A combination of anti‐interleukin 6 murine monoclonal antibody with dexamethasone and high‐dose melphalan induces high complete response rates in advanced multiple myeloma

Moreau, Philippe; Harousseau, Jean‐Luc; Wijdenes, John; Morineau, Nadine; Milpied, Noël; Bataille, Régis

doi:10.1046/j.1365-2141.2000.02093.x

Cited by 78 publications

(28 citation statements)

References 14 publications

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“…Thirteen of 16 refractory patients exhibited some clinical response, with a complete response observed in 6 patients. 114 In a similar study, BE-8 was given 1 day before dexamethasone therapy and was continued through highdose melphalan and autologous stem cell transplantation until hematologic recovery. BE-8 neutralized IL-6 activity, as evidenced by decreased C-reactive protein and significant reductions in mucositis and fever.…”

Section: Clinical Studiesmentioning

confidence: 99%

Interleukin‐6 and its receptor in cancer

Hong

Angelo

Kurzrock

2007

Cancer

343

127

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Interleukin-6 (IL-6) plays a major role in the response to injury or infection and is involved in the immune response, inflammation, and hematopoiesis. Its deregulation impacts numerous disease states, including many types of cancer. Consequently, modulating IL-6 may be an innovative therapeutic strategy in several diseases. A review of relevant published literature regarding IL-6 and its receptor was performed. In addition, a review of the relevance of this cytokine system to human illness, particularly in cancer, was undertaken. IL-6 is a pleiotropic cytokine that is involved in the physiology of virtually every organ system. Aberrant expression of this cytokine has been implicated in diverse human illnesses, most notably inflammatory and autoimmune disorders, coronary artery and neurologic disease, gestational problems, and neoplasms. In cancer, high levels of circulating IL-6 are observed in almost every type of tumor studied and predict a poor outcome.

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Section: Clinical Studiesmentioning

confidence: 99%

Interleukin‐6 and its receptor in cancer

Hong

Angelo

Kurzrock

2007

Cancer

343

127

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“…The authors conclude that a Phase II clinical study could have yielded better results with regard to the administration of different doses of a cMab. More recently, the efficacy of a combined therapy including anti-IL-6 monoclonal antibodies in association with hormonal therapy and chemotherapy was investigated by Moreau et al 17 in the treatment of patients with advanced multiple myeloma. A series of 16 patients (14 patients whose disease recurred after previous chemotherapy) was treated with a combination of BE-8 (an anti-IL-6 murine monoclonal antibody) and dexamethasone followed by high-dose melphalan and autologous stem cell transplantation.…”

Section: Immunotherapy Of Multiple Myelomamentioning

confidence: 99%

A review of the cytokine network in multiple myeloma

Lauta

2003

Cancer

197

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Because many studies have focused on growth factors in multiple myeloma, the study of the cytokine network appears to be useful for this purpose. Interleukin-6 (IL-6) and IL-2 with their soluble receptors (IL-3, IL-4, IL-10, and IL-11) have been examined. Plasma cells may produce IL-6 by an autocrine mechanism whereas a paracrine mechanism is believed to be involved in the production of IL-6 by bone However, the concomitant evaluation of all immunologic parameters could be more useful than the value of a single IL. Serum levels of IL-6, sIL-6R, sIL-2R, and the expression of membrane-bound IL-2 receptors, both on bone marrow plasma cells and on peripheral blood mononuclear cells, are correlated with disease activity and disease stage. In addition, IL-6 and sIL-6R serum levels are believed to be correlated with the duration of disease-free survival because a high serum level at the time of diagnosis is believed to be correlated with a short duration of survival. However, some laboratory parameters may express the same prognostic value as high ␤ 2 microglobulin and lactate dehydrogenase (LDH) serum levels together with a high plasma cell labeling index are correlated with disease activity.Furthermore, if the evaluation is performed at the time of diagnosis, high values of these parameters are correlated with a short disease-free survival. A correlation between laboratory parameters and the serum level of several cytokines was demonstrated. Hence, the real advantage of the prognostic evaluation of cytokines is reserved for patients who do not exhibit uniform results with regard to ␤ 2 microglobulin and LDH serum levels, or, better, for borderline cases. With regard to the differential diagnosis, all immunologic parameters should be evaluated concomitantly rather than separately to confer a real prognostic value to results. Furthermore, a particular relation was found between a high sIL-6R serum level and a poor response to chemotherapy, therefore suggesting the possibility of identifying in advance a subset of patients with a high risk of treatment failure, as has already been demonstrated in other hematologic malignancies.Finally, the majority of studies indicate that interferons are used mainly in the immunotherapy for multiple myeloma, whereas many clinical trials should still be required for the evaluation of the effectiveness of anti-I-L6 antibodies or antiidiotypic vaccines in reference to the eligible patients for these particular therapies.

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“…3,4 Interaction of myeloma cells with cellular and extracellular components results in upregulation of growth factors such as interleukin (IL)-6 [5][6][7] and vascular endothelial growth factor (VEGF). 8 However, inhibiting their activity in patients with myeloma results in partial or no response, 9,10 suggesting that additional growth factors and/or cell-to-cell interactions may be involved in the growth and survival of myeloma cells within the BM.…”

Section: Introductionmentioning

confidence: 99%

Atacicept (TACI-Ig) inhibits growth of TACIhigh primary myeloma cells in SCID-hu mice and in coculture with osteoclasts

Yaccoby

Pennisi

et al. 2007

Leukemia

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APRIL (a proliferation-inducing Ligand) and BLyS/BAFF (B-lymphocyte stimulator/B-cell-activating factor of the TNF (tumor necrosis factor) family have been shown to be the survival factors for certain myeloma cells in vitro. BAFF binds to the TNF-related receptors such as B-cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) and BAFFR, whereas APRIL binds to TACI and BCMA and to heparan sulfate proteoglycans (HSPG) such as syndecan-1. TACI gene expression in myeloma reportedly can distinguish tumors with a signature of microenvironment dependence (TACI high ) versus a plasmablastic signature (TACI low ). We tested the effect of atacicept (formerly TACI-Ig, which blocks APRIL and BAFF) and BAFFR-Ig (which blocks BAFF only) on primary myeloma growth in the SCID-hu model and in coculture with osteoclasts. With only few exceptions, atacicept and to a lesser extent BAFFR-Ig, inhibited growth of TACI high but not TACI low myeloma samples in vivo and ex vivo, and the response rate was inversely correlated with TACI expression. Most TACI high myeloma cells were molecularly classified as being low risk with our recently described 70-gene model. APRIL and BAFF were highly expressed by osteoclasts and were upregulated in myeloma cells after coculture with osteoclasts. Our findings suggest that APRIL plays an essential role in the survival of TACI high bone marrow-dependent myeloma cells and TACI gene expression may be a useful predictive marker for patients who could benefit from atacicept treatment.

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A combination of anti‐interleukin 6 murine monoclonal antibody with dexamethasone and high‐dose melphalan induces high complete response rates in advanced multiple myeloma

Cited by 78 publications

References 14 publications

Interleukin‐6 and its receptor in cancer

Interleukin‐6 and its receptor in cancer

A review of the cytokine network in multiple myeloma

Atacicept (TACI-Ig) inhibits growth of TACIhigh primary myeloma cells in SCID-hu mice and in coculture with osteoclasts

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