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Keywords:

  • plasmacytoma;
  • radiation;
  • paraprotein;
  • Bence-Jones;
  • multiple myeloma

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

BACKGROUND:

The objective of this study was to review the outcome of patients with solitary plasmacytoma (SP) after definitive radiation therapy.

METHODS:

The authors retrospectively reviewed 84 patients with SP who were diagnosed and treated at The University of Texas MD Anderson Cancer Center during 1988 to 2008. The impact of tumor anatomic site, tumor size, and the presence of serum and urinary paraprotein at diagnosis was assessed on local control, survival, and the risk of developing multiple myeloma (MM).

RESULTS:

Fifty-nine patients (70%) had bone SP, and 25 patients (30%) had extramedullary SP. Serum paraprotein was present in 39 patients (46%). The median radiation dose was 45 grays (Gy) (range, 36-53.4 Gy). Local control was achieved in 77 patients (92%). Neither radiation dose nor tumor size predicted local control. The 5-year rate of progression to MM was 47% and was higher for patients with bone SP (56% vs 30% for extramedullary SP; P = .021), and patients who had serum paraprotein detected at diagnosis (60% vs 39%; P = .016). On univariate analysis, patients aged <60 years and men had higher rates of progression to MM, although the differences were not significant (P = .048 and P = .29, respectively). Multivariate analysis revealed that bone location and serum protein at diagnosis were associated statistically with progression to MM. The 5-year overall survival rate for the entire patient cohort was 78%, and no difference was observed between patients who had bone SP versus extramedullary SP (76% vs 85%, respectively; P = .274).

CONCLUSIONS:

The current results indicated that definitive radiation therapy for SP can provide excellent local control. Progression to MM remains the main problem and is more common among patients with bone SP and those who have serum paraprotein detected at diagnosis. Cancer 2011;. © 2011 American Cancer Society.

Plasma cell neoplasms can present clinically in a heterogeneous fashion. Multiple (plasma cell) myeloma, the most common form, is a bone marrow-based, disseminated neoplasm that is usually associated with a wide spectrum of clinical, laboratory, and radiologic abnormalities. Uncommonly, a plasma cell neoplasm can be localized and is known as a solitary plasmacytoma (SP). Patients with SP have no radiologic evidence of additional skeletal lesions, and bone marrow examination is morphologically normal or may reveal a very low level of plasma cells. In addition, patients with SP lack the clinical or laboratory findings that commonly accompany the diagnosis of multiple myeloma. SP is rare and represents approximately ≤5% of all plasma cell neoplasms.

SP can be subdivided further into 2 entities, depending on whether the lesion originates in bones or extramedullary anatomic sites other than bone. Because of the rarity of SP, few large studies have been done that detail clinicopathologic features and assess the effectiveness of therapy. In addition, few studies of SP have been performed in the modern era of advanced diagnostic imaging, which also forms the basis of modern radiation therapy.

In this study, we expand and update our experience with SP at The University of Texas MD Anderson Cancer Center (MD Anderson Cancer Center) over the past 20 years.1, 2 The large number of patients in this study(n = 84) allowed us to analyze the importance of various clinicopathologic and therapy-related factors in predicting local control or progression to multiple myeloma.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Institutional review board approval was obtained for this study. We identified 84 consecutive patients with previously untreated SP who presented at MD Anderson Cancer Center from 1988 through 2008 by searching an institutional database. The diagnosis was based on the following criteria: 1) biopsy-proven plasma cell neoplasm, 2) monoclonality of plasma cells determined by immunohistochemical staining for kappa and lambda light chains, 3) a bone marrow aspirate smear with <10% plasma cells and a bone marrow biopsy specimen with no evidence of plasma cell nodules, and 4) normal findings on skeletal survey. The presence of a monoclonal band on serum protein electrophoresis, Bence-Jones protein in urine, or radiologic evidence of local bone destruction as a result of direct extension of tumor mass did not exclude any patient from this analysis. During the more recent years of the study period, patients routinely underwent magnetic resonance imaging (MRI) of both the lesion and the thoracic and lumbar spine (the latter images were obtained to detect occult disease that was not recognized on bone survey).

