Optimizing the use of anti-interleukin-6 monoclonal antibody with dexamethasone and 140 mg/m2 of melphalan in multiple myeloma: results of a pilot study including biological aspects

Rossi, Jean‐François; Fégueux, Nathalie; Lu, Zhaoqing; Legouffe, Eric; Exbrayat, C; Bozonnat, Marie-Cécile; Navarro, Robert; López, Ernesto; Quittet, Philippe; Daurès, Jean‐Pierre; Rouille, Valérie; Kanouni, Tarik; Widjenes, John; Klein, Bernard

doi:10.1038/sj.bmt.1705138

Cited by 60 publications

(40 citation statements)

References 45 publications

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“…This study confirms previous results showing elevated IL-6 plasma levels post-ASCT (21,23). This increase can be explained by the HDM-induced stress and also by the deletion of cells able to consume IL-6.…”

Section: Discussionsupporting

confidence: 82%

“…Given a blood volume of 5 l, the mean amount of circulating IL-6 is ∼39 ng. In patients with MM treated with HDM and ASCT and with anti-IL-6 mAb, we have calculated a median daily IL-6 production of 35 mg/d at day 9 post-ASCT (21). Thus, in the case of IL-6, the amount of circulating IL-6 is 1/1000 of the total amount of IL-6 produced per day.…”

Section: Discussionmentioning

confidence: 99%

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Increased Plasma-Immune Cytokines throughout the High-Dose Melphalan-Induced Lymphodepletion in Patients with Multiple Myeloma: A Window for Adoptive Immunotherapy

Condomines

Veyrune²,

Larroque³

et al. 2009

The Journal of Immunology

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High-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) is a standard treatment for patients with multiple myeloma. However, lymphocyte reconstitution is impaired after HDM. Recent work has suggested that the lymphopenia period occurring after various immunosuppressive or chemotherapy treatments may provide an interesting opportunity for adoptive antitumor immunotherapy. The objective of this study was to determine an immunotherapy window after HDM and ASCT, evaluating T cell lymphopenia, and measuring circulating immune cytokine concentrations in patients with multiple myeloma. The counts of T cell subpopulations reached a nadir at day 8 post-ASCT (day 10 post-HDM) and recovered by day 30. IL-6, IL-7, and IL-15 plasma levels increased on a median day 8 post-ASCT, respectively, 35-fold, 8-fold, and 10-fold compared with pre-HDM levels (p ≤ 0.05). The increases in IL-7 and IL-15 levels were inversely correlated to the absolute lymphocyte count, unlike monocyte or myeloid counts. Furthermore, we have shown that CD3 T cells present in the ASC graft are activated, die rapidly when they are cultured without cytokine in vitro, and that addition of IL-7 or IL-15 could induce their survival and proliferation. In conclusion, the early lymphodepletion period, occurring 4–11 d post-HDM and ASCT, is associated with an increase of circulating immune cytokines and could be an optimal window to enhance the survival and proliferation of polyclonal T cells present in the ASC autograft and also of specific antimyeloma T cells previously expanded in vitro.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Increased Plasma-Immune Cytokines throughout the High-Dose Melphalan-Induced Lymphodepletion in Patients with Multiple Myeloma: A Window for Adoptive Immunotherapy

Condomines

Veyrune²,

Larroque³

et al. 2009

The Journal of Immunology

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“…IL-6 is also an anti-apoptotic factor and a growth factor for myeloma cells. Antibodies to IL-6 have been in clinical trials for patients with myeloma, and although a pilot study indicated that blocking IL-6 may decrease the growth of myeloma cells in patients, 74 to-date, none of these trials have been exceptionally successful. These results suggest that targeting IL-6 by itself is not sufficient to inhibit bone destruction and myeloma tumor growth.…”

Section: Mechanisms Of Multiple Myeloma Bone Disease DL Galson Et Almentioning

confidence: 99%

Mechanisms of multiple myeloma bone disease

Galson¹,

Silbermann²,

Roodman³

2012

BoneKEy Reports

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Multiple myeloma is the second most common hematological malignancy and the most frequent cancer to involve the skeleton. Multiple myeloma bone disease (MMBD) is characterized by abnormal bone remodeling with dysfunction of both bone resorption and bone formation, and thus can be used as a paradigm for other inflammatory bone diseases, and the regulation of osteoclasts and osteoblasts in malignancy. Studies of MMBD have identified novel regulators that increase osteoclastogenesis and osteoclast function, repress osteoblast differentiation, increase angiogenesis, or permanently alter stromal cells. This review will discuss the current understanding of mechanisms of osteoclast and osteoblast regulation in MMBD, and therapeutic approaches currently in use and under development that target mediators of bone destruction and blockade of bone formation for myeloma patients, including new anabolic therapies.

