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A Randomized Multicenter Study to Compare the Safety and Efficacy of 166Ho-DOTMP Plus Melphalan to Melphalan Alone as Conditioning for Autologous Peripheral Blood Stem Cell Transplant in Subjects With Primary Refractory Multiple Myeloma

Phase 3
18 Years
70 Years
Not Enrolling
Multiple Myeloma

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Trial Information

A Randomized Multicenter Study to Compare the Safety and Efficacy of 166Ho-DOTMP Plus Melphalan to Melphalan Alone as Conditioning for Autologous Peripheral Blood Stem Cell Transplant in Subjects With Primary Refractory Multiple Myeloma


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.


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.

Inclusion Criteria:

A subject must meet all of the following criteria to be eligible for the study. These
will be evaluated within four weeks prior to enrollment.

- Subject must have primary refractory multiple myeloma defined as having failed to
achieve an objective response (CR or PR using EBMT/IBMTR/ABMTR criteria) to any
therapy since the initiation of induction therapy. At least one previous therapy
must be a qualifying therapy that includes high dose pulsed steroids.

- There must be < 18 months from the beginning of induction therapy to time of
enrollment on study.

- Subject must meet institutional guidelines for autologous PBSCT.

- Subject must have a minimum of 2 x 106 unmanipulated CD34+ cells/kg cryopreserved and
available for transplant.

- Age 18 and 70 years.

- Adequate pulmonary function defined by FEV1, FVC and DLCO > or = 50% of predicted.

- Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) of >
or = 45%, with no evidence of cardiac amyloidosis.

- Adequate liver function, defined as serum total bilirubin < or = 2x institutional
laboratory upper limit of normal and ALT/SGPT < or = 3x institutional laboratory
upper limit of normal.

- Adequate renal function, defined as 24 hour measured creatinine clearance of > or =
50 mL/min/1.73 m2 BSA and serum creatinine < or = 1.8 mg/dL.

- ECOG performance score (PS) of 0, 1, or 2.

- Women of childbearing potential must have a negative pregnancy test (serum or urine
beta HCG) and be using appropriate birth control methods.

- Ability to understand the study and provide informed consent.

Exclusion Criteria:

A subject meeting any of the following criteria is not eligible for participation in the

- Non-secretory multiple myeloma.

- Asymptomatic MGUS, smoldering multiple myeloma, or indolent multiple myeloma.

- Solitary bone or extramedullary plasmacytoma.

- Waldenstrom's macroglobulinemia (IgM myeloma).

- Evidence of disease progression (such as new bone lesions) in the setting of a
greater than 50% reduction in M-protein.

- Absence of previous therapy with pulsed corticosteroids for multiple myeloma.

- Previous high-dose therapy with stem cell or bone marrow transplant, including
autologous, allogeneic, and reduced-intensity or non-myeloablative allogeneic

- Life expectancy severely limited by concomitant illness (less than 6 months).

- Evidence of symptomatic spinal cord compression or pathological fracture within 3

- Cumulative external beam radiation to > 20% of marrow volume or > 40 Gy to any single
region of the spinal cord.

- Prior radiation to the bladder or kidney, defined as radiation portals that directly
include any volume of either kidney or the bladder.

- Uncontrolled arrhythmia or symptomatic cardiac disease.

- Clinical evidence of amyloidosis involving the heart, lungs, liver, kidney, autonomic
nervous system, or GI tract.

- History of hemorrhagic cystitis.

- Current microscopic or gross hematuria in the absence of vaginal bleeding.

- Obstructive uropathy.

- Inability to have bladder catheter placed.

- Evidence of HIV-seropositivity.

- Recent history of alcohol or drug abuse.

- History of non-compliance in other studies.

- Use of bisphosphonates within 14 days preceding enrollment.

- Use of any other therapy for multiple myeloma (including standard, induction,
investigational, and alternative therapies) within 4 weeks prior to enrollment.

- Experimental therapies for any other conditions in the four weeks prior to

- Pregnant or lactating women.

- Known allergy to vitamin C or bisphosphonates.

- Other prior malignancy except for: adequately treated basal cell or squamous cell
skin cancer, in situ cervical cancer, or any other cancer from which the subject has
been disease-free for 5 years.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment


United States: Food and Drug Administration

Study ID:

STR 0303



Start Date:

March 2004

Completion Date:

Related Keywords:

  • Multiple Myeloma
  • Multiple myeloma
  • Primary refractory multiple myeloma
  • STR
  • Skeletal Targeted Radiotherapy
  • Holmium-166
  • 166-Ho-DOTMP
  • Multiple Myeloma
  • Neoplasms, Plasma Cell



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