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© 2002 American Society for Clinical Oncology Prognostic Factors for Malignant Transformation in Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple MyelomaByFrom the Department of Hematology, Bone Marrow Transplantation Centre, and Laboratory of Clinical Biochemistry and Hematology, Niguarda Cà Granda Hospital, Milan; Department of Biometry and Clinical Epidemiology, Scientific Direction, Istituto di Ricovero e Cura a Carattere Scientifico San Matteo General Hospital, Pavia; and Department of Hematology, University of Parma, Parma, Italy. Address reprint requests to Enrica Morra, MD, Divisione di Ematologia, Centro Trapianti di Midollo Osseo, Ospedale Maggiore Niguarda Cà Granda, Piazza Ospedale Maggiore 3, 20162 Milano, Italy; email: morraenrica{at}hotmail.com
PURPOSE: To evaluate the natural history of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), identify early predictors of evolution, and assess whether associated conditions correlate with disease progression. PATIENTS AND METHODS: A total of 1,231 consecutive patients with either MGUS (n = 1,104) or SMM (n = 127) diagnosed from July 1975 to March 1998 were included in the study. Cumulative survival probability and cumulative probability of transformation into lymphoproliferative disease were calculated by means of the Kaplan-Meier estimator. Univariate and multivariate Cox models were used to identify possible predictors of malignant evolution. RESULTS: Cumulative transformation probability at 10 and 15 years was 14% and 30%, respectively. At a median follow-up of 65 months (range, 12 to 239 months), 64 MGUS cases (5.8%) evolved to multiple myeloma (MM) (n = 43), extramedullary plasmacytoma (n = 1), primary amyloidosis (n = 1), Waldenström’s macroglobulinemia (n = 12), non-Hodgkin’s lymphoma (n = 6), and B-chronic lymphocytic leukemia (n = 1). At a median follow-up of 72 months (range, 12 to 247 months), 25 SMMs (19.7%) evolved to overt MM. A lower evolution risk was observed in MGUS than in SMM (P < .0001). Greater than 5% marrow plasmacytosis, detectable Bence Jones proteinuria, polyclonal serum immunoglobulin reduction, and high erythrocyte sedimentation rate (ESR) were independent factors influencing MGUS transformation. SMM progression correlated with greater than 10% marrow plasma cells, detectable Bence Jones proteinuria, and immunoglobulin (Ig) A isotype. Neither concomitant diseases nor immunosuppression correlated with progression. CONCLUSION: Careful evaluation of marrow plasmacytosis, urinary paraprotein, background immunoglobulins, ESR, and paraprotein isotype might help identify at presentation patients with benign monoclonal gammopathies requiring stricter monitoring.
THE TERM MONOCLONAL gammopathy of undetermined significance (MGUS) means the presence of a monoclonal protein in patients without evidence of multiple myeloma (MM), Waldenström’s macroglobulinemia (WM), amyloidosis, or related disorders.1-3 MGUS prevalence is reported to vary from 1% to 10% in different series, and the frequency increases with age.4-6 As detected by longitudinal follow-up studies, most patients with MGUS do not require specific treatment and have a long life span. A subset, however, tends to evolve to lymphoproliferative disease.2,3,7-18 Because the benign nature of an MGUS is sometimes difficult to ascertain, repeated examinations of the patient over long periods are required. Thus it seems important to identify early factors that might predict a malignant transformation. Smoldering MM (SMM) is an uncommon form of MM that acts in a biologically similar way to MGUS.19-21 The absence of bone lesions, low plasma cell-labeling index, and stability of the clinical course during a period of many years suggest that patients should be observed without chemotherapy.20 All cases, however, eventually transform into symptomatic disease. Moreover, the existence of a small subgroup of SMM patients with a high likelihood of evolution to overt MM has been reported.21 Presently, patients at high transformation risk are not identified by the available test parameters, and careful monitoring is needed. The evaluation of peripheral blood clonal B cells and serum neural-cell adhesion molecule levels and biologic and radiologic studies of the bones have proven useful in differentiating a patient with stable MGUS from one in whom a lymphoproliferative disorder will develop during follow-up.22-25 These methods, however, are mostly expensive, difficult to standardize, and not always available to the physician. Various studies failed to identify simple