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“…40 Despite the early recognition of the importance of IL-6 for MM growth and survival, clinical studies aimed at blocking IL-6 in MM have not yet been translated into reliable long-term benefits. Ranging from the IL-6 inhibitor dexamethasone, 41,42 to specific IL-6 [43][44][45][46][47] or IL-6 receptor 48 blockade, therapeutic effects often vanish during prolonged treatment. In an environment devoid of IL-6, myeloma cells can adapt their receptor expression profile and switch to other gp130 cytokines.…”

mentioning

confidence: 99%

Due to interleukin-6 type cytokine redundancy only glycoprotein 130 receptor blockade efficiently inhibits myeloma growth

et al. 2016

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IntroductionMultiple myeloma (MM) is characterized by the expansion of clonal plasma cells within the bone marrow (BM), leading to an M-protein in serum, antibody deficiency, and skeletal destruction. Despite stem cell transplantation and novel therapies, the vast majority of patients with MM will eventually relapse and become refractory to standard therapy. Treatment strategies specifically targeting mechanisms of tumor growth and survival are being intensely explored in MM in order to improve © Ferrata Storti Foundation patient outcome. 1In the pathogenesis of MM, genetic changes drive the development of the malignant clone, but the interaction between the malignant plasma cells and the BM microenvironment has been shown to be equally important in mediating myeloma cell survival and progression.2 One of the established pathogenic key factors produced in the BM milieu is interleukin(IL)-6, which promotes the growth and survival of the malignant plasma cells and mediates drug resistance.3 While some myeloma cells produce their own IL-6, 4 bone marrow stromal cells (BMSCs) are the main source, establishing a strong paracrine growth stimulation. 5 Other sources of IL-6 in MM are macrophages, osteoblasts and osteoclasts; 2 eosinophils and megakaryocytes may also contribute. 6The receptor for IL-6 comprises a specific α-receptor, glycoprotein (gp) 80 (CD126), which, after ligand binding, recruits the gp130 receptor (IL6ST, CD130). Gp130 is the common signal transducer for a family of cytokines with pleiotropic and partly redundant activities.7 While signaling via IL-6 and IL-11 is initiated via gp130 homodimerization, the receptor complexes of other family members consist of heterodimers of gp130 with a second signaling molecule, most of which use the leukemia inhibitory factor receptor (LIFR). Leukemia inhibitory factor (LIF) and oncostatin M (OSM) directly induce gp130/LIFR heterodimerization without the involvement of other receptor components. Upon dimerization, associated Janus kinases (JAKs) become activated and phosphorylate specific tyrosine residues on the receptors, which serve as docking sites for transcription factors and adaptor proteins. The main signaling pathways induced by gp130 are the activation of STAT (signal transducer and activator of transcription)-3, the Ras-dependent mitogen-activated protein kinase (MAPK) cascade, and the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) pathway. 7,8The human plasma cell line INA-6 was generated in our laboratory from the pleural effusion of a patient with advanced plasma cell disease. 9 The survival of INA-6 cells in vitro is strictly dependent on exogenous IL-6 without growth response to other gp130 cytokines. With the establishment of a xenograft model in severe combined immune deficiency (SCID) mice using INA-6, a non-optimal environment devoid of human IL-6 was provided. Despite the fact that murine IL-6 is not active on human cells, plasma cell tumors developed over a period of up to five months. In serum and ascites of tumor-beari...

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Optimizing the use of anti-interleukin-6 monoclonal antibody with dexamethasone and 140 mg/m2 of melphalan in multiple myeloma: results of a pilot study including biological aspects

Cited by 60 publications

References 45 publications

Increased Plasma-Immune Cytokines throughout the High-Dose Melphalan-Induced Lymphodepletion in Patients with Multiple Myeloma: A Window for Adoptive Immunotherapy

Increased Plasma-Immune Cytokines throughout the High-Dose Melphalan-Induced Lymphodepletion in Patients with Multiple Myeloma: A Window for Adoptive Immunotherapy

Mechanisms of multiple myeloma bone disease

Due to interleukin-6 type cytokine redundancy only glycoprotein 130 receptor blockade efficiently inhibits myeloma growth

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