Background. Multiple myeloma (MM) is the most common primary bone malignancy, caused by proliferation of
plasma cells secreting immunoglobulins. Active MM (aMM) is characterized in many patients by
multiple lytic bone lesions, presenting with pain in the involved bones (e.g. pelvis, spine,
etc.). In a recent publication, key-opinion leaders of multiple-myeloma state "MM-induced
bone disease is a hallmark of MM; up to 80% of patients present with osteolytic bone lesions
at diagnosis and have an increased risk of skeletal-related events (SREs) associated with
increased morbidity and mortality" (Terpos et al, 2018). Approximately 60% of myeloma
patients will develop a fracture during the disease course" (Terpos et al, 2018). Current CT
scans provide qualitative measures of bone involvement detected only after irreversible
damage has occurred and which cannot predict disease evolution so to optimize treatment and
enhance life quality and longevity.
Medical treatment modalities, including multi-agent chemotherapy and bone marrow
transplantation, may stop progression of MM, and prevent further bone lesions. Myeloma
response to therapy is usually monitored by measurement of the monocloncal protein which is
secreted by the malignant plasma cells into the blood and urine. This protein includes an
intact immunoglobulin
- - M-SPIKE - which is measured by serum protein electrophoresis (SPEP)
and, Circulating free light chains - kappa and lambda.
Usually one of the chains is
"involved" in the disease; The level of M-SPIKE and the ratio of the "involved" to
"uninvolved" chains is used to monitor disease progression. The role of imaging technologies
in monitoring progression of the disease is less defined. Low-dose total body CT scans are
recommended as second-line imaging (total body MRI is first-line) during the initial
diagnostic workup of MM by the most current guidelines of National Institute for Healthcare
Excellence (NICE, 2016). The guidelines encourage further research of the role of various
imaging modalities in treatment of MM:
"Newer imaging techniques are replacing skeletal surveys for assessing myeloma related bone
disease in people with newly diagnosed myeloma. However, the most effective tech-nique is not
known. Outcomes of interest are lesion detection, sensitivity and specificity for myeloma
related bone disease, patient acceptability, incremental upstaging, radiation exposure, risk
of second primary cancer, the impact of additional information on predicting progression-free
survival, overall survival and skeletal related events." (NICE, 2016) As previously stated,
current imaging modalities visualize bone lesions but do not quantify their progression, any
response to therapy or their impact on bone strength. A novel scientific tool that describes
bone's response by mathematical equations and is based on CT scans of MM patients, allows to
construct a 3-D model of patient's femurs and vertebrae including the inhomogeneous material
properties, virtually loads the bones by physiological loads associated with patient's weight
and determine the deformations and strains by a computer simulation. This technology, termed
CTFEA, allows a quantitative evaluation of bone's strength and risk of fracture, was
double-blinded validated ex-vivo, and clinically validated in a retrospective clinical trial
on a cohort of 50 patients with metastatic tumors to their femurs (Sternheim et al, 2018).
Combining the engineering and scientific expertise with the clinical knowledge and database
of MM patients accumulated during the past ten years, may identify by monitoring femurs' and
vertebrae' strength the evolution of MM, and trigger the need of prophylactic surgeries. Such
CTFEA has the potential to revolutionize MM treatment by providing the MDs quantitative
scientific measures to monitor and change treatment options so to optimize medication
prescription and enhance life-quality and longevity of MM patients on one hand, and determine
with high level of accuracy the risk of impending fracture due to metastatic tumors to the
femurs and vertebrae.
Preliminary results on a cohort of seven MM patients (Cohen et al, 2017), has recently been
presented in Dec 2017 at the ASH conference in the USA. These results showed the potential of
assisting MDs to determine disease evolution and treatment. Since the vertebrae are prone to
MM involvement, we plan to validate the CTFEA methods for such vertebrae with MM involvement
by comparing experiments performed on cadaveric human vertebrae with the computational
simulation. In addition, we propose to in-vivo validate the accuracy and predictability of
patient specific CTFEA of vertebrae and femurs by a clinical trial on a cohort of MM patients
treated at Sourasky medical center.
Rationale CTFEA may add efficacy to CT scans used for follow-up of disease progression. This
analysis can detect differences of as little as 10% in bone strength. It has the ability to
detect changes even in normal looking bone on CT and not just in lytic lesions. In addition,
CTFEA characterises the effect of each myeloma lesion on bone structure and calculates the
risk of a pathologic fracture.
Study hypothesis:
We hypothesize that CTFEA analysis of LDTBCT will detect changes over time in patients with a
dynamic disease, even when these changes in CT are undetectable to the human eye.
Study objectives:
Primary objective:
To observe CTFEA-determined bone strength changes over time in patients with Active MM.
Secondary objectives. 1. To measure CTFEA changes over a period of 12 months in lumbar vertebrae and femurs of
patients with AMM.
2. To determine correlation between CTFEA and clinical indicators of response to treatment
(e.g. light chains, clinical staging of bone lesions).
3. To compare CTFEA changes over time between patients responding to AMM treatment and
those who do not respond to treatment.
Methods Study design This is a prospective study with one patient group. All patients will
undergo three Low-Dose Total Body CT (LDTBCT) scans as part of diagnostic workup for MM,
which represents our current common practice: at 0, 6 and 12 months into treatment (or 3 CT
scans at least 6 months apart).
All three scans will be sent for CTFEA, which is not part of the common practice. The CTFEA
results will be compared to clinical assessments as per patient files and light chain values
on blood work. Changes in lesion size will be compared to changes that the lesion inflicts in
bone structure and changes in the risk of fracture.
Bone strength in both femurs and lower lumbar vertebra will be analyzed even where there are
no lytic lesions for changes in bone strength.
Results will be correlated with Myeloma clinical variables including baseline demographic and
disease charateristics, therapy details and response to treatment over time.
Patients will continue followup, for recording of skeletal related events (fratures or new
lytic lesions)
Measured parameters. 1. Primary and secondary disease diagnoses and their ICD-9 codes.
2. Patient ambulatory status at time of MM diagnosis: independent walker; cane ambulator;
walker ambulator; wheel chair bound.
3. Time since patient was independent walker, ECOG performance status (Oken et al,
1982)(Appendix A).
4. Treatment for osteoporosis and duration.
5. Date of diagnosis of active MM (and preceding plasma cell dyscrasia if relevant)
6. Myeloma treatment details (dose & dates) and response to therapy according to IMWG
criteria (IMWG, 2010)(Appendix B)
7. CT scans (used for CTFEA) dates.
8. Last patient follow-up date.
10) Medical center at which the patient received their oncology treatment before the
hematology referral.
11) Laboratory results, specifically: Myeloma paraprotein measures including SPEP,
quantitative immunoglobulins and free light chain values; kidney function; CBC; LDH; B2MG;
FISH cytogenetics; BM PC% at diagnosis 12) active myeloma clinical presentation: CRAB
criteria (hypercalcemia / renal / anemia / bone lesions); and or SLIM-CRAB criteria (FLC
ratio>100; focal lesions on MRI or PETCT; BM PC>60%); 13) clinical status at time of CT scan
(newly diagnosed MM (NDMM); relapsed refractory MM [RRMM]) 14) VAS (Visual Analogue Scale)
for pain and Harris Hip Score
