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21 - Plasmacytoma

Chapter 21

Summary:

  • An abnormal κ/λ sFLC ratio at baseline is associated with increased risk of progression to multiple myeloma and reduced overall survival in patients with solitary plasmacytoma of bone.
  • Risk stratification models incorporating sFLC analysis identify solitary plasmacytoma patients at greater risk of progression to multiple myeloma.

21.1. Introduction

Solitary plasmacytoma is characterized by the presence of a single mass of clonal bone marrow plasma cells with no or minimal (<10%) bone marrow plasmacytosis, and no other symptoms except those relating to the primary lesion. Plasmacytomas can also occur as a feature of multiple myeloma (MM) when a lesion occurs alongside one or more myeloma defining events, such as the evidence of end organ damage or a biomarker of malignancy (Section 25.2.1). If a patient with solitary plasmacytoma is found to have at least one myeloma defining event, they would be re-classified as multiple myeloma [42].

About two thirds of solitary plasmacytomas occur in the bone as a single mass, and are termed ‘solitary bone plasmacytoma (SBP)’. The remaining third are extramedullary plasmacytoma (EMP), where the solitary lesion occurs outside the bone in soft tissues such as the head and neck mucosa [1101].

The estimated incidence rate of plasmacytoma is 0.15 per 100,000 per year [473], which represents 3 - 5% of all plasma cell neoplasms. It is approximately twice as common in men as it is in women, and the median age at diagnosis is 60 years, approximately 10 years younger than that of MM patients [473][469][1102]. The median overall survival for solitary plasmacytoma patients is between 7 and 12 years [474].

When solitary plasmacytoma occurs in the bone, the majority (83%) of tumours locate in the axial skeleton, particularly the vertebrae [469], but tumours can also occur in the femur, tibia, pelvis, humerus, skull, ribs and sternum [1103][1104]. An example of a tumour affecting the mandible is presented in Figure 21.1. When solitary plasmacytoma arises outside the bone marrow as an EMP, the tumour is most frequently detected in the head and neck mucosa (85%), but can also occur in the gastrointestinal tract, lung, thyroid, testis, parotid, lymph nodes and central nervous system [1101][1105][1106]. EMP located outside of the head and neck have been linked to an increased risk of dissemination and worse outcome [1101].

Regardless of whether the solitary lesion is located within the bone or soft tissue, the current International Myeloma Working Group (IMWG) guidelines divide solitary plasmacytoma into two categories based on the absence or presence of minimal (<10%) clonal bone marrow plasma cells, as determined by bone marrow aspirate [42].

Local tumour irradiation with or without surgery is the treatment of choice for solitary plasmacytoma, with nearly all patients successfully achieving local control [472]. However, in some patients there is recurrence at the site of the original lesion [471], and around half progress to MM [474][472][471][1107]. Those who do not progress can remain clinically stable for more than a decade [474].

Solitary plasmacytoma patients without bone marrow plasmacytosis have the lowest risk of progression to MM, with 10% progressing 10 years after diagnosis. For those with bone marrow plasmacytosis, the risk of progression increases to 20% for EMP patients and 60% for SBP patients at 10 years [1108][1109]. If all patients with and without plasmacytosis are included, the median time to MM progression for EMP patients is 1.5-2.5 years, compared to 2-3 years for SBP [474].

Up to 5% of patients with solitary plasmacytoma go on to develop multiple lesions in the bone or elsewhere, without evidence of MM [1107][470]. This is referred to as multiple solitary plasmacytoma or macrofocal plasmacytoma [1104].

21.2. Monoclonal proteins in solitary plasmacytoma

Approximately half of SBP patients will have a small M-protein, typically around 5 g/L [472] and the most common monoclonal protein type is IgG followed by light chain only. More than 40% of SBP patients have an abnormal sFLC ratio with negative serum and urine immunofixation electrophoresis (sIFE and uIFE) [1104][472]. For patients with EMP, sIFE and uIFE are abnormal in less than a quarter of patients [1101][1104][481].

Presence of an M-protein can be useful for guiding therapy and may provide prognostic value post-treatment. In most patients the monoclonal protein is markedly reduced upon completion of local radiotherapy, but it only disappears entirely in a minority of patients. Persistence of the monoclonal protein during follow up is prognostic of outcome (Section 21.3), and may indicate the presence of a tumour outside the field of radiotherapy [473].

The potential utility of sFLC analysis has been investigated in a number of studies, the most comprehensive of which was a retrospective study by Dingli et al. [472] at the Mayo Clinic. Of 116 patients with a serum sample taken at diagnosis and prior to therapy, the κ/λ sFLC ratio was abnormal in 54 (47%); this included 40% of patients who were negative by sIFE. Consistent with these findings, three smaller studies have reported abnormal κ/λ sFLC ratios in 30 - 68% of patients at diagnosis [475][476]. A number of other studies have also demonstrated the utility of sFLCs for monitoring patients with elevated involved FLC (iFLC) concentrations [486], particularly those previously classified as having nonsecretory disease [474].

