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

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 the treatment of extramedullary disease.

#### **4.1. Palliation for pain**

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

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

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 underly-

The solitary plasmacytoma is a localised accumulation of monoclonal plasma cells without systemic plasma cell disease manifestation. Regarding location, it can be classified into solitary plasmacytoma of bone (SBP) and extramedullary plasmacytoma (EMP) [25]. SBP generally occurs in the vertebra and skull; however, EMP is most frequently observed in head and neck [25]. Plasmacytomas are radiosensitive neoplasms, and radiotherapy has a potentially

Radiotherapy with a curative intent is the treatment of choice, resulting in local control in more than 80% of patients with SBP [25, 26]. In some cases, as bone instability, rapid progression of neurological symptoms and surgical intervention are required, the results of surgery alone are not optimal and carry high rates of local relapse [27]. Currently, the standard of treatment for SBP is radiotherapy. Optimal-dosing guidelines have not been established due to the absence of prospective randomised studies. The United Kingdom Myeloma Forum recommend radiotherapy at least 40 Gy in 20 fractions [28]. For bulky disease (>5 cm), a higher-dose 50 Gy in 25 fractions was recommended [28]. Approximately 30% of patients who received higher doses than 50 Gy remained without evidence of any local disease failures [25]. In clinical practice, a radiation dose of 45–50 Gy in 20–25 fractions is recommended for the treatment of SBP.

The optimal target volume for radiotherapy planning in SBP is to encompass the tumour volume plus a margin of at least 1.5–2 cm on the tumour detectable by MRI [25, 26]. In case of vertebral involvement, fields typically include one to two uninvolved vertebrae above and below the affected level [25]. Prophylactic regional lymph node irradiation is not necessary in SBP.

Like SBP, EMPs are highly radiosensitive; almost all patients (80–100%) achieve local control, and approximately 50–65% of patients remain free of disease longer than 10 years [26]. Due

patients with nonsecretory or oligosecretory MM for the detection of active lesions.

negative PET/CT [24].

164 Update on Multiple Myeloma

**3. Radiotherapy for solitary plasmacytomas**

**3.1. Radiotherapy for solitary plasmacytoma of bone**

**3.2. Radiotherapy for extramedullary plasmacytoma**

curative effect for both SBP and EMP [4].

ing diseases.

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 dose on pain relief.

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 of studies dealing with various radiotherapy regimens for the treatment of patients with multiple myeloma as well as impact of the radiotherapy regimen on pain relief at the sites of bone destructions [5–12]. However, final recommendations concerning the choice of the radiation therapy regime have not been presented yet.

Univariate statistical analysis revealed that the age under 65 years (p = 0.016), stage II of the disease (according to Durie-Salmon classification) (p = 0.03) and recalcification in the irradiated site (p = 0.011) were significant parameters for analgesic response after radiotherapy, whereas other parameters (gender, Karnofsky index, paraprotein type, haemoglobin level, surgery, pain score at the admission, total radiation dose, bisphosphonates and concurrent

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All parameters mentioned earlier were included in binary logistic regression model for the analysis of their influence to pain relief. Using a stepwise variable removal method (backward conditional), it was found that the following attributes have a significant impact on analgesic response after radiation treatment for pain relief: female gender, age under 65, IgG MM type and the presence of recalcification in the irradiated site. Other factors analysed, including the total radiation dose, were not significant for pain relief after radiation treatment. Results of analgesic response from clinical trials of palliative radiotherapy in the treatment of MM

The study performed by Rudzianskiene et al. involved analysis of 12 gene polymorphisms of six cytokines (IL-6, IL-10, TNFα, IL-1α, IL-1β and IL-1RA) participating in the pathogenesis of the pain syndrome in bone destruction sites. The aim was to evaluate the influence of interleu-

Univariate statistical analysis was used to assess associations between severe pain status (8–10 points on VAS) before radiation treatment and genotype groups of each cytokine gene studied. None of the genotypes analysed was found to be significant for the perception of severe pain before treatment; yet, a marginal relation was observed that patients with GG genotype of IL1RN c.1812G > A polymorphism more often indicated severe pain before radiotherapy, compared to patients with GA and AA genotypes (relative risk (RR) 0.43; 95% confidence

