Abstract 1829

Proinflammatory cytokines are suspected to play a role in the pathogenesis of multiple myeloma (MM). TNF-a, a potent mediator of inflammation, is involved in the malignant transformation of plasma cells and plasma cell proliferation. TNF-a determination was also reported to be a good parameter for monitoring therapy outcome during treatment with different protocols. Variation in TNF-a levels can be related to gene expression, which is regulated at transcriptional level, as well as to genetic polymorphism (SNP). Specifically, a G to A substitution at position -308 is associated with higher levels of TNF-a.

From September 2006 to April 2010 we selected 202 MM patients and 234 control cases matched for age and sex. TNF-a SNP at position -308 was determined on genomic DNA extracted from blood samples. These genotypes frequencies obtained were in Hardy-Weinberg equilibrium. Our results indicate that the cytokine TNF-a gene SNP do not confer differences in the susceptibility of MM. Then, we studied the correlation between the SNPs of TNF-a -308 and the outcome of 91 MM patients that underwent to autologous bone marrow transplantation (ASCT) after a similar induction therapy (DAV or TAD). Melphalan 200 mg/mq (or 100 mg/mq, for the elderly patients) was used as conditioning regimen (table I).

In the MM carrying the rarest A allele of TNF-a the overall response to chemotherapy and outcome to ASCT were similar to patients carriers G allele. On the contrary TNF-a seems to be an independent factor to predict the outcome in patients affected by MM modifying the progression free survival age related, if patients are > 60 yrs (p= 0.02). In particular pts > 60 years carrying the G/G genotype showed a better progression free survival compared to the same age patients carrying A/A or G/A genotypes (table II and table III ). Previous studies demonstrated that an higher plasma TNF-a concentration is significantly associated with advancing age and the combination of TNF-a and melphalan results in high response rates. Several mechanisms could be responsible for this, in particular a direct effect of TNF-a on the anti-tumour activity of melphalan. In our population the high dose of melphalan used in the youngest population is able to mask the role of TNF-a, but in the elderly patients it is clear as the impact of polymorphism plays a role in the better PFS of patients carrying the G/G genotype. To conclude we confirm the interesting role of TNF-a SNP in the outcome of MM in particular in the subset of pts characterized by a physiological high production of TNF-a.

Table 1

Characteristics of 91 MM Patients undergoing autologous-SCT.

CharacteristicsCases
Age at diagnosis (years)  
    Mean 58.27 ± 8.55 (35–75)a 
   Median 59 
Sex  
    Male 48 (52.7)b 
    Female 43 (47.3)b 
Stage at diagnosis  
    Durie-Salmon (I/II/III) 21/20/50 
    ISS (I/II/III) 60/20/11 
Prognostic Markers  
    b2-microglobulin (mg/dl) 2.18 (1.1–35)c 
    Creatinin (mg/dl) 0.9 (0.5–4.4)c 
    Albumin (g/l) 4.1 (2.1–4.9)c 
Hemoglobin (g/dl) 11.9 (5.7–16.8)c 
Progression Free Survival (months) 12 (1–94)c 
CharacteristicsCases
Age at diagnosis (years)  
    Mean 58.27 ± 8.55 (35–75)a 
   Median 59 
Sex  
    Male 48 (52.7)b 
    Female 43 (47.3)b 
Stage at diagnosis  
    Durie-Salmon (I/II/III) 21/20/50 
    ISS (I/II/III) 60/20/11 
Prognostic Markers  
    b2-microglobulin (mg/dl) 2.18 (1.1–35)c 
    Creatinin (mg/dl) 0.9 (0.5–4.4)c 
    Albumin (g/l) 4.1 (2.1–4.9)c 
Hemoglobin (g/dl) 11.9 (5.7–16.8)c 
Progression Free Survival (months) 12 (1–94)c 

Clinical and demographical characteristics of MM patients undergoing auto-SCT.

a

Range.

b

Percent.

c

Median (Range).

