Chemotherapy, Holmium Ho 166 DOTMP, and Peripheral Stem Cell Transplantation in Treating Patients With Multiple Myeloma
Chemotherapy, Holmium Ho 166 DOTMP, and Peripheral Stem Cell Transplantation in Treating Patients With Multiple Myeloma
RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing
 so they stop growing or die. Holmium Ho 166 DOTMP may deliver radiation directly to cancer
 cells and cause less damage to normal tissue. Combining chemotherapy and holmium Ho 166 DOTMP
 with peripheral stem cell transplantation may allow the doctor to give higher doses of
 chemotherapy and holmium Ho 166 DOTMP and kill more tumor cells.

 PURPOSE: Phase I/II trial to study the effectiveness of combining holmium Ho 166 DOTMP with
 melphalan and peripheral stem cell transplantation in treating patients who have multiple
 myeloma.
OBJECTIVES:

 -  Determine the radiation absorbed dose of holmium Ho 166 DOTMP to the kidney in patients
 with multiple myeloma, based on whole body gamma camera image data for comparison with
 that obtained using an ICRP mathematical model.

 -  Determine the average marrow dose of this drug in these patients using gamma camera
 whole body counts in patients receiving this drug.

 -  Determine the pharmacokinetics of this drug in these patients.

 -  Compare marrow dose estimates determined from gamma camera whole-body counts and thyroid
 uptake probe counts in patients receiving this drug.

 -  Evaluate intra-patient variability of the uptake of this drug in the bone with repeat
 tests.

 -  Determine whether the biodistribution and dosimetry is influenced by administering this
 drug as a bolus compared to a 15-minute infusion in these patients.

 -  Compare the reduction in dose rate from the 15-minute infusion vs the bolus injection of
 this drug to estimate the effect on kidney exposure in these patients.

 -  Determine the renal transit time for each patient after bolus injection of this drug and
 assess whether this information improves the dose estimate to kidney with the
 mathematical model.

 -  Determine whether there is correlation of renal transit time from technetium Tc
 99m-diethylenetriaminepentaacetic acid (DTPA) with holmium Ho 166 DOTMP.

 -  Determine the adverse events in patients receiving this drug.

 -  Determine the efficacy of a targeted therapy dose of holmium Ho 166 DOTMP with melphalan
 followed by autologous peripheral blood stem cell transplantation in these patients.

 OUTLINE: This is a multicenter study. Patients are entered into one of two cohorts.

 -  Cohort A: Patients receive a diagnostic dose of holmium Ho 166 DOTMP IV over 15 minutes
 on day 1 and then IV bolus on day 8.

 -  Cohort B: Patients receive a diagnostic dose of holmium Ho 166 DOTMP IV over 15 minutes
 on days 1 and 8.

 After each diagnostic dose, patients in both cohorts also undergo gamma camera imaging of the
 whole body on days 1 and 8.

 Approximately 1-3 weeks later, patients in both cohorts who demonstrate adequate uptake of
 the first diagnostic dose of holmium Ho 166 DOTMP into the bone marrow then receive
 therapeutic holmium Ho 166 DOTMP IV over 15 minutes once between days -13 to -10 followed by
 melphalan IV over 20-30 minutes once between days -10 to -1. Patients undergo autologous
 peripheral blood stem cell transplantation on day 0.

 Patients are followed monthly for 1 year and then every 3 months for 1 year.

 PROJECTED ACCRUAL: A minimum of 12 patients (6 per cohort) will be accrued for this study.
DISEASE CHARACTERISTICS:

 -  Diagnosis of multiple myeloma (MM)

 -  Patients with a prior diagnosis of monoclonal gammopathy of undetermined
 significance (MGUS) or smoldering myeloma are eligible if they progressed and met
 the criteria for diagnosis of MM

 -  No non-secretory MM

 -  No symptomatic MGUS, smoldering MM, or indolent MM

 -  No solitary bone or extramedullary plasmacytoma

 -  No immunoglobulin M myeloma

 -  Prior induction therapy for myeloma required

 -  Responding, stable, or progressive disease after induction therapy, or relapsed
 disease

 -  Candidate for autologous hematopoietic stem cell transplantation

 -  Prior stem cell mobilization with chemotherapy and growth factors according to
 institutional procedures

 -  Availability of at least 2,000,000 CD34+ cells/kg

 PATIENT CHARACTERISTICS:

 Age

 -  18 to 70

 Performance status

 -  ECOG 0-2

 Life expectancy

 -  Not specified

 Hematopoietic

 -  Not specified

 Hepatic

 -  Bilirubin no greater than 2 mg/dL

 -  SGPT no greater than 2 times upper limit of normal

 -  No clinical evidence of amyloidosis of the liver

 Renal

 -  Creatinine no greater than 2.0 mg/dL

 -  Creatinine clearance at least 45 mL/min

 -  Renal ultrasound normal

 -  No clinical evidence of amyloidosis of the kidney

 -  No urinary obstruction in the renal pelvis, ureter, or bladder outlet by ultrasound

 Cardiovascular

 -  Ejection fraction at least 50% with no evidence of amyloidosis by echocardiogram

 -  No clinical evidence of amyloidosis of the heart

 -  No uncontrolled arrhythmia

 -  No symptomatic cardiac disease

 Pulmonary

 -  FEV1, FVC, and DLCO at least 60%

 -  No symptomatic pulmonary disease

 -  No clinical evidence of amyloidosis of the lungs

 Other

 -  No known allergy to vitamin C or bisphosphonates

 -  No known hypersensitivity to technetium Tc 99m phosphorus radiopharmaceuticals (e.g.,
 technetium Tc 99m-methylene diphosphonate)

 -  No concurrent illness that would severely limit life expectancy

 -  No symptoms, physical findings, or radiographic evidence of cord compression

 -  No clinical evidence of amyloidosis of the autonomic nervous system or
 gastrointestinal tract

 -  No prior noncompliance in other studies

 -  No other malignancy within the past 5 years except treated indolent skin cancers or
 carcinoma in situ of the cervix

 -  HIV negative

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception

 PRIOR CONCURRENT THERAPY:

 Biologic therapy

 -  See Disease Characteristics

 -  No prior stem cell or bone marrow transplantation

 -  No concurrent maintenance therapy comprising interferon or thalidomide

 Chemotherapy

 -  See Disease Characteristics

 Endocrine therapy

 -  See Disease Characteristics

 -  No concurrent maintenance therapy comprising dexamethasone

 Radiotherapy

 -  No prior cumulative external-beam radiotherapy (EBRT) to more than 20% of bone marrow

 -  No prior cumulative EBRT dose of 30 Gy or more to the spinal cord

 -  No prior radiotherapy to the bladder

 Surgery

 -  See Disease Characteristics

 Other

 -  At least 4 weeks since prior investigational agents for MM

 -  At least 4 weeks since other prior experimental therapies for any other condition

 -  No bisphosphonates for at least 4 weeks before study, during study, and for at least
 30 days posttransplantation