hematologic parameters useful for distinguishing patients with benign monoclonal gammopathies who do not progress and those in whom a malignant transformation will subsequently occur.7,9,12,14 The results of routine laboratory techniques, such as quantification of monoclonal component (MC), immunoglobulin (Ig) class, Bence Jones (BJ) proteinuria, polyclonal Ig, and percentage of bone marrow (BM) plasma cells (BMPCs), would be of particular practical value as predictors of evolution, because such parameters are easy to obtain and available at the same time as the information of the finding of a monoclonal serum protein. These factors were variably detected to predict a malignant evolution in previous studies.13,15-17 However, because data were mostly compiled from small groups of patients with inadequate long-term follow-up studies, results were controversial and of uncertain importance. A body of evidence suggests that some forms of MGUS may occur as a result of antigenic stimulation, such as monoclonal immune response being hypothesized in infections, connective tissue disorders, chronic liver disease, and cancer.2,7,26,27 Moreover, a high MGUS incidence has been described in graft recipients receiving immunosuppression and may reflect a T-cell defect-related oligoclonal or monoclonal B-cell proliferation.28-31 Whether a chronic antigenic stimulation may be associated with a higher MGUS tendency to evolve has not been systematically investigated, and the predictive role of monoclonal gammopathies for the development of a lymphoproliferative disorder in the transplantation setting is controversial.29,30 The aims of this study were to evaluate the natural history of 1,231 patients with either MGUS or SMM during long-term follow-up, assess the predictive value for malignant transformation of simple hematologic parameters detected in the patients at diagnosis, and evaluate whether associated clinical conditions may be involved in disease progression.
Patients and Diagnostic Criteria A total of 1,231 consecutive patients (634 men and 597 women) with either MGUS (IgG, n = 811; IgA, n = 114; IgM, n = 130; IgD, n = 1; and double MC, n = 48) or SMM (IgG, n = 91; IgA, n = 31; and double MC, n = 5) diagnosed in our center from July 1975 to March 1998 with a minimum follow-up of 1 year were included in the study (Table 1).
IgG, IgA, and IgD MGUS were defined by the evidence of MCs 3.5 g/dL or less, 2 g/dL or less, and 3 g/dL or less, respectively, BJ proteinuria 1 g/24 hours or less, BMPCs less than 10%, absence of bone lesions, anemia, hypercalcemia, and renal insufficiency. IgM MGUS was defined by the evidence of serum MC 3 g/dL or less, BJ proteinuria 1 g/24 hours or less, BM infiltration with lymphoplasmacytoid cells less than 30%, normal or nodular BM histologic pattern, no symptoms, and normal cell counts. SMM was defined as follows: IgG MC 3.6 to 6.9 g/dL or IgA MC 2.1 to 4.9 g/dL, and/or BJ proteinuria greater than 1 g/24 hours, and/or BMPCs 11% to 19%, absence of bone lesions, anemia, hypercalcemia, and renal insufficiency. The diagnosis of MGUS and SMM required 1 year of observation. Criteria for the diagnosis of MM were as follows.32 Criteria for MM were as follows: major criteria (A): (I) plasmacytoma on BM biopsy; (II) BMPCs greater than 30%; (III) IgG MC greater than 3.5 g/dL, IgA MC greater than 2 g/dL, or BJ proteinuria greater than 1 g/24 hours in the absence of amyloidosis; minor criteria (B): (a) BMPCs 10% to 30%; (b) IgG MC 3.5 g/dL or less, or IgA MC 2 g/dL or less, or BJ proteinuria 1 g/24 hours or less; (c) lytic bone lesions; or (d) reduced levels of normal serum Ig. MM diagnosis required a minimum of one major plus one minor criterion (I + b, I + c, I + d, or II + b, II + c, II + d, or III + a, III + b, or III + d) or three minor criteria (a + b + c or a + b + d) and was confirmed by the presence of symptoms. The reference limits of serum Ig levels were calculated on the basis of the mean value (± SD) of a series of serum Ig level evaluations in healthy subjects (IgG, 680 to 1,445 mg/dL; IgA, 70 to 373 mg/dL; and IgM, 50 to 248 mg/dL). WM was defined as follows: serum IgM MC (generally > 3 g/dL), anemia, and BM infiltration with lymphoplasmacytoid cells 30% or greater with a diffuse histologic pattern, with or without thrombocytopenia, monoclonal lymphocytosis, or splenomegaly. Detection of typical laboratory and clinical features, described elsewhere,33 allowed for the diagnosis of amyloidosis. Non-Hodgkin’s lymphoma and chronic lymphocytic leukemia were diagnosed by means of lymphonodal and BM histology and immunophenotype analysis.
