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ABSTRACT

Background Smoldering (asymptomatic) multiple myeloma is an asymptomatic plasma-cell proliferative disorder associated with a high risk of progression to symptomatic multiple myeloma or amyloidosis. Prognostic factors for the progression and outcome of this disease are unclear.

Methods We searched a computerized database and reviewed the medical records of all patients at Mayo Clinic who fulfilled the criteria of the International Myeloma Working Group for the diagnosis of smoldering multiple myeloma between 1970 and 1995. Bone marrow aspirate and biopsy specimens were studied, and patients were followed throughout the course of disease.

Results During the 26-year period, 276 patients fulfilled the criteria for smoldering multiple myeloma. During 2131 cumulative person-years of follow-up, symptomatic multiple myeloma or amyloidosis developed in 163 persons (59%). The overall risk of progression was 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% per year for the last 10 years; the cumulative probability of progression was 73% at 15 years. At diagnosis, significant risk factors for progression included the serum level and type of monoclonal protein, the presence of urinary light chain, the extent and pattern of bone marrow involvement, and the reduction in uninvolved immunoglobulins. The proportion of plasma cells in the bone marrow and the serum monoclonal protein level were combined to create a risk-stratification model with three distinct prognostic groups.

Conclusions The risk of progression from smoldering multiple myeloma to symptomatic disease is related to the proportion of bone marrow plasma cells and the serum monoclonal protein level at diagnosis.

We report here on the prognosis and risk factors for progression of smoldering multiple myeloma in a large cohort of patients for whom long-term follow-up data were available and in whom the disease was defined with the use of criteria of the International Myeloma Working Group. These criteria do not include karyotyping, fluorescence in situ hybridization (FISH), or magnetic resonance imaging for detection of bone lesions.⁸ Instead, the group defined smoldering multiple myeloma as a disorder in which the patient has a serum monoclonal protein level of 3 g per deciliter or more or a proportion of plasma cells in the bone marrow of 10% or more but no end-organ damage. The diagnosis of active multiple myeloma requires the presence of a monoclonal protein in serum or urine, plasma cells in the bone marrow, or plasmacytoma and end-organ damage related to plasma-cell proliferation. End-organ damage was defined as hypercalcemia, renal insufficiency, anemia, bone lesions, or recurrent bacterial infections.⁸

The study cohort was stratified into three prognostic groups at initial diagnosis: group 1 had a proportion of bone marrow plasma cells of 10% or more and a serum monoclonal protein level of 3 g per deciliter or more; group 2, 10% or more bone marrow plasma cells and a serum monoclonal protein level of less than 3 g per deciliter; and group 3, less than 10% bone marrow plasma cells and a serum monoclonal protein level of 3 g per deciliter or more.

Methods

Study Cohort

After the study was approved by the Mayo Clinic's institutional review board, we searched a computerized database and reviewed the medical records of all patients who had been seen at the Mayo Clinic within 30 days after detection of an IgG or IgA monoclonal protein level of 3 g per deciliter or more or bone marrow containing 10% or more plasma cells. Patients were evaluated from 1970 to 1995, an interval allowing for a minimum potential follow-up of 10 years. Patients with active multiple myeloma or primary amyloidosis were excluded, as were patients who had ever received chemotherapy.

Bone Marrow Examination

We estimated the proportion of plasma cells in bone marrow aspirates and in paraffin-embedded bone marrow biopsy specimens stained with hematoxylin and eosin, with a differential count of 200 to 500 cells. In addition, immunoperoxidase stains were applied to paraffin sections of the bone marrow biopsy specimens according to previously published methods⁹ with the use of antibodies directed against CD138, an antigen normally expressed on the surface of plasma cells (Dako Cytomation), multiple myeloma oncogene 1 (MUM1, Dako Cytomation), and cyclin D1 (Biocare). Cyclin D1 expression is thought to be a surrogate for the translocation t(11;14)(q14;q32); CD138 is a cytoplasmic and Golgi stain, and MUM1 is a nuclear stain. The bone marrow–aspirate, biopsy, and immunoperoxidase stains were reviewed by one of two hematopathologists.

