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Myeloma

Extensive bone marrow infiltration and abnormal free light chain ratio identifies patients with asymptomatic myeloma at high risk for progression to symptomatic disease

Abstract

Asymptomatic multiple myeloma (AMM) is characterized by a constant risk of progression to symptomatic myeloma. To evaluate previously recognized risk factors and to identify high-risk features we analyzed 96 patients with AMM and at least 18 months of follow-up. The progression rate at 1,2, and 3 years was 8%, 15% and 26%, respectively, and the projected 5-year progression rate was 38%. Extensive bone marrow (BM) infiltration, abnormal free light chain (FLC) ratio and serum monoclonal (M)-protein3 gr/dl were the most significant factors for progression, whereas the type of heavy (IgG vs IgA) or light chain or immunoparesis of the uninvolved immunoglobulins were not. Abnormal marrow signal of magnetic resonance imaging of the spine was associated with a significant risk of progression (median 15 months, P=0.001). Extensive BM infiltration 60% (hazard ratio, HR: 13.7, P<0.001) and FLC ratio100 (HR: 9, P=0.003) independently identified a ‘very high-risk’ group, which included 12.5% of patients with AMM and who progressed 18 months from initial diagnosis. Development of anemia and/or lytic bone lesions were the most common features of symptomatic progression. In conclusion, there is a subgroup of patients who have a substantial risk of progression to symptomatic disease that can be detected at diagnosis (either by extensive BM infiltration60% or FLC ratio100) and may be considered for immediate treatment.

Introduction

Asymptomatic multiple myeloma (AMM) is a proliferative but asymptomatic plasma cell disorder, which is characterized by a constant risk of progression to symptomatic myeloma.1, 2 According to the definition by the International Myeloma Working Group (IMWG), AMM is characterized by the presence of either 3 gr/dl or more of M-protein in the serum and/or 10% or more of clonal plasma cells in the bone marrow (BM), whereas there is no related organ or tissue impairment (that is no end-organ damage) or symptoms.1 According to the current recommendations, which have been recently updated,3 patients with AMM should be followed without treatment until they develop symptomatic disease.

The risk of progression of AMM to symptomatic myeloma varies between different series, depending also on the criteria for the characterization of asymptomatic myeloma and the criteria for progression to symptomatic disease requiring therapy.3, 4 Furthermore, there are significant differences in the risk of progression for individual patients: some individuals may not require therapy for several years, even decades, whereas others may progress to symptomatic myeloma within months. Several factors which are associated with an increased risk of progression have been identified, the most established being BM plasmacytosis 10% and serum monoclonal (M)-protein levels3 gr/dl.2, 5 In the series by Kyle et al.2 the overall risk of progression was 10% per year for the first 5 years, 3% per year for the next 5 years and 1% per year for the past 10 years; however, the median time to progression for patients with BM plasma cells 10% and M-protein level, 3 g/dl was 27 months, for patients with BM plasma cells 10% but M-protein level <3 g/dl was 93 months and for those with plasma cells <10% but a M-protein level 3 g/dl exceeded 220 months. The first two groups included 40% and 50%, respectively, of those with AMM in this report. Additional factors that have been identified include an abnormal free light chain (FLC) ratio,5 uninvolved immunoglobulin suppression,6 the presence of aberrant plasma cells by multiparametric flow cytometry,6 an abnormal magnetic resonance imaging (MRI)7 or the ‘evolving’ type characterized by the gradual increase of M-protein.8

Both for prognostic reasons and for monitoring planning, treatment strategy and intervention, it is important to identify those patients who are at a very high risk for early progression and which may be considered for immediate treatment. Thus, we considered that patients who progress to symptomatic multiple myeloma (MM) early that is within 18 months from the diagnosis of AMM, as ‘very high-risk’ group. The aim of our analysis was to identify features that could help in the identification of this group of individuals with ‘very high-risk’ AMM.

Patients and methods

Our analysis included 96 patients with AMM and a minimum follow-up of at least 18 months.

