The occurrence of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs) following multiple myeloma has been recognized for decades.1 Alkylating agents have long been considered to be part of the cause.2–5 Some, but not all, smaller investigations have reported that higher cumulative melphalan dose and longer duration of melphalan therapy are associated with an increased risk of AML.6,7 The role of nontreatment-related factors is largely unknown.
We were impressed with our observation that the G/G genotype of the single-nucleotide polymorphism (SNP) rs1617640 in the erythropoietin (EPO) promoter is significantly (P<0.001) more prevalent in MDS patients (47/187; 25.1%) compared with healthy controls (6/95; 6.3%).8 Therefore, using peripheral blood obtained at the time of diagnosis of multiple myeloma, we determined whether the rs1617640G/G genotype was associated with the development of MDS during the course of multiple myeloma.
We conducted a nested case–control study including 17 multiple myeloma patients who subsequently developed MDS and 17 multiple myeloma patients who did not develop MDS. Matching factors were age (±4 years), sex, year of multiple myeloma diagnosis (±1 year) and duration of follow-up (±6 months). All patients were diagnosed and treated at the Mayo Clinic (Rochester, MN, USA). Peripheral blood (germline DNA) was obtained at multiple myeloma diagnosis for all patients. Two patients were excluded due to poor DNA quality. The remaining 32 patients were tested for the EPO rs1617640 genotype. The SNP genotype was determined for each patient using TaqMan MGB (minor groove binding) probes for allele discrimination (Applied Biosystems, Foster City, CA, USA). As described previously,8 the rs1617640 EPO SNP was PCR amplified in the presence of MGB probes specific for the G and T SNP alleles. Bound probes were cleaved by the Taq polymerase in the process of PCR amplification, releasing the reporter dyes. Following PCR, plates were read using the 7900HT Fast Real-Time PCR system, and the data were analyzed using Allele Discrimination software (Applied Biosystems).
The median age at multiple myeloma diagnosis was 66 years and the median year of diagnosis was 1992 (Table 1). For multiple myeloma patients who subsequently developed MDS, in accord with prior studies,9 the median time between the two diagnoses was 3.9 years (range: 1.8–14.3). When we assessed the results from the genotyping, we found 4 out of 15 (27%) of the multiple myeloma patients who developed MDS had the G/G genotype, whereas only 2 out of 17 (12%) of the patients who did not develop MDS showed the G/G genotype. The G/T genotype was found in 47% of both groups; multiple myeloma patients who did not develop MDS had a higher fraction of T/T genotype (41% vs 27%).
Table 1.
Patients’ characteristics
| Variable | |
|---|---|
| Age (years) at multiple myeloma, median (range) | 66 (41–82) |
| Male gender, n (%) | 26 (76) |
| Year of multiple myeloma diagnosis, median (range) | 1992 (1983–2005) |
| Year of MDS diagnosis, median (range) | 1997 (1989–2008) |
| Years from multiple myeloma to MDS, median (range) | 3.9 (1.8–14.3) |
Abbreviation: MDS, myelodysplastic syndrome.
Our novel findings support a role for susceptibility genes in the development of second malignancies following the diagnosis of multiple myeloma, likely in combination with multiple myeloma therapies. Future studies are needed to replicate and expand on our observations, with the overall goal of characterizing the role for treatment- and nontreatment-related factors underlying the development of secondary malignancies subsequent to multiple myeloma.
Acknowledgements
The study was approved by the Mayo Clinic Institutional Review Board; informed consent was obtained from all participants in this study. An exemption from institutional review board review was obtained from the National Institutes of Health Office of Human Subjects Research because we used anonymous data/samples.
Footnotes
Conflict of interest
The authors declare no conflict of interest.
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