CTFEA Myeloma Study
CTFEA Myeloma Study
Patients with Multiple Myeloma are monitored for disease progression and for response to
 treatment by the treating hematologist or oncologist. Laboratory tests are usually utilized
 for these purposes. The role of imaging is confined to follow-up the progression of visible
 bone lesions. We suggest that microscopic bone lesions impair bone structure well before they
 grow enough to be visible on a CT scan. This impairment of bone strength can probably be
 captured by application of CT-based finite element analysis to the CT scans that were
 performed for monitoring of progression of the disease.
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
Inclusion Criteria:

 -  All patients with Active Multiple Myeloma

 Exclusion Criteria:

 -  Inability to provide informed consent or lack of consent.

 -  Inadequate CT scans