AMM was defined as serum M-protein (IgG or IgA) level of 3 g/dl and/or BM plasma cells 10%, in the absence of end-organ damage, such as lytic bone lesions, anemia, hypercalcemia or renal failure, that can be attributed to a plasma cell proliferative disorder.1

Progression of asymptomatic to symptomatic myeloma was defined according to the IMWG criteria.1, 3 More specifically the development of any of the following was considered as progression to symptomatic disease: serum calcium >1 mg/dl above the upper limit of normal or>11 mg/dl, increased serum creatinine>2 mg/dl (when no other obvious cause was present), development of anemia (hemoglobin 2 g/dl below the lower limit of normal or <10 g/dl), development of lytic bone lesions or osteoporosis with compression fractures, development of symptomatic hyperviscosity, amyloidosis, or of a new soft tissue plasmacytoma.

In all cases the BM biopsies were assessed for clonality of plasma cells to ensure that the clonal plasma cell population was 10% and were reviewed by an experienced haemopathologist (AT).

Evaluation of MRI pattern of marrow infiltration

Patients had an MRI of the spine for the evaluation of BM involvement. T1-weighted (TR/TE: 641/10, turbo factor: 4), Short TI Inversion Recovery (STIR) (TR/TE/TI:2000/70/150) and contrast-enhanced T1-weighted magnetic resonance (MR) images (TR/TE were obtained in the sagittal plane for the thoracic spine and for the lumbar spine and in the axial plane for the pelvis with a 1.5T unit (Phillips Medical Systems, Eindhoven, The Netherlands). MR images were analyzed for pattern of myelomatous involvement. The pattern of marrow involvement on MR images was characterized as: (1) normal when there was no evidence of abnormal signal intensity; (2) focal, which consisted of localized areas of abnormal marrow; the lesions are darker than yellow marrow and slightly darker than or isointense to red marrow on T1-weighted images, whereas on T2-weighted images focal lesions are brighter than both red and yellow marrow, and on enhanced T1-weighted images they enhance to various degrees; (3) diffuse, in which normal BM signal intensity is completely absent; the intervertebral disks appear brighter than or isointense to the diseased marrow; there is a diffuse decrease in the BM signal intensity of the marrow on T1-weighted images, a variable increase in the signal intensity of abnormal marrow on T2-weighted images, and after the administration of intravenous contrast, the abnormal marrow enhances and the intervertebral disks appear darker than the enhanced spine; and finally(4) variegated that consists of innumerable small foci of disease on a background of intact marrow, with small dark lesions on T1-weighted images, which become bright on T2-weighted image and enhance after the administration of intravenous contrast.9, 10, 11

Statistical analysis

For comparisons of differences among various groups we used the χ2-test for categorical variables (using Fisher’s exact test when appropriate) and with the Mann–Whitney test or analysis of variance for continuous variables. Time to progression to symptomatic myeloma was calculated from the date of initial diagnosis of AMM until the date when criteria for progression were first met. Death before progression to symptomatic myeloma was treated as competing risk and the cumulative incidence estimate is provided.12 Survival after progression to symptomatic myeloma was calculated from the date of treatment initiation until the date of death or last follow-up. Time to event curves were plotted with the Kaplan–Meier method and comparisons were made with log rank test. Multivariate analysis was performed with the use of Cox proportional hazards. Receiver-operating characteristic analysis was used to identify optimal cutoffs for progression to symptomatic myeloma at 18 months.

Results

The characteristics of the 96 patients who were included in the analysis are depicted in Table 1. Median age was 63 years (range 33–88 years); 7 (7%) were 40 years of age. Median hemoglobin was 12.6 gr/dl and 96% had hemoglobin >10 gr/dl. For patients presenting with anemia (hgb<10 gr/dl), extensive investigation excluded the myeloma as the cause of their anemia. In all cases the patients were heterozygotes of beta-thalassemia, a common trait in the Greek population. Median BM infiltration in patients with a hemoglobin<12 gr/dl was 15% and for patients with 12 gr/dl was 20% and this difference was not significant. Similar results were obtained when we used as a cutoff value of 14 gr/dl for hemoglobin.

