Impact on Response and Survival of DNA Repair Single Nucleotide Polymorphisms In Relapsed or Refractory Multiple Myeloma Patients Treated with Thalidomide

Thalidomide was the first of the so-called new drugs incorporated in the treatment of multiple myeloma (MM). In this era of emerging novel agents, there is a real need for increased knowledge of the pre-treatment genetic profile of patients who will potentially benefit from each drug. The analysis of polymorphisms in drug metabolism pathways and in immune system genes can help to identify patients with possible different treatment response and outcome. Single nucleotide polymorphisms (SNPs) are the most frequent type of genomic polymorphisms and are involved in chemotherapy response in different tumors, including MM. We examined SNPs in 12 genes and correlated our findings with response, toxicity and overall survival (OS) to thalidomide in patients with relapsed MM.

Twenty-eight patients (13M/15F; median age 59 years, range 40 to 82 years) with relapsed or refractory MM from November 1999 to December 2003 were treated with single agent thalidomide at a single institution. The median duration of thalidomide treatment was 4 months and the median dose was 400 mg/day. Median follow-up for alive patients was 103 months (range 86 to 112). Genomic DNA was isolated from bone marrow slides using a commercial assay (Qiagen). SNPs were analyzed by TaqMan assay in an ABI Prism 7500 Sequence Detection system (Applied Biosystems). The genes explored were those related to multidrug resistance (ABCB1 [rs3842, rs1045642]), drug metabolic pathways (NR1I2 [rs1523130, rs1523127], GSTT1 [rs4630], SULT1C2 [rs1402467]), DNA repair systems (XPA [rs1800975], ERCC1 [rs735482], ERCC2 [rs13181], ERCC5 [rs17655, rs1047768], XRCC1 [rs25487], XRCC5 [rs1051677, rs1051685], TOP2A [rs13695]) and cytokines (VEGFA [rs10434, rs2010963]).

Partial response (PR) was attained in 17.9% (5/28) and minimal response (MR) in 28.6% (8/28), while 3 (10.7%) and 12 (42.9%) patients showed no response (NR) or progressive disease (PD), respectively. The response rate (PR+MR vs. NR+PD) to thalidomide was higher (66.7%) in patients with hetero- (AC) or homozygous (CC) SNPs in ERCC1 (rs735482) than in those with wild type (AA) (33.3%) (p=0.006). Patients with the ERCC5 heterozygous SNP rs17655 (CG) had a higher response rate (77.8%) than those with the homozygous SNP (GG) or wild type (CC) (31.6%) (p=0.04). Patients with heterozygous XRCC5 (AG) polymorphism rs1051685 showed a higher response rate (100%) than those with wild type (AA) (34.8%) (p=0.013). Longer OS was associated with the homo- and the heterozygous SNP in ERCC1 (AC + CC vs. AA; p=0.005) and with the heterozygous SNP in XRCC5 (rs1051685) (AG vs. AA; p=0.02) (Figures 1 and 2). A trend to longer OS was also observed in patients with polymorphisms in XRCC1 (p=0.06). The heterozygous polymorphism in GSTT1 (CT vs. TT) was associated with a lower frequency of thalidomide-induced peripheral neuropathy (p=0.04).

SNPs in ERCC1 and XRCC5 were strongly associated with higher response rate and longer OS to thalidomide in patients with relapsed/refractory MM. SNPs in ERCC5 were also associated with greater response rate. Since the polymorphism in XRCC1 was not related to a better response to thalidomide, it can be speculated that the trend to prolonged OS could be related to other molecular mechanisms. Our findings could be useful to identify patients with MM who are more likely to benefit from thalidomide-based therapies.

Figure 1.

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Overall survival of relapsed/refractory MM patients treated with thalidomide according to ERCC1 (rs735482) genotype (AA=wild-type, CC=homozygous SNP, AC=heterozygous SNP).

Figure 1.

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Overall survival of relapsed/refractory MM patients treated with thalidomide according to ERCC1 (rs735482) genotype (AA=wild-type, CC=homozygous SNP, AC=heterozygous SNP).

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Figure 2.

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Overall survival of relapsed/refractory MM patients treated with thalidomide according to XRCC5 (rs1051685) genotype (AA=wild type, AG=heterozygous SNP).

Figure 2.

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Overall survival of relapsed/refractory MM patients treated with thalidomide according to XRCC5 (rs1051685) genotype (AA=wild type, AG=heterozygous SNP).

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Cibeira:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosiñol:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blade:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.