Study Comparing STR (Skeletal Targeted Radiotherapy) Plus Melphalan to Melphalan Alone, With Stem Cell Transplant in Multiple Myeloma

PRIMARY OBJECTIVE: 1.To determine the efficacy of STR (166Ho-DOTMP). The primary endpoint of this study is to compare the CR rate at 6 months post-transplant (in the absence of further therapy) in subjects with primary refractory multiple myeloma after treatment with 750 mCi/m2 166Ho-DOTMP plus 200 mg/m2 melphalan followed by autologous PBSCT to treatment with 200 mg/m2 melphalan alone followed by autologous PBSCT. SECONDARY OBJECTIVES: 1. To compare the treatment groups with respect to survival and progression-free survival. 2. To compare treatment groups with respect to overall response rate (CR+VGPR+PR), best response within 6 months, and duration of response. 3. To compare the safety profile of the treatment groups. 4. To assess the biodistribution and estimated radiation absorbed dose to kidney in the first 20 subjects. METHODOLOGY: Informed consent for participation in the study will be obtained, eligibility determined, and the subject registered. All subjects will receive a tracer dose of 30 mCi 166Ho-DOTMP to determine skeletal uptake and biodistribution of 166Ho-DOTMP therapy. Subjects may receive a therapy dose only if 1) the tracer dose shows no aberrant distribution, and 2) if the skeletal residence time is at least 5.8 hours (equivalent to F x Te \> 4 hr). Subjects with adequate skeletal uptake and no aberrant distribution will be stratified based on the length of time since first induction therapy, and on response to prior therapy, and will undergo randomization to determine whether they will receive 166Ho DOTMP plus melphalan (Arm A) or melphalan alone (Arm B) as the conditioning regimen prior to autologous PBSCT. Subjects randomized to Arm A will be treated with 750 mCi/m2 166Ho DOTMP intravenously 4 to 12 days after the tracer dose, with a total dosage not to exceed 1500 mCi. Five to 9 days after the 166Ho-DOTMP therapy dose, subjects will receive 200 mg/m2 melphalan IV. Subjects randomized to Arm B will receive 200 mg/m2 melphalan at least 10 days and no more than 3 weeks after the tracer dose. For all patients, cryopreserved hematopoietic stem cells will be infused 24 to 48 hours after melphalan. Subjects will be followed for safety assessments for 10 years or until death. Efficacy will be evaluated for up to 3 years in responding subjects, and disease relapse or progression and survival will be documented until Year 10. An analysis to estimate radiation dose to the kidney will be performed in the first 20 patients. Additionally, after 6 months of follow-up have been completed on the first 20 subjects in each arm, an analysis of the CR rate will be conducted to rule out lack of efficacy of 166Ho-DOTMP. A planned interim analysis to determine the efficacy of the treatment will be performed when 60 patients on each arm have completed 6 months of follow-up. Enrollment on trial will continue while these interim analyses are performed. NUMBER OF SUBJECTS: Two hundred and forty subjects who meet the eligibility criteria and receive study treatment will be followed on this protocol.