Table 1 Characteristics of the patients (N=96)

Median serum M-protein was 1.65 gr/dl (range 0.1–5 gr/dl), whereas 12% of patients had M-protein levels 3 gr/dl. In 15% urine immunofixation was positive for either κ or λ light chains, whereas median levels of Bence Jones proteinuria was 85 mg/day; monoclonal urine protein 200 mg/day was not detected in any patient. Median epidermal growth factor receptor at the time of diagnosis was 81 ml/min/1.73 m2 (range 15–167 ml/min/1.73 m2); only 17% of the patients had epidermal growth factor receptor <60 ml/min/1.73 m2 (chronic kidney disease (CKD) stage 3 or greater) and only 3 (3%) patients had serum creatinine 2 mg/dl. In all these patients renal dysfunction was due to a cause other than myeloma. In 86 (91%) of the patients a BM trephine biopsy was available. Median BM infiltration was 20% (range 20–90%).

Progression to symptomatic MM and risk factors for progression

After a median follow-up of 45 months (a cumulative of 381 person/years, median 3 person/years), 38 patients have progressed to symptomatic MM (35 patients) or light chain (AL): amyloidosis (three patients). Two patients died before the development of symptomatic myeloma. The respective rates of progression, accounting for death as a competing risk, at 1, 2 and 3 years was 8%, 15% and 26%, respectively; the projected 5-year progression rate is 38% and the median time to progression is estimated at 66 months (Figure 1). Thus, during the first 5 years after the diagnosis of AMM the rate of progression to symptomatic MM is about 8% per year. However, after about 8 years the curve becomes less steep and the rate of progression is slower.

Figure 1
figure1

Progression to symptomatic myeloma for patients with AMM and a minimum follow-up of at least 18 months.

Several factors that have been associated with increased risk of progression to symptomatic MM were validated in our patients (Table 2). The extent of BM infiltration was the most significant factor for progression to symptomatic disease. Median time to progression for patients with a BM infiltration 10–19% was 90 months (95% confidence interval (CI) 62–117) vs 42 months (95% CI 20–60) for patients with a BM infiltration 20–49% and 31 months (95% CI 13.5–49) for patients with BM infiltration 50% (P<0.001) (Figure 2a). An increase of the BM infiltration by 10% was associated with a 57% increase (95% CI 33–85%, P<0.001) of the risk for progression to symptomatic disease.

Table 2 factors associated with progression to symptomatic myeloma for patients with AMM
Figure 2
figure2

(a) Progression to symptomatic myeloma for patients with BM plasma cell infiltration 10–19%, 20–49% and 50% (b) progression to symptomatic myeloma for patients with BM plasma cell infiltration 60% vs <60%.

In univariate analysis the type of heavy chain (IgG vs IgA) or light chain (κ vs λ) were not associated with increased risk of progression to symptomatic myeloma. Patients with 3 gr/dl of M-protein had a significant risk of progression vs those with 3 gr/dl (hazard ratio (HR): 2.36, 95% CI 1.001–5.4; P=0.046). In patients with BM plasma cells 10% and M-protein level 3 g/dl median time to progression was 19 months and for patients with BM plasma cells 10% but M-protein level <3 g/dl was 73 months. All our patients had BM infiltration 10% so we could not validate the risk of progression for patients with <10% infiltration and 3 gr/dl of M-protein.

