To identify the clinical usefulness of serum M protein and to establish a rationale for regular follow-up with serum protein electrophoresis in solitary plasmacytoma.
Sixty-nine patients with solitary plasmacytoma and solitary plasmacytoma with minimal marrow involvement according to the International Myeloma Working Group criteria were retrospectively reviewed.
At a median follow-up of 6.2 years, 5-year local control (LC), 5-year multiple myeloma-free survival (MMFS), 5-year failure-free survival (FFS), and 5-year overall survival (OS) were 82.6%, 44.1%, 41.8%, and 85.1%, respectively. Among the patients whose initial serum M protein was present or not evaluated, 37.3% of patients showed disappearance of serum M protein after various treatment. MMFS of these patients were comparable to non-secretory plasmacytoma with undetectable levels of M protein, and significantly better than patients with persistent M protein. Increase of serum M protein ≥0.1 g/dL was most predictive of treatment failure with area under the curve of 0.731.
Patients who eventually showed persistence of serum M protein after treatment showed worse MMFS and FFS compared to those whose serum M protein disappeared or who had initially non-secretory disease. The increase of serum M protein level ≥0.1 g/dL from current nadir was predictive of treatment failure. Therefore, regular follow-up with serum M protein is highly recommended especially unless the patient had initially non-secretory disease.
Solitary plasmacytoma is a rare disease which accounts for less than 10% of plasma cell neoplasm [
Owing to its rarity, there were no randomized trials to identify the standard treatment for solitary plasmacytoma. Although multiple myeloma (MM) is generally treated with chemotherapy and is thought to be incurable, solitary plasmacytoma is treated well with excellent 5-year local control (LC) rate ranging from 81 to 95% after local radiation therapy (RT) [4–6]. Although there is no consensus regarding the optimal dose of RT, but RT dose ≥40 Gy was reported to improve LC [
Although there is a consensus criteria for treatment response assessment for multiple myeloma [
Myeloma protein, which is also called M protein, is an abnormal protein produced in excess by an abnormal monoclonal proliferation of plasma cells and is typically detected in serum or urine of patients with MM or plasma cell tumors. Although only 3% of MM patients are non-secretory [
However, the usefulness of serum M protein as a biomarker to assess treatment response and to predict treatment failures in solitary plasmacytoma is yet to be studied. In MM, randomized trials implemented the increase in serum M protein more than 0.5 g/dL from nadir to define disease progression [
Medical records of patients with solitary plasmacytoma and solitary plasmacytoma with minimal marrow involvement according to the International Myeloma Working Group (IMWG) criteria [
The characteristics of all patients are shown in
All patients received a curative treatment; definitive RT alone (46.4%), surgical resection (24.6%), and surgical resection plus adjuvant RT (17.4%). The median total radiation dose was 45.0 Gy (range, 23.4 to 70.0 Gy). Curative surgical resection was performed in 33 patients (47.8%) and 90.9% of them underwent complete resection. Chemotherapy was administered to 8 patients (11.6%). After the completion of treatment, patients were followed up with work-ups including radiological imaging studies, serum protein electrophoresis, and serum free light chain ratio. The median time from the initial serum protein electrophoresis at the time of diagnosis to first post-treatment serum protein electrophoresis was 3.5 months (range, 1.3 to 36.5 months). In this study, we defined the “disappearance of serum M protein” in order to assess treatment response. When post-treatment serum M protein of a patient whose initial serum M protein was present or not evaluated was measured and showed no detectable serum M protein during follow-up, it was regarded as disappearance of serum M protein.
Patients were defined as progression to MM, whenever meeting the criteria of IMWG for the diagnosis of MM during follow-up [
The characteristics according to various treatments were compared using Fisher's exact test. The actuarial LC, multiple myeloma-free survival (MMFS), failure-free survival (FFS), and overall survival (OS) were calculated with Kaplan-Meier analysis. All survivals were calculated from the first day of initial treatment. The events were local failure before progression to MM for LC, progression to MM or death from any cause for MMFS, any failure or death from any cause for FFS, and death from any cause for OS. Log-rank test was used for univariate analysis of the prognostic factors. Based on prognostic factors with p < 0.05, multivariate analysis was conducted. To identify a set of independent predictive factors a multivariate analysis with Cox proportional hazards model or Cox regression with Firth’s penalized likelihood was performed as appropriate. In all analyses p < 0.05 was considered statistically significant. All statistical analyses were conducted in R version 3.5.0.
At a median follow-up of 6.8 years (range, 0.1 to 29.3 years), 9 patients (13.0%) experienced a local failure; 8 within 3 years and one at 9 years after treatment (
Overall, 32 patients (46.8%) progressed to MM. Most of the progressions to MM (96.9%) occurred within the first 5 years after treatment. The 5- and 10-year MMFS were 44.1% and 36.7%. In univariate analysis and multivariate analysis, SPB (hazard ratio [HR] = 8.63, p = 0.036), tumor size ≥ 5 cm (HR = 2.84, p = 0.012), and anaplastic histology (HR = 50.9, p = 0.002) were adverse prognostic factors for MMFS (
At the time of the analysis, 22 deaths (31.9%) were reported, and 6 patients died from the progression of MM. There were two deaths related to treatments; one from complications after surgical resection and another from side effects of salvage chemotherapy. Five deaths were unrelated to plasmacytoma or treatment and the cause of death of remaining 9 patients was unknown.
In the subgroup of patients treated with any treatment that includes RT, tumor location, tumor size, and serum free light chain ratio were significant prognostic factors for MMFS and FFS in the univariate analysis. In the multivariate analysis, SPB (HR = 22.1, p < 0.001), tumor size ≥5 cm (HR = 2.64, p = 0.045), and abnormal serum free light chain ratio (HR = 6.29, p = 0.008) were associated with poor MMFS. For FFS, SPB (HR = 22.7, p < 0.001) and abnormal serum free light chain ratio (HR = 7.38, p = 0.003) were statistically significant adverse prognostic factors. However, there were no significant prognostic factors identified for LC and OS for patients treated with RT. The addition of surgical resection, chemotherapy, or RT dose ≥45 GyEQD2 did not result in significantly improved prognosis.
At the time of diagnosis, 18 patients were non-secretory. Among the remaining 51 patients who had serum M protein or whose pre-treatment serum M protein level was not evaluated, serum M protein disappeared in 19 patients after a median period of 2.4 months (range, 0.0 to 51.1 months) following treatment. The 5-year MMFS of patients with non-secretory plasmacytoma, disappearance of serum M protein, persistence of serum M protein, and unknown post-treatment serum M protein level were 55.7%, 78.0%, 10.8%, and 20.8%, respectively (
Among patients who initially had serum M protein, the post-treatment serum M protein level was available from 20 patients. Two patients who did not receive RT showed persistence of serum M protein after treatment, whereas disappearance of serum M protein was observed in 7 patients (38.9%) after RT (
Next, we tried to predict treatment failures with the level change of serum M protein. Overall, 40 patients were followed up with at least two serum protein electrophoresis tests during follow-up before any treatment failure, defined as local failure and progression to MM. The median value of post-treatment nadir value of serum M protein was 0.0 g/dL (range, 0.0 to 3.2 g/dL). During follow-up, 17 patients experienced an increase of serum M protein level at least once before clinically detected treatment failure. The median of maximum increase of serum M protein from nadir was 0.7 (range, 0.02 to 2.1 g/dL).
Considering the high incidence of non-secretory M protein and low level of serum M protein in solitary plasmacytoma at diagnosis, we evaluated the increase of serum M protein level ≥0.1 g/dL from current nadir instead of 0.5 g/dL, which is implemented in MM, to predict treatment failure. The area under the curve (AUC) of the prediction model with this criterion was 0.731 (
In addition, three other criteria were evaluated, which are two increases of serum M protein level, two consecutive increases of serum M protein level, and increase of serum M protein above double the value of nadir. The AUC of the prediction models with these criteria were 0.690, 0.662, and 0.614, respectively (
In this study, we evaluated the prognostic value of serum M protein level at diagnosis and its level change or conversion during follow-up to assess treatment response and predict treatment failures of solitary plasmacytoma.
Prognostic factors with contradictory prognostic values for solitary plasmacytoma were demonstrated in previous studies due to different treatment profiles and small number of patients included in each study. Although local control was excellent in this study and was also consistent with that of previous studies, progression to MM remained to be the main obstacle for failure-free survival as observed in
In addition to SPB and tumor size ≥5 cm, anaplastic plasmacytoma was associated with poor LC, MMFS, and FFS. Anaplastic plasmacytoma is an extremely rare type of plasmacytoma which can develop in patients with immunosuppression and combined Epstein-Barr virus infection [
In this study, patients with non-secretory plasmacytoma and patients whose serum M protein disappeared after treatment showed superior MMFS compared to patients who had persistent serum M protein after treatment. However, the prognostic value of serum M protein level at diagnosis is controversial. Non-secretory plasmacytoma showed better MMFS in the study by Reed et al. [
Immunofixation and free light chain ratio are another tests to evaluate serum M protein. It has been reported that 9.7% of normal serum protein electrophoresis showed positive immunofixation result [
RT has been known as the treatment of choice for solitary plasmacytoma [
In this study, since solitary plasmacytoma without evidence of MM is very rare in nature, we could find only a small number of patients. Patients who were incidentally diagnosed as solitary plasmacytoma after surgical resection lacked the pre-treatment work-up for solitary plasmacytoma as shown in
In conclusion, we found that patients who eventually showed persistent serum M protein after treatment had worse prognosis compared to those whose serum M protein disappeared or initially had non-secretory disease. Also, the increase of serum M protein level ≥0.1 g/dL from current nadir was predictive of treatment failure. Therefore, we recommend a regular follow-up with serum protein electrophoresis after the treatment of solitary plasmacytoma to assess treatment response and predict treatment failure. Also, closer follow-up with serum protein electrophoresis is needed for patients who initially had serum M protein or whose serum M protein level was not evaluated.
