166Ho-DOTMP plus melphalan followed by peripheral blood stem cell transplantation in patients with multiple myeloma: results of two phase 1/2 trials.
Holmium-166 1, 4, 7, 10-tetraazcyclododecane-1, 4, 7, 10-tetramethylenephosphonate (166Ho-DOTMP) is a radiotherapeutic that localizes specifically to the skeleton and can deliver high-dose radiation to the bone and bone marrow. In patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation two phase 1/2 dose-escalation studies of high-dose 166Ho-DOTMP plus melphalan were conducted. Patients received a 30 mCi (1.110 Gbq) tracer dose of 166Ho-DOTMP to assess skeletal uptake and to calculate a patient-specific therapeutic dose to deliver a nominal radiation dose of 20, 30, or 40 Gy to the bone marrow. A total of 83 patients received a therapeutic dose of 166Ho-DOTMP followed by autologous hematopoietic stem cell transplantation 6 to 10 days later. Of the patients, 81 had rapid and sustained hematologic recovery, and 2 died from infection before day 60. No grades 3 to 4 nonhematologic toxicities were reported within the first 60 days. There were 27 patients who experienced grades 2 to 3 hemorrhagic cystitis, only 1 of whom had received continuous bladder irrigation. There were 7 patients who experienced complications considered to be caused by severe thrombotic microangiopathy (TMA). No cases of severe TMA were reported in patients receiving in 166Ho-DOMTP doses lower than 30 Gy. Approximately 30% of patients experienced grades 2 to 4 renal toxicity, usually at doses targeting more than 40 Gy to the bone marrow. Complete remission was achieved in 29 (35%) of evaluable patients. With a minimum follow-up of 23 months, the median survival had not been reached and the median event-free survival was 22 months. 166Ho-DOTMP is a promising therapy for patients with multiple myeloma and merits further evaluation.
The University of Texas, MD Anderson Cancer Center, Houston, TX 77030-4006, USA. sgiralt@mail.mdanderson.org
Sergio
S
Giralt
William
W
Bensinger
Mark
M
Goodman
Donald
D
Podoloff
Janet
J
Eary
Richard
R
Wendt
Raymond
R
Alexanian
Donna
D
Weber
David
D
Maloney
Leona
L
Holmberg
Joseph
J
Rajandran
Hazel
H
Breitz
Richard
R
Ghalie
Richard
R
Champlin
D000328:Adult; D000368:Aged; D001842:Bone and Bones / Q000378:metabolism; D003131:Combined Modality Therapy; D003556:Cystitis / Q000209:etiology; D018572:Disease-Free Survival; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006470:Hemorrhage / Q000209:etiology; D006695:Holmium / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D015994:Incidence; D007674:Kidney Diseases / Q000453:epidemiology / Q000209:etiology; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000401:mortality / Q000532:radiotherapy*; D009190:Myelodysplastic Syndromes / Q000209:etiology; D009943:Organophosphorus Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011868:Radioisotopes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012079:Renal Circulation; D015996:Survival Rate; D013927:Thrombosis / Q000209:etiology; D014018:Tissue Distribution; D016896:Treatment Outcome
D009943:Organophosphorus Compounds; D011868:Radioisotopes; C082084:1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylenephosphonic acid); D006695:Holmium