All patients in this study received definitive megavoltage radiation, which was delivered as 3-dimensional conformal radiation or intensity-modulated radiation therapy. Treatment techniques were site-specific and were designed to encompass the entire tumor. The gross tumor volume (GTV) was defined as any abnormal lesion observed on computed tomography (CT) or any enhancing lesion/edema observed on MRI when available. The enhancing abnormality was considered to represent infiltration of the tumor into adjacent tissue or adjacent bone marrow. Adding 3-cm margins around the GTV inside the bone or 2-cm margins around the GTV in the soft tissue created clinical tumor volumes. When lesions were in the spine, the margin included 1 normal vertebra above and below the affected vertebra. In extramedullary SP, the decision whether to use elective neck radiation was made according to our institutional guidelines for squamous cell carcinoma of the same presentation.3-5

Analysis

Local control included either a complete or partial response and was defined as follows: A complete response was defined as the complete disappearance of all previously observed abnormalities on radiographic imaging. A partial response was defined if lesions had partial resolution or no resolution but were stable radiographically and had no evidence of disease progression. Follow-up and survival rates were calculated from the date of diagnosis to the time of the patient's last follow-up. Survival curves were calculated with the Kaplan-Meier method from the start of radiation therapy and were compared between groups by using log-rank tests.6 Multivariate analysis was used to examine the influence of different clinical parameters on the risk of developing multiple myeloma and included all factors that had a P < .25 on univariate analysis. Race and ethnicity are considered 2 different entities at MD Anderson Cancer Center, and our basic coding includes whites, African Americans, Asians, and Hispanics, although the later is not a race; therefore, we tried to make the distinction in current our analysis to address this issue with a subset analysis, as detailed below (see Results). The evolution of SP to multiple myeloma was defined as the onset of new bone lesions, a bone marrow plasmacytosis level >10%, or a rising paraprotein level. Several prognostic factors were assessed for their potential ability to predict progression to multiple myeloma, including age >60 years or <60 years, sex, race/ethnicity, anatomic site (bone vs extramedullary), tumor size at presentation, radiation dose, presence of serum paraprotein and urinary Bence-Jones protein at diagnosis, and the use of spinal MRI for disease assessment/staging.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

The median age of the 84 patients (59 men and 25 women) was 56 years (range, 19-92 years), 55 patients were aged ≤60 years, and 29 patients were aged >60 years. Most patients were white (51 were of Caucasian ethnicity, and 14 were Hispanic), 14 patients were African American, and 4 patients were Asian. The median radiation dose was 45 grays (Gy) (range, 36-53.4 Gy) given in 1.8-Gy to 2.0-Gy fractions. Disease characteristics are summarized in Table 1. Fifty-nine patients (70%) had bone SP, and 25 patients (30%) had extramedullary SP. The most common anatomic site for bone SP was the vertebrae (42%), and the most common site for extramedullary disease was the paranasal sinuses (40%). The tumor size, which was measured as the greatest dimension of the lesion, was recorded for 65 patients. Forty-three patients (51%) had tumors that measured ≤5 cm, 17 patients (20%) had tumors that measured >5 cm but ≤10 cm, and 5 patients (6%) tumors that measured >10 cm. Fifty-six patients (67%) had MRI studies of the primary site, and 49 patients (58%) had MRI studies of the thoracic and lumbar spine for staging purposes. Serum paraprotein was present in 39 patients (46%). The median paraprotein level was 0.7 g/dL (range, 0.2-4.2 g/dL). Urinary Bence-Jones protein was present in 25 patients (30%), and the median level was 44.8 mg/24 hours (range, 3-384 mg/24 hours). Serum immunoglobulin-free light chain values at diagnosis were available for only 15 patients, mainly because this test became routine at our institution in 2004. The median follow-up from the start of radiation therapy was 64 months (range, 4-208 months).

Table 1. Patient Characteristics
CharacteristicNo. of Patients (%)
  1. MRI indicates magnetic resonance imaging.

Sex 
 Men60 (71)
 Women24 (29)
Age, y 
 <6055 (65)
 ≥6029 (35)
Race/ethnicity 
 White65 (77)
  Caucasian51 (78)
  Hispanic14 (22)
 African-American15 (18)
 Asian4 (5)
Staging workup 
 MRI of primary tumor site56 (67)
 MRI of spine49 (58)
Lesion site 
 Bone plasmacytoma, n=59 
  Vertebrae25 (42)
  Pelvis9 (15)
  Ribs7 (12)
  Lower extremities7 (12)
  Upper extremities6 (10)
  Facial or skull bones4 (7)
  Sternum1 (2)
 Extramedullary plasmacytoma, n=25 
  Paranasal sinus10 (40)
  Nasal cavity4 (16)
  Cheek3 (12)
  Nasopharynx2 (8)
  Larynx1 (4)
  Oropharynx1 (4)
  Orbit1 (4)
  Brain1 (4)
  Neck1 (4)
  Duodenum1 (4)
Maximum tumor size, cm 
 ≤543 (51)
 5.1-1017 (20)
 ≥10.15 (6)
 Unknown19 (23)
Serum myeloma protein present39 (46)
 Median value [range], g/dL0.7 [0.2-4.2]
Urinary Bence-Jones protein present25 (30)
 Median value [range], mg/d44.8 [3-384]