Laboratory and Clinical Studies In each patient, the following data were evaluated: hemoglobin, WBC count, platelet count, serum albumin, serum creatinine, serum liver function tests, size of the serum MC, presence of urine MC, quantification of polyclonal serum Ig, erythrocyte sedimentation rate (ESR), ß2-microglobulin, BM biopsy and aspirate, and skeleton x-ray. Laboratory tests and the serum and urine qualitative and quantitative MC evaluations were performed every 3 months during the first year, every 6 months during the second year, and then every 12 months. BM biopsy and aspirate and skeleton x-rays were obtained every time they were considered necessary during follow-up. The BMPC percentages were the mean value of two 300-cell counts separately made by two experienced hematologists.
Statistical Analysis Stata 6.0 (StataCorp, College Station, TX) was used for computation. P < .05 was considered statistically significant.
Characteristics of Patients at Diagnosis The median age was 63 years (range, 23 to 93 years). Clinical characteristics of the patients according to different MC classes are summarized in Table 1. Median serum MC concentrations were 1.5 g/dL (range, 0.16 to 3.49 g/dL) and 2 g/dL (range, 0.38 to 4.3 g/dL) in patients with MGUS and SMM, respectively. BJ proteinuria was detected in 139 (12.6%) patients with MGUS and 39 (30.7%) patients with SMM. Median levels of BJ proteinuria were 0.2 g/24 hours (range, 0.03 to 0.95 g/24 hours) and 0.4 g/24 hours (range, 0.1 to 1.1 g/24 hours) in patients with MGUS and SMM, respectively. One and two serum polyclonal Ig reductions were found in 10.6% and 2.2% of MGUS patients, respectively, and in 21.4% and 2.7% of SMM patients, respectively. Median levels of serum polyclonal IgG, IgA, and IgM in MGUS were 1,030 mg/dL (range, 8 to 2,960 mg/dL), 181 mg/dL (range, 3 to 1,491 mg/dL), and 96 mg/dL (range, 7 to 1,470 mg/dL), respectively. Median levels of serum polyclonal IgG, IgA, and IgM in SMM were 842 mg/dL (range, 208 to 1,680 mg/dL), 154 mg/dL (range, 10 to 1,720 mg/dL), and 81 mg/dL (range, 14 to 375 mg/dL), respectively. Although BM biopsy was not evaluated in 22 patients older than 80 years, BM aspiration was performed in all patients. BM lymphoplasmacytoid infiltration was 10% in seven IgM MGUS patients. In the SMM group, 113 patients had BMPC 10% or greater; in the remainder, BMPCs were less than 10% and SMM diagnosis was performed on the basis of IgG and IgA MC levels greater than 3.5 and 2 g/dL, respectively. Serum ß2-microglobulin was greater than 2.6 µg/mL (upper limit of normal) in 21.5% of patients with MGUS and in 33.7% of patients with SMM. Serum albumin was less than 3.1 g/dL (lower limit of normal) in 1.1% of patients with MGUS and in 3.5% of patients with SMM. ESR was 21 mm/h (upper limit of normal) to 39 mm/h in 17.9% of patients with MGUS and in 25.5% of patients with SMM. ESR levels 41 mm/h or greater were found in 11.8% of patients with MGUS and 26.4% of patients with SMM.
