PHARMACOKINETICS, DOSIMETRY AND TOXICITY OF HOLMIUM-166-DOTMP FOR BONE-MARROW ABLATION IN MULTIPLE-MYELOMA

In this Phase I clinical trial, six multiple myeloma patients who had not responded to conventional therapy and were scheduled for bone marr ow transplantation received a bone-seeking radiopharmaceutical for bon e marrow ablation. The pharmacokinetics, dosimetry, and toxicity of th is radiopharmaceutical were studied. Methods: Patients received from 5 19 mCi to 2.1 Ci (19.2 GBq to 77.7 GBq) of holmium-166 (Ho-166) comple xed with a bone-seeking agent, DOTMP (1,4,7,10- zacyclododecane-1,4,7, 10-tetramethylene-phosphonic acid). The reproducibility of pharmacokin etics from multiple injections of Ho-166-DOTMP administered to these m yeloma patients was demonstrated from blood (r(2) = 0.926) and whole-b ody retention (r(2) = 0.983), which allowed therapeutic parameters to be determined from a diagnostic study. Results: Over 50% of the Ho-166 -DOTMP injected dose was excreted within 2-3 hr postinjection, increas ing to 75%-85% over a 24-hr period. Rapid blood clearance minimized ra diation dose to nontarget tissue: less than 10% of the injected activi ty was retained in the blood pool at 1 hr postinjection, and less than 2% remained after 5 hr. The total radiation absorbed dose delivered t o the bone marrow for the six patients ranged from 7.9 Gy to 41.4 Gy. Conclusion: All patients demonstrated severe bone marrow toxicity with a white blood cell (WBC) count <1,000 cells/mu l, two patients exhibi ted marrow ablation (WBC count <100 cells/mu l), and no other toxicity greater than or equal to grade 2 was observed in any of the patients.