**2. The role of imaging**

Around 70–80% of patients have osteolytic lesions at diagnosis of MM, and up to 90% develop lytic lesions during the course of the disease [17]. The International Myeloma Working Group updated criteria for the diagnosis of symptomatic MM and revealed the value of modern imaging such as computed tomography (CT), whole-body low-dose computed tomography (LDCT), positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging (MRI) [18]. Modern imaging techniques had a greater sensitivity than conventional radiographic skeletal survey for the detection of MM bone lesions with as many as 80% or more lesions detected by the newer imaging techniques [18]. A summary of different imaging techniques is detailed in **Table 1**.

#### **2.1. Conventional radiographic skeletal survey**

Whole-body X-rays imagine (including plain radiographs of the whole skeleton) have been widely used for the detection of bone lesions at diagnosis and during the course of the disease. Osteolytic bone lesions are more common in the scull, vertebrae, ribs and pelvis. Although the


survival [3]. Radiotherapy is a treatment approach used in patients with solitary plasmacytomas. However, the role of radiation treatment of MM is palliative: to induce an analgesic effect in osteolytic lesions, to promote recalcification in the sites of impending pathological

Despite the enormous development in MM treatment approaches and response to systemic therapy, patients are often in need of pain control due to slow repair of bone lesions. Chemotherapy treatment alone is insufficient for patients suffering from pain caused by osteolytic bone destruction or in case of an impending fracture at the destruction site. Seventy percent of patients receive radiation at least once during their MM therapy [5]. Where radiotherapy is applied, pain can be reduced by 75–100% from the starting level [5–12]. Recalcification of bone destructions caused by MM is observed in 40–60% of the cases after radiation treatment [5, 7, 12, 13]. Good results in the treatment of bone damages due to MM can be achieved when applying other supportive therapy measures, such as bisphosphonates,

It has been known for a long time that pain perception is not the same for all patients. The response to analgesics, pain relief and the effect of radiotherapy are very individual. The above can be determined by a different secretion of anti-inflammatory cytokines (IL-6, IL-10, TNFα, IL-1), which participate in the pathogenesis of the pain caused by a chronic disease and their concentration in blood serum. Circulating cytokines and inflammatory proteins are related to pain, cognitive functions, depression, fatigue and sleep disturbances [14–16]. The secretion of anti-inflammatory cytokines is regulated genetically. Cytokine genes are very polymorphous. Polymorphisms in regulatory regions, including promoters and non-transmittable areas, in a majority of the cases can change the gene expression in vitro [15]. Thus, the above has an impact on the secretion of cytokines and their concentration in blood serum, which determines the pain perception threshold and a different response of patients to analgesics and radiotherapy.

Around 70–80% of patients have osteolytic lesions at diagnosis of MM, and up to 90% develop lytic lesions during the course of the disease [17]. The International Myeloma Working Group updated criteria for the diagnosis of symptomatic MM and revealed the value of modern imaging such as computed tomography (CT), whole-body low-dose computed tomography (LDCT), positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging (MRI) [18]. Modern imaging techniques had a greater sensitivity than conventional radiographic skeletal survey for the detection of MM bone lesions with as many as 80% or more lesions detected by the newer imaging techniques [18]. A summary of different imaging tech-

Whole-body X-rays imagine (including plain radiographs of the whole skeleton) have been widely used for the detection of bone lesions at diagnosis and during the course of the disease. Osteolytic bone lesions are more common in the scull, vertebrae, ribs and pelvis. Although the

fractures and symptom control in spinal cord compression [4].

vertebroplasty and surgery methods, alongside radiation therapy.

**2. The role of imaging**

160 Update on Multiple Myeloma

niques is detailed in **Table 1**.

**2.1. Conventional radiographic skeletal survey**

**Table 1.** A summary of different imaging techniques for multiple myeloma patients.

whole-body X-ray was the standard of care for many years, it has several limitations: for a lytic lesion to become apparent, more than 30% loss of trabecular bone must occur; it is difficult to assess certain areas, such as the pelvis and the spine; there are limitations: the detection of lytic lesion response to anti-myeloma therapy because of a delayed evidence of healing; specificity is reduced for the differential diagnosis of myeloma-related fracture and benign fracture (very important, particularly in cases of new vertebral compression fractures in the absence of other criteria of relapse); it is dependent on the observer, and studies are long and often not tolerable for patients in severe pain [19].

compared modern and conventional imaging techniques in the detection of bone lesions and confirmed the superiority of MRI over conventional skeletal X-ray, mainly in the axial

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Because of its high sensitivity in revealing bone marrow involvement, MRI is now used for the discrimination between smouldering and symptomatic multiple myeloma. Several studies have shown that approximately 40–50% of patients with normal whole-body X-ray scan

