Serum paraprotein persistence and size determine outcome in a cohort of patients with a modern definition of plasmacytoma with up to 19 years of follow up

Serum paraprotein persistence and size determine outcome in a cohort of patients with a modern definition of plasmacytoma with up to 19 years of follow up Elisabet E. Manasanch , Chutima Kunacheewa , Catherine M. Claussen, Hans C. Lee, Sheeba K. Thomas, Jill Gunther, Chelsea C. Pinnix, Bouthaina S. Dabaja, Behrang Amini , Raymond Alexanian, Robert Z. Orlowski , Wenli Dong, Lei Feng and Donna M. Weber

0.083; Fig. S2). In all, 3-, 5-, and 10-year TTM rate were 34%, 38%, and 50% for the entire cohort (Table S1). The median TTM for the entire patient cohort was not reached (NR) and was shorter in SBP patients (6.7 years) than SEP patients (NR; p = 0.138). All SEP patients who progressed to myeloma did so within 5 years of diagnosis. Similar results were reported that showed that 84% of patients with SEP progressed within the first 3 years of the diagnosis 7 . In contrast, in our series, SBP patients continued to progress after 14 years of diagnosis.
The presence of SMP at baseline and 1 year after treatment and plasmacytoma size of ≥10 cm were associated with increased risk of progression to MM. Patients who had presence of a serum monoclonal protein (SMP) at baseline and a plasmacytoma size of ≥10 cm, compared to those who did not, had a lower median TTM of 5.3 years versus NR (p = 0.002), and 1.5 years versus NR (p =  If no additional (n =) is present, then that particular variable's information is available for all 71 patients 0.033), respectively. Those patients that had persistent SMP 1 year after treatment had a shorter TTM, 1.8 years versus NR compared to those who did not (p < 0.001; Fig. S2).
We included age, LDH, gender, β2-microglobulin, plasmacytoma type, size, immunoparesis, SMP presence at baseline, SMP persistence at 1 year after treatment, involved/uninvolved sFLC ratio, Bence Jones proteinuria, and radiation dose in univariate analysis (Tables S1 and  S2). SMP at baseline, its persistence after treatment, and plasmacytoma size ≥10 cm. were significant in univariate analysis for TTM. Multivariate analysis backwards selection model identified both SMP persistence at 1 year and plasmacytoma ≥10 cm. as independent variables for TTM rate with hazard ratios of 4.9 (95% CI 1.9-12.5; p = 0.001) and 4.5 (95% CI = 1.4-14.5; p < 0.012), respectively (Table  S3 and Fig. S3). We used these two variables to create a model predicting the rate of progression to MM. Sixty-six patients with available data were included in this model (Table S4 and Fig. 1).
The median PFS for the entire cohort was 9.4 years (0.3-19.5 years). Baseline immunoparesis and presence of paraprotein at diagnosis and at 1 year after treatment were associated with unfavorable PFS. For these factors, the median PFS was 10 versus 6 years (p = 0.043), NR versus 4.5 years (p < 0.001), and NR versus 1.8 years (p < 0.001), respectively (Table S5/S6 and Fig. S3).
At the median follow-up time, 23 out of 71 patients (32%) had died (14/50 (28%) patients in SBP and 9/21 (42%) patients in SEP). In the SBP and SEP group, six (n = 6/14; 43%) vs three (n = 3/9; 33%) patients had a plasma cell disorder related death, respectively (p = 0.904). SBP patients were more likely to have a plasma cell disorder related death when compared to SEP patients. Because the cause of death was unknown in half of the patients: 35% (n = 5/14) in SBP and 55% (n = 5/9) in SEP, it is difficult to draw conclusions regarding this.
The median OS for the entire cohort was NR with 10year OS of 76%. No OS difference was observed between SBP and SEP with a 10-year OS of 77 and 74% (p = 0.437), respectively. Patients with plasmacytoma size ≥10 cm had poorer OS (Table S7/S8 and Fig. S3).
Our study demonstrated comparable 3-and 5-year SP progression rates to MM with previous studies (14-38 and 45%, respectively) and confirmed that SBP patients have a shorter TTM than SEP patients. SBP tended to have worse PFS than SEP in our cohort, however it was not statistically significant (p = 0.263) [7][8][9] .
Several studies identified the presence of paraprotein at diagnosis, abnormal involved sFLC ratio, OMD, and residual paraprotein after treatment as poor prognosis factors for progression to MM 7,10,11 . Surprisingly, OMD did not predict progression in our cohort. This could be explained by flow analysis sensitivity in comparison to other published studies. For example, Paiva et al. used additional markers including CD20, CD27, CD28, CD81, and CD117 to determine clonality, which were not used in  Fig. 1 Model of high and low-risk SP by two risk factors (plasmacytoma size >10 cm. At diagnosis and persistent serum paraprotein 1 year after treatment) divided in to 2 groups: 0 risk factors and 1 and/or 2 risk factors. The rate of progression to MM was significantly higher in patients who had either a plasmacytoma size of ≥10 cm at diagnosis and/or persistent presence of serum paraprotein 1 year after treatment. our analysis 7 . The impact of plasmacytoma size remains controversial. Our study found that patients with plasmacytomas ≥10 cm had unfavorable TTM, PFS, and OS. These patients may need treatment with higher RT doses for bulkier tumors and/or the addition of systemic therapy to local RT control. This model (plasmacytoma >10 cm. and persistence of paraprotein 1 year after diagnosis) predicted, in our cohort, the progression risk to MM in SP patients (19% vs 65%, 30% vs 70%, and 39% vs 82% in patients with 0 and 1 or 2 factors, respectively). These rates are very similar (and even higher) than published rates of progression from studies for high-risk smoldering MM (SMM). Two randomized studies have shown improved PFS in SMM patients treated with lenalidomide ± dexamethasone 2,3 . One of these studies has also shown better OS for patients treated with lenalidomide/dexamethasone versus observation 3 . Adjuvant systemic therapy after radiation for SP patients to decrease the rate of progression to MM has been studied in the past. In 2019, a cooperative group study of 110 patients with SBP randomized to either ixazomib, lenalidomide, dexamethasone with zoledronic acid vs zoledronic acid (NCT02516423) after radiation therapy in the USA, was stopped due to lack of accrual. Thus, most studies investigating adjuvant therapy in SBP are either retrospective and/or in a small number of patients and the results remain controversial [12][13][14] . A recently published study of 61 SBP patients following a modern definition of plasmacytoma in France compared 37 patients treated with RT alone to 24 patients treated with the combination of RT and various adjuvant agents 15 . This study demonstrated a PFS benefit of the combination treatment, particularly in patients younger than 60 years of age.
Our study has several limitations including the retrospective nature of our data, no known cause of death for about half of the patients, inability to analyze SBP and EMP separately due to small EMP cohort size and absence of molecular/genetic analysis of plasmacytomas. Despite this, all patients underwent advanced imaging, BM MFC testing, and met IMWG 2014 criteria. We describe an easy to use clinical model including two variables: plasmacytoma >10 cm. at baseline and persistence of paraprotein after one year after treatment to predict progression to MM and may provide insights into the progression of patients in the clinic. These data need to be validated in other cohorts. International efforts are needed to lead adjuvant treatment studies in solitary plasmacytoma.