Haematologica, Vol 94, Issue 9, 1274-1281 doi:10.3324/haematol.2008.004572
Copyright © 2009 by Ferrata Storti Foundation
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Multiple Myeloma

A polymorphism in NFKB1 is associated with improved effect of interferon-{alpha} maintenance treatment of patients with multiple myeloma after high-dose treatment with stem cell support

Annette J. Vangsted1,2, Tobias W. Klausen2, Peter Gimsing3, Niels F. Andersen4, Niels Abildgaard5, Henrik Gregersen6, Ulla Vogel7

1 Dept. of Oncology and Haematology, Roskilde Hospital, Copenhagen Univesity, Roskilde
2 Dept. of Haematology, University Hospital of Copenhagen at Herlev
3 Dept. of Haematology, University Hospital of Copenhagen at Rigshospitalet, Copenhagen
4 Dept. of Haematology, Aarhus University Hospital, Aarhus
5 Dept. of Haematology, Odense University Hospital, Odense
6 Dept. of Haematology, Aalborg University Hospital, Aalborg
7 National Food Institute, Technical University of Denmark, Copenhagen and Institute for Science, Systems and Models, Roskilde University, Roskilde, Denmark

Correspondence: Annette Vangsted, MD, Department of Oncology and Haematology, Roskilde Hospital, Copenhagen University, Køgevej, 9-13, 4000 Roskilde. E-mail:avag{at}regionsjaelland.dk

Background: Maintenance therapy with interferon-{alpha} after high-dose treatment with stem cell support in multiple myeloma has been intensively debated. In this study, we evaluated the response to treatment with interferon-{alpha} in relation to genetic variation in genes related to inflammation.

Design and Methods: In a retrospective study of 296 patients with multiple myelom undergoing high-dose therapy between 1994 and 2004, 146 patients were treated with interferon-{alpha} as maintenance therapy. We tested the polymorphisms IL1B T-31C, IL6 G-174C, NFKB1-94ins/delATTG, CD3EAP G-21A and PPP1R13L IVS1 A4364G for associations with time to treatment failure and overall survival with and without interferon-{alpha} treatment.

Results: The wild type ins-allele of polymorphism NFKB1-94 ins/delATTG was, by multivariate Cox analysis, associated with longer time to treatment failure (p=0.01) and overall survival (p=0.0084) when tested between treatment arms and in the subgroup of patients treated with interferon-{alpha} the wild type ins-allele was associated with longer overall survival (p=0.002). In the absence of interferon-{alpha} treatment, there was no association between the polymorphisms and treatment outcome, except for patients homozygous for the wild type G allele of IL6 G-174C who survived longer (p= 0.0074) than variant allele carriers. There was no association between the polymorphisms IL1B T-31C, CD3EAP G-21A and PPP1R13L IVS1 A4364G and treatment outcome for interferon-{alpha}.

Conclusions: Patients who are homozygous carriers of the wild type ins-allele of the NFKB1 -94ins/delATTG polymorphism may benefit from treatment with interferon-{alpha}, in contrast to patients carrying the variant allele. This result may indicate that the effect of interferon-{alpha} treatment is dependent on the availability of nuclear factor-{kappa}B and the polymorphism in NFKB1 may, therefore, be a good prognostic marker for multiple myeloma patients on maintenance treatment with interferon-{alpha} after high-dose therapy. A prospective study of interferon-{alpha} treatment in relation to NFKB1 -94ins/delATTG is highly warranted.

Key words: polymorphism, multiple myeloma, interferon, NF-{kappa}B, treatment outcome.