MRI has the ability to detect spinal cord or nerve compression and the presence of soft-tissue masses and is recommended in patients with extraosseous lesions. MRI is the approach to define the degree of involvement and to evaluate for cord compression for surgical intervention or radiation therapy. Unfortunately, almost any skeletal tumour has the same signalintensity profile as multiple myeloma. MRI is not disease-specific, and additional tests should be used to establish the diagnosis of multiple myeloma. MRI is also recommended for patients with a solitary bone plasmacytoma. MRI may demonstrate unsuspected bone lesions, and for such patients, systemic treatment must be given instead of radiation therapy, which is the

MRI also can provide important information for prognosis. Patients with diffuse MRI pattern experienced a poorer overall survival (OS) compared with patients with focal or normal patterns [19]. One study of 611 multiple myeloma patients showed that the presence of more than seven focal lesions was an independent predictor of poorer prognosis and that resolution of

The major advantage of MRI over the whole-body LDCT or conventional CT is the discrimination between myelomatous and normal marrow. This is extremely helpful to differentiate

PET/CT is a new imaging technique, which can be applied in the diagnosis, stage and prognosis of tumour and to evaluate the efficacy of the treatment. PET/CT provides information about the sites and number of lesions, hypermetabolic activity of the involved area (depending on F-18 fluorodeoxyglucose (FDG) uptake). Furthermore, PET/CT detects osseous and extramedullary disease in patients at diagnosis and relapse. PET/CT is a higher accuracy approach than traditional imaging techniques in the diagnosis of multiple myeloma. However, there is no uniform conclusion about the diagnostic accuracy of PET/CT for multiple myeloma because

The large meta-analysis has shown that PET/CT is more sensitive compared with conventional skeletal X-ray for the detection of bone lesions in multiple myeloma [22]. The higher detection rate of PET/CT over conventional skeletal X-ray scan for the presence of osteolytic lesions is especially important for patients with smouldering multiple myeloma. In the studies related to smouldering multiple myeloma, 16–39% of patients with normal whole-body X-ray had positive PET/CT results [19]. The probability of progression to symptomatic mul-

tiple myeloma within 2 years was 58–75% for patients with a positive PET/CT [19].

skeleton [22].

had abnormal findings on MRI examinations [19].

treatment of choice for solitary bone plasmacytoma.

all focal lesions was an indicator of superior survival [23].

**2.4. Positron emission tomography/computed tomography**

of the controversy on the variety of results.

myeloma from osteoporotic fractures in more than 90% of cases [19].

#### **2.2. Whole-body low-dose computed tomography**

Whole-body LDCT allows the detection of osteolytic bone lesions in the whole skeleton with a greater sensitivity and a low radiation dose compared with standard CT. Advantages of whole-body LDCT over conventional skeletal survey include a higher diagnostic sensitivity for the detection of osteolytic lesions, especially in areas where the whole-body X-ray detection rate is low (i.e. pelvis and spine); superiority in estimating fracture risk and bone instability; shorter duration of the examination, which is an important issue for patients in pain; the production of higher-quality images for planning biopsies and therapeutic interventions; and the demonstration of unsuspected manifestations of myeloma or other diseases [19]. Major deficiencies of whole-body LDCT are the lack of specificity for the differential diagnosis between malignant and osteoporotic fractures and also the fact that this diagnostic approach is available in some centres only. In several studies, whole-body LDCT was found to be superior to whole-body X-ray for the detection of osteolytic lesions [19]. In one retrospective study, the total number of bone lesions detected by whole-body LDCT was 968 and the number of bone lesions detected by whole-body X-ray was only 248 (p < .001), which means that 61% of patients with normal whole-body skeleton X-ray images had more than one osteolytic bone lesion on the whole-body LDCT scan, and such patients should receive antimyeloma therapy [20]. This was confirmed by another prospective study, where whole-body LDCT revealed osteolytic bone lesions in 23% of patients with negative conventional radiographic skeletal X-ray scans, especially in the axial skeleton (p < .001) [21]. The same study proved that wholebody LDCT is superior in detecting lesions in patients with osteopaenia and osteoporosis [21].

#### **2.3. Magnetic resonance imaging**

MRI has been established as a valuable technique for imaging multiple myeloma because of its superior soft-tissue contrast resolution. MRI has a high sensitivity for the early detection of marrow infiltration by myeloma cells. Five MRI patterns of marrow involvement have been recognised in multiple myeloma: a focal pattern that consists of localised areas of myeloma cell infiltration of 5 mm or greater in diameter, a diffuse pattern characterised by an almost complete replacement of normal marrow by myeloma cells, a combined diffuse and focal pattern, a normal bone marrow pattern and a variegated or "salt and pepper" pattern with innumerable small bone marrow focal lesions [19].