Plasma-cell estimates by all three methods were combined to provide the proportion of bone marrow plasma cells, categorized as 0 to 4%, 5 to 9%, 10 to 14%, and so on. Cases with discordance between the plasma-cell estimates in bone marrow aspirate and biopsy specimens were reviewed individually, and the final plasma-cell estimate represented an average of the aspirate and biopsy estimates. The pattern of involvement of plasma cells in bone marrow (singly distributed cells, small clusters of cells, cells filling at least one interfatty marrow space, or sheets of cells spanning the interfatty spaces)¹⁰ and the overall bone marrow cellularity were recorded in each case. Monoclonal proteins were identified with cellulose acetate or agarose-gel electrophoresis in combination with immunoelectrophoresis or immunofixation.¹¹

Follow-up and Study End Point

Follow-up included a review of the medical records of patients at the Mayo Clinic and of death certificates for patients who had died. Patients were sent letters of inquiry if they had not visited the Mayo Clinic in the preceding year. The primary study end point was progression to active multiple myeloma (anemia, hypercalcemia, renal insufficiency, or bone lesions) or amyloidosis (positive results on Congo red staining and characteristic clinical features), with either one requiring therapy.

Statistical Analysis

Progression was calculated in terms of both the cumulative probability and the cumulative incidence of progression. The cumulative probability was calculated by means of a Kaplan–Meier analysis¹² in which data from patients who had died were censored; curves were compared with use of the log-rank test.¹³ The cumulative incidence curve, which explicitly accounted for death as a competing risk, was computed with the method of Gooley et al.¹⁴ Effects of potential risk factors on progression rates were examined in a Cox proportional-hazards model.¹⁵

The risk of progression to active multiple myeloma or amyloidosis, as compared with that in the general population, was assessed with standardized incidence ratios,¹⁶ whereby observed cases were compared with the number expected by applying age-specific and sex-specific incidence rates for multiple myeloma in the white cohort from the Iowa Surveillance, Epidemiology, and End Results program¹⁷ to the person-years of follow-up specific for age, sex, and calendar year in our study cohort. The age-specific and sex-specific incidence rates of amyloidosis were based on data from Olmsted County, Minnesota.¹⁸

Results

Characteristics of the Patients

Of the 3549 patients with myeloma diagnosed between 1970 and 1995, 276 (8%) fulfilled the criteria for smoldering multiple myeloma. The median age at diagnosis was 64 years (range, 26 to 90), and only eight patients (3%) were younger than 40 years of age. A total of 171 patients (62%) were men, and 105 (38%) were women.

Laboratory and Bone Marrow Findings

The initial hemoglobin level ranged from 10.0 to 16.8 g per deciliter (median, 13.0). The hemoglobin level was 12 g per deciliter or more in 76% of patients.

The serum monoclonal protein level at the time of diagnosis ranged from 0.5 to 5.4 g per deciliter (median, 2.9). The levels for 11% of the patients were 4 g per deciliter or more (including 1% with 5 g per deciliter or more), those for 37% were 3 to 3.9 g per deciliter, and those for 52% were less than 3 g per deciliter. The monoclonal protein level in the 27 patients in group 3 (with a monoclonal protein spike of 3 g per deciliter and <10% plasma cells) ranged from 3.0 to 3.9 g per deciliter (median, 3.1). Of these 27 patients, 26 had monoclonal IgG present in serum, whereas only 2 had a urinary monoclonal protein level of more than 200 mg per 24 hours (240 and 450 mg per 24 hours). Of the 276 patients, 74% had monoclonal IgG, 22.5% had IgA, 0.5% had IgD, and 3% had biclonal immunoglobulins. The light-chain type was in 67% and in 33%. Concentrations of uninvolved (normal, polyclonal, or background) immunoglobulins were reduced in 83% of 230 patients whose immunoglobulin levels were determined quantitatively. A single reduction in immunoglobulin was found in 31% of patients, whereas 52% had a reduction of both uninvolved immunoglobulins (e.g., reduced IgM and IgA in a patient with a monoclonal IgG).

Immunoelectrophoresis or immunofixation was performed on urine samples from 259 of the patients (94%). Of those patients, 92 (36%) had a monoclonal light chain, 43 (17%) had a light chain, and 123 (47%) had negative results for monoclonal light chain. A urinary monoclonal protein level of 0.1 g or less per 24 hours was found in 84%; only four patients (1.5%) had a level of more than 1.0 g per 24 hours.