Immunoparesis of at least one of the uninvolved immunoglobulins (defined as IgG<700 mg/dl, IgA<70 mg/dl or IgM<40 mg/dl) has been recognized as a risk factor for progression;6 however, in our patients we did not found any significant impact on the risk of progression (Table 2). Immunoparesis of both the uninvolved Igs was present in 37% of our patients and was not associated with increased risk of progression to symptomatic disease (median TTP 56 months for both Igs suppressed vs 73 months for 1 Ig suppressed vs not reached if there was no suppressed Ig, P=0.608). We then explored the importance of >25% decrease below the lower limit of normal of the uninvolved Igs: 48% of our patients had a decrease of at least one uninvolved Ig >25% below the lower limit of normal. In this case there was a trend for shorter TTP in patients with severely decreased (<25% below lower normal limit) at least one of the uninvolved Igs (median TTP 43 months vs 73 months, P=0.062). Then we analyzed patients that had both uninvolved immunoglobulins >25% below the lower limit: 16% of our patients had two uninvolved Igs >25% below lower limit and the median TTP was 56 months (95% 22–91 months).

A pattern of progressive increase of the levels of the M-protein8 was also associated with a shorter time to development of symptomatic myeloma: patients who had an increase 10% in at least two consecutive visits within the first year from diagnosis had a shorter time to progression compared with those without an increase of M-protein (35 vs 66 months, P=0.1).

Abnormal FLC ratio has been considered as a risk factor for progression to symptomatic myeloma and a FLC ratio 8 (either κ/λ or λ/κ) has been used to identify patients at risk:5 we also found that a FLC ratio 8 (or1/8) was associated with increased risk for progression to symptomatic MM. Thus, patients with FLC ratio 8 (or1/8) had a median time to progression of 55 months vs 73 months for those with FLC ratio <8 (or >1/8) (P=0.005) (Figure 3a). In accordance with the risk stratification model proposed by Dispenzieri et al. those with two of three risk features (BM plasma cells 10%, FLC ratio 8 and M-protein 3 gr/dl) had a median time to progression of 55 months vs 73 months for those with one risk factor. The number of patients with all three risk factors was very small.

Figure 3
figure3

(a) Progression to symptomatic myeloma for patients with a FLC ratio 8 vs those with FLC ratio <8 (b) progression to symptomatic myeloma for patients with a FLC ratio 100 vs those with FLC ratio <100.

Thirty seven patients had available MRI at diagnosis and 8 (22%) had an abnormal MRI signal (either focal (n=2) or diffuse pattern (n=6)9). Abnormal MRI was associated with a significant risk of progression (median time to progression 15 months, HR: 5.8, 95% CI 1.84–18.35; P=0.001) and 5 of 8 patients with abnormal MRI progressed within 18 months (Figure 4). There was also a significant correlation of abnormal MRI signal with extensive BM infiltration 60% (P=0.001) and abnormal FLC ratio (P=0.038).

Figure 4
figure4

Progression to symptomatic myeloma for patients with abnormal MRI vs patients with normal MRI.

Patterns of disease progression

Among the 35 patients who progressed to symptomatic myeloma, 17 (47%) developed at least one bone lesion, 1 (3%) developed also hypercalcemia, 20 (55%) developed anemia and 4(11%) had an increase of their serum creatinine (median serum creatinine at progression in these patients 3.1 mg/dl, range 2.1–6.2 mg/dl) (Table 3). Among the four patients who developed renal dysfunction, all had positive urine immunofixation for clonal light chains and estimated glomerular filtration rate (eGFR) 60 ml/min/1.73 m2 at diagnosis of AMM, due to unrelated conditions; only one of the patients who developed renal dysfunction required dialysis, but she had preexisting stage 4 kidney disease due to diabetes and hypertension.

Table 3 Patterns of disease progression in 38 patients who developed symptomatic myeloma (35 patients) or systemic light chain amyloidosis (3 patients)

The median survival after initiation of therapy, for the patients (n=35) who progressed to symptomatic myeloma was 85 months. The median survival of patients with symptomatic myeloma treated in our center in the same time period was 47 months. However, at progression to symptomatic MM, 31% of the patients were International Staging System (ISS)-1, 56% were ISS-2 and only 12.5% ISS-3.

We then analyzed our data in order to identify whether certain factors at diagnosis of AMM were predictive of the development of specific myeloma-defining features. The development of bone lesions was more common in patients who had abnormal MRI signal at diagnosis of AMM (71% vs 34%, P=0.1); the development of renal dysfunction was more common in patients with lambda light chain myeloma (15% vs 0%, P=0.13), whereas extensive BM infiltration and M-protein 3 gr/dl were more commonly associated with the development of anemia.

