Multiple myeloma (MM) is a hematological malignancy characterized by the proliferation of neoplastically transformed plasmocytes (terminally differentiated B-cells) which produce monoclonal immunoglobulin (M-protein) detectable in serum and/ or urine of the patients. Multiple myeloma differs from its “precursor” condition monoclonal gammopathy of undetermined significance (MGUS) by arbitrarily defined bone marrow involvement (≥ 10% of clonal plasmocytes and/or solid tissue plasmocytoma) or higher level of serum M-protein (≥ 30 g/l), and by the presence of organ involvement CRAB (C = hypercalcemia, R = renal failure, A = anemia, B = bone lesions) [1]. Patients with >10% of clonal plasma cells in the bone marrow or serum M-protein ≥ 30 g/l without the presence of associated organ involvement are now being described as having asymptomatic multiple myeloma (AMM). Similarly as MGUS individuals, AMM patients do usually not undergo treatment until the evolvement into the symptomatic form, i.e. symptomatic multiple myeloma.

The treatment of multiple myeloma (MM) is thus based upon the presence of organ involvement. The presence of hypercalcemia, elevation of N-catabolites or anemia are detectable from the blood, and can be easily repeated and reproduced. Bone involvement in the form of myeloma bone disease (MBD) is a challenge. Up to now, the “golden standard” for the assessment of MBD in MM patients was conventional radiography (skull, chest, pelvis, cervical, thoracic, lumbar and sacral spine, arm bones and thigh bones), although new methods emerged such as whole-body MRI or PET/CT scans [2]. Recent guidelines by the International Myeloma Working Group (IMWG) state the insufficient sensitivity of conventional radiography, still, they are too conservative in the use of modern imaging techniques [3-5].

MRI is the most considered one, and according to the IMWG guidelines it is recommended in “MM patients with normal conventional radiography and in all patients with apparently solitary plasmocytoma of bone”, and as an urgent procedure in the suspition of cord compression [3]. The use of MRI in MGUS has prognostic potential but it did not qualify for standard assessment as well as in MM with clear osteolytic lesions without signs of cord damage - for these conventional radiography should be sufficient.

A clinical study was therefore initiated to determine the role of imaging methods in patients with monoclonal gammopathies. The study was approved by local and government authorities as well as by local Ethical comittee. All patients with newly diagnosed monoclonal gammopathy (i.e. patients with newly diagnosed MM or MGUS) during the period 2013-2015 were included based on their voluntary written consent.

The study, which is still recruiting patients, will be reported in detail elsewhere. In the current report, we provide preliminary data on 2 patients. They were selected for immediate reporting because they would not be indicated for „advanced imaging“ based on IMWG criteria, however, the introduction of MRI and LD-CT into the diagnostic algorithm changed the therapeutic approach in both of them.

A 62 year male visited our department for a few episodes of joint pain, upper back pain, subfebrilia and weakness. He presented these symptoms to his doctor and received antibiototic therapy (clarithromycine) with improvement of the overall condition, still with persistent intermitent arthralgia. Personal history was insignificant with substituted hypothyreosis and impaired fasting glycemia only. The tests for infectious diseases were negative with low inflammation markers, blood count including differential was completely physiological, and there were no abnormalities in biochemical screening except of slightly elevated erythrocyte sedimentation rate (ESR 24/hour). The joints were clinically without arthritis, with normal radiography, and we performed radiography of the chest and of thoracic spine with the finding of osteochondrosis and incipient osteoarthrosis only (spondylophytes). The patient improved rapidly after non-steroid anti-rheumatics, and did not need further treatment. As a standard screening we performed serum immunoelectrophoresis with an unexpected finding of monoclonal immunoglobulin IgG lambda 19.71 g/l. The patient was then indicated for hematological examination.

We performed blood tests including blood count with computed and manual differential (normal finding), complete biochemistry including ESR, sodium, potassium, chlorides, BUN, creatinine, uric acid, CRP, ALT, AST, ALP, GMT, bilirubin, cholesterol, triacylglycerides, total protein, albumin and serum free light chains test. The only abnormal results were total protein (88.9 g/l, normal 65-85 g/l), ESR (13/hour, normal 0-10/hour), and free light chains (kappa 15.58 mg/l, lambda 144.71 g/l, kappa/lambda 0.108). The patient underwent trephine biopsy from the pelvis (left iliac crest) including cytogenetics and immunophenotyping. There were only about 5% of plasma cells in both the bone marrow smears and in histological sample, flow cytometry showed minor presence of abnormal plasmocytes (82% clonal cells out of total 0.9% of plasma cells) with no abnormality in cytogenetics and chromosomal analysis by FISH.

