Few studies have examined the association between methylenetetrahydrofolate reductase (MTHFR) SNPs, epigenetic changes, and multiple myeloma (MM). We wished to determine genotype distributions for MTHFR 1298AC SNP in cases of MM and healthy controls and to examine whether there is any correlation between the methylation status of the CpG island of CDKN2A and Snk/Plk2 and MTHFR genotypes and with overall survival (OS) and other relevant clinical parameters. Bone marrow and peripheral blood were obtained from 45 patients with MM and 77 controls, respectively. The frequencies of the MTHFR 1298AA, 1298AC, and 1298CC genotypes were 53.3%, 40%, and 6.7% for the patient population and 50.6%, 41.6%, and 7.8% for the controls. No statistically significant difference was found in genotype distribution between cases and controls. No correlation was noted between MTHFR genotypes and OS, disease stage, bone disease, anemia, and extramedullary disease. Regarding CDKN2A and Snk/Plk2 CpG island methylation analysis, we found 12 of 45 patients and 27 of 45, respectively, to be methylated. CDKN2A and Snk/Plk2 methylation did not correlate with MTHFR genotypes. Herein, we report the identification of Snk/Plk2 as a novel methylated gene in MM and show that methylation is not influenced in this CpG island or in that of a previously described methylated gene, CDKN2A, in MM. Further evaluation in a larger sample of patients is needed in order to better define the prognostic and clinical value, if any, of MTHFR 1298 polymorphisms and CDKN2A and Snk/Plk2 methylation in the pathogenesis of MM.