A phase i/ii study of 166holmium-dotmp in combination with high dose chemotherapy and autologous stem cell transplant(Asct) For the treatment of patients with multiple myeloma(Mm)

MM is largely confined to the bone and bone marrow. It has been shown to be responsive to alkylating agents and external radiation. High dose therapy (HDT) with ASCT has been shown to prolong remission and survival. The delivery of targeted radiation using a bone seeking radiopharmaceutical with HDT/ASCT could enhance cytoreduction, improving response rate and survival. 166Ho-DOTMP is a high energy, beta emitting, phosphonate chelate which localizes to bone and produces aplasia. 166Ho-DOTMP is eliminated through the urinary tract; with minimal extramedullary toxicity. Two phase I-II studies combined 166Ho-DOTMP, in escalating doses in combination with HDT have been completed. The HDT consisted of three arms of melphalan at the following doses: 1)140 mg/m2, 2)200 mg/m2 or 3)140 mg/m2 in combination with TBI (800cGy in 4 fractions), MM. Doses of 166Ho-DOTMP to bone marrow began at 20 Gy and escalated in 10 Gy increments up to 40 Gy. 31 pts have been evaluated to date for response and 59 for safety. 57/59 pts experienced rapid neutrophil and platelet engraftment. The complete response rate to date is 42%, with an overall response rate of 48%. These data demonstrate that a marrow dose as high as 40 Gy can be achieved with little toxicity using 166Ho-DOTMP. A phase III, multi-center, randomized trial will start in mid-2000 using a targeted dose of 40 Gy 166Ho-DOTMP in combination with melphalan (200 mg/m2) and ASCT.