Fifty-three patients presented a double monoclonal gammopathy. The distribution of isotype pairs among 48 patients with MGUS was IgGk/IgGk (n = 5), IgGk/IgG
Previous and Concomitant Diseases
Survival and Probability of Evolution Median survival time was 19.5 years. The overall survival rate at 10 and 15 years was 79% (95% CI, 76% to 83%) and 71% (95% CI, 64% to 77%), respectively. Total observation time amounted to 86,925 person-months. Figure 1 summarizes graphically the overall survival (A) and event-free survival (B) of both the MGUS and SMM groups.
At a median follow-up of 65 months (range, 12 to 239 months), the MC remained stable in 907 patients (82.2%) with MGUS, and 111 patients (10.1%) died from nonrelated diseases. The IgD  patient, a heart transplantation recipient, died of cardiac complications 15 months after MGUS diagnosis. In 22 patients (IgG, n = 16; IgA, n = 3; and IgM, n = 3), MC disappearance was registered at a median of 9 months (range, 3 to 192 months) after first detection. One and two patients, respectively, were heart and allogeneic BM recipients. In the latter cases, MC disappearance occurred 4 and 6 years, respectively, after cyclosporine withdrawal. In 64 (5.8%) patients with MGUS, a malignant transformation was registered into MM (n = 43), extramedullary plasmacytoma (n = 1), primary amyloidosis (n = 1), WM (n = 12), non-Hodgkin’s lymphoma (n = 6), and B-chronic lymphocytic leukemia (n = 1). At a median follow-up of 72 months (range, 12 to 247), the MC remained stable in 91 patients (71.7%) with SMM, and 11 patients died from unrelated diseases. In 25 patients (19.7%), malignant transformation was registered into overt MM.
The distribution of lymphoproliferative disorders according to the MC isotype for both the MGUS and SMM groups is summarized in Table 3. Among the 53 patients with biclonal gammopathy, four developed MM and one developed non-Hodgkin’s lymphoma. Biclonal pairs were IgGk/IgGk (n = 2), IgAk/IgAk (n = 2), and IgAk/IgA
The cumulative probability of transformation into lymphoproliferative disease at 10 and 15 years was 14% (95% CI, 11% to 17%) and 30% (95% CI, 18% to 46%), respectively. The median interval before the diagnosis of MM, WM, and non-Hodgkin’s lymphoma was 61.5, 89, and 46 months, respectively (ranges, 9 to 159, 6 to 131, and 6 to 144 months). Extramedullary plasmacytoma, primary amyloidosis, and B-chronic lymphocytic leukemia were found 24, 111, and 43 months, respectively, after the recognition of the serum MC. Thirty-two (MM, n = 28; WM, n = 2; and non-Hodgkin’s lymphoma, n = 2) of 92 patients who developed malignant transformation have died, the median survival from diagnosis of this complication being 36 months (range, 2 to 131 months). The main clinical and laboratory parameters of patients who evolved to MM are summarized in Table 4. Three patients with MGUS evolved to SMM and did not require therapy for 72, 103, and 140 months, respectively, after SMM diagnosis.
Prognostic Factors for Malignant Transformation A higher risk of evolution was detected in SMM patients than in MGUS patients (HR, 3.1; 95% CI, 1.9 to 4.9; P < .0001), and this parameter was colinear with the percentage of BMPCs. Table 5 lists the incidence rates of malignant transformation together with 95% CI for a series of potential risk factors and the P value of the univariate Cox regression. Variables associated with an increased probability of evolution in MGUS were the Ig isotype, with a higher incidence of transformation for the IgA and IgM subgroups; serum MC levels, with the highest incidence when higher than 1.92 g/dL; detectable BJ proteinuria; the reduction of one or two serum polyclonal Ig; and ESR and BMPC levels. Variables associated with an increased probability of evolution in SMM patients were the IgA isotype, detectable BJ proteinuria, and greater than 10% BMPC levels. Age, sex, serum ß2-microglobulin, serum albumin, presence of double MC, connective tissue disorder, viral hepatitis, or solid tumor, as well as a previous transplantation, was not associated with a higher incidence of disease evolution (data not shown).