Local Control

Seven patients had progressive local disease; therefore, the 5-year local control rate was 92%. Table 2 summarizes the characteristics of the patients who had local progression. Two of these 7 patients had a marginal recurrence, which we defined as a tumor recurrence within 2 cm of the initial radiation portal. The remaining 5 patients had in-field recurrences. A tumor size >5 cm, an MRI of primary site, and a radiation dose ≥45 Gy did not predict local control (P = .575, P = .854, and P = .303, respectively). Although only 4 of 25 patients with extramedullary SP had received radiation therapy to the lymph node basins, no patient with extramedullary SP developed a recurrence in regional lymph nodes after radiation therapy.

Table 2. Characteristics of Patients With Local Recurrence of Solitary Plasmacytoma
Patient No.Disease TypePrimary Disease SiteRadiation Dose, GySite of Recurrent DiseaseType of Recurrence
  1. Gy indicates grays; T10, 10th thoracic vertebrae.

15ExtramedullaryLeft maxillary sinus45Left cheekMarginal
16BoneT1045T7 and T8Marginal
35ExtramedullaryDuodenum45DuodenumIn-field
37ExtramedullaryBilateral maxillary, ethmoid, frontal sinuses, right nasal cavity50Right maxillary sinusIn-field
54ExtramedullaryRight maxillary sinus45Right maxillary sinusIn-field
57BoneRib50RibIn-field
74ExtramedullaryLeft maxillary sinus50Left maxillary sinusIn-field

Treatment Toxicity

Xerostomia was common in patients who received radiation therapy to the head and neck. No patient experienced grade 4 or 5 late radiation toxicity according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late-effects scoring system.7

Progression to Multiple Myeloma

Thirty-eight patients (45%) developed multiple myeloma, and the 5-year probability of occurrence was 47%. Patients with bone SP had a higher 5-year probability of progression to multiple myeloma than patients with extramedullary SP (56% vs 30%; P = .021). Figure 1 illustrates the actuarial probability of progression to multiple myeloma according to SP site (bone vs extramedullary). The presence of serum myeloma protein at diagnosis was linked to the development of multiple myeloma: Patients who had serum myeloma protein detected at diagnosis had a 5-year probability of progression to multiple myeloma of only 60% compared with 39% for patients without serum myeloma protein (P = .016) (Fig. 2). Age <60 years was correlated with the 5-year probability of progression to multiple myeloma, although the correlation was not strongly significant (P = .048). Although men tended to progress to multiple myeloma more than women; the 5-year probability of progression to multiple myeloma for men was 49% compared with 44% for women, but the difference did not reach statistical significance (P = .29). Race/ethnicity did not significantly affect the risk of progression to multiple myeloma in univariate analysis. Because Hispanics were lumped with Caucasians in the same race, using univariate analysis, we tried to compare Hispanics with non-Hispanics, but we did not observe any difference in the risk of progression to multiple myeloma. The presence of urinary Bence-Jones protein at diagnosis did not correlate with progression to multiple myeloma. Patients who had undergone MRI studies of the spine for staging purposes did not have a significantly different rate of progression to multiple myeloma (49% with MRI vs 43% without MRI; P = .366).

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Figure 1. Progression to multiple myeloma was more common among patients with bone solitary plasmacytoma (SP) than among those with extramedullary SP (P = .021).

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Figure 2. Progression to multiple myeloma was more likely for patients who had serum myeloma paraprotein at diagnosis than for those who did not have paraprotein detected in the serum (P = .039).

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The 5-year overall survival rate for all patients in this study was 78%. No difference was noted in the 5-year overall survival rate for patients with bone SP versus extramedullary SP (76% vs 85%, respectively; P = .274).

We performed a multivariate analysis of all factors from the univariate analysis that influenced the risk of progression to multiple myeloma, including those with P values <.25. Bone SP location (P = .021), the presence of serum protein at diagnosis (P = .008), and age <60 years (P = .048), were statistically significant; whereas sex, race, and the presence of urinary Bence-Jones protein were not significant (P = .07, P = .07, and P = .9, respectively) (Table 3).

Table 3. Multivariate Analysis of Factors That Influence Progression to Multiple Myeloma
VariableHR95% CIP
  1. HR indicates hazard ratio; CI, confidence interval.

