RADIOPHARMACEUTICAL THERAPY OF 5T33 MURINE MYELOMA BY SEQUENTIAL TREATMENT WITH SM-153 ETHYLENEDIAMINETETRAMETHYLENE PHOSPHONATE, MELPHALAN, AND BONE-MARROW TRANSPLANTATION

Background: Total-body irradiation, followed by hematopoietic system r escue by bone marrow transplantation (BMT), has been found to improve the response of patients with multiple myeloma to treatment with melph alan. The problems of non-hematopoietic toxicity from whole-body irrad iation might be circumvented by using a bone-seeking radiopharmaceutic al, such as samarium-153 ethylenediaminetetramethylene phosphonate (Sm -153-EDTMP), to ablate the bone marrow. Purpose: A mouse model system for multiple myeloma was used to evaluate the potential therapeutic ef ficacy of sequential therapy with Sm-153-EDTMP, melphalan, and BMT. Me thods: Female C57BL/KaLwRij mice were inoculated with 8 x 10(5) 5T33 m urine myeloma cells. Treatment protocols were begun 3 or 10 days later , when the myeloma was either confined to bone marrow or disseminated in liver, spleen, and lymph nodes, simulating human multiple myeloma. Sm-153, a potent beta particle-emitting radioisotope of short half-lif e (46.7 hours), was linked to the bone-seeking chelate EDTMP. Animals in the first treatment group were each given 22.5 MBq Sm-153-EDTMP via the jugular vein (day 3 or 10), followed by 18.5 mg/kg melphalan (max imum tolerated dose) given intraperitoneally 5 days later (day 8 or 15 ) and syngeneic BMT another 2 days later (day 10 or 17). Survival in g roups of six to 10 animals for each time series was compared with that in mice left untreated (control cohort), in mice treated with Sm-153- EDTMP alone (day 3 or 10), or in mice treated with melphalan alone (da y 8 or 15). The hematopoietic systems of animals in the latter two tre atment groups recovered full function, obviating the necessity of BMT. The end point was onset of paraparesis, at which time the animals wer e immediately killed by carbon dioxide asphyxiation. Results: Median s urvival in untreated control animals was 23 days in those with localiz ed disease and 24 days in those with disseminated myeloma. Treatment w ith Sm-153-EDTMP alone improved survival to a median of 29 days when c ommenced on day 3 and 30 days when begun on day 10. Melphalan treatmen t alone improved the median survival to 31 days for animals with local ized myeloma and 34 days in animals with disseminated disease. Additio nal improvement in survival to a median of 42 days was achieved in ani mals treated 3 days after tumor inoculation with sequential Sm-153-EDT MP, melphalan, and BMT; median survival was 40 days using this regimen in animals with disseminated myeloma. Conclusions: Animals in all thr ee treatment protocols survived longer than those left untreated after inoculation with myeloma cells (P<.001). Sequential treatment with Sm -153-EDTMP, melphalan, and BMT was significantly more effective than s ingle-agent treatment (P<.01). No evidence of radiotoxicity was detect ed in non-hematopoietic organs. Implications: The survival advantage c onferred by our sequential treatment protocol suggests its potential c linical usefulness in the treatment of multiple myeloma and other hema tologic malignancies in humans.