The bone marrow aspirate and biopsy specimens were examined in all 276 patients (Figure 1). In the plasma-cell category, the most common proportion was 15 to 19%. Of the 276 patients, 10% had less than 10% plasma cells in the marrow, and 10% had 50% or more plasma cells. Cyclin D1 was expressed by the plasma cells in 18% of the bone marrow specimens.

View larger version (97K): [in this window] [in a new window]   Figure 1. Bone Marrow–Biopsy Specimens from Two Patients with Smoldering Multiple Myeloma. In Panel A, in which bone marrow cells from one patient have been stained with hematoxylin and eosin, plasma cells are difficult to discern by morphologic analysis alone. In Panel B, cells from the same specimen have undergone immunohistochemical staining for MUM1. Strong nuclear staining is present in the plasma cells, but this pattern leads to a slight underestimation of the number of plasma cells. In Panel C, immunohistochemical staining for CD138 on the same specimen shows strong cytoplasmic and Golgi staining in plasma cells, but this pattern results in a slight overestimation of the number of plasma cells. Thus, it is essential to combine the estimates of all methods to estimate the number of plasma cells accurately. In Panel D, a specimen from another patient with smoldering multiple myeloma shows monotonous plasma-cell aggregates filling interfatty marrow spaces (hematoxylin and eosin). In Panel E, immunohistochemical staining for CD138 on the same specimen shows plasma-cell aggregates filling interfatty marrow spaces.

 
Outcome

During 2131 cumulative person-years of follow-up (range, 0 to 29; median, 6.1), 85% of the patients with smoldering multiple myeloma died (median follow-up of those still living, 11.6 years). During this period, active multiple myeloma developed in 158 patients (57%), who had a median survival after the time of diagnosis of 3.4 years; amyloidosis developed in 5 (2%) (Table 1). The cumulative probability of progression to active multiple myeloma or amyloidosis was 51% at 5 years, 66% at 10 years, and 73% at 15 years; the median time to progression was 4.8 years (Figure 2). The overall risk of progression was 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% per year for the last 10 years.

View this table: [in this window] [in a new window]   Table 1. Relative Risk of Progression among 276 Patients with Smoldering Multiple Myeloma, According to Prognostic Group.

 

View larger version (18K): [in this window] [in a new window]   Figure 2. Probability of Progression to Active Multiple Myeloma or Primary Amyloidosis in Patients with Smoldering Multiple Myeloma or Monoclonal Gammopathy of Undetermined Significance (MGUS). I bars denote 95% confidence intervals.

 
The number of patients with progression to active multiple myeloma was 522 times the number of persons without smoldering multiple myeloma who would be expected to have active disease, and the risk of amyloidosis was increased by a factor of 50 (Table 1). Of 16 patients with Durie–Salmon stage II disease, 15 had progression to active multiple myeloma; both patients with Durie–Salmon stage III had progression to active multiple myeloma (median time to progression, 13.8 months and 15.1 months). Among patients with progression of smoldering multiple myeloma, 97% had progression to active multiple myeloma. Rates of death owing to other diseases, including cardiovascular and cerebrovascular disease and non–plasma-cell cancers, were 18% at 5 years, 26% at 10 years, 30% at 15 years, and 35% at 20 years. The overall rate of survival was 60% at 5 years, 34% at 10 years, and 20% at 15 years (median, 6.3). In the 128 patients who did not have progression to active disease after more than 10 years after diagnosis, the disease was of the IgG subtype in 81%, the baseline median level of plasma cells in the bone marrow was 16%, the median spike in the serum monoclonal protein level was 2.8 g per deciliter, and uninvolved immunoglobulins were reduced in 78%.

Risk Factors for Progression

We evaluated baseline factors with respect to progression of smoldering multiple myeloma to active disease or amyloidosis in 163 patients. These factors included sex, hemoglobin level, a spike in the serum monoclonal protein level of 4 g per deciliter or more, the type of serum heavy chain, the serum albumin level, the presence and type of urinary light chain, a reduction in levels of uninvolved immunoglobulins, the expression of cyclin D1, the proportion of plasma cells in the bone marrow, involvement of the interfatty marrow space, decreased proportion of normal hematopoietic elements (10% or more below the expected level for age), and assignment to prognostic group 1, 2, or 3 (as defined in the Methods section). Significant baseline risk factors for progression of smoldering multiple myeloma to active disease or amyloidosis in the univariate analysis included the level of serum monoclonal protein (P<0.001), the presence of IgA monoclonal protein (P=0.004), the presence of urinary light chain (P=0.04), the extent of bone marrow involvement (plasma cells, 20%; P<0.001), a reduction in levels of uninvolved immunoglobulins (P=0.001), and the pattern of plasma-cell involvement in bone marrow (sheets of cells spanning the interfatty marrow spaces) (P<0.001) (Table 2).