Location   
 Bone4.21.2-8.8.018
 Extramedullary0.320.1-0.8.018
Serum protein present at diagnosis2.51.2-5.4.008
Age, y   
 <602.21.0-4.8.048
 ≥600.450.2-0.9.048
Sex   
 Women0.460.2-1.0.07
 Men2.10.9-4.8.07

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

In the current study, we observed that definitive radiation therapy resulted in excellent local control of SP, in agreement with other studies.8-11 We also demonstrated a relation between the presence of myeloma protein at presentation and the risk of progression to myeloma, which agrees with our previously published data as well as others on the correlation between persistence of myeloma protein after radiation and the development of myeloma.1, 12 Dingli et al13 also reported on the value a persistent serum protein level ≥5 g/L as a risk factor for progression along with an abnormal serum immunoglobulin-free light chain ratio at diagnosis. The corresponding progression rates at 5 years were significantly worse when both factors were present (62% vs 1%; P < .001). Two other series14, 15 also reported adverse outcomes for patients with persistent myeloma paraproteins after radiation. Thus, we believe that the presence of serum paraprotein at diagnosis has value as a prognostic factor in this patient population.

The small size of our patient population compared with published data on other populations, including the Surveillance, Epidemiology, and End Results (SEER) data reported by Jawad and Scully,16 made it difficult to confirm some of the known risk factors, including age, sex, and race of the patients. Both age <60 years and men were associated with a higher risk of progression to multiple myeloma in our study. Race/ethnicity was not identified as a significant factor on univariate analysis or multivariate analysis. It is noteworthy that our current results must be interpreted with caution because of the small numbers in each cohort.

We could not demonstrate a dose-response relation between radiation doses >45 Gy and better local control. This finding is in contrast to the study by Mill and Griffith, who reported better local control rates among patients who received >50 Gy,17 and the findings of Tournier-Rangeard et al, who reported that doses ≥45 Gy improved local control among patients with extramedullary SP.18 Similarly, Mendenhall and colleagues reported that radiation doses ≥40 Gy resulted in a local control rate of 94% compared with 69% in patients who received <40 Gy.19 In our series, only 2 patients received <40 Gy (39.6 Gy and 36 Gy), so we could not assess local control for doses <40 Gy. However, a multicenter Rare Cancer Network study of 258 patients with SP and a Princess Margaret Hospital series of 46 patients produced no evidence of improvement in local control with radiation doses >30 to 35 Gy.8, 9 We could not demonstrate a significant association between tumor size and local control, but this may have been confounded by 2 factors. First, the maximum tumor size was not recorded for 23% of the patients in this series. Second, we used doses >40 Gy for most patients and no dose modification, even for patients who had SP <4 cm. In contrast, both the Princess Margaret Hospital series and the Rare Cancer Network study series produced improved local control in patients who had tumors <4 or 5 cm.8, 9

In our series, no patients with extramedullary SP experienced regional lymph node failure. The role of elective neck radiation therapy for patients with extramedullary SP is controversial. Some investigators recommend elective neck radiation for patients with extramedullary SP of the head and neck, because cervical lymph node involvement is present in 7% to 30% of patients at the time of diagnosis.20-23 However, other series have observed low rates of lymph node relapse without elective regional lymph node radiation therapy24, 25 and advocate not using elective regional lymph node radiation to minimize toxicity. We have taken an intermediate position and advise elective regional lymph node radiation therapy only for patients with the highest risk of cervical lymph node disease (oral cavity, oropharynx, and nasopharynx), consistent with the Guidelines Working Group of the United Kingdom Myeloma Forum.26 Note that, although the majority of our patients did not receive elective lymph node radiation, we had no failures in these areas.

Fifty-eight percent of the patients in the current study had undergone MRI of the spine for staging purposes to rule out occult multiple myeloma. Our institutional experience has been that MRI of the spine can detect occult disease in patients with SP.27 The current series covered the years from 1988 through 2008, and MRI of the spine was not performed uniformly in all patients during that period. It is noteworthy that patients who underwent MRI of the spine did not have a lower risk of progression to multiple myeloma. However, because patients with SP can develop multiple myeloma long after treatment, longer follow-up and additional numbers of patients may clarify the impact of staging spinal MRI in this disease entity.

Local definitive radiation up to a dose of 40 to 50 Gy remains the standard of care for patients with SP in view of the excellent local control offered. Bone location and the presence of serum paraprotein at presentation are associated statistically with progression to myeloma. Other factors, including: age, sex, and race, also should be taken into consideration. Defining the risk factors associated with progression to myeloma is vital in this disease; because, despite the excellent local control reported in our study and by other series, progression to multiple myeloma remains the main problem in these patients. Therefore, patients at high risk can be considered for adjuvant therapy. For instance, Aviles et al reported that chemotherapy with melphalan and prednisone in a small, randomized study produced an overall survival advantage.28 The recent improvement in overall survival observed with bortezomib and thalidomide29-31 also suggests evidence that these agents can be introduced as an adjuvant modality along with radiation in patients who have a higher risk of progression to myeloma.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES