INTRODUCTION — Plasma cell neoplasms (plasma cell dyscrasias) are a group of entities characterized by the neoplastic proliferation of a single clone of plasma cells, typically producing a monoclonal immunoglobulin. Plasma cell neoplasms can present as a single lesion (solitary plasmacytoma) or as multiple lesions (multiple myeloma [MM]). Solitary plasmacytomas most frequently occur in bone (plasmacytoma of bone), but can also be found outside bone in soft tissues (extramedullary plasmacytoma) [1-4]. Why some patients develop MM and others plasmacytoma is not understood, but might be related to differences in cellular adhesion molecules or chemokine receptor expression profiles of the malignant plasma cells [5].
Solitary plasmacytoma of bone (SPB, also called osseous plasmacytoma) is a localized tumor in the bone comprised of a single clone of plasma cells in the absence of other features of MM (ie, anemia, hypercalcemia, renal insufficiency, or multiple lytic bone lesions) [6,7].
The diagnosis and management of SPB will be reviewed here. The diagnosis and treatment of other plasma cell disorders (eg, solitary extramedullary plasmacytoma, MM, primary AL amyloidosis, monoclonal gammopathy of undetermined significance) are discussed separately.
●(See "Diagnosis and management of solitary extramedullary plasmacytoma".)
●(See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)
●(See "Multiple myeloma: Overview of management".)
●(See "Overview of amyloidosis".)
●(See "Diagnosis of monoclonal gammopathy of undetermined significance".)
EPIDEMIOLOGY — Approximately 5 percent of all cases of plasma cell disorders are SPB [8]. In the United States, the incidence is approximately 0.15 cases/100,000 person-years accounting for approximately 450 new cases per year. The incidence is highest in Black Americans and lowest in Asian/Pacific Islanders [8]. Men are diagnosed twice as frequently as women. The median age at diagnosis is 55 to 65 years, which compares with a median age at diagnosis of 71 years for patients with multiple myeloma (MM) [8-10]. SPB has been reported in patients as young as 15 years [11,12]. Although an increased risk of plasma cell dyscrasia has been reported in first-degree relatives of patients with monoclonal gammopathy of undetermined significance and patients with MM [13], there are no data on familial predisposition in solitary plasmacytoma.
CLINICAL FEATURES — Most patients present with skeletal pain or a pathologic fracture of the affected bone. Patients with vertebral involvement may have severe back pain or neurologic compromise (eg, cord compression). Less commonly, SPB can extend into the surrounding soft-tissue, resulting in a palpable mass.
The most common bones involved are those with active hematopoiesis; the axial skeleton is more commonly involved than is the appendicular skeleton, while disease in the distal appendicular skeleton below the knees or elbow is extremely rare [10,14]. The following bone sites are listed in order of decreasing frequency of involvement: the vertebrae, pelvis, ribs, upper extremities, face, skull, femur, and sternum [15]. The thoracic vertebrae are more commonly involved than the lumbar, sacral, or cervical spine [7].
By definition, patients with SPB do not have anemia (ie, hemoglobin <10 g/dL or 2 g/dL below normal), hypercalcemia (ie, serum calcium >11.5 mg/dL [2.875 mmol/liter]), or renal insufficiency (ie, serum creatinine >2 mg/dL [176.8 µmol/liter]) attributable to the underlying plasma cell disorder.
EVALUATION — The evaluation of a patient with a suspected SPB should include the following studies in addition to a complete history and physical examination:
●A biopsy of the suspected lesion can usually be obtained using computed tomography (CT) or magnetic resonance imaging (MRI) guidance.
●A complete blood count and differential with examination of the peripheral blood smear.
●A chemistry screen that includes measurements of serum calcium, creatinine, albumin, lactate dehydrogenase, beta-2 microglobulin, and C-reactive protein. (See "Multiple myeloma: Staging and prognostic studies".)
●A serum protein electrophoresis (SPEP) with immunofixation and quantitation of immunoglobulins, and a serum free light chain assay. (See "Laboratory methods for analyzing monoclonal proteins".)
●A routine urinalysis and a 24-hour urine collection for electrophoresis (UPEP) and immunofixation. Serum free monoclonal light chain (FLC) analysis is not an adequate replacement of a 24-hour urine collection in conjunction with SPEP and immunofixation in patients with a confirmed plasma cell proliferative disorder. (See "Laboratory methods for analyzing monoclonal proteins".)
●A unilateral bone marrow aspiration and biopsy [16].
●Cross sectional imaging with a whole body MRI [17,18]. If whole body MRI is not available, acceptable alternatives are whole body combined positron emission tomography/computed tomography (PET/CT) and MRI of the spine and pelvis. It has been estimated that one-third of patients with an apparently SPB by bone survey have evidence of other plasma cell tumors on PET/CT or MRI of the spine [19-22]; these patients are at greater risk for progression to multiple myeloma. (See 'Imaging' below.)
DIAGNOSIS
Solitary plasmacytoma of bone (SPB) — The diagnosis of SPB requires the following (table 1) [7,23]:
●Biopsy-proven solitary tumor of bone with evidence of clonal plasma cells (picture 1). (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Morphology and immunophenotype'.)
●Cross sectional imaging must show no other lytic lesions.
●Bone marrow aspirate and biopsy must contain no clonal plasma cells.
●There is no anemia, hypercalcemia, or renal insufficiency that could be attributed to a clonal plasma cell proliferative disorder. (See 'Clinical features' above.)
The presence of a monoclonal (M) protein does not exclude the diagnosis of SPB, and a small M protein may be present in 30 to 75 percent of cases. This M protein may or may not disappear with treatment. Patients with true solitary plasmacytoma of bone who meet the strict criteria listed above have a recurrence/progression rate of approximately 10 percent within three years [24,25].
There are two entities that are not considered solitary plasmacytoma, but nevertheless are managed similarly. These are defined below in the following sections.
SPB with minimal marrow involvement — The bone marrow of patients with SPB should have no clonal plasma cells. Some patients may demonstrate up to 10 percent clonal plasma cells, and are considered as having SPB with minimal marrow involvement [23]. In one study, approximately 40 percent of patients with apparent SPB had evidence of clonal plasma cells on bone marrow examination [16]. These patients are treated in a similar fashion to SPB but have a higher risk of progression to symptomatic myeloma with a 60 percent chance of recurrence or progression within three years [24,25]. (See "Diagnosis of monoclonal gammopathy of undetermined significance".)
SPB meeting criteria for multiple myeloma — If patients suspected to have SPB have 10 percent or more clonal plasma cells in the bone marrow, they are considered to have multiple myeloma rather than SPB [23] (table 2). These patients may be treated in a similar fashion to SPB if the bone marrow plasmacytosis is modest and there are no other myeloma defining events. Most of these patients will be staged as Durie-Salmon stage I myeloma. If patients have more extensive plasmacytosis, systemic therapy can be considered in addition, although there are limited data available to guide therapy. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Diagnosis'.)
DIFFERENTIAL DIAGNOSIS — It is important to distinguish SPB both from benign causes, which can present with similar manifestations and from other plasma cell dyscrasias for the purposes of prognosis and treatment.
The main conditions to consider in the differential diagnosis are multiple myeloma, POEMS syndrome, and metastatic carcinoma. This differential diagnosis is discussed in more detail separately. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Differential diagnosis'.)
Multiple myeloma — SPB is composed of plasma cells that are histologically identical to those seen in multiple myeloma (MM); however, the treatment of these two entities differs dramatically, necessitating a careful review of the diagnosis. A distinction between these two conditions is made based upon the exclusion of additional lesions in patients with SPB. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)
As mentioned above, the diagnosis of SPB requires the exclusion of many features of MM as evidenced by the following:
●Normal bone marrow with no evidence of clonal plasma cells. As noted above, occasional patients with an apparent SPB may have <10 percent clonal plasma cells in the marrow. These patients are considered to have SPB with minimal bone marrow involvement. (See 'SPB with minimal marrow involvement' above.)
●Magnetic resonance imaging (MRI) is normal except for the primary solitary lesion.
Absence of additional lytic lesions, anemia, hypercalcemia, and renal insufficiency.
Patients found to have 10 percent or more clonal plasma cells in the bone marrow during an evaluation for suspected SPB may be treated in a similar fashion to SPB if the bone marrow plasmacytosis is modest and there are no other myeloma defining events. Most of these patients will be staged as Durie-Salmon stage I myeloma. (See 'SPB meeting criteria for multiple myeloma' above.)
POEMS syndrome — POEMS syndrome (osteosclerotic myeloma: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes) is a monoclonal plasma cell disorder accompanied by symptoms and/or signs of peripheral neuropathy, osteosclerotic lesions, Castleman's disease, organomegaly, endocrinopathy (excluding diabetes mellitus or hypothyroidism), edema, typical skin changes, and/or papilledema. These patients typically have elevated serum vascular endothelial growth factor (VEGF) levels. (See "POEMS syndrome".)
