Evaluation of TNF superfamily molecules in multiple myeloma patients: Correlation with biological and clinical features

Lemancewicz, Dorota; Bołkuń, Łukasz; Jabłońska, Ewa; Kulczyńska, Agnieszka; Bolkun-Skornicka, U.; Kłoczko, Janusz; Dzięcioł, J

doi:10.1016/j.leukres.2013.05.014

Cited by 36 publications

(26 citation statements)

References 34 publications

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“…In the undertaken study, we found MM patients to have higher serum levels of BAFF and APRIL compared to controls, which falls in line with the previous reports [22, 43]. Furthermore, we confirmed the increased concentration of BAFF and APRIL in advancing disease stages since patients in stage III had significantly higher levels of both ligands compared to those in stage I and II.…”

Section: Discussionsupporting

confidence: 92%

BAFF and APRIL as TNF superfamily molecules and angiogenesis parallel progression of human multiple myeloma

et al. 2013

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Tumour necrosis factor alpha (TNF-α) is an inflammatory cytokine with a wide spectrum of biological activity, including angiogenesis. B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are members of the TNF-α family. Vascular endothelial growth factor (VEGF), on the other hand, is one of the most characteristic pro-angiogenic cytokines produced by multiple cell types in multiple myeloma (MM). We have analysed BAFF and APRIL concentrations in parallel with pro-angiogenic cytokines in serum and trephine biopsy, and the bone marrow microvascular density (MVD) in 50 patients with newly diagnosed IgG MM and 24 healthy volunteers. The study showed statistically higher concentrations of BAFF, APRIL and TNF-α, as well as VEGF and its receptor, in MM patients compared to healthy volunteers and patients in advanced stages of the disease. A statistically positive correlation between the concentration of TNF-α and the expression of VEGF was demonstrated, and so was a positive link between BAFF, APRIL, MVD and lactate dehydrogenase (LDH). Furthermore, we observed a significant decrease in all studied cytokines after anti-angiogenic therapy, with meaningful differences between responders (at least partial remission) and patients with stable disease. It was also established that APRIL, but not BAFF, correlated with pro-angiogenic cytokines such as VEGF with its receptor, MVD and syndecan-1. Finally, our results showed that serum BAFF and APRIL levels could be useful biomarkers of MM disease activity and its progression which suggests that APRIL could be a possible novel therapeutic target in MM.

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Section: Discussionsupporting

confidence: 92%

BAFF and APRIL as TNF superfamily molecules and angiogenesis parallel progression of human multiple myeloma

et al. 2013

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“…18 The second group reported much less soluble APRIL in MM patients sera with a level in newly diagnosed patients (2.56 ng/ml ± 0.44), and more advanced treated patients (3.01 ng/ml ± 0.27) in the range of healthy individuals (1.59 ng/ml ± 0.41). 35 Our study of APRIL expression performed directly in BM also reveals a quite stable expression despite BM infiltration. The cellular source of APRIL has also been previously investigated by ex vivo/in vitro experimentation.…”

Section: Discussionsupporting

confidence: 52%

Myelopoiesis dysregulation associated to sustained APRIL production in multiple myeloma-infiltrated bone marrow

Matthes

Mckee²,

Dunand-Sauthier³

et al. 2015

Leukemia

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Multiple myeloma (MM) is a non-curable tumor developing in the bone marrow (BM). The BM microenvironment rich in hematopoietic precursors is suspected to have a role in MM development. Here we show that a proliferation-inducing ligand (APRIL) mediated in vivo MM promotion. In MM-infiltrated BM, APRIL originated from differentiating myeloid cells with an expression peak in precursor cells. Notably, APRIL expression stayed stable in BM despite MM infiltration. The pool of APRIL-producing cells changed upon MM infiltration. Although CD16(+) mature myeloid cells constituted about half of the APRIL-producing cells in healthy BM, CD16(-) Elastase(+) myeloid precursor cells were predominant in MM-infiltrated BM. Myeloid precursor cells secreted all the APRIL they produced, and binding of secreted APRIL to MM cells, strictly dependent of heparan sulfate carried by CD138, resulted in an in situ internalization by tumor cells. This indicated APRIL consumption by MM in BM. Taken together, our data show that myelopoiesis dysregulation characterized by an increased proportion of precursor cells occurs in MM patients. Such dysregulation correlates with a stable expression of the MM-promoting factor APRIL in infiltrated BM

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“…Our data suggested that BAFF was produced by the stromal compartment, specifically the osteoclast compartment, and that treatment with an anti-BAFF antibody resulted in antitumor activity and decreased osteoclast numbers (4). Others have shown that elevated BAFF and APRIL levels are associated with poorer outcome and more aggressive disease (9,10). This association of elevated BAFF levels with poorer outcomes, along with the role of BAFF in the survival of multiple myeloma cells, provided the rationale for targeting BAFF in relapsed/refractory multiple myeloma.…”

Section: Introductionmentioning

confidence: 67%

Phase 1 Study of Tabalumab, a Human Anti-B-Cell Activating Factor Antibody, and Bortezomib in Patients with Relapsed/Refractory Multiple Myeloma

Raje

Faber

Richardson

et al. 2016

Clinical Cancer Research

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Purpose: Tabalumab, a human mAb that neutralizes B-cellactivating factor (BAFF), demonstrated antitumor activity in xenograft models of multiple myeloma. Here we report on a phase I study of relapsed/refractory multiple myeloma patients in which the primary objective was to identify a tolerable and potentially efficacious dose of tabalumab when combined with bortezomib.Experimental Design: Forty-eight patients were enrolled; 20 to the dose-escalation cohort, and 28 to cohort expansion in which a dose of 100 mg of tabalumab was evaluated. All patients had received either prior bortezomib or an immunomodulatory drug; the median number of prior therapies was 3. Bortezomib was administered intravenously on days 1, 4, 8, and 11 of a 21-day schedule. Tabalumab was given every 21 days for 3 cycles, then every 42 days thereafter. Results:The most common grade 3/4 toxicities included thrombocytopenia, neutropenia, pneumonia, and peripheral sensory neuropathy. There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Pharmacokinetic data suggested serum exposure increased in a greater than doseproportional manner up to a dose of 100 mg. Out of 46 evaluable patients, 20 had confirmed responses. The median time to progression (9 patients censored) was 4.8 months, and the median response duration (4 patients censored) was 7.2 months.Conclusions: A dose of 100 mg tabalumab in combination with bortezomib was well tolerated and active and is currently under further investigation.

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Evaluation of TNF superfamily molecules in multiple myeloma patients: Correlation with biological and clinical features

Cited by 36 publications

References 34 publications

BAFF and APRIL as TNF superfamily molecules and angiogenesis parallel progression of human multiple myeloma

BAFF and APRIL as TNF superfamily molecules and angiogenesis parallel progression of human multiple myeloma

Myelopoiesis dysregulation associated to sustained APRIL production in multiple myeloma-infiltrated bone marrow

Phase 1 Study of Tabalumab, a Human Anti-B-Cell Activating Factor Antibody, and Bortezomib in Patients with Relapsed/Refractory Multiple Myeloma

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