Assessment of Dynamic Contrast Enhanced Whole Body MRI (DCE-WB-MRI) as Independent Prognostic Factor for Disease-free Survival in Multiple Myeloma (After Intensification Therapy and Autologous Stem Cell Transplantation Suppressed by Amendment n°3)
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.
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic
Maximal percentage of bone marrow measurement on last WB DCE MRI
Bone marrow enhancement : Enhancement (%) = (SIpost - SIpre) x 100/SIpre, where SIpre is the signal intensity before injection and SIpost is the signal intensity after injection
Measurements will be performed on initialWB DCE MRI Examination. Follow-up = Five year
Assistance Publique - Hôpitaux de Paris
France: Ministry of Health