Characteristics of patients at ‘very high risk’ and identification of prognostic features

Owing to the heterogeneity of the natural history of AMM, it is important to identify those patients who are at high risk for early progression and for whom immediate treatment may be appropriate. Thus, we considered patients who progressed within the first 18 months from the initial diagnosis as a ‘very high-risk’ group and we sought to identify their characteristics and factors that are associated with this type of rapidly progressing AMM.

We identified 12 (12.5%) patients who progressed within 18 months from initial diagnosis (‘very high-risk’ group); their characteristics are depicted in Table 4. We also identified 15 (16%) patients with AMM who have not progressed to symptomatic disease after at least 5 years of follow-up and their characteristics are also presented in Table 2. Patients who remained stable without progression for at least 5 years have significantly less-extensive BM infiltration, lower levels of M-protein, usually normal MRI and a normal FLC ratio.

Table 4 Characteristics of patients with ‘very high-risk’ AMM, who progressed within 18 months from diagnosis and comparison with patients who have not progressed after at least 5 years of follow-up

To identify the best cutoff for the recognition of patients at high risk we used receiver-operating characteristic analysis for progression at 18 months. A BM infiltration 60% or higher had a specificity of 95.5% to identify patients who progressed at 18 months. Among eight patients with a BM infiltration 60% all have progressed to symptomatic myeloma and median time to progression to symptomatic disease was 15 months (range from 3 to 56 months); however, three patients with BM infiltration 60% progressed >30 months after initial diagnosis (Figure 2b). A BM infiltration 70% or higher had a specificity of 99% to identify patients who progressed at 18 months (median time to progression to symptomatic myeloma was 10 months, range 3–30 months), however, only 4% of our patients with AMM had BM infiltration 70%. We performed similar analysis to identify cutoffs for FLC ratio for progression to symptomatic disease within 18 months. A FLC ratio 50 had 88% specificity and a FLC ratio 100 had 98% specificity for progression at 18 months: 20% of patients had FLC ratio 50 and only 7% FLC ratio 100 (Figure 3B). Median time to disease progression for patients with FLC ratio 100 was 13 months (95% CI 3–23 months). An analysis to identify optimal cutoffs for progression within 24 months resulted in similar cutoff values.

We then performed a multivariate analysis, in which a highly abnormal FLC ratio (100 or 1/100) (P=0.003, HR: 9, 95% CI 2.15–39) and BM infiltration 60% (P<0.001, HR: 13.7, 95% CI 4.44–42.2) were the only independent risk factors for progression. In multivariate analysis for progression at 18 months (very high-risk AMM), the only independent factors that identified these patients were again FLC ratio 100 (OR: 17, 95% CI 1.4–212; P=0.028) and BM infiltration 60% (OR: 12.5, 95% CI 1.7–91; P=0.013). Thus, median time to progression for patients without any of the above risk factors was 73 vs 18 months for patients with any one of the above risk factors vs 8 months for patients with both risk factors present (P<0.001). Among patients with none of the above risk factors, 10% progressed within 18 months, among those with any one of the above factors 66% progressed at 18 months and of those with both these risk factors present, all progressed within 18 months.

Discussion

In recent years an increasing number of patients are diagnosed by chance with AMM. The risk of progression to symptomatic myeloma for patients with AMM is substantial compared with the general population, about 180–1000-fold higher.2 We found that the risk of progression is about 8% per year after the diagnosis of AMM, at least during the first 5 years, a rate which is not different than the one reported by Kyle et al. (about 10% per year in the first 5 years)2 or Musto et al. (about 8% per year).13 However, the natural history of asymptomatic MM is heterogeneous. Thus, a major task is the identification of those individuals with the highest risk of progression to the symptomatic state in which case very close monitoring and/or therapeutic intervention is required; on the other hand, in patients at low risk for progression it is important to avoid unnecessary treatments and interventions and to reduce the frequency of monitoring. The aim of our analysis was to identify factors that could improve the detection of patients which are at highest risk of progression.