Multivariate logistic analysis included all the earlier clinical, demographic and symptom factors, as well as genotype groups of each cytokine gene analysed. Based on multivariate logistic regression, the following factors were determined to have a significant impact on severe pain before radiation treatment: Karnofsky index ≥60% and IL1RN c.1812G > A polymorphism GG genotype. Other factors analysed were not significant for the perception of severe pain before

A comparison of a decrease in pain perception points before radiotherapy and during the monitored period, that is, after 4, 12 and 24 weeks, among patients with different genotypes was carried out. The analysis revealed that patients with IL-1α-encoding gene IL1A c.889C > T CC genotype had a significantly better response to radiation therapy and indicated milder pain after 12 and 24 weeks, compared to patients with TT and CT genotypes. Furthermore, patients with IL-1β-encoding gene IL1B c. 3953C > T CC genotype indicated significantly more often milder pain scores after radiotherapy in 12 and 24 weeks, compared to patients with TT and CT genotypes. Patients with IL-1RA-encoding gene IL1RN c.11100 T > C CC genotype had a faster response to radiation therapy, that is, a significant decrease in pain points

was observed after 4 weeks, compared to patients with TT and CT genotypes [44].

kins on the perception of pain and response to radiotherapy in MM patients [44].

chemotherapy) were not significant.

patients are shown in **Table 2**.

interval (CI) 0.18–1.06; p = 0.068) [44].

radiation treatment [44].

Some clinical studies did not find a significant difference between the radiation dose and pain relief after radiotherapy [5, 8, 10, 12]; however, Adamietz et al. [6] and Minova et al. [11] reported that for adequate pain relief, higher doses would be obtained. Pain relief occurred in 80–92% [6, 11]. Adamietz et al. affirmed that local long-term palliation effect can only be achieved by a high radiation dose [6], whereas Leigh et al. analysed 101 patients and observed pain reduction in 97% of patients (complete in 26%) with a median dose 3–60 Gy. Only 6% of patients were retreated for the relapse which occurred after a median interval of 16 months [10]. This study showed the durable symptom relief after a mean total dose of 10 Gy [10].

Clinical, laboratory and genetic factors may influence pain perception and analgesic effects of radiotherapy. Retrospective studies published by Adamietz et al. [6] and Mose et al. [12] indicated that the incidence of pain relief was higher in patients treated with concurrent chemotherapy which had a significant impact on a positive response to radiotherapy, but other studies did not show this relationship [5, 10]. Mose et al. reported that not only concurrent chemotherapy but also the Karnofsky performance above 70% had a significant impact on a positive analgesic response to radiation treatment, whereas the total radiation dose, gender, age, irradiated site and bisphosphonates had no effect on pain relief [12]. In other study performed by Stolting et al., significant parameters for pain relief in the multivariate analysis were completeness of therapy, patients younger than 60 years and a single dose of 2 Gy; other parameters like Karnofsky index, concurrent chemotherapy and total dose were insignificant [5].

Medical literature provides several studies which have revealed that the polymorphism of inflammatory cytokine genes influences pain perception and analgesics dose. Furthermore, the altered levels of fatigue, depression and response to analgesics in pancreatic, lung or breast cancer have been described [15, 36–43]. These types of studies, however, have not been conducted for patients with multiple myeloma, though during the formation of bone destructions, anti-inflammatory cytokines are emitted by plasma cells and bone marrow stroma cells. No study has been performed worldwide, which would deal with the impact of polymorphism of genes encoding for cytokines in response to radiotherapy.

Hundred and one patients were involved in a randomised prospective clinical study performed at the Lithuanian University of Health Sciences [44]. Two different radiation treatment regimens of bone destructions due to multiple myeloma were compared. MF radiotherapy regime (3 Gy × 10 fr) was applied to 58 patients and SF (8 Gy × 1 fr) regime was applied to 43 patients. Pain relief was obtained in 84.5% of patients in MF regimen group (complete response 69.4%) and 74.4% of patients in SF regimen group (complete response 68.8%). No significant differences were observed in analgesic response between the groups. No significant differences were observed in the period of time before reaching the analgesic effect of radiotherapy: in both groups, analgesic effect was achieved in the first 4 weeks.

Univariate statistical analysis revealed that the age under 65 years (p = 0.016), stage II of the disease (according to Durie-Salmon classification) (p = 0.03) and recalcification in the irradiated site (p = 0.011) were significant parameters for analgesic response after radiotherapy, whereas other parameters (gender, Karnofsky index, paraprotein type, haemoglobin level, surgery, pain score at the admission, total radiation dose, bisphosphonates and concurrent chemotherapy) were not significant.

of studies dealing with various radiotherapy regimens for the treatment of patients with multiple myeloma as well as impact of the radiotherapy regimen on pain relief at the sites of bone destructions [5–12]. However, final recommendations concerning the choice of the radiation

Some clinical studies did not find a significant difference between the radiation dose and pain relief after radiotherapy [5, 8, 10, 12]; however, Adamietz et al. [6] and Minova et al. [11] reported that for adequate pain relief, higher doses would be obtained. Pain relief occurred in 80–92% [6, 11]. Adamietz et al. affirmed that local long-term palliation effect can only be achieved by a high radiation dose [6], whereas Leigh et al. analysed 101 patients and observed pain reduction in 97% of patients (complete in 26%) with a median dose 3–60 Gy. Only 6% of patients were retreated for the relapse which occurred after a median interval of 16 months [10]. This study showed the durable symptom relief after a mean total dose of

Clinical, laboratory and genetic factors may influence pain perception and analgesic effects of radiotherapy. Retrospective studies published by Adamietz et al. [6] and Mose et al. [12] indicated that the incidence of pain relief was higher in patients treated with concurrent chemotherapy which had a significant impact on a positive response to radiotherapy, but other studies did not show this relationship [5, 10]. Mose et al. reported that not only concurrent chemotherapy but also the Karnofsky performance above 70% had a significant impact on a positive analgesic response to radiation treatment, whereas the total radiation dose, gender, age, irradiated site and bisphosphonates had no effect on pain relief [12]. In other study performed by Stolting et al., significant parameters for pain relief in the multivariate analysis were completeness of therapy, patients younger than 60 years and a single dose of 2 Gy; other parameters like Karnofsky index, concurrent chemotherapy and total dose were

Medical literature provides several studies which have revealed that the polymorphism of inflammatory cytokine genes influences pain perception and analgesics dose. Furthermore, the altered levels of fatigue, depression and response to analgesics in pancreatic, lung or breast cancer have been described [15, 36–43]. These types of studies, however, have not been conducted for patients with multiple myeloma, though during the formation of bone destructions, anti-inflammatory cytokines are emitted by plasma cells and bone marrow stroma cells. No study has been performed worldwide, which would deal with the impact of polymor-

Hundred and one patients were involved in a randomised prospective clinical study performed at the Lithuanian University of Health Sciences [44]. Two different radiation treatment regimens of bone destructions due to multiple myeloma were compared. MF radiotherapy regime (3 Gy × 10 fr) was applied to 58 patients and SF (8 Gy × 1 fr) regime was applied to 43 patients. Pain relief was obtained in 84.5% of patients in MF regimen group (complete response 69.4%) and 74.4% of patients in SF regimen group (complete response 68.8%). No significant differences were observed in analgesic response between the groups. No significant differences were observed in the period of time before reaching the analgesic effect of

phism of genes encoding for cytokines in response to radiotherapy.

radiotherapy: in both groups, analgesic effect was achieved in the first 4 weeks.

therapy regime have not been presented yet.

10 Gy [10].

166 Update on Multiple Myeloma

insignificant [5].

All parameters mentioned earlier were included in binary logistic regression model for the analysis of their influence to pain relief. Using a stepwise variable removal method (backward conditional), it was found that the following attributes have a significant impact on analgesic response after radiation treatment for pain relief: female gender, age under 65, IgG MM type and the presence of recalcification in the irradiated site. Other factors analysed, including the total radiation dose, were not significant for pain relief after radiation treatment. Results of analgesic response from clinical trials of palliative radiotherapy in the treatment of MM patients are shown in **Table 2**.

The study performed by Rudzianskiene et al. involved analysis of 12 gene polymorphisms of six cytokines (IL-6, IL-10, TNFα, IL-1α, IL-1β and IL-1RA) participating in the pathogenesis of the pain syndrome in bone destruction sites. The aim was to evaluate the influence of interleukins on the perception of pain and response to radiotherapy in MM patients [44].