View this table: [in this window] [in a new window]   Table 2. Risk Factors for Disease Progression among 276 Patients with Smoldering Multiple Myeloma (1970–1995).

 
On the basis of a fitted model containing the proportion of plasma cells in the bone marrow and the serum monoclonal protein level, the risk of progression to active multiple myeloma or amyloidosis at 10 years was 55% for patients with an initial plasma-cell level of 10 to 14%; progression occurred in 70% of the 27 patients who had more than 50% plasma cells in bone marrow (median time to progression, 21 months) (Table 2). The risk of progression to active multiple myeloma or amyloidosis at 10 years was 57% in patients with an initial monoclonal protein level of 2 g per deciliter and 70% in those whose initial level was 5 g per deciliter. Such factors as hemoglobin, sex, serum albumin level, proportion of normal hematopoietic elements, and expression of cyclin D1 were not significantly associated with progression.

On multivariate analysis, the serum monoclonal protein level and the proportion of plasma cells in the bone marrow emerged as significant independent risk factors for progression. On the basis of these findings and the fact that these two variables were also the main components of the definition of smoldering multiple myeloma, we constructed a risk-stratification model containing three risk groups. The cumulative probability of progression at 15 years was 87% for the 106 patients in group 1 (10% plasma cells and 3 g of monoclonal protein per deciliter), 70% for the 142 patients in group 2 (10% plasma cells and <3 g of monoclonal protein per deciliter), and 39% for the 27 patients in group 3 (<10% plasma cells and 3 g of monoclonal protein per deciliter) (Figure 3). The median time to progression was 2 years in group 1, 8 years in group 2, and 19 years in group 3 (P<0.001). The type of serum heavy chain added significantly to the multivariate model containing the three prognostic risk groups (Table 2).

View larger version (18K): [in this window] [in a new window]   Figure 3. Probability of Progression to Active Multiple Myeloma or Primary Amyloidosis in Patients with Smoldering Multiple Myeloma among Three Risk Groups. The proportion of plasma cells in bone marrow and the serum monoclonal protein level were combined to create a risk-stratification model with three distinct prognostic groups. At 15 years, the cumulative probability of progression was 87% for the 106 patients in group 1 (bone marrow plasma cells, 10%; monoclonal protein level, 3 g per deciliter), 70% for the 142 patients in group 2 (plasma cells, 10%; monoclonal protein level, <3 g per deciliter), and 39% for the 27 patients in group 3 (plasma cells, <10%; monoclonal protein level, 3 g per deciliter).

 
Discussion

The currently accepted definition of smoldering multiple myeloma requires a serum monoclonal protein level of 3 g per deciliter or more, 10% or more plasma cells in the bone marrow, or both in the absence of end-organ damage. It would be interesting to correlate cytogenetic abnormalities with the outcome of smoldering multiple myeloma, but the bone marrow in patients with this disease has few metaphases, and interphase FISH studies are therefore necessary. FISH may identify patients at increased risk, but since our cohort was studied before 1996, FISH was not available. Smoldering multiple myeloma resembles monoclonal gammopathy of undetermined significance (MGUS) in that end-organ damage is absent, but clinically it is far more likely to progress to active multiple myeloma or amyloidosis at 20 years (a 78% probability for smoldering multiple myeloma vs. 21% for MGUS).¹⁹

MGUS is characterized by a serum monoclonal protein level of less than 3 g per deciliter, a proportion of plasma cells in the bone marrow that is less than 10%, and an absence of related organ or tissue impairment (i.e., no end-organ damage such as hypercalcemia, renal insufficiency, anemia, or lytic bone lesions related to the plasma-cell disorder). MGUS and smoldering multiple myeloma are asymptomatic and should not be treated. Active multiple myeloma is characterized by a serum monoclonal protein level that is usually more than 3 g per deciliter or a urinary monoclonal protein, usually more than 10% plasma cells in the bone marrow, and most important, end-organ damage caused by plasma-cell proliferation (Figure 4).

