Interferon-α as maintenance therapy in patients with multiple myeloma

Schaar, C. G.; Kluin-Nelemans, Hanneke C.; Marvelde, C. te; Cessie, Saskia le; Breed, W.P.M.; Fibbe, W. E.; Deijk, W. A. Van; Fickers, M. M. F.; Roozendaal, K. J.; Wijermans, P. W.

doi:10.1093/annonc/mdi125

Cited by 46 publications

(31 citation statements)

References 10 publications

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“…Despite a variety of therapeutic approaches, less than 20% of multiple myeloma patients achieve longterm survival, relapses are common and cures are rare. IFN-α, growth inhibitory for many human multiple myeloma cell lines, has been used as a maintenance therapy although it is not effective in all cases (Schaar et al, 2005). In addition to IFN-α, IFN-γ also inhibits myeloma cell growth and could be useful as a treatment (Portier et al, 1993;Yi et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-γ

Zhao

Flynt

Hong

et al. 2007

Molecular Immunology

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The MHC Class II transactivator (CIITA) acts in the cell nucleus as the master regulator of MHC class II (MHC II) gene expression. It is important to study CIITA regulation in multiple myeloma since MHC expression is central to ability of myeloma cells to present antigen and to the ability of the immune system to recognize and destroy this malignancy. Regulation of CIITA by IFN-γ in B lymphocytes occurs through the CIITA type IV promoter (pIV), one of the four potential promoters (pI-pIV) of this gene. To investigate regulation of CIITA by IFN-γ in multiple myeloma cells, first the ability of these cells to respond to IFN-γ was examined. RTPCR analyses show that IFN-γR1, the IFN-γ-binding chain of the IFN-γ receptor, is expressed in myeloma cells and IRF-1 expression increases in response to IFN-γ treatment. Western blotting demonstrates that STAT1 is activated by phosphorylation in response to IFN-γ. RT-PCR and functional promoter analyses show that IFN-γ up regulates the activity of CIITA pIV, as does ectopic expression of IRF-1 or IRF-2. In vivo protein/DNA binding studies demonstrate protein binding at the GAS, E box and IRF-E sites. In vitro studies confirm the binding of IRF-1 and IRF-2 to CIITA pIV. Although multiple myeloma cells express PRDI-BF1/Blimp-1, a factor that represses both the CIITA type III and IV promoters, they retain the capability to up regulate CIITA pIV and MHC II expression in response to IFN-γ treatment. These findings are the first to demonstrate that although PRDI-BF1/Blimp-1 diminishes the constitutive ability of these cells to present antigen by limiting CIITA and MHC II expression, it is possible to enhance this expression through the use of cytokines, like IFN-γ.

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Section: Discussionmentioning

confidence: 99%

MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-γ

Zhao

Flynt

Hong

et al. 2007

Molecular Immunology

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“…However, when interferon-α-2b was studied as a maintenance regimen in a randomized fashion compared with observation alone in patients initially treated with MP, a benefit was not seen. 52 While Schaar et al did find an improved PFS, there was no statistically significant benefit in OS, and one-third of patients discontinued interferon due to a drug-related toxicity. 52 Compared with interferon, steroids offer the advantage of an oral, outpatient administration option, and have also been studied as a maintenance therapy.…”

Section: Maintenance Therapymentioning

confidence: 97%

“…52 While Schaar et al did find an improved PFS, there was no statistically significant benefit in OS, and one-third of patients discontinued interferon due to a drug-related toxicity. 52 Compared with interferon, steroids offer the advantage of an oral, outpatient administration option, and have also been studied as a maintenance therapy. Berenson et al evaluated the use of prednisone at either 50 mg every other day or 10 mg every other day in patients who had responded to infusional vincristine, doxorubicin, and oral dexamethasone.…”

Section: Maintenance Therapymentioning

confidence: 97%

Initial Therapy of Multiple Myeloma Patients Who Are Not Candidates for Stem Cell Transplantation

Orłowski¹

2006

Hematology

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Multiple myeloma patients deemed to not be candidates for high-dose therapy followed by stem cell rescue who nonetheless need chemotherapy have traditionally received an oral regimen combining melphalan and prednisone. With the advent of novel agents, however, such as immunomodulatory drugs and proteasome inhibitors that are active in the relapsed/refractory setting, there has been an impetus to incorporate these new options into front-line therapy. Several phase II studies have recently revealed that addition of either thalidomide, lenalidomide, or bortezomib to melphalan and prednisone increased the overall and complete response rates, albeit at the cost of some increased toxicity. Randomized phase III studies of melphalan and prednisone with thalidomide have already shown that, compared to melphalan and prednisone alone, the three-drug regimen prolonged time to progression and overall survival in this population, thereby defining a new standard of care. Moreover, our increasing knowledge of the molecular role that cytogenetic abnormalities play in the biology of multiple myeloma and our growing chemotherapeutic armamentarium are beginning to allow us to rationally select therapies based on these characteristics of each patient's disease. Such a risk-and molecular-adapted strategy to the therapy of multiple myeloma promises to revolutionize and personalize our care of these patients and bring us closer to a cure for this disease.Using the diagnostic criteria recommended by the International Working Group, patients with multiple myeloma are classified as having either asymptomatic or symptomatic (Table 1) disease. 1 The latter population, generally considered candidates for a chemotherapy-based intervention, are then further divided into those who either are or are not eligible for high-dose chemotherapy followed by stem cell rescue. 2 Criteria that are weighed to help make this second distinction have generally included age, performance status, and co-morbid medical conditions. 2 There is some variability in these parameters and how they are applied, since studies examining stem cell transplantation have used different criteria. In regard to age, for example, which is the most objective of these measures, initial studies tended to enroll patients younger than 65 years of age, 3 while more recent studies suggest that transplant is safe in at least some who are over the age of 70 (for example 4,5 ). On the other hand, data suggesting that patients with poor-risk chromosomal features have a short time to progression after autologous transplantation have led to suggestions that even younger patients with these abnormalities may not be candidates for standard approaches. Nonetheless, as little as two years ago, there was general agreement that the standard of care for patients who were not eligible for transplantation and yet needed chemotherapy was melphalan

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“…It is in wide use to treat chronic myelogenous leukemia, CML, 2,3 melanoma, 4,5 myeloma 6,7 and renal cell carcinoma, RCC. 8,9 IFNa is actually a family of a dozen related, approximately 166 amino acid, 16 to 20 kDa proteins.…”

Section: Ifnamentioning

confidence: 99%

Potential for all-trans retinoic acid [tretinoin] to enhance interferon-alpha treatment response in chronic myelogenous leukemia, melanoma, myeloma, and renal cell carcinoma

Kast¹

2008

Cancer Biology & Therapy

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Interferon-α as maintenance therapy in patients with multiple myeloma

Cited by 46 publications

References 10 publications

MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-γ

MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-γ

Initial Therapy of Multiple Myeloma Patients Who Are Not Candidates for Stem Cell Transplantation

Potential for all-trans retinoic acid [tretinoin] to enhance interferon-alpha treatment response in chronic myelogenous leukemia, melanoma, myeloma, and renal cell carcinoma

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