Patients with either SPB or POEMS syndrome may present with a single osteolytic bone lesion with a sclerotic rim, or a single osteosclerotic bone lesion and a small amount of a monoclonal protein in the serum or urine. Although not always straightforward, the presence of an osteosclerotic component to the bone lesion and/or other minor criteria for POEMS should distinguish patients with POEMS from those with SPB (table 3).
Metastatic carcinoma — The presence of a lytic bone lesion in a patient with a monoclonal gammopathy suggests the possibility of SPB or MM. However, metastatic carcinoma (eg, kidney, breast, non-small cell lung cancer) can produce lytic lesions, and a subset of patients presenting in this way will have metastatic cancer with an associated, unrelated monoclonal gammopathy (eg, MGUS). Typically, however, patients with metastatic carcinoma have multiple lytic bone lesions rather than a single lesion such as that seen with SPB. Persons presenting with lytic bone lesions, constitutional symptoms, a small M component, and fewer than 10 percent clonal plasma cells in the bone marrow, are more likely to have metastatic carcinoma with an unrelated MGUS rather than SPB. This can be confirmed with a biopsy of the bone lesion.
TREATMENT — The primary treatment for patients with SPB is localized radiation therapy. Surgery may be required for patients with structural instability of the bone, retropulsed bone, or rapidly progressive symptoms from cord compression. (See "Multiple myeloma: Overview of management", section on 'Skeletal lesions and bone health' and "Treatment and prognosis of neoplastic epidural spinal cord compression".)
The use of concurrent, adjuvant, or prophylactic systemic therapy in this population is controversial. Bisphosphonates are not recommended for patients with SPB, except in the setting of underlying osteopenia. (See "Multiple myeloma: The use of osteoclast inhibitors", section on 'Indications'.)
The median overall survival of patients with SPB is approximately 10 years [10,14,26-30]. Overall survival rates at 5 and 10 years are approximately 75 and 45 percent, respectively, with corresponding disease-free survival rates of 45 and 25 percent [10]. A little more than half of patients with SPB will eventually develop overt MM.
Radiation — Localized radiation therapy (RT), given at a dose of 35 to 50 Gy over approximately four weeks, is the treatment of choice for SPB. Localized RT directed at the tumor site should be given even if the plasmacytoma appears to have been completely excised for diagnostic purposes. The local response rate to RT exceeds 80 to 90 percent [26,31-34] and appears to be highest in tumors <5 cm in maximum diameter [15,32,35].
The use of RT for the treatment of SPB is largely based upon data from retrospective studies. There have been no randomized trials of RT for patients with SPB.
The largest retrospective study included 5056 patients with SPB (3528 patients) or extramedullary plasmacytoma (1528 patients). Details on treatment were available for 3967 patients; treatment consisted of RT alone (1803 patients), RT plus surgery (1013 patients), surgery alone (643 patients), and neither modality (508 patients) [36]. Median radiation dose used was 45 Gy. RT doses over 40 Gy improved survival over that seen with lower doses (HR 0.62; 95% CI 0.54-0.72). Although treatment with both RT and surgery improved survival over that seen with either modality alone, since treatment differed significantly by site of involvement, it is not known whether these survival differences are due to treatment given, site involved, or a combination of the two.
Another retrospective study included 258 patients with SPB (206 patients) or extramedullary plasmacytoma (52 patients) [15]. Treatments included RT alone (214 patients), RT plus chemotherapy (34 patients), and surgery alone (8 patients). Five-year rates of overall survival, disease-free survival, and local control were 74, 50, and 86 percent, respectively. Patients who received localized RT had a lower rate of local relapse than those who did not receive radiation (12 versus 60 percent).
The ideal radiation dose for SPB is unknown and guidelines differ in their suggested dose range [2,37,38]. Published papers have reported doses ranging from 30 to 60 Gy, with most radiation oncologists advocating the use 35 to 50 Gy [10,15]. Doses in the lower range (eg, 35 to 40 Gy) may be used for tumors <5 cm, while doses in the higher range (eg, 40 to 50 Gy) are preferred for larger tumors.
For patients with SPB, we recommend initial localized RT rather than chemotherapy or observation. RT should be delivered at a dose of 35 to 50 Gy over four weeks directed at the tumor or site of tumor resection (in the case of complete diagnostic excision).
Systemic therapy — The use of concurrent, adjuvant, or prophylactic systemic therapy for SPB is controversial. Some studies have suggested no benefit with systemic therapy [9,27,39], while others suggest that systemic therapy prevents or delays the median time to progression to MM [26,31,40]. For patients with SPB, we suggest observation after initial radiation therapy rather than the use of concurrent or adjuvant systemic therapy.
