Abstract 3970

Background and aim: The anti metastatic effects of heparin have been known for many decades. Such effects are dependent on the protease activated receptor expression (PAR-1 and/or CD24) by the cancer cells. The genes controlling PARs are located on chromosome 5q13. Recurrent amplification of chromosome 5q and 5p have been shown to increase survival (Avet-Loiseau H et al 2009 and Tapper W et al 2011) in myeloma. Low molecular weight heparin (LMWH) either for prophylaxis or treatment of venous thromboembolism, is frequently used in the treatment of myeloma. With an aim to separate the effect of heparin from the response achieved following Melphalan and Prednisolone (MP) plus Thalidomide, this study was initiated.

Patients and methods:

Individual data on 797 patients who were randomized to MP(n:393) or MPT(n:404) and published by the GIMEMA, Nordic, and the Turkish Myeloma Groups were analyzed using the SPSS 15.0 windows version. Except for the Nordic trial, LMWH was given as routine for the MPT patients. Patients who received anticoagulation as routine or following a thrombotic event were assigned to the LMWH group. Response equal to and more than partial response was included in the analysis. Comparisons were made using the Chi-Square or Mann Whitney U tests. Assessment of risk factors for response was done by the Backward- Stepwise Logistic Regression analysis. Survival analysis was performed using the Kaplan-Meier test.

MPP*MP+LMWHP#MPT+LMWHp@MPT
Number 376  17  152  252 
Age 72 (49–92) 0,470 72 (65–88) 0,260 72 (63–89) 0,144 73 (55–89) 
Gender        
    Male 57.2% 0,728 52.9% 0,855 55.3% 0,588 52.3% 
    Female 42.8%  47.1%  44.7%  47.7% 
ISS        
    1 38.7% 0,335 20.0% 0,192 43.4% 0,007 26.2% 
    2 32.1%  46.7%  28.7%  36.9% 
    3 29.3%  33.3%  27.9%  36.9% 
Creatinine 1 (0.5–8.2) 0,176 1.3 (0.6–3.1) 0,179 0.9 (0.7–12.7) 0,111 1 (0–8) 
Creatinine        
    22,0 89,6% 1,000 94.1% 1,000 90.8% 0,077 84.4% 
    >2,0 10.4%  5.9%  9.2%  15.6% 
B2mg 4.1 (0.4–42.3) 0,184 4.9 (2.8–25.3) 0,217 4.1 (0.3–35) 0,300 4.4 (0.3–80) 
B2mg        
    23,5 39.3% 0,134 20.0% 0,174 37.8% 0,897 37.1% 
    >3,5 60.7%  80.0%  62.2%  62.9% 
Albumin 3.6 (1.8–5.0) 0,293 3.4 (2.5–4.4) 0,428 3.6 (2.0–4.9) 0,030 3.3 (1.9–4.9) 
DVT+PE 0.0% <0,001 94.1% <0,001 25.0 % <0,001 0.0% 
Response 38.4% 0.022 70.6% 0,396 60.0 % 0.715 57.9 % 
Survival        
    Median 36 (31.3–40.7) 0,840 39 (19.3–58.7) 0,755 45 (38–52) 0,046 31 (23.5–38.5) 
    1 Year 77.9%  94.1%  70.5%  65.9% 
    5 Years 30.2%  31.9%  47.7%  18.4% 
MPP*MP+LMWHP#MPT+LMWHp@MPT
Number 376  17  152  252 
Age 72 (49–92) 0,470 72 (65–88) 0,260 72 (63–89) 0,144 73 (55–89) 
Gender        
    Male 57.2% 0,728 52.9% 0,855 55.3% 0,588 52.3% 
    Female 42.8%  47.1%  44.7%  47.7% 
ISS        
    1 38.7% 0,335 20.0% 0,192 43.4% 0,007 26.2% 
    2 32.1%  46.7%  28.7%  36.9% 
    3 29.3%  33.3%  27.9%  36.9% 
Creatinine 1 (0.5–8.2) 0,176 1.3 (0.6–3.1) 0,179 0.9 (0.7–12.7) 0,111 1 (0–8) 
Creatinine        
    22,0 89,6% 1,000 94.1% 1,000 90.8% 0,077 84.4% 
    >2,0 10.4%  5.9%  9.2%  15.6% 
B2mg 4.1 (0.4–42.3) 0,184 4.9 (2.8–25.3) 0,217 4.1 (0.3–35) 0,300 4.4 (0.3–80) 
B2mg        
    23,5 39.3% 0,134 20.0% 0,174 37.8% 0,897 37.1% 
    >3,5 60.7%  80.0%  62.2%  62.9% 
Albumin 3.6 (1.8–5.0) 0,293 3.4 (2.5–4.4) 0,428 3.6 (2.0–4.9) 0,030 3.3 (1.9–4.9) 
DVT+PE 0.0% <0,001 94.1% <0,001 25.0 % <0,001 0.0% 
Response 38.4% 0.022 70.6% 0,396 60.0 % 0.715 57.9 % 
Survival        
    Median 36 (31.3–40.7) 0,840 39 (19.3–58.7) 0,755 45 (38–52) 0,046 31 (23.5–38.5) 
    1 Year 77.9%  94.1%  70.5%  65.9% 
    5 Years 30.2%  31.9%  47.7%  18.4% 
*

MP vs MP+LMWH

#

MP+LMWH vs MPT+LMWH

@

MPT+LMWH vs MPT

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Results:

Treatment groups (MP vs MPT) were well balanced according to prognostic factors. LMWH was given as prophylaxis (n:124, n:4) or as treatment (n: 38, n:16) in the MPT and MP groups respectively. Patients who received LMWH in the MP group exerted similar characteristics to MP patients, but more patients in the MPT+LMWH group had advanced ISS (p=0.007) compared to MPT patients. Response (≥ PR) was observed more frequently among the patients who received MP and LMWH than those who did not receive LMWH (38.4 % vs 70.6%,p=0.022). Similar effect was not observed in the MPT group. Within the MP and MPT groups responders had lower b2mg (3.8 vs 4.2, p=0.068 and 3.9 vs 4.5, p=0.028). Higher s-albumin (3.7 vs 3.4, p=0.002) was associated with better response only in the MP group. When age, creatinine, b2mg, ISS, gender, and anticoagulation were introduced into the logistic regression model including all patients, LMWH (odds ratio (OR): 1.948, 95 % CI: 1.319–2.877,p=0.001) and b2mg (OR:0.956, 95% CI:0.925–0.988, p=0.007) were found to be independent risk factors. Logistic regression performed for MP or MPT groups revealed LMWH to be significant in the MP arm (OR: 4.168, 95% CI: 1.288–13.492, p=0.017) but not in the MPT arm (OR:1.031, 95% CI: 0.61–1.745, p=0.908). Within the MPT arm, creatinine (>2 mg/dL)(OR:0.453,95 %CI: 0.218–0.939,p=0.033) and advanced ISS (OR:0.764,95% CI:0.562–1.038,p=0.085) were additional risk factors. Survival was extended when LMWH was introduced to patients who were in the MPT group (p=0.046).

Conclusion:

In this study, based on individual data from three large randomized trials comparing MPT and MP, we found the addition of LMWH to be significantly associated with a better response in MP patients and improved survival in MPT patients. Although the cytogenetic and molecular profile of the patients are unknown and this is a retrospective analysis, improvement of response and survival following introduction of LMWH to the MP or MPT treatment suggests an anti-myeloma activity of LMWH.

Disclosures:

Beksac:Janssen Cilag: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Waage:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees. Bringhen:Celgene: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria; Merck Sharp & Dhome: Membership on an entity's Board of Directors or advisory committees. Gimsing:janssen Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees. Juliusson:Merck Serono: Membership on an entity's Board of Directors or advisory committees. Palumbo:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Amgen: Honoraria.

Topics:
heparin, multiple myeloma, turkish, low-molecular-weight heparin, creatinine, albumins, anticoagulation, endopeptidases, melphalan, partial response

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2011 by The American Society of Hematology
2011
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