Several studies showed that MRI is generally more sensitive in detecting multiple lesions compared to conventional radiographic skeletal survey. The systematic review of studies compared modern and conventional imaging techniques in the detection of bone lesions and confirmed the superiority of MRI over conventional skeletal X-ray, mainly in the axial skeleton [22].

Because of its high sensitivity in revealing bone marrow involvement, MRI is now used for the discrimination between smouldering and symptomatic multiple myeloma. Several studies have shown that approximately 40–50% of patients with normal whole-body X-ray scan had abnormal findings on MRI examinations [19].

MRI has the ability to detect spinal cord or nerve compression and the presence of soft-tissue masses and is recommended in patients with extraosseous lesions. MRI is the approach to define the degree of involvement and to evaluate for cord compression for surgical intervention or radiation therapy. Unfortunately, almost any skeletal tumour has the same signalintensity profile as multiple myeloma. MRI is not disease-specific, and additional tests should be used to establish the diagnosis of multiple myeloma. MRI is also recommended for patients with a solitary bone plasmacytoma. MRI may demonstrate unsuspected bone lesions, and for such patients, systemic treatment must be given instead of radiation therapy, which is the treatment of choice for solitary bone plasmacytoma.

MRI also can provide important information for prognosis. Patients with diffuse MRI pattern experienced a poorer overall survival (OS) compared with patients with focal or normal patterns [19]. One study of 611 multiple myeloma patients showed that the presence of more than seven focal lesions was an independent predictor of poorer prognosis and that resolution of all focal lesions was an indicator of superior survival [23].

The major advantage of MRI over the whole-body LDCT or conventional CT is the discrimination between myelomatous and normal marrow. This is extremely helpful to differentiate myeloma from osteoporotic fractures in more than 90% of cases [19].

#### **2.4. Positron emission tomography/computed tomography**

whole-body X-ray was the standard of care for many years, it has several limitations: for a lytic lesion to become apparent, more than 30% loss of trabecular bone must occur; it is difficult to assess certain areas, such as the pelvis and the spine; there are limitations: the detection of lytic lesion response to anti-myeloma therapy because of a delayed evidence of healing; specificity is reduced for the differential diagnosis of myeloma-related fracture and benign fracture (very important, particularly in cases of new vertebral compression fractures in the absence of other criteria of relapse); it is dependent on the observer, and studies are long and often not tolerable

Whole-body LDCT allows the detection of osteolytic bone lesions in the whole skeleton with a greater sensitivity and a low radiation dose compared with standard CT. Advantages of whole-body LDCT over conventional skeletal survey include a higher diagnostic sensitivity for the detection of osteolytic lesions, especially in areas where the whole-body X-ray detection rate is low (i.e. pelvis and spine); superiority in estimating fracture risk and bone instability; shorter duration of the examination, which is an important issue for patients in pain; the production of higher-quality images for planning biopsies and therapeutic interventions; and the demonstration of unsuspected manifestations of myeloma or other diseases [19]. Major deficiencies of whole-body LDCT are the lack of specificity for the differential diagnosis between malignant and osteoporotic fractures and also the fact that this diagnostic approach is available in some centres only. In several studies, whole-body LDCT was found to be superior to whole-body X-ray for the detection of osteolytic lesions [19]. In one retrospective study, the total number of bone lesions detected by whole-body LDCT was 968 and the number of bone lesions detected by whole-body X-ray was only 248 (p < .001), which means that 61% of patients with normal whole-body skeleton X-ray images had more than one osteolytic bone lesion on the whole-body LDCT scan, and such patients should receive antimyeloma therapy [20]. This was confirmed by another prospective study, where whole-body LDCT revealed osteolytic bone lesions in 23% of patients with negative conventional radiographic skeletal X-ray scans, especially in the axial skeleton (p < .001) [21]. The same study proved that wholebody LDCT is superior in detecting lesions in patients with osteopaenia and osteoporosis [21].

MRI has been established as a valuable technique for imaging multiple myeloma because of its superior soft-tissue contrast resolution. MRI has a high sensitivity for the early detection of marrow infiltration by myeloma cells. Five MRI patterns of marrow involvement have been recognised in multiple myeloma: a focal pattern that consists of localised areas of myeloma cell infiltration of 5 mm or greater in diameter, a diffuse pattern characterised by an almost complete replacement of normal marrow by myeloma cells, a combined diffuse and focal pattern, a normal bone marrow pattern and a variegated or "salt and pepper" pattern with

Several studies showed that MRI is generally more sensitive in detecting multiple lesions compared to conventional radiographic skeletal survey. The systematic review of studies

for patients in severe pain [19].

162 Update on Multiple Myeloma

**2.3. Magnetic resonance imaging**

innumerable small bone marrow focal lesions [19].

**2.2. Whole-body low-dose computed tomography**

PET/CT is a new imaging technique, which can be applied in the diagnosis, stage and prognosis of tumour and to evaluate the efficacy of the treatment. PET/CT provides information about the sites and number of lesions, hypermetabolic activity of the involved area (depending on F-18 fluorodeoxyglucose (FDG) uptake). Furthermore, PET/CT detects osseous and extramedullary disease in patients at diagnosis and relapse. PET/CT is a higher accuracy approach than traditional imaging techniques in the diagnosis of multiple myeloma. However, there is no uniform conclusion about the diagnostic accuracy of PET/CT for multiple myeloma because of the controversy on the variety of results.

The large meta-analysis has shown that PET/CT is more sensitive compared with conventional skeletal X-ray for the detection of bone lesions in multiple myeloma [22]. The higher detection rate of PET/CT over conventional skeletal X-ray scan for the presence of osteolytic lesions is especially important for patients with smouldering multiple myeloma. In the studies related to smouldering multiple myeloma, 16–39% of patients with normal whole-body X-ray had positive PET/CT results [19]. The probability of progression to symptomatic multiple myeloma within 2 years was 58–75% for patients with a positive PET/CT [19].

PET/CT may be used for the diagnosis of solitary bone plasmacytoma and extramedullary disease. It is not clear whether PET/CT or MRI is more preferable. PET/CT also has a value for patients with nonsecretory or oligosecretory MM for the detection of active lesions.

to a lesser number of patients and the absence of randomised prospective studies, the optimal dose of radiotherapy is not established. Current evidence-based recommendations by the United Kingdom Myeloma forum are similar to those for SBP [28]. The recommendations include radiotherapy dose of 40 Gy in 20 fractions for tumours of <5 cm and up to 50 Gy in 25 fractions for tumours of ≥5 cm with at least a 2-cm margin encompassing the primary tumour [28]. If cervical nodes are involved (or in Waldeyer's ring tumours), these should be included

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Surgery may be an acceptable treatment method combined with radiotherapy. A combination of a higher dose of radiation and surgery predicted for better PFS [25]. Surgical procedures of the head and neck are not recommended, but surgery may be considered for other sites of

Radiotherapy can produce a curative effect for both solitary plasmacytoma of bone and extramedullary plasmacytomas; however, its role in the treatment of MM patients is only palliative. The most common indications for radiotherapy in MM are pain relief in the sites of bone destructions, the prevention of pathological fractures or to decrease the pain in the fracture site, to evoke the recalcification, the management of spinal cord compression syndrome and

Pain is the most common symptom experienced by MM patients. Up to 67% of patients report pain at diagnosis, and it may be present for several months before the diagnosis [29]. Local radiotherapy is effective for pain relief. It produces an analgesic effect by inhibiting chemical pain mediators and causing tumour shrinkage. There is a debate on the effect of radiation

Results of randomised clinical studies revealed the same effect of pain relief when applying two different radiotherapy regimens (8 Gy/1 fr and 3 Gy × 10 fr) for the treatment of patients with solid tumour metastases, though the application of a single fraction of 8 Gy treatment produces more recurrent treatment episodes [30–33]. The earlier data, however, cannot be directly applied in the treatment of patients with MM, since their future prospects are better (the average survival reaches 30–40 months), whereas the average survival among the patients with solid tumour metastases in bones is about 9 months [5]. In the meta-analyses by Sze et al. [34] and Wu et al. [35], no significant difference in the overall and complete response in pain reduction between single- (SF) and multiple-fraction (MF) palliative radiotherapy was observed. Chow et al. in the systematic review analysed 16 randomised trials comparing SF versus MF for bone metastases: no significant difference was found regarding response rates [30]. An increased risk for pathological fractures and spinal cord compressions was observed in the SF regimen, which was statistically insignificant, while retreatment in the SF regimen was 2.5-fold higher [30]. The role of different palliative radiotherapy regimens for MM is not well established due to lack of clinical trials. Medical literature provides only a small number

**4. Indications for radiotherapy in multiple myeloma**

in the radiotherapy field [28].

the treatment of extramedullary disease.

**4.1. Palliation for pain**

dose on pain relief.

the disease [26].

PET/CT has been tested for a better definition of complete response (CR) to MM therapy and as an independent factor for survival prognosis at diagnosis and after treatment. Approximately 30% of patients at CR had a positive PET/CT. In addition, PET/CT negativity was an independent predicted factor for prolonged PFS and OS in patients with a CR, patients with a positive PET/CT in CR and median PFS was 50 months compared to 90 months for patients with a negative PET/CT [24].

However, PET/CT remains a high-cost method, and there is lack of availability in many centres and may be limited by false-positive results caused by inflammation from other underlying diseases.