The patient underwent conventional radiography (skull, chest, spine, pelvis, arm bones and thigh bones) with normal finding, even without the presence of osteoporosis. Based on these findings, the patient would be diagnosed with MGUS, “high-intermediate” risk according to Mayo clinic criteria (IgG type, M-protein above 15 g/l, abnormal kappa/lambda ratio), and would not be treated but only followed in 6 month periods [6,7].

We offered the patient the participance in our grant aimed at imaging techniques in monoclonal gammopathies, and he agreed on further investigation using whole-body LD-CT and WB-MRI. These techniques, despite normal X-ray finding, revealed osteolytic involvement in C5, Th6, L1 and S2, minor lesions were found in C2, Th1, Th6, Th9, Th12 and L4, with 2 osteolytic lesions of the neurocranium (Figure 1). Based on these results we indicated neurosurgery which confirmed the diagnosis of multiple myeloma in the affected vertebrae. The patient underwent vertebroplasty of Th6 and L1 followed by radiotherapy and systemic chemotherapy using bortezomib-based regimen followed by autologous stem cell transplantation. At the moment, he reached near complete remission (respectively very good partial remission according to IMWG criteria), with only positive immunofixation.

Low dose computed tomography (LD-CT) – A, B, and whole-body magnetic resonance imaging (WB-MRI) – C, D (STIR collections), revealed vast osteolytic lesions of cervical, tharacic, lumbar and sacral area, some of them with a risk of near compression despite „normal“ X-ray finding.
Figure 1: Low dose computed tomography and whole-body magnetic resonance imaging in a patient with negative X-ray finding.

A 60-year old male was presented at our department with newly diagnosed symptomatic multiple myeloma IgG lambda. He was anemic (Hb 104 g/l), without renal insufficiency, serum calcium was normal, and he had typical osteolytic lesions throughout the skull, pelvis and long bones with compressive fractures of Th10, Th12 and L1 without neurological deficit. The patient was poorly compliant; he refused further investigation or any treatment, and he was released only with symptomatic therapy. After 6 months he made up his mind and agreed on both, investigation and treatment. The control results after this long period of time were surprisingly no worse than at the time of his first presentation. There was just a substantial increase in serum M-protein (15.87 g/l..30.85 g/l) and lambda light chains (369.54 mg/l..641.83 mg/l). There was no renal impairment (creatinine 90 ug/l) or calcium elevation (serum calcium 2.52 mmol/l), hemoglobin levels stayed stable (Hb 104 g/l..111 g/l) when compared to his last visit. He did not have any further complications resulting from advanced disease, the lower back pain was well-treated with pain-killers, and the patient did not have any other neurological deficit.

At this time we performed bone marrow examination which confirmed bone marrow infiltration with„packed“ clonal plasma cells (92% abnormal plasma cells by flow-cytometry), serum M-protein was 30.85 g/l, serum free light chains kappa 11.81 mg/l, lambda 641.83 mg/l, kappa/lambda 0.018, with the presence of cytogenetic changes - IgH deletion, chromosome 15 trisomy and FGFR3 trisomy. The patient refused injection-based treatment or stem cell transplantation, and agreed on thalidomide-based regimen, which was well-tolerated. As the diagnosis was clear, the extent of skeletal involvement was confirmed by conventional radiography and the patient had no other symptoms, he would not require further imaging based on recent guidelines. Nevertheless, we recommended whole-body LD-CT and whole-body MRI assessment, which revealed extramedullary masses of plasmocytoma from the damaged vertebrae, reaching and embedding the spinal cord, still not being symptomatic yet (Figure 2). Based on this finding, the patient was indicated for radiation therapy of the masses, and for a switch from thalidomide to bortezomib based regimen. This decision turned out to be correct as the previous therapy after 6 cycles reached minor response (respectively stable disease based on IMWG criteria) only with 34% decrease of M-protein. After the switch of chemotherapy and introduction of radiation treatment the patient improved, reaching partial remission, with no further symptoms of the disease. Control MRI described less significant but still severe skeletal involvement, the extramedullary masses being significantly reduced and not reaching the spine any more.

