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Article first published online: 11 JUL 2012
Copyright © 2012 American Cancer Society
Volume 118, Issue 22, pages 5544–5549, 15 November 2012
How to Cite
Rago, A., Grammatico, S., Za, T., Levi, A., Mecarocci, S., Siniscalchi, A., De Rosa, L., Felici, S., Bongarzoni, V., Piccioni, A. L., La Verde, G., Pisani, F., Franceschini, L., Paviglianiti, A. L., Caravita, T., Petrucci, M. T., De Stefano, V., Cimino, G. and on behalf of the Multiple Myeloma GIMEMA-Latium Region Working Group (2012), Prognostic factors associated with progression of smoldering multiple myeloma to symptomatic form. Cancer, 118: 5544–5549. doi: 10.1002/cncr.27657
We are grateful to professor Giovanni Codacci Pisanelli for his critical review of the manuscript.
In addition to the authors, the following investigators (listed in alphabetic order) participated in the study: A. Andriani, MD, Hematology, Nuovo Regina Margherita Hospital (Rome); L. Annino, MD, Hematology, S. Giovanni Addolorata Hospital (Rome); G. Avvisati, MD, PhD, Hematology, Stem Cell Transplantation, Transfusion Medicine and Cellular Therapy Unit, University “Campus Bio-Medico” (Rome); A. Bagnato, MD, Hematology, Sandro Pertini Hospital (Rome); m. Cantonetti is Hematology Unit , Tor Vergata, Rome; p De Fabritis IS Hematology Unit, S. Eugenio Hospital Rome; I. Majolino, MD, Hematology Unit, S. Camillo Hospital (Rome); B. Monarca, MD, Hematology, S. Andrea Hospital (Rome); C. Petti, MD, Department of Hematology, Regina Elena National Cancer Institute (Rome).
- Issue published online: 30 OCT 2012
- Article first published online: 11 JUL 2012
- Manuscript Accepted: 16 APR 2012
- Manuscript Revised: 5 APR 2012
- Manuscript Received: 16 FEB 2012
Vol. 119, Issue 6, 1289, Article first published online: 26 NOV 2012
- smoldering multiple myeloma;
- bone marrow plasma cells;
- symptomatic multiple myeloma;
- bone marrow aspirate;
- bone marrow biopsy
Smoldering multiple myeloma (SMM) presents a high risk of progression to symptomatic MM (sy-MM). Herein, we analyzed some predictors of development of sy-MM. In 144 patients with SMM, we also compared the risk of progression predicted by bone marrow plasma cell (BMPC) involvement on the bone marrow biopsy (BMB) versus bone marrow aspirates (BMA).
From January 1980 to July 2010, 397 patients with SMM observed in 12 centers of the Multiple Myeloma GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) Latium Working Group have been analyzed. At progression to sy-MM, the severity of clinical presentation was graded according to the need of intensive supportive care.
After a median follow-up of 135 months, the cumulative incidence of progression rates to sy-MM were 45%, 55%, and 75% at 10, 15, and 20 years, respectively. Hemoglobin ≤12.5 g/dL, monoclonal component ≥2.5 g/dL, and BMPC ≥60% were the only parameters negatively affecting the cumulative incidence of progression. In particular, 10 of 397 (2.5%) patients with BMPC ≥60% had a 5.6-fold increased risk of fast progression (within 2 years), which occurred with severe clinical manifestations in 62% of cases. BMB was more sensitive for the detection of BMPC involvement, even though BMA was a more reliable indicator of a rapid progression to sy-MM.
The highest risk of rapid evolution to sy-MM and the severity of clinical manifestation at the progression suggest that SMM patients with a BMPC ≥60% should be treated soon after diagnosis. Moreover, BMPC is a more reliable index for progression to sy-MM if assessed by BMA. Cancer 2012. © 2012 American Cancer Society.