Several earlier studies have identified several factors that are associated with increased risk of progression to symptomatic myeloma. In their seminal work, Kyle et al.2 from Mayo Clinic found that patients with both plasmacytosis10% and an M-peak3 gr/dl have significantly higher risk for progression to symptomatic disease compared with patients with either of the above. In our cohort, 12% of patients could be considered as high risk based on the above criteria with a median time to progression of 19 months (vs 27 months in the series of Kyle et al. and 25 months in the control arm of the randomized study by Mateos et al.14). In our cohort no patients had 3 gr/dl of M-protein with <10% of plasma cells. In the study by Kyle et al.2 <10% of the patients had plasma cells <10% and M-protein >3 gr/dl. However, in our study, 91% of patients had available BM trephine biopsy, which is more sensitive to identify patients with >10% plasma cells and it also assesses clonality, in contrast to morphology only by optical microscopy of the BM aspirate. Thus, our study had perhaps higher sensitivity in detecting patients with 10% of plasma cells, which is consistent with published data, which indicate that BM biopsy is more sensitive for direct estimation of the tumor load in MM compared with BM aspirates, especially in patients with a focal growth pattern.15, 16, 17 The median time to progression for the other patients (that is those with M-peak<3 gr/dl but BM plasmacytosis 10%), which are rated as ‘intermediate risk’ had a median time to progression of 73 months (95% CI 61–85 months) compared with 93 months in the series of Kyle et al.2 Dispenzieri et al.5 from the same group added the immunoglobulin FLC ratio 8 (or 1/8) in the previous criteria and stratified patients into three groups.

Perez-Persona et al.6 have used multiparametric flow cytometry to identify patients with AMM at high risk for progression. The authors reported also that immunoparesis was associated with increased risk of progression. However, multiparametric flow cytometry is not widely available and a certain degree of expertise and standardization is required. In our series we did not find that immunoparesis was a significant risk factor for progression to symptomatic MM. An evolving pattern of AMM has also been recognized by Rosinol et al.,8 in which patients with gradual increase of M-protein levels progress to symptomatic myeloma sooner and at higher rates that those with non-increasing M-protein. We also found that patients who had an increase 10% of their M-protein in at least two consecutive visits within the first year from diagnosis had a shorter time to progression compared with those without an increase of M-protein (35 vs 66 months, P=0.1), but this variable cannot be used at diagnosis to discriminate high-risk patients.

Recently, the Mayo Clinic group recognized that 3.2% of patients with a diagnosis of AMM had extensive plasmacytosis 60% and were at very high risk for early progression (median 7 months) and they proposed that these patients should be considered for immediate therapy at the time of diagnosis.18 In our series, we identified that 8% of patients had 60% of plasma cells at diagnosis of AMM and that these patients had a median time to disease progression of 15 months. On the basis of our data and the Mayo group data18 we believe that such patients with extensive plasmacytosis, which have a short time to disease progression, should not be considered ‘asymptomatic’ but rather ‘pro-symptomatic’ and may be candidates for immediate treatment. If such a patient is not treated promptly, more extensive workup, probably including MRI of the spine, whole-body MRI or positron emission tomography–computed tomography should be considered. Frequent hematologic assessment should also be considered because anemia develops commonly in patients with extensive BM infiltration and descending levels of hemoglobin should alert the physician to initiate treatment even before clinically significant anemia or other complications develop.

