The leukemogenic potential of hematopoietic stem cell-toxic alkylating agents (melphalan, nitrosoureas) and of topoisomerase inhibitors are well established. We have previously reported, among 1,326 patients treated at our institution with melphalan-based tandem autotransplants, that the incidence of cytogenetically-defined MDS (CG-MDS) was directly related to the duration of prior alkylating agent therapy, patient age, and could be anticipated in those with poor stem cell mobilization. Using appropriate FISH probes applied to interphase nuclei, we have also reported that the MDS cytogenetic abnormality (MDS-CA) was usually already present in the cryopreserved PBSC. We have now examined the post-transplant incidence of MDS-CA among 195 patients receiving a first autotransplant as part of TT 1 and among 569 patients as part of TT 2. MDS-CA included del 20q11 in 4, t(1;7) (q10; p10) in 4, del 7q22/-7 in 4, del 13q in 3, del 5q22 in 3 and del 16q22 in 1 patient. 16 total events were observed, 10 on TT 1 and 6 on TT 2, with a low 5-yr estimate of MDS-CA of 1% with TT 2 and 4% with TT 1. Of these 16 patients, 3 have developed overt AML. Subsequent management included anthracycline/ara-C combination chemotherapy, as well as further autotransplant in 2 patients. 8 of the 16 patients have died, 2 due to AML, 3 due to progressive MM, and 3 to other causes. These findings indicate that limited exposure to chemotherapy and the use of non-genotoxic agents as induction treatment for myeloma reduce the risks of the potential development of t-MDS after autologous transplantation. Given the observed survival benefit for patients treated on these 2 protocols, these findings also support the notion of an aggressive approach to myeloma treatment using intensive, hematopoietic stem cell sparing induction and post-transplant consolidation therapy as administered in TT2.

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