At the time of diagnosis, magnetic resonance revealed vast osteolytic involvement of the spine with extramedullary plasmocytoma of Th10 and L1, embedding the spinal cord (left) - T1 weighed sequence (A) and STIR (B). After induction chemotherapy and local radiotherapy, the tumor masses reduced their volume significantly (right) - T1 weighed sequence (C) and STIR (D).
Figure 2: Comparison of magnetic resonance imaging before and after radiotherapy of extramedulary myeloma in the spine.

Myeloma bone disease is present in 80-90% patients with MM, and it is the major cause of morbidity and mortality of MM patients [3]. For a long time, skeletal survey has been the „golden standard“ for MM imaging. Typical plain radiography findings include multiple osteolytic lesions, diffuse osteoporosis and the eventual presence of pathologicalfractures. It has fair sensitivity in areas such as skull, pelvis, arm bones and thigh bones. However, it might have up to 30-70% false negative findings in the spine which is usually the most frequent localization of pain [8].

Modern imaging methods in the diagnostics of MBD are significantly more sensitive and specific than conventional radiography [8-16]. In the study of Shortt et al., PET/CT, whole body MRI and bone marrow biopsy confirmed higher sensitivity and specificity of MRI over PET/CT which corresponds to recent IMWG recommendations by Dimopoulos et al. [3,17]. Similar results brought the analyses of Lutje et al., Hanrahan et al., and Myslivecek et al. [11,12,15]. Other authors declared the benefits of novel imaging, and potentially compared the methods with skeletal survey [9,10,13,14,16]. MRI has a great advantage in its sensitivity and specificity. It is able to distinguish tumorous and benign structural changes, and even to distinguish incipient form of MBD in the form of “pepper and salt” involvement in comparison with sole osteoporosis. Its advantage is also in the precise detection of extramedullary processes including potential spinal cord compression. CT-based imaging has far better detection of skeletal involvement than conventional radiography. Similarly as MRI, it is able to detect extramedullary processes. Due to high radiation exposure, several efforts have been made at its reduction using “lowdose” schedules. The final image is not as sensitive for soft tissue visualistation but it is still good enough for the detection of bone involvement. Despite the contribution of modern imaging methods, they are often being omitted due to additional costs or due to relying on conventional radiography as modern imaging methods predominatly bring additional information but do not change the clinical approach. Even recent guidelines for the assessment of MBD do not put enough stress on the use of modern techniques in monoclonal gammopathies but recommend them only in specific situations despite the evidence of significantly better outcomes in comparison with conventional radiography.

For the purpose of our study, we chose the comparison of wholebody MRI, LD-CT and plain radiography. MRI is now being considered as an optimal and the most sensitive and specific imaging method but it is significantly more expensive than skeletal survey and it is not always available in routine practice [3,9,11]. LD-CT is less sensitive than MRI, however, it is cheaper with similar expenses as plain radiography with just slightly increased radiation exposure and still significantly higher sensitivity than conventional radiography, and the examination is fast and undemanding [16,18].

Unlike previous studies, we have shown the clinical benefit of modern imaging. Both MRI and LD-CT confirmed identically serious impairment not visible on plain radiography. Based on these findings we changed therapeutic approach in the patients and probably saved them from further disability. Our paper cannot state a solid recommendation for an adequate imaging method as it presents only two cases. They are, however, specific as that they do not belong to any of the groups indicated for modern imaging methods based on IMWG guidelines; still, the present recommendations would not have led to a correct approach. We expect more information from our prospective study intended to assess the MBD from the point of imaging, biochemical and molecular changes as well as histomorphometry but the preliminary results are persuasive enough and useful for clinical practice to be published in advance.

We conclude that patients with monoclonal gammopathies should be examined with novel techniques and not only with X-ray as their diagnosis might be underestimated. Based on our findings, MRI and LDCT revealed similar involvement including bone destruction and extramedullary plasmocytoma.

Supported by the grant IGA MZ CR NT14393.