Whole Body Diffusion Weighted Magnetic Resonance Imaging (DW-MRI) in Multiple Myeloma
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Study type: Interventional

Summary: 
      Bone disease in multiple myeloma (MM) is routinely assessed by skeletal X-ray (XR) and
      magnetic resonance of the spine (S-MRI). Diffusion-weighted MRI (DW-MRI) is a functional MRI
      that detects water diffusion through cells. This prospective phase II study compared
      whole-body DW-MRI with XR and S-MRI for the assessment of MM bone lesions.

      METHODS. Thirty-six consecutive symptomatic patients at diagnosis or at relapse performed XR,
      S-MRI, whole-body MRI, and whole-body DW-MRI before treatment, after treatment, and 6 months
      after treatment. A substudy evaluated 12 asymptomatic patients at diagnosis, after 6 and 12
      months. Radiology exams were independently read by 3 experienced radiologists, and the
      techniques were compared by the count of segments with focal lesions (FL) (>=5mm).
    

Detailed description: 
      PROTOCOL SYNOPSIS -

      Study Type Monocentric prospective clinical trial Study Object Comparison of Whole Body
      Diffusion Weighted Magnetic Resonance Imaging (DW-MRI) with skeletal X-Ray and MRI of the
      spine for the assessment of bone disease in Multiple Myeloma (MM) Objectives

      Primary objective 1) To assess whether DW-MRI can detect a higher number of bone lesions than
      standard X-Ray and MRI of the spine in Stage I-III symptomatic MM patients Secondary
      objectives

        1. To assess whether the change in the number of lesions detected with DW-MRI at follow up
           correlate with disease response to therapy

        2. To assess whether the change in the number of lesions detected with DW-MRI at follow up
           correlate with time to re-treatment (TTR)

        3. To assess whether DW-MRI detects a higher number of bone lesions than Whole Body
           Magnetic Resonance Imaging (WB-MRI) Exploratory objective

      1) To assess whether DW-MRI detects more bone lesions than standard X-Ray and MRI of the
      spine in Stage I asymptomatic MM patients at diagnosis not requiring treatment Study
      population and design The study population consists consecutive Stage I-III (Durie and
      Salmon) symptomatic Multiple Myeloma at the start of the first-line treatment or at relapse
      after disease response (CR or PR) lasting at least 6 months.

      Study procedures

      The patients will perform a DW-MRI, a whole body MRI (WB-MRI), a MRI of the spine and a plain
      skeletal X-Ray with clinical and laboratory evaluations with the following timing:

        1. Patients at first-line treatment for MM:

             1. Within 15 days before the start of the treatment

             2. Within one month after the end of the first-line treatment

             3. 6 months after the end of the first-line treatment

        2. Patients at relapse after disease response (CR or PR) lasting at least 6 months

             1. At relapse

             2. Within 15 days after the end of the treatment of relapse

             3. 6 months after the end of the treatment of relapse The DW-MRI, WB-MRI and MRI of
                the spine will be performed in the same session. Each DW-MRI, WB-MRI, MRI of the
                spine and skeletal X-Ray will be independently read and interpreted by two
                radiologists with proven experience in MM. Each radiologist will read and interpret
                the exams performed; the lecture of each exam will be blinded; the identity of the
                patient and the result of the lecture by the other radiologist will be blinded. In
                case the number of lesions detected by the radiologists would not match, the number
                of lesions will be determined by consensus between the radiologists.

      In case of more bone lesions detected by DW-MRI compared to MRI and skeletal X-Ray, a PET
      scan will be performed.

      Sample size The trial is designed to demonstrate a 30% increase in the number of bone lesions
      detected by DW MRI (experimental method) as compared to standard X-Ray and MRI of the spine
      (standard method). To detect such an effect size with a one sided Student t test at the 5%
      significance and 90% power, 27 patients need to be investigated, that we round to 30 to
      account for a 10% patient drop out. A midcourse sample size reassessment according to the
      approach proposed by Proschan, Liu & Hunsberger (2003) will use interim data from the first
      20 patients to decide to either maintain or increase the original sample size in a range
      between 30 and 60 patients, depending on whether the estimated effect size is aligned or not
      with the anticipated value.

      Substudy The substudy for the assessment of the exploratory objective will enroll 10
      consecutive Stage I (Durie and Salmon) asymptomatic MM patients at diagnosis not requiring
      treatment. The patients will perform the radiological and laboratory evaluations at diagnosis
      and at 6 and 12 months after diagnosis.

      Study duration The estimated duration of enrolment ranges between 15 and 30 months. The
      follow up duration is 6 months. The estimated total duration of the study is 3 years. A
      midcourse assessment of interim data is planned at the end of the first phase of enrolment
      (20 patients) to determine the sample size of the second phase.

      Selection criteria Inclusion criteria

        -  Age ≥18 years

        -  Stage I-III (Durie-Salmon) symptomatic MM at the start of first-line treatment or at
           relapse after disease response (CR or PR) lasting at least 6 months

        -  Stage I (Durie-Salmon) asymptomatic MM at diagnosis not requiring treatment (substudy
           for assessment of exploratory objectives)

        -  Written informed consent Exclusion criteria

        -  Pregnancy or lactation

        -  Active secondary malignancy

        -  Type I hypersensitivity or anaphylactic reactions to Gadolinum contrast agent

        -  Mental disorders including claustrophobia (ICD 10, F40.2)

        -  Electronically, magnetically and mechanically activated implants

        -  Ferromagnetic or electrically operated active devices like automatic cardioverter
           defibrillators

        -  Cardiac pacemakers

        -  Metallic splinters in the eye

        -  Ferromagnetic haemostatic clips in the central nervous system (CNS) or in the body

        -  Cochlear implants or stapedial implants

        -  Insulin pumps and nerve stimulators

        -  Prosthetic hearth valves Study Procedures at baseline • Medical history and physical
           examination

        -  Cell blood count and differential

        -  Clinical laboratory evaluations: Na+, K+, Ca2+, BUN, creatinine, LDH, PCRq, uric acid,
           AST, ALT, GGT, ALP, bilirubin (total and direct/indirect), albumin, protein
           electrophoresis, IgA, IgG, IgM, serum immunofixation, serum free light chains, 24h
           proteinuria, 24h Bence-Jones proteinuria, urine immunofixation, beta2microglobulin;
           HIV-Ab, HBsAg, HCV-Ab; pregnancy test for females of childbearing potential

        -  ECG

        -  DW-MRI (whole body Diffusion Weighted Magnetic Resonance Imaging)

        -  WB-MRI (Whole Body Magnetic Resonance Imaging)

        -  Skeletal survey including skull, cervical, thoracic and lumbar spine, pelvis, right and
           left humerus and femur, sternum and bilateral ribs

        -  MRI of the spine

        -  Bone marrow biopsy and bone marrow aspirate for morphology, FISH analysis for del(13),
           t(4:14), t(11:14), t(14:16), del(17), and flow cytometric immunophenotyping of CD138+,
           CD19+, CD28+ and CD117+.
    

Intervention name(s): DW-MRI
Intervention type(s): Other
Intervention description(s): MRI imaging with diffusion weighted sequences of the whole body
Other intervention name(s): Whole Body Diffusion Weighted Magnetic Resonance Imaging
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic