"WB-DCE-MRI" in Multiple Myeloma as an Independent Prognostic Factor for Disease-free Survival
"WB-DCE-MRI" in Multiple Myeloma as an Independent Prognostic Factor for Disease-free Survival
The main objective of this study is to examine if absence of a satisfactory response on
 DCE-WB-MRI (see MR criteria of responders section) after completion of HDT followed by
 autologous stem-cell transplantation (ASCT) is an independent prognostic factor for EFS in
 patients with MM, compared with established ones including beta2-microglobulin and
 cytogenetic abnormalities. Secondary objectives are to examine if the microcirculation
 parameters obtained from baseline DCE-WB-MRI have prognostic significance and to examine if
 early DCE-WB-MRI performed after the induction HDT and before ASCT might also provide
 independent prognostic information for patient outcome, which might help in patient
 stratification and be integrated into the response criteria in the future.
Introduction Bone marrow angiogenesis is increased in multiple myeloma (MM) and is an
 important prognostic factor for survival. Newly diagnosed MM patients have higher microvessel
 density (MVD) than controls on bone marrow biopsies. In addition, patients with higher MVD,
 receiving conventional chemotherapy or high-dose therapy with autologous stem cell
 transplantation, have shorter median overall survival than those with lower MVD by using the
 median MVD as the cutoff. In a study with 81 patients with MM treated with thalidomide with
 or without dexamethasone, MVD decreased significantly in responders while no significant
 change in MVD was seen in those failing to respond to thalidomide.

 Microcirculation variables derived from dynamic contrast-enhanced magnetic resonance (DCE-MR)
 imaging, i.e. maximum enhancement and the exchange rate constant, correlate well with the
 histologic infiltration grade, MVD and serum markers of disease activity. Recently, the
 maximal amplitude of lumbar bone marrow enhancement on DCE-MR examination has been identified
 as a prognostic variable for event-free survival (EFS) in progressive MM. These parameters
 may serve as non-invasive surrogate biomarkers for determining prognosis and for assessing
 treatment response in myeloma patients. However, these studies used techniques which were
 limited to a maximal 400-mm field of view, whereas myeloma can involve the bone marrow
 focally, diffusely throughout the body, or even outside the marrow space. With the
 advancement of MR technologies, unenhanced whole-body MR imaging has proven more reliable
 than radiological skeletal survey and whole-body multidetector computed tomography in
 patients with MM.

 Recently, whole-body single-phase contrast-enhanced sequence was applied in combination with
 unenhanced sequences for the detection of myeloma lesions. However, single-phase
 post-contrast MR examinations do not provide detailed enhancement curves, and this limitation
 possibly hinders the assessment of disease activity. On the other hand, segmental dynamic MR
 examinations do not enable assessment of the dynamic enhancement of focal lesions in
 different bone marrow segments. That was the reason which led us to develop a dynamic
 contrast-enhanced whole-body magnetic resonance imaging (DCE-WB-MRI) protocol, which was
 never explored in MM.

 The treatment of patients with MM was largely palliative until, with the advent of high-dose
 melphalan, high rates of complete response (CR) could be obtained. For previously untreated
 patients aged 70 years (amendment n°5)or younger, high-dose therapy (HDT) followed by
 treatment (amendment n°3) with growth-factor-mobilized peripheral-blood stem cells (PBSCs)
 have been demonstrated superior to conventional chemotherapy with not only higher CR rates
 but also significantly extending EFS and overall survival. Recently, the International
 Myeloma Working Group proposed new uniform response criteria to facilitate precise
 comparisons between new evolving treatment strategies. As a functional imaging providing
 parameters related to angiogenesis and disease activity in MM, DCE-WB-MRI might provide
 additional information on prognostically important microcirculation variables on a whole-body
 scale. It might also prove helpful in assessing treatment response and further treatment
 strategy decision for patients with oligo- or nonsecretory disease.

 Study Description :

 Treatment regimen: the HDT followed by ASCT with PBSCs will be given. The ASCT will be
 conditioned by high-dose melphalan (HDMel) 200 mg/m2 with or without bortezomib following the
 actual guidelines.

 Response assessment: clinical response will be assessed on the same day of each
 post-treatment MR examination and recorded according to the uniform response criteria. After
 completion of HDT followed by ASCT, patients will be followed every 4 months for the first
 two years and every 6 months thereafter for a total of at least 5 years. An event is defined
 as disease progression, relapse from clinical CR/VGPR, or death from any cause.

 DCE-WB-MRI schedule: three MR examinations will be performed, the first at diagnosis and
 before initiation of chemotherapy, the second after induction chemotherapy and before ASCT,
 and the third exam three months after ASCT. The results of each DCE-WB-MRI will not influence
 further treatment strategy.

 MR Criteria of Responders:

 A satisfactory response on DCE-WB-MRI is defined by the presence of a maximal percentage of
 bone marrow enhancement below 100%. All focal lesions, if present, must not present an early
 enhancement but a progressive, delayed type maximal enhancement.
Inclusion Criteria:

 -  Patient referred to one of the hematology departement associated with the research
 project, with confirmed multiple myeloma defined according to uniform international
 criteria.

 -  Whatever stage classification according to Salmon and Durie with a life expectancy of
 more than 3 months.

 -  Age under 70 years old (amendment n°5) and eligible for autologous stem cell
 transplantation.

 -  Free and informed consent.

 Exclusion Criteria:

 -  Patient unfit physically, mentally or legally to give informed consent.

 -  Patient non affiliate with social security scheme

 -  Patient with myeloma without measurable monoclonal immunoglobulin, including
 measurement of serum free light chains.

 -  Patient with another malignancy excluding basal cell cancer.

 -  Patient who could not undergo MRI (incompatible metallic foreign body, pacemaker,
 allergy to contrast, claustrophobia despite premedication, pregnancy, renal failure
 with creatinine clearance <30 ml/min