Most of the studies evaluating systemic therapy in SPB used outdated treatment regimens (eg, melphalan plus prednisone) and outdated radiation techniques. There are few studies using modern systemic therapy.
As an example, the use of concurrent lenalidomide plus dexamethasone (Rd) was evaluated in a retrospective study of 46 patients with SPB (40 patients) or extramedullary plasmacytoma treated with intensity modulated radiation therapy (IMRT) to a median total dose of 40 Gy [41]. Administration of Rd was left at the discretion of the treating hematologist. The entire study population experienced good five-year rates of local control (96 percent), multiple myeloma-free survival (MMFS, 85 percent), and progression-free survival (PFS, 60 percent). When compared with those who received IMRT alone, the 19 patients receiving concurrent Rd had better rates of MMFS (100 versus 77 percent) and PFS (82 versus 48 percent). Rd did not impact local control, plasmacytoma recurrence, or overall survival.
Studies evaluating systemic therapy are small, and overall we believe that the available literature does not support the use of systemic therapy in patients with SPB [6]. This approach treats patients with locally treated SPB in a similar fashion to those with asymptomatic MM. For this group of patients there is an absence of clear benefit from systemic therapy with currently available therapies and reports that some patients remain stable without treatment over extended periods of time.
Patients with multiple plasmacytomas — Approximately 30 to 50 percent of patients with suspected SPB will have multiple asymptomatic lesions detected by combined positron emission tomography/computed tomography (PET/CT) or magnetic resonance imaging (MRI) of the spine. The management of patients with "multiple solitary plasmacytomas," defined as the presence of more than one plasmacytoma (occurring concurrently or sequentially) in the absence of bone marrow evidence of MM, is challenging. (See 'Prognosis' below.)
Many clinicians advocate the use of local radiation directed at the symptomatic site with further treatment postponed until the development of symptoms. In contrast, our approach depends on the number and location of involved sites:
●If a patient has two concurrent distinct plasmacytomas with no bone marrow involvement, we would proceed with radiation to both sites followed by observation provided the radiation fields are limited. If the radiation fields will be large and may interfere with stem cell collection or bone marrow reserve, we administer systemic therapy identical to that used for MM instead of radiation. (See "Multiple myeloma: Overview of management".)
●If a patient has more than two concurrent lesions, we administer systemic therapy identical to that used for MM, even if the bone marrow is normal.
●If the patient develops two or three apparently solitary lesions within a period of one to two years, subsequent therapy should be as if the patient has MM.
PROGNOSIS
General — The median overall survival of patients with SPB is approximately 10 years. Overt multiple myeloma (MM) ultimately develops in 50 to 60 percent of patients with SPB after initial radiation therapy [2,26,28,32,33,42-44]. This disease progression is thought to arise from previously undetectable myeloma cells in areas outside the radiation field or from myeloma within the radiation field in the setting of sublethal radiation doses.
The prognosis of SPB varies depending on the adequacy of initial staging. In one study, among 91 patients seen at the Mayo Clinic with newly diagnosed SPB and no clonal bone marrow plasma cells by immunofluorescence, approximately 40 percent were free of recurrence at eight years [16]. The risk of recurrence decreases further among patients with no evidence of disease elsewhere on combined positron emission tomography/computed tomography (PET/CT). In contrast, there is almost always recurrence if there are detectable clonal bone marrow plasma cells at the time of initial diagnosis. In two retrospective studies, detection of phenotypically aberrant clonal plasma cells by flow cytometry of the bone marrow was associated with a higher likelihood of progression to MM at 26 months (approximately 70 versus 6 to 12 percent) [24,25].
While most patients will progress to MM within the first four years, others may demonstrate progression more than a decade after completion of therapy. As an example, two retrospective analyses found that approximately two-thirds of the patients who progress do so within four years [10,28], although progression can occur as late as 13 years [10]. Three patterns of failure were seen:
●Development of MM – 54 percent
●Local recurrence – 11 percent
●Development of new lesions (multiple plasmacytomas) in the absence of MM – 2 percent
Relapse rates are higher in older patients and in those with axial skeletal lesions [14,32,33], while patients younger than 60 years and with tumors <5 cm have a better overall survival rate [33]. Other reported predictors for conversion to MM include a large solitary lesion [26], the presence of osteopenia, reduction in uninvolved immunoglobulin levels (eg, low levels of IgA and/or IgM in a patient with an IgG plasmacytoma) [45], and the presence of high-grade angiogenesis in the tumor sample [46].