Smoldering multiple myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells with a high risk of progression to symptomatic multiple myeloma (sy-MM). This risk is estimated at 10% per year during the first 5 years.1-4
Progression represents the most serious clinical problem of patients with SMM. Therefore, several groups2, 5, 6 proposed different score systems to distinguish between patients with slowly and rapidly progressive SMM.
However, all these systems, not only failed to identify very rapidly progressive SMM, but in some cases are difficult to use in clinical practice, requiring complex or expensive tools such as multiparametric flow cytometry of bone marrow plasma cells (BMPCs), or comparative genomic hybridization. Several reports considering the high rate of progression of SMM to sy-MM have analyzed the value of an early treatment. However, none of these studies demonstrated a clear benefit for patients in terms of overall survival when they were treated in the absence of symptoms.7-13 Therefore, at present, in the absence of reliable elements to predict disease progression, the standard care for SMM patients remains a close follow-up without treatment until MM symptoms develop.3 Recently, however, Rajkumar et al13 proposed that a high BMPC involvement identifies a subset of patients who invariably progress to sy-MM within 2 years from diagnosis.
Here, we analyzed clinical and biological characteristics of patients who received a diagnosis of SMM from January 1980 to July 2010 in 12 hematological centers adhering to the Multiple Myeloma GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) district of the Latium Region, Italy, including the parameters proposed by Rajkumar et al.13
MATERIALS AND METHODS
Detailed medical records were obtained from 12 hematological centers of the Multiple Myeloma GIMEMA Latium Working Group. In all cases, the diagnosis of SMM and the progression to sy-MM was established according to the criteria of the International Myeloma Working Group.4 In particular, SMM was characterized by the presence of a monoclonal component (MC) of ≥3 g/dL and/or BMPC infiltration of ≥10%, and/or the presence of Bence-Jones proteinuria ≥1 g/dL in the absence of end-organ damage, which is signaled by lytic bone lesions, hypercalcemia, renal insufficiency, and/or anemia (CRAB). MC of serum and urine were identified with cellulose acetate or agarose-gel electrophoresis in combination with immunofixation.
Evaluation of BMPC Infiltrate
The BMPC involvement rate was established at diagnosis of SMM in all cases by optical examination of a May-Grunwald Giemsa staining bone marrow aspirate (BMA) with a differential count of 200 nucleated cells. A total of 144 cases also had an examination of paraffin-embedded bone marrow biopsy (BMB) specimens stained with hematoxylin and eosin and immunohistochemically stained with anti-CD138 antibody.
Grading of Clinical Manifestation
The end-organ damage occurring at the time of progression to sy-MM was defined by the appearance of 1 or more of the following findings: hypercalcemia, renal insufficiency, anemia, or bone lesions (CRAB). To grade the level of end-organ damage, we grouped our SMM patients according to the severity of their clinical manifestation. We defined patients with severe clinical manifestation as those in which clinical signs of MM required any of the following therapeutic interventions: red cell transfusions for anemia, dialysis for acute renal insufficiency (ARI), treatment of pathological fractures for bone lesions or treatment of metabolic coma for hypercalcemia. All cases who did not undergo at least 1 of the aforementioned therapeutic procedures were defined as having a mild clinical manifestation of MM.
The risk of progression to sy-MM was assessed according to the following factors: hemoglobin (Hgb) level (<12.5 g/dL vs ≥12.5 g/dL), MC level (<2.5 g/dL vs ≥2.5 g/dL), BMPC involvement rate as evaluated by BMA (group 1 [<15%] vs group 2 [15%-59%] vs group 3 [≥60%]), β2-microglobulin (<2.7 ng/mL vs ≥2.7 ng/mL), VES (erythrocyte sedimentation rate) <50 vs ≥50), serum calcium (<8.9 mg/dL vs ≥8.9 mg/dL), sex (male vs female), and age (<60 years vs ≥60 years).