At multivariate analysis, BMPC infiltration, the presence of BJ proteinuria, polyclonal serum Ig reduction, and ESR levels were independently associated with MGUS malignant transformation. Hazard ratios and 95% CIs are reported in Table 6. Assuming a label (x) for each variable (x1 for BMPCs % 6 to 9, x2 for BMPCs %  10, x3 for detectable BJ proteinuria, x4 for one polyclonal serum Ig reduction, x5 for two polyclonal serum Ig reductions, x6 for ESR 30 to 40 mm/h, and x7 for ESR > 40 mm/h), a prognostic index (0.37x1 + 1.90x2 + 1.05x3 + 0.67x4 + 3.01x5 - 0.29x6 + 0.94x7) was calculated for each patient. The higher the prognostic index, the higher the risk of malignant transformation. Four different risk groups were identified on the basis of quartiles of distribution of the prognostic index. As shown in Fig 2, this model allowed identification of patients with a higher risk of evolution (fourth quartile, prognostic index > 2.10) but was not able to discriminate additionally between patients less at risk.
Monoclonal serum components are mostly characterized by a limited and controlled clonal lymphoplasmacytic expansion with benign course.1-3 However, a substantial proportion of patients will eventually develop MM, WM, amyloidosis, or other lymphoproliferative disorders, and progression can be abrupt.2,3,7-18 Clinical observation is required, and the identification of factors predicting the possibility of evolution is mandatory. The prevalence of MGUS malignant transformation reported by Paladini et al12 and Kyle14 cannot be compared with that observed in our series because of significantly different follow-up times. The 6.8% MGUS frequency of progression at 70 months of median follow-up reported by Baldini et al16 is similar to ours (5.8% at 65 months), and the 10.2% frequency of progression at 56 months of median follow-up reported by Blade et al13 in MGUS plus SMM is only a little higher than that observed in our patients all together (7.3% at 67 months). In our study, twice as many patients evolved to WM as to non-Hodgkin’s lymphoma. The 9.2% prevalence of evolution to WM observed in our IgM MGUS group, however, was similar to prevalences previously described (11.8%,12 7.1%,13 11.1%,14 and 13%16), and the 0.5% prevalence of non-Hodgkin’s lymphoma development in patients with any MGUS isotype was similar to prevalences reported by others (0.7%,12 0.4%,14 and 0.3%16). In terms of cumulative probability of evolution, our findings are in agreement with those previously reported.13-17 Although it has been suggested that patients with SMM are biologically and clinically similar to patients with MGUS, such reports are based on small numbers.19,21 In our study, a significantly higher probability of transformation was detected in the SMM group than in the MGUS group. This result and the reported possibility of early transformation in patients with SMM21 suggest that more attention must be paid to such forms of benign monoclonal gammopathy and that the existence of predictive factors for disease progression might be essential in selecting patients in whom strict monitoring is required. Few data are available concerning the possibility of evolution of biclonal gammopathies. Although in the study by Kyle et al34 of 37 patients, symptomatic MM developed after 2 years in only one patient, in our series of 53 patients, MM and non-Hodgkin’s lymphoma were detected in four and one patients, respectively. Although the presence of a clonal pair was not detected to influence malignant transformation at univariate analysis, the lack of statistical significance was probably attributable to the relatively small number of patients. The detected higher risk of evolution than that found in previous series34 suggests that particular attention must be paid to such occurrences. As previously found,7,9,13,15,17,35 in our series, age, sex, serum ß2-microglobulin levels, and serum albumin levels had no prognostic value for malignant transformation. Other investigators found serum paraprotein levels to be a factor influencing the probability of malignant conversion.16,17 On the contrary, in our study, the multivariate model excluded a significant relation of serum MC size with disease progression. Moreover, none of the fourteen patients in which SMM was diagnosed on the basis of an IgG MC level greater than 3.5 gr/dL or an IgA MC level greater than 2 g/dL but who had less than 10% BMPCs evolved to overt MM. This finding is in keeping with previous suggestions that, although discrimination levels of serum paraprotein are generally used to distinguish between asymptomatic and symptomatic monoclonal gammopathies,1,2 serum MC concentrations higher than the given cutoffs may remain stable for prolonged periods.9,11,13 The upper limit of safety of BMPCs has been suggested at 5%,2 10%,1 or 20%13 by different studies. Although in some studies the degree of