We also found that aberrant FLC ratio was associated with a higher risk of progression, but we further identified that a FLC ratio 100 (or 1/100) is also associated with a substantial risk of progression within 18 months from the initial diagnosis of AMM. The highly abnormal FLC ratio with a similar cutoff has also been identified as a predictor of imminent progression in patients with AMM.19 An extensive BM infiltration, especially by 60% clonal plasma cells and a highly abnormal FLC ratio (100 or 1/100) may identify a subgroup of patients with a substantial risk of progression within 18 months from diagnosis; actually all patients with both risk features present at the time of diagnosis progressed within 18 months. These two variables are readily and widely available. Furthermore, we found that abnormal signal of MRI of the spine may help identify patients at imminent risk for progression, but further validation in a larger number of patients is needed. Notably, abnormal MRI was also associated with the development of lytic bone lesions at the time of progression to symptomatic MM.

The development of symptomatic bone lesions such as compression fractures of the spine or fractures of long bones is associated with significant morbidity and compromises the patients’ quality of life. The use of bisphosphonates may reduce the risk of a skeletal complication in patients with AMM but do not alter the natural history of the disease.13, 20 Currently, the use of bisphosphonates is not recommended in all patients with asymptomatic myeloma but only in those with osteoporosis.3, 4 However, significant additional prognostic information can be obtained by MRI of the spine.9 In our patients with available MRI of the spine an abnormal signal was associated with a very high risk of progression and also with the development of lytic bone lesions. The importance of the presence of focal MRI lesions as a major adverse prognostic factor for the progression of AMM to symptomatic myeloma has also been published by Hillengass et al.,7 which reported that patients with more than one focal lesion in whole-body MRI had a median time to progression of 13 months, whereas a diffuse infiltration pattern of the BM was an additional independent risk factor. Recently, data from the SWOG S0120 Observational Trial were presented which showed that focal lesions in MRI of the spine were associated with >25-fold increase in the risk of progression to symptomatic myeloma.21 Thus, in patients with AMM MRI of the spine can guide the physicians to institute bisphosphonates therapy, monitor the patient closely for the development of bone disease and start therapy before a devastating skeletal complication occurs.

It is also important to note that only 4 (11%) of our patients developed renal dysfunction and all were patients who had preexisting renal dysfunction for reasons other than myeloma. This indicates that with standard follow-up of patients with AMM, significant renal dysfunction should not be a common complication. The IMWG has recently published recommendations on the monitoring and management of patients with AMM.3 According to these recommendations, patients with AMM should have a blood tests (including protein serum protein electrophoresis) every 2–3 months for the first year, followed by every 4–6 months for 1 year, with eventual 6- to 12-month evaluations if clinically stable thereafter; an MRI of the spine and pelvis is advised because it can detect occult lesions and, if present, predict for a more rapid progression to MM. We believe that for patients at high risk for progression close monitoring, every 1–2 months for 1–2 years and MRI of the spine at diagnosis should be considered. Also, we believe that a FLC measurement should be performed at least at initial evaluation, and that at initial assessment and at 3–6 month intervals all patients should have a 24 h urine collection for protein electrophoresis. The development of amyloidosis should also be considered as a complication of a long-standing plasma cell dyscrasia. The role of positron emission tomography–computed tomography needs to be further evaluated, but data indicate that may increase significantly the sensitivity of detection of extramedullary disease,22 although may be less sensitive for spine involvement.23

In conclusion, in our series of patients the 3-year probability of progression to symptomatic myeloma is 26% and 5-year about 40%, corresponding on a risk of progression of about 8% per year. There is a subgroup of patients with extensive BM infiltration (60%) and/ or highly abnormal FLC ratio (100), who have a substantial risk of progression to symptomatic disease within the first two years from the diagnosis of AMM. These high-risk patients may also have other features such as abnormal MRI of the spine. Patients at very high risk for progression should be considered for immediate treatment.

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Correspondence to M A Dimopoulos.

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Kastritis, E., Terpos, E., Moulopoulos, L. et al. Extensive bone marrow infiltration and abnormal free light chain ratio identifies patients with asymptomatic myeloma at high risk for progression to symptomatic disease. Leukemia 27, 947–953 (2013). https://doi.org/10.1038/leu.2012.309

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Keywords

  • free light chains
  • risk
  • smoldering myeloma
  • bone marrow
  • trephine biopsy
  • immunoparesis

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