No potential conflict of interest relevant to this article was reported.
Supplementary materials can be found via
Table S1. Risk factors associated with treatment outcome of solitary plasmacytoma treated with RT (univariate analysis)
Table S2. Characteristic of the patients according to their treatments
(A) Treatment outcomes of solitary plasmacytoma after various treatments. (B) Multiple myeloma-free survival of solitary plasmacytoma after various treatment with respect to serum M protein. (C) Receiver operating characteristic (ROC) curve and area under the curve (AUC) of increase of serum M protein level ≥0.1 g/dL from current nadir to predict treatment failure. LC, local control; MMFS, multiple myeloma-free survival; FFS, failure-free survival; OS, overall survival. *p < 0.05.
Patient characteristics of solitary plasmacytoma
Characteristic | Number of patients (%) |
---|---|
Age (yr) | |
<60 | 32 (46.4) |
≥60 | 37 (53.6) |
Sex | |
Male | 41 (59.4) |
Female | 28 (40.6) |
Site of lesion | |
SPB | 51 (73.9) |
Craniofacial bone | 11 (15.9) |
Vertebra | 21 (30.4) |
Pelvic bone | 9 (23.1) |
Extremity | 4 (5.8) |
Others | 6 (8.7) |
SEP | 18 (26.1) |
Head and neck | 14 (20.3) |
Others | 4 (5.8) |
Anaplastic histology | |
No | 67 (97.1) |
Yes | 2 (2.9) |
Serum M protein at diagnosis (g/dL) | |
0 | 18 (26.1) |
0.1–1.0 | 11 (15.9) |
≥1.1 | 14 (20.3) |
Unknown | 26 (37.7) |
Type of M protein | |
IgG | 18 (72.0) |
Light chain only | 2 (8.0) |
Unknown | 5 (20.0) |
Bence Jones proteinuria | |
Absent | 32 (46.4) |
Present | 6 (8.7) |
Unknown | 31 (44.9) |
Serum free light chain ratio | |
Normal | 11 (15.9) |
Abnormal | 11 (15.9) |
Unknown | 47 (68.1) |
Treatment | |
RT only | 32 (46.4) |
Surgery only | 17 (24.6) |
Surgery + RT | 12 (17.4) |
Chemotherapy alone | 3 (4.3) |
RT + chemotherapy | 2 (2.9) |
Surgery + chemotherapy | 1 (1.4) |
Surgery + RT + chemotherapy |
2 (2.9) |
Radiation therapy |
|
No radiation therapy | 22 (31.9) |
<45 GyEQD2 | 31 (44.9) |
≥45 GyEQD2 | 15 (21.7) |
Surgical resection | |
No surgical resection | 36 (52.2) |
Partial resection | 3 (7.7) |
Complete resection | 30 (43.5) |
SPB, solitary plasmacytoma of bone; SEP, solitary extramedullary plasmacytoma; RT, radiation therapy; EQD2, equivalent dose in 2-Gy fractions at α/β of 10.
One patient received additional radiosurgery.
One patient with unknown dose excluded.
Risk factors associated with treatment outcome of solitary plasmacytoma (univariate analysis)
Number of patients | 5-yr LC (%) | p-value | 5-yr MMFS (%) | p-value | 5-yr FFS (%) | p-value | 5-yr OS (%) | p-value | |
---|---|---|---|---|---|---|---|---|---|
Age (yr) | |||||||||
<60 | 32 | 68.7 | 0.150 | 40.8 | 0.680 | 37.3 | 0.550 | 89.5 | 0.320 |
≥60 | 37 | 94.3 | 47.4 | 45.9 | 81.5 | ||||
Sex | |||||||||
Male | 41 | 72.5 | 0.130 | 37.4 | 0.220 | 34.0 | 0.098 | 85.8 | 0.190 |
Female | 28 | 94.4 | 53.4 | 53.4 | 84.2 | ||||
Tumor location | |||||||||
Extramedullary | 18 | 80.2 | 0.820 | 80.2 | 0.007 | 80.2 | 0.004 | 94.4 | 0.120 |
Bone | 51 | 82.9 | 32.1 | 29.4 | 81.2 | ||||
Tumor size (cm) | |||||||||
<5 | 33 | 83.8 | 0.710 | 70.2 | <0.001 | 63.7 | 0.001 | 93.2 | 0.076 |
≥5 | 30 | 87.1 | 22.6 | 22.8 | 74.9 | ||||
Anaplastic histology | |||||||||
No | 67 | 85.4 | <0.001 | 45.5 | 0.001 | 43.1 | <0.001 | 84.6 | 0.260 |
Yes | 2 | 0.0 | 0.0 | 0.0 | 100.0 | ||||
Serum M protein present | |||||||||
No | 18 | 90 | 0.470 | 55.7 | 0.220 | 55.7 | 0.130 | 87.1 | 0.650 |
Yes | 25 | 85.2 | 27.3 | 29.2 | 79.8 | ||||
Unknown | 26 | 77.0 | 47.8 | 43.1 | 88.1 | ||||
Bence Jones proteinuria | |||||||||
Absent | 32 | 88.0 | 0.160 | 37.9 | 0.820 | 39.2 | 0.790 | 85.2 | 0.890 |
Present | 6 | 100.0 | 50.0 | 50.0 | 100.0 | ||||
Unknown | 31 | 74.1 | 49.1 | 43.2 | 82.9 | ||||
Serum free light chain ratio | |||||||||
Normal | 11 | 100.0 | 0.320 | 67.5 | 0.046 | 67.5 | 0.019 | 90 | 0.910 |
Abnormal | 11 | 78.8 | 21.8 | 18.2 | 75.0 | ||||
Unknown | 47 | 79.6 | 45.2 | 43.0 | 86.3 | ||||
Treatment | |||||||||
RT alone | 32 | 79.8 | 0.340 | 31.3 | 0.560 | 31.4 | 0.530 | 83.6 | 0.260 |
Surgery alone | 17 | 72.9 | 55.8 | 49.0 | 94.1 | ||||
Surgery + RT | 12 | 100 | 50.9 | 50.9 | 75.0 |
LC, local control; MMFS, multiple myeloma-free survival; FFS, failure-free survival; OS, overall survival; RT, radiation therapy.
Risk factors associated with treatment outcome of solitary plasmacytoma (multivariate analysis)
LC |
MMFS |
FFS |
||||
---|---|---|---|---|---|---|
HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | |
Tumor location | ||||||
Extramedullary | - | Ref. | 0.036 | Ref. | 0.023 | |
Bone | - | 8.63 (1.15–64.9) | 10.28 (1.37–76.9) | |||
Size of lesion (cm) | ||||||
<5 | - | Ref. | 0.012 | Ref. | 0.043 | |
≥5 | - | 2.84 (1.26–6.42) | 2.18 (1.03–4.65) | |||
Anaplastic histology | ||||||
No | Ref. | <0.001 | Ref. | 0.002 | Ref. | 0.001 |
Yes | 50.6 (7.01–366) | 50.9 (4.14–626) | 66.6 (5.39–822) |
LC, local control; MMFS, multiple myeloma-free survival; FFS, failure-free survival; HR, hazard ratio; CI, confidence interval.
Correlation of disappearance of serum M protein and radiation therapy
RT dose |
Number of patients | Serum M protein |
|
---|---|---|---|
Disappearance (%) | Persistence (%) | ||
No RT | 2 | 0 (0.0) | 2 (100.0) |
<45 GyEQD2 | 12 | 3 (25.0) | 9 (75.0) |
≥45 GyEQD2 | 6 | 4 (66.7) | 2 (33.3) |
RT, radiation therapy; EQD2, equivalent dose in 2-Gy fractions at α/β of 10.
One patient with unknown dose excluded.
Correlation of various increases of serum M proteins with treatment failure
Number of patients (%) | Sensitivity (%) | Specificity (%) | AUC | Median time to treatment failure (mo) | |
---|---|---|---|---|---|
Increase ≥0.1 g/dL from current nadir | 16 (40.0) | 61.9 | 84.2 | 0.731 | 16.9 |
Two increases | 13 (37.1) | 55.6 | 82.4 | 0.690 | 20.8 |
Two consecutive increases | 12 (34.3) | 50.0 | 82.4 | 0.662 | 17.4 |
Increase double above nadir | 9 (22.5) | 33.3 | 89.5 | 0.614 | 4.0 |
AUC, area under the curve.