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Table 2

TNF SNP (rs) effect on PFS modified by age

TNF SNP (rs)Genotypes HR 95% C.Ip value
 Cases N (%)    
Total 91    
G/G 69(75.8) 1   
G/A 17 (18.7) 1.39 0.73–2.62 0.31 
A/A 5 (5.5) 1.06 0.38–2.95 0.91 
G/A+A/A 22 (24.2) 1.29 0.73–2.27 0.38 
Age ≤ 60     
G/G 36 (76.6) 1   
G/A+A/A 11 (23.4) 0.75 0.30–1.84 0.53 
Age > 60     
G/G 33 (75.0) 1   
G/A+A/A 11 (25.0) 2.51 1.18–5.34 0.02 
TNF SNP (rs)Genotypes HR 95% C.Ip value
 Cases N (%)    
Total 91    
G/G 69(75.8) 1   
G/A 17 (18.7) 1.39 0.73–2.62 0.31 
A/A 5 (5.5) 1.06 0.38–2.95 0.91 
G/A+A/A 22 (24.2) 1.29 0.73–2.27 0.38 
Age ≤ 60     
G/G 36 (76.6) 1   
G/A+A/A 11 (23.4) 0.75 0.30–1.84 0.53 
Age > 60     
G/G 33 (75.0) 1   
G/A+A/A 11 (25.0) 2.51 1.18–5.34 0.02 
*

Likelihood-ratio test p-value = 0.04. HR: Hazard Ratio; C.I.: Con?dence Interval.

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Table 3

Clinical characteristic divided by age and TNF SNP (rs1800629) and PFS.

CharacteristicsAge ≤60 (years)Age >60 (years)TNF rs1800629G/GTNF rs1800629G/A+A/ATNF rs1800629G/GTNF rs1800629G/A+A/A
Sex (male/female) 19/17 6/5 17/16 6/5 
Durie-Salmon (I/II/III) 9/6/21 2/5/4 8/9/16 2/–/9 
ISS (I/II/III) 26/9/1 7/3/1 23/5/5 4/3/4 
b2-microglobulin (mg/dl) 2.0ü(1.2–6.2)a 1.9ü(1.2–5.9)a 2.3ü(1.2–10.1)a 4.6ü(1.1–35.0)a 
Creatinin (mg/dl) 0.9ü(0.5–3.1)a 0.9ü(0.7–1.3)a 0.9ü(0.5–2.5)a 1.0ü(0.5–4.4)a 
Albumin (g/l) 4.1ü(2.8–4.9)a 4.0ü(3.5–4.5)a 4.1ü(2.1–4.6)a 3.8ü(3.5–4.3)a 
Hemoglobin (mg/dl) 12.0ü(5.7–15.7)a 11.9ü(8.7–16.6)a 12.4ü(7.6–16.8)a 11.2ü(8.5–13.9)a 
PFS (months) 12.5ü(1–94)a 12.0ü(4–60)a 16.0ü(2–71)a 11.0ü(1–24)a 
CharacteristicsAge ≤60 (years)Age >60 (years)TNF rs1800629G/GTNF rs1800629G/A+A/ATNF rs1800629G/GTNF rs1800629G/A+A/A
Sex (male/female) 19/17 6/5 17/16 6/5 
Durie-Salmon (I/II/III) 9/6/21 2/5/4 8/9/16 2/–/9 
ISS (I/II/III) 26/9/1 7/3/1 23/5/5 4/3/4 
b2-microglobulin (mg/dl) 2.0ü(1.2–6.2)a 1.9ü(1.2–5.9)a 2.3ü(1.2–10.1)a 4.6ü(1.1–35.0)a 
Creatinin (mg/dl) 0.9ü(0.5–3.1)a 0.9ü(0.7–1.3)a 0.9ü(0.5–2.5)a 1.0ü(0.5–4.4)a 
Albumin (g/l) 4.1ü(2.8–4.9)a 4.0ü(3.5–4.5)a 4.1ü(2.1–4.6)a 3.8ü(3.5–4.3)a 
Hemoglobin (mg/dl) 12.0ü(5.7–15.7)a 11.9ü(8.7–16.6)a 12.4ü(7.6–16.8)a 11.2ü(8.5–13.9)a 
PFS (months) 12.5ü(1–94)a 12.0ü(4–60)a 16.0ü(2–71)a 11.0ü(1–24)a 

Clinical and demographical characteristics of MM patients undergoing auto-SCT.

a

üMedian (Range)

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Disclosures:

No relevant conflicts of interest to declare.

Topics:
autologous stem cell transplant, multiple myeloma, polymorphism, progression-free survival, tumor necrosis factors, tumor necrosis factor-alpha, melphalan, albumins, brachial plexus neuritis, cytokine

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2010 by The American Society of Hematology
2010
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