melphalan and 1-4-7-10-tetraazacyclododecane-1-4-7-10-tetrakis(methylenephosphonic-acid)

A study was undertaken to determine the maximum tolerated dose of (166)Ho-DOTMP that could be administered safely, without negatively impacting marrow re-engraftment, in patients with multiple myeloma treated with melphalan prior to transplant. Ho-166 DOTMP is a tetraphosphonate that localizes rapidly to bone surface. The Ho-166 physical half-life is 26.8 hr and the maximum beta energy is 1.8 MeV. Standard dosimetry models were adapted for radiation absorbed dose estimates using data obtained from whole body counting of the low abundance photons emitted by (166)Ho. Eighty-three patients received high dose (166)Ho-DOTMP followed by melphalan and transplant of peripheral blood stem cells. Twenty-five patients also received 8 Gy total body radiation (TBI). Dosages administered ranged from 460 to 4476 mCi (166)Ho-DOTMP. Marrow dose was derived using the assumption that all radioactivity not excreted by 20 hours was localized to the bone surfaces, and applying the Eckerman bone and marrow dose model to the calculated bone residence times. The dosimetry of the urinary bladder and kidneys was important because of the rapid excretion of the non-targeted radioactivity via the urinary pathway. The dynamic bladder model was used for bladder wall surface dose, and the ICRP 53 kinetic model was used to model kidney kinetics with an additional blood component included. Marrow doses ranged from 13 to 59 Gy and successful hematapoietic recovery occurred. Bladder doses ranged from 4.7 to 157 Gy. Hemorrhagic cystitis occurred in some patients who received more than 40 Gy to the bladder wall surface. Bladder irrigation was successful in protecting patients from bladder toxicity. Kidney doses ranged from 0.5-7.9 Gy. Kidney toxicity in the form of thrombotic microangiopathy with renal dysfunction was observed, with the severity being related to Ho-166-DOTMP radiation dose and probably the dose rate as well. In a future trial, kidney dosimetry will be assessed using early serial gamma camera imaging and modifications will be implemented to reduce renal toxicity.

Topics: Antineoplastic Agents, Alkylating; Cohort Studies; Combined Modality Therapy; Holmium; Humans; Maximum Tolerated Dose; Melphalan; Multiple Myeloma; Muscle, Skeletal; Organophosphorus Compounds; Radioisotopes; Radiometry; Radiotherapy Dosage; Tissue Distribution

Thirty-two patients with multiple myeloma were treated with high doses of 166Ho-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic acid (DOTMP) and were a subset of patients enrolled in a multicenter phase I/II dose escalation myeloablative trial. 166Ho with beta-emission (half-life, 26.8 h; beta-particle energies, 1.85 MeV [51%] and 1.77 MeV [48%]; gamma-photons, 80.6 keV [6.6%] and 1.38 MeV [0.9%]) was complexed to DOTMP, a macrocyclic tetraphosphonate. Pharmacokinetics, dosimetry, and biodistribution were studied.. Patients were treated at escalating dose levels of 20, 30, and 40 Gy to the bone marrow in combination with high-dose melphalan, with or without total-body irradiation, to evaluate toxicity and efficacy. After infusion with 1,110 MBq (30 mCi) of 166Ho-DOTMP for evaluation of biodistribution and dosimetry calculation, patients received the calculated amount of radioactivity for therapy in a single administration based on estimated dose calculations.. Thirty-two patients participated in the study and were then treated. The average amount of administered radioactivity was 74.3 GBq (2,007 mCi) (range, 21.5-147.5 GBq [581-3,987 mCi]) of 166Ho-DOTMP.. 166Ho-DOTMP has physical and pharmacokinetic characteristics compatible with high-dose myeloablative treatment of multiple myeloma.

Topics: Antineoplastic Agents, Alkylating; Bone Marrow Purging; Female; Holmium; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Organophosphorus Compounds; Radioisotopes; Radiometry; Radiotherapy Dosage; Tissue Distribution