Data are presented as median (range) for quantitative variables and as absolute numbers for qualitative variables. Comparisons of groups were performed by using the nonparametric Mann-Whitney test for quantitative variables and chi-square test for qualitative variables. P values <.05 were considered statistically significant. Multivariate analysis was performed to explore the independent effect of variables that showed a significant influence on progression-free survival in the univariate analysis. Cumulative incidence of progression (CIP) was defined as the time from diagnosis to progression to sy-MM. Survival curves were plotted according to the Kaplan-Meier method, using the log-rank test for comparison. Data processing and analysis were performed with NCSS 2007 for Windows.14
We analyzed 397 SMM subjects who received such a diagnosis between January 1980 and December 2010. The MC isotypes were as follows: IgAk, 48 of 397 patients (12.1%); IgAλ, 31 of 397 patients (7.8%); IgDλ, 1 of 397 patients (0.2%); IgGk, 202 of 397 patients (60%); IgGλ, 103 of 397 patients (25.9%); IgGk + IgMk, 2 of 397 patients (0.5%); IgGk + IgAk, 2 of 397 patients (0.5%); IgEλ, 1 of 397 patients (0.2%); IgMk, 1 of 397 patients (0.2%); IgGλ + IgAλ, 1 of 397 patients (0.2%); monoclonal κ and λ light chain, 2 of 397 patients (0.5%); and 3 of 397 patients (0.7%), respectively. Immuno-electrophoresis or immunofixation was performed on urine samples from 259 of the patients (94%). Of those, 92 (36%) had a monoclonal κ light chain, 43 (17%) had a λ light chain, and 262 (47%) did not present monoclonal light chains in their urine. The other main diagnostic clinicobiological characteristics observed in the 397 SMM cases are reported in Table 1.
|Median age, y (range)||63.1 (19-89)|
|Median β2-microglobulin (range)||2.5 (0.1-30)|
|≥12.5 g/dL||74/227 (32.6%)|
|11-12.5 g/dL||64/170 (37.6%)|
|Monoclonal component levels|
|>2.5 g/dL||90/197 (45.6%)|
|≤2.5 g/dL||58/200 (29%)|
|Bone marrow plasma cell rate:|
|Group 1 (<15%)||52/155 (33%)|
|Group 2 (15%-60%)||89/232 (38%)|
|Group 3 (>60%)||8/10 (80%)|
|No. of progressed patients (%)||149 (37.5)|
|Grade of clinical manifestation at progression, no. patients (%)|
All 397 patients underwent BMA that showed a median percentage of BPMC involvement of 19% (range, 1%-70%).
At the time of analysis, among the total group of 397 cases, 332 were alive, 51 had died, and 14 were lost to follow-up. The resulting actuarial overall survival rates were 43%, 38%, and 24% at 10, 15, and 20 years, respectively. After a median follow-up of 54 months (range, 4-373 months) progression to sy-MM occurred in 149 cases (37.5%) with an actuarial CIP to sy-MM of 45%, 55%, and 75% at 10, 15, and 20 years, respectively.
At the univariate analysis, levels of Hgb, MC, and BMPC rate were the only prognostic factors significantly affecting the actuarial CIP rates, that, at 120 months, were, respectively, 65% and 50% (P = .02) for patients with Hgb levels ≥12.5 or between 10.5 and 12.5 g/dL, 65% and 35% (P < .001) for patients with MC levels ≥ or <2.5 g/dL and 50%, 60%, and 100% (P < .001) for patients with BMPC involvement rate <15% or 15%-30% or >60%.