Univariate statistical analysis was used to assess associations between severe pain status (8–10 points on VAS) before radiation treatment and genotype groups of each cytokine gene studied. None of the genotypes analysed was found to be significant for the perception of severe pain before treatment; yet, a marginal relation was observed that patients with GG genotype of IL1RN c.1812G > A polymorphism more often indicated severe pain before radiotherapy, compared to patients with GA and AA genotypes (relative risk (RR) 0.43; 95% confidence interval (CI) 0.18–1.06; p = 0.068) [44].

Multivariate logistic analysis included all the earlier clinical, demographic and symptom factors, as well as genotype groups of each cytokine gene analysed. Based on multivariate logistic regression, the following factors were determined to have a significant impact on severe pain before radiation treatment: Karnofsky index ≥60% and IL1RN c.1812G > A polymorphism GG genotype. Other factors analysed were not significant for the perception of severe pain before radiation treatment [44].

A comparison of a decrease in pain perception points before radiotherapy and during the monitored period, that is, after 4, 12 and 24 weeks, among patients with different genotypes was carried out. The analysis revealed that patients with IL-1α-encoding gene IL1A c.889C > T CC genotype had a significantly better response to radiation therapy and indicated milder pain after 12 and 24 weeks, compared to patients with TT and CT genotypes. Furthermore, patients with IL-1β-encoding gene IL1B c. 3953C > T CC genotype indicated significantly more often milder pain scores after radiotherapy in 12 and 24 weeks, compared to patients with TT and CT genotypes. Patients with IL-1RA-encoding gene IL1RN c.11100 T > C CC genotype had a faster response to radiation therapy, that is, a significant decrease in pain points was observed after 4 weeks, compared to patients with TT and CT genotypes [44].


the quality of life. According to the study, recalcification is achieved after some months and occurs in 40–50% of the irradiated bone destructions in patients with multiple myeloma [5, 7, 12, 13]. Palliative radiotherapy can be applied to avoid the impending or actual pathological fracture. However, the high-risk lesions should be first stabilised by orthopaedic measures and combined with post-operative radiation treatment for the improvement of pain and local control. Several retrospective studies, a majority of which included small patients' cohorts, have demonstrated that there is no relation between the total radiation dose and recalcifica-

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Mose et al. found that the stabilisation of the irradiated bone could be achieved in 46.4% of cases, and concurrent chemotherapy reinforces this effect [12]. Also, Stolting et al. reported a recalcification rate of 44.7% and the importance of concurrent chemotherapy for recalcification [5]. The study performed by Rudzianskiene et al. showed an overall response of recalcification with single-fraction radiotherapy of 35.9%, and in multi-fraction radiotherapy group, the response rate was 32.1% [44]. Binary logistic regression did not show a significant impact

Koswig and Budach [45] found that an MF regimen (3 Gy × 10) significantly increases the bone density in the area of metastases from solid tumours compared with single fraction (8 Gy) in contrast to pain relief effect; also, Stolting et al. reported that recalcification was detected at total doses of >40 Gy for MM patients [5]. Balducci et al. found recalcification in 50% cases with a median total dose of 38 Gy and reported the importance of the early using of radiotherapy to avoid pathological fractures [7]. However, the studies published by Mose et al. [12] and Rudzianskiene et al. [44] did not show any influence of the total radiation dose on recalcification. Mose et al. reported that not only concurrent chemotherapy but also the Karnofsky index above 70% and bisphosphonates had a significant impact on a positive recalcification effect to radiation treatment [12]. Also, in a clinical study performed by Rudzianskiene et al., the Karnofsky index more than 60% has a positive impact on recalcification in the irradiated site [44]. This study also founded that a haemoglobin level of less than 80 g/l, clinical stage II according to Durie-Salmon and a decrease in pain in the irradiated site are significant param-

The clinical study performed by Mose et al. showed that higher recalcification rates depend on the usage of bisphosphonates [12], but other study did not demonstrate such a relation [5]. In the clinical study reported by Rudzianskiene et al., the use of bisphosphonates was also an insignificant parameter but this may be due to the small sample of patients (only 18%) taking

Results of recalcification response from clinical trials of palliative radiotherapy in the treat-

Epidural spinal cord compression that can cause pain and neurological impairment occurs in 5–20% of all patients with multiple myeloma at various disease stages and leads to disability [46, 47]. Pain is the first and more common presenting symptom followed by motor

tion in the sites of bone destructions.

eters for the recalcification [44].

ment of MM patients are shown in **Table 3**.

