow-up are scarce. We conducted a multisite retrospective study aimed to assess safety and efficacy of belantamab mafodotin monotherapy administered via the GSK expanded access compassionate care programme. One-hundred and six RRMM patients were treated with belantamab mafodotin between July 2019 and March 2021. The median age was 69.4 years. Patients were heavily pretreated with a median of six (range 2-11) prior therapy lines. Major adverse effects included ocular toxicity (keratopathy 68.4%, grade ≥3: 40.5%; blurred vision 36.8%, grade ≥3: 6.3%), thrombocytopenia (27.4%, grade ≥3: 17.9%) and infections (11.3%, grade ≥3: 7.5%). Median follow-up time was 11.9 [95% confidence interval (CI) 10.0-13.8] months. Overall response rate was 45.5%. Median progression-free survival was 4.7 (95% CI 3.5-5.9) months in the entire cohort and 8.8 (95% CI 6.6-10.9) months among responders. Median overall survival was 14.5 (95% CI 9.5-19.6) months, and not reached for responders. To conclude, in a real-world setting, belantamab mafodotin monotherapy showed efficacy comparable with the prospective clinical trials, with a tolerable toxicity profile.

COVID-19 among patients with hematological malignancies: a national Israeli retrospective analysis with special emphasis on treatment and outcome.

This national Israeli multicenter retrospective study aimed to characterize the clinical course of COVID-19 infection among patients with hematological malignancies, with special emphasis on treatment efficacy and outcome. Clinical and laboratory data from haemato-oncological patients diagnosed with COVID-19 from 16 medical centers were centrally reported. Multivariate regression analyses were used to determine variables associated with severe disease, hospitalization, and mortality. In total, 313 patients were included: 103 (35.7%) developed severe/critical respiratory infection, 178 (61.4%) were hospitalized, and 60 (20.0%) died. Age > 70 years was associated with severe/critical disease (p = 0.036) and mortality (p = 0.023), hypertension with severe/critical disease (p = 0.046) and hospitalization (p = 0.001), active haemato-oncological treatment with hospitalization (p = 0.009), and remdesivir treatment was associated with decreased mortality (p = 0.021). Convalescent plasma, enoxaparin, and corticosteroids resulted in no clinical benefit. In conclusion, COVID-19 infection seems particularly severe in patients with hematological malignancies, and of all examined therapies, remdesivir appears to be the most effective.

BM-MSCs-derived ECM modifies multiple myeloma phenotype and drug response in a source-dependent manner.

Multiple myeloma (MM) malignant plasma cells accumulate in the bone marrow (BM) where their interaction with the microenvironment promotes disease progression and drug resistance. Previously, we have shown that MM cells cocultured with BM-mesenchymal stem cells (MSCs) comodulated cells' phenotype in a MAPKs/translation initiation (TI)-dependent manner. Dissection of the coculture model showed that BM-MSCs secretomes and microvesicles (MVs) participate in this crosstalk. Here, we addressed the role of the BM-MSCs extracellular matrix (ECM). MM cell lines cultured on decellularized ECM of normal donors' (ND) or MM patients' BM-MSCs were assayed for phenotype (viability, cell count, death, proliferation, migration, and invasion), microRNAs (MIR125a-3p, MIR199a-3p) and targets, MAPKs, TI epithelial-to-mesenchymal transition (EMT), CXCR4, and autophagy. Drug (doxorubicin, velcade) response of MM cells cultured on ND/MM-MSCs' ECM with/without adhered MVs was also evaluated. ECM evoked opposite responses according to its origin: MM cells cultured on ND-MSCs' ECM demonstrated a rapid and continued decrease in MAPK/TI activation (↓10%-25%, P < 0.05) (15-24 hours) followed by diminished viability, cell count, proliferation, migration, and invasion (16-72 hours) (↓10%-50%, P < 0.05). In contrast, MM cells cultured on MM-MSCs' ECM displayed activated MAPK/TI, proliferation, EMT, and CXCR4 (↑15%-250%, P < 0.05). Corresponding changes in microRNAs relevant to the MM cells' altered phenotype were also determined. The hierarchy and interdependence of MAPKs/TI/autophagy/phenotype cascade were demonstrated. Finally, we showed that the ECM cooperates with MVs to modulate MM cells drug response. These data demonstrate the contribution of BM-MSCs' ECM to MM niche design and underscore the clinical potential of identifying targetable signals.

Primary plasma cell leukemia in the era of novel agents for myeloma - a multicenter retrospective analysis of outcome.

Primary plasma cell leukemia (PPCL) is a rare form of multiple myeloma with a dismal prognosis. This retrospective multi-center study examines the national experience of PPCL in the era of novel agents. During 2002-2016, thirty-nine patients with PPCL were identified in 11 Israeli centers. One-fifth of them died in the first 2 months after diagnosis. The overall survival (OS) of those who survived the first 3 months was 22.5 months. About 70% of patients received at least one type of immunomodulatory drug (IMiD) and similarly proteasome inhibitor (PI) during treatment. There was a survival advantage for those who received IMiD but not for those who received PI or other type of standard dose chemotherapy. In multivariate analysis, low performance status and increased uric acid were also associated with shorter OS. In conclusion, this study demonstrates favorable impact of treatment with IMiDs and hematopoietic cell transplantation on the survival of PPCL patients.