The data of the multivariate analysis, reported in Table 2, showed that despite these 3 risk factors remaining as independent variables negatively affecting the actuarial CIP rates, BMPC rate ≥60% was the only factor associated with the highest relative risk (5.6), and the earliest CIP (within 24 months; Fig. 1). Therefore, in Table 3, we reported the main clinical characteristics of SMM patients grouped according to BMPC rate. As shown, group 1 included 155 patients (39%), group 2 had 232 patients (58%), and group 3 had 10 patients (2.5%). Progression to sy-MM occurred in 52 (35%), 90 (38.6%), and 8 (80%) patients of the groups 1, 2, and 3 (P < .001), respectively. Patients of group 3 also differed from the other 2 groups for a significantly lower level of Hgb (P = .02), a higher level of serum MC (P < .001) and for a higher rate of severe clinical manifestations at progression (P = .002). In particular, among the 8 patients of group 3 who progressed to sy-MM, 3 cases presented an ARI needing dialysis and 2 pathological fractures. A BMPC rate ≥60% did not affect the probability of overall survival.
|Risk Factors||RR||95% CI||P|
|Hgb < 12.5 g/dL||0.6||0.4-0.9||.0074|
|MC > 2.5 g/dL||2.0||1.4-2.9||.0001|
|BMPC > 60%||5.6||2.5-12.4||<.0001|
|Characteristic||Group 1 (BMPC < 15%) No. of pts = 155 (39%)||Group 2 (BMPC 15%-59%) No. of pts = 232 (58.5%)||Group 3 (BMPC ≥ 60%) No. of pts. = 10 (2.5%)||P|
|Median age, y||61||66||63||NS|
|Median Hgb, g/dL||13||12.9||12.5||.02|
|Median MC, g/L||2.2||2.7||4.2||<.001|
|Median BMPC %||11||23||61||<.001|
|No. of progressed pts.(%)||52 (33)||89 (38)||8 (80)||<.001|
|Grade of clinical manifestation at progression, no. of patients (%)|
|Mild||119 (77%)||146 (63%)||4 (37%)||.002|
|Severe||36 (23%)||86 (37%)||6 (63%)|
The comparison between the role of BMA versus BMB in evaluating BMPC involvement rate and in terms of prediction of progression to sy-MM was performed in the 144 patients who underwent both procedures. The mean BMPC rates evaluated by BMB or by BMA were 19% and 25%, respectively (P < .001; Table 4). As a result, the distributions of patients within the 3 prognostic groups determined by the BMPC rate estimated at BMA or at BMB was also significantly different (P < .001). At BMB, 7 patients had a BMPC ≥60% (group 3). In these 7 patients, a concordance between BMA and BMB was observed in only 1 case. All the other 6 discordant cases at BMA showed a BMPC rate <60%, that in 2 cases resulted in <15%, and in 4 cases was between 15% and 60%. An evolution to sy-MM occurred in 5 of these 7 cases. The concordant patient evolved early after 1 year from diagnosis, whereas the remaining 4 cases progressed more slowly to sy-MM at 24, 52, 56, and 96 months. The 7 patients classified as group 3 at BMB had a CIP rate rising to 100% at 96 months, whereas the CIP rates of group 1 and group 2 patients were 65% and 75%, at 240 months, respectively (P < .002; Fig. 2).
|Median BMPC rate||19||25||<.001|
In this group of 144 patients, no case with a BMPC rate <60% at BMA showed a corresponding higher BMPC involvement rate at BMB.
In this study, we retrospectively analyzed the clinical outcome, in terms of disease progression to sy-MM, of a cohort of 397 patients with SMM followed over a period of 3 decades, at 12 hematological units of the Multiple Myeloma GIMEMA Latium Region Working Group. As far as we know, the present series is one of the largest reported in the literature. With the exception of a slight prevalence of females, accounting for 55% of the total group of patients, the demographic and clinicobiological characteristics and actuarial CIP rate of our series were similar to those of the 2 largest groups of SMM previously reported.2, 6
The stratification of our patients according to the BMPC involvement rate allowed us to confirm the data recently reported by Rajkumar et al,13 on the high risk of a rapid progression to sy-MM in patients with a BMPC involvement of >60%. In fact, these patients who, similar to that reported by Rajkumar et al,13 accounted for 2.5% of the total group (10 of 397 patients), showed a CIP rate of 100% at 24 months. This CIP rate was significantly worse than that of the 2 other patient groups (Fig. 2).