21.3. Prognostic factors in solitary plasmacytoma

A number of groups have identified prognostic factors that are associated with inferior disease-free survival and progression to MM. These include tumour location and size [481][1111], presence of a monoclonal protein at diagnosis [478], and levels of uninvolved immunoglobulins [480][1112]. In addition, bone marrow plasmacytosis [1109][1113][1114] and the persistence of a serum monoclonal protein after treatment [42][472][479] have both been consistently associated with inferior progression-free survival (PFS). However, as persistence of a monoclonal protein can only be assessed 1 or 2 years after initiation of therapy, there is a clear need for alternate reliable prognostic markers that can be measured at diagnosis [472].

The prognostic utility of baseline sFLC measurements in SBP was first evaluated by Dingli et al. [472]. During follow-up, a total of 43/116 patients progressed to MM with a median time to progression of 1.8 years. Patients with an abnormal κ/λ sFLC ratio had an increased risk of progression compared to those with a normal ratio (44% vs. 26% at 5 years, p=0.039) (Figure 21.2). Patients with an abnormal κ/λ sFLC ratio at diagnosis also had a shorter overall survival (Figure 21.3). Persistence of a serum monoclonal immunoglobulin (≥5 g/L) after 1-2 years of therapy was an additional risk factor for progression to MM. A risk stratification model was constructed based on these two risk factors, which defined low-, intermediate- and high-risk groups with 0, 1 or 2 risk factors, and with 5-year progression rates of 13%, 26% and 62%, respectively (Figure 21.4). The authors commented that sFLC analysis provided important prognostic information in solitary plasmacytoma. A subsequent study by Koch et al. [475] confirmed the prognostic value of baseline sFLC ratio measurements.

Fouquet et al. [476][477] assessed the prognostic utility of sFLCs and whole body fluorodeoxyglucose positron emission tomography – computed tomography (FDG-PET CT) in 43 patients with solitary plasmacytoma (33 SBP and 10 EMP). By univariate analysis, an abnormal iFLC concentration, an abnormal κ/λ sFLC ratio or the presence of ≥2 hypermetabolic lesions on initial PET CT were associated with significantly shorter time to MM progression (Figure 21.5, p=0.002; and data not shown). On multivariate analysis, an abnormal iFLC concentration and the presence of ≥2 hypermetabolic lesions on PET-CT were the strongest independent prognostic factors identifying patients at greatest risk of progression to MM. A risk stratification model based on the presence of 0, 1, or 2 risk factors demonstrated that the median time to progression to MM for each group was “Not reached”, 41 and 21 months, respectively (Figure 21.6).

Leleu et al. [483] monitored 10 SBP patients and observed a trend towards shorter time to progression to MM in patients with no change in sFLCs following radiotherapy. The same group [484] later described a patient with monoclonal κ sFLCs. At disease relapse, sFLCs were abnormal while electrophoresis and MRI were both unremarkable. A subsequent MRI scan and biopsy confirmed relapse 6 months later, whilst electrophoresis results remained normal.

In summary, these reports indicate that baseline sFLC abnormalities consistently associate with increased risk of progression of solitary plasmacytoma to MM, and that sFLCs may be useful for monitoring response to treatment and disease relapse.


21.4. Guideline recommendations

Assessment of baseline sFLCs is recommended by IMWG guidelines [42][20] and a European expert panel [1108] (Section 25.3.1) to assess risk of progression.

National Comprehensive Cancer Network® (NCCN®) guidelines also recommend sFLC analysis alongside serum protein electrophoresis (SPE) and sIFE in a panel of tests for surveillance/follow-up of solitary plasmacytoma after primary treatment (Section 25.8) [485]. Similar recommendations were recently reported by a European expert panel [1108]. They recommend that when measurable concentrations of a monoclonal protein or sFLCs are present, the IMWG uniform response criteria [905] be used for response assessment (Section 25.3.5).

Questions

  1. What is the reported 5-year risk of progression to MM in SPB patients with an abnormal κ/λ sFLC ratio?
  2. Based on the risk stratification model reported by Dingli et al. [472], which two factors can effectively discriminate SPB patients at low, medium and high risk of progression to MM?
  3. Which two risk factors were defined by Fouquet et al. [476] to identify solitary plasmacytoma patients at risk of progression to MM?

Answers

  1. 44% (Section 21.3).
  2. The κ/λ sFLC ratio at baseline and the persistence of a monoclonal immunoglobulin after 1 - 2 years (Section 21.3).
  3. An abnormal iFLC concentration and the presence of ≥2 hypermetabolic lesions by PET CT at baseline (Section 21.3).
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