Monoclonal protein and abnormal free light chain ratio — The presence or absence of a monoclonal (M) protein at the time of diagnosis of SPB does not appear to have a major effect on long-term outcome [10], although persistence of a serum M protein after radiation therapy appears to be a significant predictor of subsequent progression to MM [14,19,26-28]. In one series, for example, the 10-year myeloma-free survival was superior for those whose M protein resolved at one year following radiation therapy (91 versus 29 percent) [19].
In another study of 116 patients with SPB, two factors were predictive of disease progression to myeloma at five years [47]:
●A persistent serum M protein level ≥ 0.5 g/dL one to years after diagnosis
●An abnormal free light chain ratio at the time of diagnosis
A risk stratification model consisting of these two variables yielded five-year progression rates of 13, 26, and 62 percent for those with zero (low risk), one (intermediate risk), or two (high risk) of these risk factors, respectively.
Imaging — Cross sectional imaging with a whole body magnetic resonance imaging (MRI) is included in the initial evaluation of a patient with suspected SPB because patients with multiple bone lesions have a worse prognosis and should be considered as having early MM rather than SPB.
●In three separate studies, MRI of the spine showed unsuspected bone lesions in one-quarter to one-third of patients with presumed SPB [19-21]. Patients with bone lesions on MRI were at greater risk for progression to symptomatic MM.
●In another retrospective study, patients diagnosed with SPB based upon plain radiographs alone developed MM much more frequently than those diagnosed with plain radiographs plus MRI of the spine (7 of 8 patients versus 1 of 7 patients, respectively) [48].
●Another retrospective study evaluated the impact of PET scan results in 21 patients with apparently solitary plasmacytoma of the bone (11 patients) or soft tissue (6 patients) [22]. Pretreatment PET scans influenced management 35 percent of the time, either by demonstrating multiple lesions or by demonstrating normal activity in a previously suspected lesion.
FOLLOW-UP — After completion of radiotherapy, patients should undergo laboratory testing with urine and serum protein electrophoresis with immunofixation, complete blood count, serum creatinine, and serum calcium every four to six months for one year, and annually thereafter. A whole body MRI should be performed if the patient develops an M protein, or if a persistent M protein increases in magnitude. (See "Laboratory methods for analyzing monoclonal proteins".)
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 1), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Solitary plasmacytoma".)
SUMMARY AND RECOMMENDATIONS
●Clinical presentation – Solitary plasmacytoma of bone (SPB) is a localized tumor in the bone comprised of a single clone of plasma cells in the absence of other features of multiple myeloma (ie, anemia, hypercalcemia, renal insufficiency, or multiple lytic bone lesions). Most patients present with skeletal pain or a pathologic fracture of the affected bone. (See 'Clinical features' above and 'Diagnosis' above.)
●Diagnostic evaluation – The evaluation of a patient with a suspected SPB should include a biopsy of the suspected lesion, a unilateral bone marrow aspirate and biopsy, and laboratory studies. Cross sectional imaging with a whole body magnetic resonance imaging (MRI) scan should be performed. (See 'Evaluation' above.)
The diagnosis of SPB requires the following (table 1):
•Biopsy-proven solitary tumor of bone with evidence of clonal plasma cells.
•Cross sectional imaging must show no other lytic lesions.
•Bone marrow aspirate and biopsy must contain no clonal plasma cells.
•There is no anemia, hypercalcemia, or renal insufficiency that could be attributed to a clonal plasma cell proliferative disorder.
The presence of clonal plasma cells (less than 10 percent) in the bone marrow is considered solitary plasmacytoma of bone with minimal marrow involvement. Presence of 10 percent or more clonal bone marrow plasma cells in a patient with solitary plasmacytoma of bone will automatically meet required criteria for multiple myeloma.
●Management – For patients with SPB, we recommend initial therapy with localized radiation rather than chemotherapy or observation (Grade 1C). Radiation should be delivered at a dose of 35 to 50 Gy over four weeks directed at the tumor or site of tumor resection (in the case of complete diagnostic excision). (See 'Radiation' above.)
After initial radiation therapy for patients with SPB, we suggest observation rather than the use of concurrent or adjuvant systemic therapy (Grade 2C). (See 'Systemic therapy' above.)
●Limited role for bisphosphonates – Bisphosphonates are not recommended for patients with SPB, except in the setting of underlying osteopenia. (See "Multiple myeloma: The use of osteoclast inhibitors", section on 'Indications'.)