In addition, compared to the other 2 patient groups, the 10 patients of group 3 presented at diagnosis a significantly lower Hgb level, a higher MC amount and, most importantly, at progression to sy-MM, a higher rate of severe clinical manifestations. In fact, among the 8 patients progressing to sy-MM, 3 cases presented an ARI needing dialysis and 2 patients experienced pathological fractures. Even if the small sample size of the high-risk SMM patients did not allow us to draw final conclusion of the probability of survival, the present data demonstrate that the simple and easily detectable evaluation of BMPC infiltration at BMA could identify SMM patients at very high and rapid risk of progression to sy-MM. We believe that this observation, although confirmatory of that recently reported by Rajkumar et al,13 and limited to a very small subset of patients, is extremely relevant because it contributes to reinforcing the suggestion that this subset of SMM patients should be treated right away, before the appearance of CRAB.
To date, several other biological markers such as cytogenetic evidence,15 gene expression signatures,16 genomic hybridization,17 and multiparametric flow cytometry18, 19, 20 were reported to correlate with a higher probability to progress to sy-MM. Rosiñol et al21 have recently identified 2 types of SMM defined as evolving and nonevolving, according to their likelihood to evolve into sy-MM. However, all these studies, even employing the aforementioned sophisticated indicators, failed to identify patients with very rapidly progressive SMM (within 2 years).
In addition to what was demonstrated by the study of Rajkumar et al,13 we showed that a lower BMPC rate <15% did not identify SMM patients with a more favorable clinical outcome in terms of progression to sy-MM. In fact, this group of SMM patients did present clinicobiological characteristics and actuarial CIP rates similar to those of patients with a BMPC rate between 15% and 60%.
Moreover, although it is well established that in characterization of MM, BMB is superior to BMA for the direct estimation of the tumor load,22, 23 it is still debated whether 1 of these 2 procedures might have superior prognostic value. This is particularly true in the setting of SMM, where, as far as we know, no comparative data are available at the moment. Herein, in 144 SMM cases, in which the BMPC involvement rate was estimated either by BMA and BMB, we confirmed that the rate of ≥60% plasma cells detected by BMA was more prognostic for rapid progression of SMM to sy-MM compared with BMB. However, it is worth noting that, in our experience, the higher sensitivity of BMB did not translate into a higher clinical impact in predicting disease progression. In fact, of the 7 cases with a ≥60% BMPC rate at BMB, only the concordant case showed a rapid (within 12 months) progression to sy-MM, whereas the other 6 cases, with an inferior BMPC involvement rate at BMA, progressed more slowly. This finding may suggest that, more often than is usually observed with BMB, a high percentage of BMPC in BMA likely reflects a diffuse growth pattern of MM. Therefore, in instances where the BMB is 60% or more but the BMA is lower, a careful re-review of the slides may be warranted. If unclear, it is advisable to repeat BMA more often than usual.
In conclusion, the present data show that SMM patients with ≥60% BMPC rate at diagnosis presented a very rapid progressions to sy-MM, which in the majority of cases were also characterized by more severe clinical manifestations, strongly reinforcing the recommendations of Rajkumar et al13 and suggesting that these SMM patients should probably be candidates for treatment already at diagnosis. Furthermore, with respect to the identification of these very high-risk SMM patients, in our study, BMPC of 60% or higher detected by BMA was more prognostic for rapid progression to sy-MM compared with BMB. This finding strongly suggests that BMB is not helpful in the assessment of patients with SMM.
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURE
The authors made no disclosure.
- 14NCSS, PASS, and GESS [computer program]. Kaysville, UT: NCSS, LLC; 2007..
- 20Risk of progression in smouldering myeloma and monoclonal gammopathies of unknown significance: comparative analysis of the evolution of monoclonal component and multiparameter flow cytometry of bone marrow plasma cells. Br J Haematol. 2010; 148: 110-114., , , et al.