**4.3. The treatment of spinal cord compression**

bisphosphonates [44].

of concurrent chemotherapy on recalcification [44].

**Table 2.** A summary of published data on palliative radiotherapy analgesic response in the treatment of patients with MM.

#### **4.2. To evoke the recalcification**

Multiple myeloma is a disease inducing osteolytic process which leads to an increased risk of pathologic fracture or spinal cord compression and severe pain with a negative impact on the quality of life. According to the study, recalcification is achieved after some months and occurs in 40–50% of the irradiated bone destructions in patients with multiple myeloma [5, 7, 12, 13]. Palliative radiotherapy can be applied to avoid the impending or actual pathological fracture. However, the high-risk lesions should be first stabilised by orthopaedic measures and combined with post-operative radiation treatment for the improvement of pain and local control. Several retrospective studies, a majority of which included small patients' cohorts, have demonstrated that there is no relation between the total radiation dose and recalcification in the sites of bone destructions.

Mose et al. found that the stabilisation of the irradiated bone could be achieved in 46.4% of cases, and concurrent chemotherapy reinforces this effect [12]. Also, Stolting et al. reported a recalcification rate of 44.7% and the importance of concurrent chemotherapy for recalcification [5]. The study performed by Rudzianskiene et al. showed an overall response of recalcification with single-fraction radiotherapy of 35.9%, and in multi-fraction radiotherapy group, the response rate was 32.1% [44]. Binary logistic regression did not show a significant impact of concurrent chemotherapy on recalcification [44].

Koswig and Budach [45] found that an MF regimen (3 Gy × 10) significantly increases the bone density in the area of metastases from solid tumours compared with single fraction (8 Gy) in contrast to pain relief effect; also, Stolting et al. reported that recalcification was detected at total doses of >40 Gy for MM patients [5]. Balducci et al. found recalcification in 50% cases with a median total dose of 38 Gy and reported the importance of the early using of radiotherapy to avoid pathological fractures [7]. However, the studies published by Mose et al. [12] and Rudzianskiene et al. [44] did not show any influence of the total radiation dose on recalcification.

Mose et al. reported that not only concurrent chemotherapy but also the Karnofsky index above 70% and bisphosphonates had a significant impact on a positive recalcification effect to radiation treatment [12]. Also, in a clinical study performed by Rudzianskiene et al., the Karnofsky index more than 60% has a positive impact on recalcification in the irradiated site [44]. This study also founded that a haemoglobin level of less than 80 g/l, clinical stage II according to Durie-Salmon and a decrease in pain in the irradiated site are significant parameters for the recalcification [44].

The clinical study performed by Mose et al. showed that higher recalcification rates depend on the usage of bisphosphonates [12], but other study did not demonstrate such a relation [5]. In the clinical study reported by Rudzianskiene et al., the use of bisphosphonates was also an insignificant parameter but this may be due to the small sample of patients (only 18%) taking bisphosphonates [44].

Results of recalcification response from clinical trials of palliative radiotherapy in the treatment of MM patients are shown in **Table 3**.

#### **4.3. The treatment of spinal cord compression**

**4.2. To evoke the recalcification**

Without concurrent chemotherapy.

Rudzianskiene et al.

[44]

\*

MM.

**Clinical study Number** 

168 Update on Multiple Myeloma

**of patients** **Number of irradiated sites**

**Total dose (Gy)**

Adamietz et al. [6] 70 70 2–30 39.6–80\* n/a Local long-term palliation

Leigh et al. [10] 101 306 3–60 91 n/a There was no significance

Mose et al. [12] 42 71 18–45 85 34.3 There was no significance

Yaneva et al. [9] 87 87 17–20 89.6 26.9 The total dose relationship

Stolting et al. [5] 138 272 2–60 85.3 22.2 There was no significance

Minowa et al. [11] 29 53 4–60 92 n/a Longer analgesic response was

Balducci et al. [7] 52 52 16–50 91 51.2 The total dose and concurrent

74.4 vs. 84.5

30 Gy

101 101 8 Gy vs.

**Overall response (%)**

**Complete response (%)**

**Comments**

effect can only be achieved by high radiation dose and concurrent chemotherapy.

difference between analgesic response and higher radiation dose, and there was no influence of concurrent chemotherapy.

difference between analgesic response and higher radiation dose, response is better with concurrent chemotherapy.

with an analgesic response has not been evaluated. Radiotherapy has no influence

difference between analgesic response and higher radiation dose, and there was no influence of concurrent chemotherapy.

after higher radiation dose

chemotherapy relationship with an analgesic response has

difference between analgesic response and higher radiation dose, and there was no influence of concurrent chemotherapy.

not been evaluated.

treatment.

68.8 vs. 69.4 There was no significant

on overall survival.

Multiple myeloma is a disease inducing osteolytic process which leads to an increased risk of pathologic fracture or spinal cord compression and severe pain with a negative impact on

**Table 2.** A summary of published data on palliative radiotherapy analgesic response in the treatment of patients with

Epidural spinal cord compression that can cause pain and neurological impairment occurs in 5–20% of all patients with multiple myeloma at various disease stages and leads to disability [46, 47]. Pain is the first and more common presenting symptom followed by motor


SCC from myeloma [52]. Several fractionation regimens: single-fraction, short-course multifraction and longer-course multi-fraction regimens are used for the treatment of spinal cord compression. Radiotherapy either 30 Gy in 10 fractions or lower radiation doses must be provided as an optimal approach causing the long-lasting local control [50]. Several clinical studies have examined the impact of multi-fraction regimens versus single-fraction regimens on pain relief and functional outcomes, local tumour control and overall survival [12, 52–55]. Rades et al. compared short-course 8 Gy in one fraction or 20 Gy in five fraction regimens with long-course 30–40 Gy in 10–20 fraction regimens [53]. There were no significant differences in functional or overall survival between the groups. However, a better local control (77 vs. 61%) and a 12-month progression-free survival (72 vs. 55%) were significantly better in long-course radiotherapy regimen group [53]. A phase III randomised multicentre Italian trial demonstrated a similar effect in functional outcomes and overall survival between two fractions of 8 Gy (16 Gy total dose) or a single dose of 8 Gy radiotherapy in patients with spinal

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Multiple myeloma patients with spinal cord compression have a comparably good survival, living for years after treatment in the era of novel drugs [55]. Only very few clinical studies can be found in the study, investigating radiotherapy of spinal cord compression in MM patients [12, 52, 55], and the appropriate radiotherapy regimen for the treatment of spinal cord compression in MM patients has not been defined yet. Rades et al. reported that the improvement of motor function was more frequent after long-course radiotherapy than after short-course at 6 months (67 vs. 43%) and at 12 months (76 vs. 40%) [55]. However, Mose et al. demonstrated that 65% of patients with spinal cord compression after radiotherapy experienced neurological improvement, and Karnofsky index, gender, age, site of myelocompres-

One retrospective study was performed to find a predictive tool that allows the estimation of overall survival (OS) of elderly myeloma patients (aged ≥65 years) presenting with myelomainduced spinal cord compression [52]. Rades et al. found that myeloma type (HR 3.31; 95% CI 1.75–6.49; p < 0.001), ECOG-PS (HR 5.33; 95% CI 2.67–11.11; p < 0.001), ambulatory status (HR 2.71; 95% CI 1.65–4.57; p < 0.001) and age (HR 1.95; 95% CI 1.03–3.78; p = 0.040) were significantly associated with survival, but fractionation regimen was not a predictive tool for OS [52]. The choice of radiotherapy regimen in the treatment of spinal cord compression should be based on the expectancy of patient's life. Longer-course programs, which result in a better local control than single-fraction and short-course programs, are the preferred treatment for patients with a more favourable survival prognosis. By contrast, patients with a poor prognosis are better candidates for multi-fraction short-course or single-fraction radiotherapy [52].

Surgical management of MM-related bone lesions sometimes is carried out due to disease sensitivity of radiation treatment and chemotherapy. The most common indications for surgical procedures are unstable fractures and spinal cord compression when bone fragments

cord compression and a short life expectancy [54].

**5. Surgery and radiation treatment**

sion and the total radiation dose did not influence this effect [12].

**Table 3.** A summary of published data on palliative radiotherapy recalcification response in the treatment of patients with MM.

deficiency, sensory symptoms and bowel and bladder dysfunction [48]. Immediate diagnosis and treatment are very important in the preservation of neurological function in patients with spinal cord compression. Pain control, relief of spinal cord compression and improvement of neurologic function are the main goals of treatment. High-dose steroids must soon be initiated upon spinal cord compression diagnosed to obtain an antineoplastic and an antioedema effect [49]. In patients with neurologic symptoms directly due to cord compression, radiation therapy is given along with dexamethasone, and up to half of patients may have improvement of motor function [50]. In the largest retrospective studies, radiotherapy alone improves motor function in 75% of patients with spinal cord compression due to MM. A 1-year local control was 100% and a 1-year survival was 94% [51].

Radiation treatment can be used as fractionated external beam radiotherapy (EBRT) or stereotactic body RT (SBRT). Both methods are effective for palliative treatment and local tumour control. SBRT is a non-invasive treatment option for spinal disease in the absence of a high-grade spinal cord compression. SBRT allows the treatment of small- or moderate-sized tumours, even in close proximity to the spinal cord, in either a single or a limited number of dose fractions [48]. SBRT with a single 24 Gy fraction gives excellent tumour control [48].

Since myeloma is a very radiosensitive tumour, EBRT is an appropriate approach for patients who are not considered surgical treatment and it is also indicated after decompression intervention. There was no randomised trial that compared radiotherapy alone to radiotherapy plus upfront neurosurgery. Thus, radiotherapy alone is considered the standard treatment of SCC from myeloma [52]. Several fractionation regimens: single-fraction, short-course multifraction and longer-course multi-fraction regimens are used for the treatment of spinal cord compression. Radiotherapy either 30 Gy in 10 fractions or lower radiation doses must be provided as an optimal approach causing the long-lasting local control [50]. Several clinical studies have examined the impact of multi-fraction regimens versus single-fraction regimens on pain relief and functional outcomes, local tumour control and overall survival [12, 52–55]. Rades et al. compared short-course 8 Gy in one fraction or 20 Gy in five fraction regimens with long-course 30–40 Gy in 10–20 fraction regimens [53]. There were no significant differences in functional or overall survival between the groups. However, a better local control (77 vs. 61%) and a 12-month progression-free survival (72 vs. 55%) were significantly better in long-course radiotherapy regimen group [53]. A phase III randomised multicentre Italian trial demonstrated a similar effect in functional outcomes and overall survival between two fractions of 8 Gy (16 Gy total dose) or a single dose of 8 Gy radiotherapy in patients with spinal cord compression and a short life expectancy [54].

Multiple myeloma patients with spinal cord compression have a comparably good survival, living for years after treatment in the era of novel drugs [55]. Only very few clinical studies can be found in the study, investigating radiotherapy of spinal cord compression in MM patients [12, 52, 55], and the appropriate radiotherapy regimen for the treatment of spinal cord compression in MM patients has not been defined yet. Rades et al. reported that the improvement of motor function was more frequent after long-course radiotherapy than after short-course at 6 months (67 vs. 43%) and at 12 months (76 vs. 40%) [55]. However, Mose et al. demonstrated that 65% of patients with spinal cord compression after radiotherapy experienced neurological improvement, and Karnofsky index, gender, age, site of myelocompression and the total radiation dose did not influence this effect [12].

One retrospective study was performed to find a predictive tool that allows the estimation of overall survival (OS) of elderly myeloma patients (aged ≥65 years) presenting with myelomainduced spinal cord compression [52]. Rades et al. found that myeloma type (HR 3.31; 95% CI 1.75–6.49; p < 0.001), ECOG-PS (HR 5.33; 95% CI 2.67–11.11; p < 0.001), ambulatory status (HR 2.71; 95% CI 1.65–4.57; p < 0.001) and age (HR 1.95; 95% CI 1.03–3.78; p = 0.040) were significantly associated with survival, but fractionation regimen was not a predictive tool for OS [52].

The choice of radiotherapy regimen in the treatment of spinal cord compression should be based on the expectancy of patient's life. Longer-course programs, which result in a better local control than single-fraction and short-course programs, are the preferred treatment for patients with a more favourable survival prognosis. By contrast, patients with a poor prognosis are better candidates for multi-fraction short-course or single-fraction radiotherapy [52].
