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.
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.


METHODS
In a retrospective study of 296 patients with multiple myeloma 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-kappaB 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.
Vangsted
Annette J
AJ
Department of Oncology and Haematology, Roskilde Hospital, Copenhagen University, Køgevej 9-13, Roskilde, Denmark. avag@regionsjaelland.dk
Klausen
Tobias W
TW
Gimsing
Peter
P
Andersen
Niels F
NF
Abildgaard
Niels
N
Gregersen
Henrik
H
Vogel
Ulla
U
D000328:Adult; D000368:Aged; D000483:Alleles; D017252:CD3 Complex; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage*; D016898:Interferon-alpha / Q000008:administration & dosage*; D053583:Interleukin-1beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D052002:NF-kappa B p50 Subunit / Q000235:genetics*; D011110:Polymorphism, Genetic; D033581:Stem Cell Transplantation; D015996:Survival Rate; D014184:Transplantation, Homologous
D017252:CD3 Complex; C508600:IL6 protein, human; D007155:Immunologic Factors; D016898:Interferon-alpha; D053583:Interleukin-1beta; D015850:Interleukin-6; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human