View larger version (25K): [in this window] [in a new window]   Figure 4. Characteristics of Active Multiple Myeloma and Its Precursors. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma are asymptomatic precursors of active multiple myeloma. Serum protein electrophoresis in each of these disorders shows a prominent monoclonal protein in the region that can be easily identified as a dense band or spike. Other clinical features that can be used to distinguish these disorders are also shown. End-organ damage is defined as hypercalcemia, anemia, renal failure, or lytic bone lesions attributable to a plasma-cell disorder. Alb denotes albumin.

 
Estimates of the frequency of smoldering multiple myeloma have been affected by the variability in the criteria used to establish the diagnosis.^3,6 Inconsistent diagnostic criteria in previous studies have resulted in the reporting of variable median times to progression.^{1,2,3,4,5,6,7} Our study shows that the risk of progression is significantly affected by the level of monoclonal protein, the proportion of bone marrow plasma cells, or both. There were also substantial differences in the median time to progression among the three risk groups (2, 8, and 19 years).

Our study shows that the overall risk of progression in smoldering multiple myeloma is greatly influenced by the time elapsed since diagnosis, in contrast to the risk of progression in MGUS,¹⁹ which remains constant over time. We found that the overall risk of progression among patients with smoldering multiple myeloma was approximately 10% per year in the first 5 years and 3% per year in the next 5 years with a decrease to 1% per year thereafter. No such time-dependent change in risk occurs with MGUS.¹⁹

Other investigators have reported that the IgA isotype and the presence of urinary monoclonal protein are adverse prognostic factors for patients with smoldering multiple myeloma.^5,6,20 In contrast to these findings, the presence of urinary monoclonal protein, although significant on univariate analysis in our study, did not achieve statistical significance in the multivariate analysis. The roles of the serum free light-chain ratio and magnetic resonance imaging in determining the outcome of smoldering multiple myeloma are unknown and require investigation.

The age and sex of the patients in our study and the distribution of heavy-chain and light-chain types were similar to those in patients with active multiple myeloma.²¹ However, other findings, such as a reduction in the level of uninvolved immunoglobulins^19,21 and the presence of monoclonal urinary light chains, were intermediate between those in patients with active multiple myeloma and those in patients with MGUS.

On the basis of our experience, we suggest that the standard of care for patients with smoldering multiple myeloma should be close follow-up every few months. Physicians should repeat the pertinent laboratory tests 2 to 3 months after the initial recognition of the disease to rule out an early active form; if the results are stable, the studies should initially be repeated every 4 to 6 months. However, given the high risk of progression among patients in prognostic groups 2 and 3, along with the availability of new active agents for the treatment of active multiple myeloma, investigational approaches may be considered for selected patients in appropriate clinical trials. Ongoing trials are testing the use of bisphosphonates, interleukin-1β inhibitors, clarithromycin, dehydroepiandrosterone, and thalidomide in the treatment of smoldering multiple myeloma in an attempt to delay progression to active multiple myeloma.^22,23

Supported in part by grants (CA62242 and CA107476) from the National Cancer Institute.

No potential conflict of interest relevant to this article was reported.

We thank the Mayo Clinic Cancer Center, which provided hematoxylin and eosin staining and immunohistochemical processing of the bone marrow–biopsy specimens; Barbara A. Todd, for obtaining the bone marrow material for evaluation; and the Section of Scientific Publications at Mayo Clinic, for providing assistance with the preparation of the manuscript.

Source Information

From the Division of Hematology (R.A.K., A.D., R.F., S.V.R.), the Department of Laboratory Medicine and Pathology (E.D.R., P.J.K., J.M.H.), the Division of Biostatistics (T.M.T., D.R.L., M.F.P.), the Department of Immunology (D.F.J.), and the Department of Health Sciences Research (L.J.M.), Mayo Clinic, Rochester, MN.

Address reprint requests to Dr. Kyle at the Division of Hematology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, or at kyle.robert{at}mayo.edu.

References

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Related Letters:

Smoldering Multiple Myeloma
Prasad H. K., Zhan F., Shaughnessy J., Focosi D., Andrews A. T., Kyle R. A., Rajkumar S. V.
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N Engl J Med 2007; 357:1048-1050, Sep 6, 2007. Correspondence

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