marrow plasmacytosis had no prognostic value for malignant transformation,7,13 Baldini et al16 showed the importance of 10% as the upper limit for a diagnosis of benign gammopathy in IgG patients, higher percentages being significantly associated with a worse clinical outcome. Our results are in keeping with those of Baldini et al, because BMPCs greater than 10% were shown to identify patients with higher risk of disease transformation regardless of the Ig class. Considering the MGUS group apart, greater than 5% BMPCs was associated with a higher evolution risk. The highest probability of transformation, however, was found in patients with 10% BM infiltration and regarded IgM MGUS, because according to inclusion criteria, IgG and IgA patients had less than 10% BMPCs. No transitional clinical or biologic entity exists between IgM MGUS and WM. Our data, however, suggest that the presence of a BM lymphoplasmacytoid infiltration greater than 10% might identify IgM MGUS with a higher likelihood of transformation into symptomatic disease. A decreased level of background Ig was detected to influence MGUS progression significantly in the study by Vuckovic et al,17 and Baldini et al16 identified in the presence of both uninvolved Ig reduction and BJ proteinuria a higher probability of evolution. In our MGUS series, a prognostic significance of both parameters was confirmed, probably indicating their correlation with disease activity. A relationship between detectable BJ proteinuria and SMM progression was also observed at univariate analysis. Although this is the first study suggesting a prognostic value for BJ proteinuria in SMM, such a finding is guaranteed by similar results obtained in the larger MGUS group. Higher ESR levels have been detected in patients with MGUS than in the population without MGUS, and the presence of an occult monoclonal gammopathy has been suggested as one possible cause of an otherwise clinically unexplained ESR elevation in the elderly.6 In our study, the absence of a clear relationship between ESR levels and the size of MC in MGUS patients was confirmed,6 suggesting variability in the interaction of individual MCs with red cells to create rouleaux formation. Moreover, ESR elevation was strongly associated with a higher MGUS evolution risk. Whether the biologic properties of the MC reflecting ESR elevation are eventually associated with disease aggressiveness is unknown. Because in previous studies the ESR was not evaluated as a predictor for evolution,12,13,15-17 the involvement of ESR levels in MGUS prognosis needs additional investigation.
Most previous studies found no influence of Ig class on disease evolution probability.7,9,16-18 Although at univariate analysis the IgA/IgM and IgA isotypes were detected to correlate with malignant transformation in the MGUS and SMM groups, respectively, we did not find that Ig class was an independent prognostic factor for MGUS malignant transformation at the multivariate model. The latter could not be performed in the SMM group because of the small number of patients. Interestingly, however, the only study13 in which an influence of IgA isotype on malignant transformation was detected included patients with SMM (ie, with BMPCs Chronic antigenic stimulation and T-lymphocyte dysfunction induced by prolonged immunosuppression may play a role in the development of the plasma cell clone responsible for MGUS. Whereas the former mechanism seems involved in infections, connective tissue disorders, chronic liver disease, and cancer,2,26,27 the second may be responsible for posttransplantation MC development.28,29 The prevalence of connective tissue diseases detected in our series was lower than that reported by Kyle,7 confirming previous suggestions that the coexisting conditions might be coincidental.2 On the contrary, the prevalence of both viral hepatitis (7.6%) and cancer (6.1%) was significant. In keeping with other reports,26,27 MCs of such groups were small and often transient. Similarly, although cases of progression have been reported in the transplantation setting,28,29,31,36 our immunosuppressed graft recipients had disappearance or stability of their MC during up to 20 years of posttransplantation follow-up. Indeed, no statistical significance was reached when a predictive value of associated conditions was assessed. Although our findings suggest that the so-called secondary MGUS might be benign monoclonal gammopathies, this has to be verified on higher patient numbers. Our results suggest that the evaluation of simple criteria such as BMPCs, BJ proteinuria, background Ig levels, and ESR might permit recognition of a greater probability of malignant evolution in patients with MGUS. Although unable to discriminate additionally between patients with less risk of transformation, our statistical model reliably identified higher risk patients needing strict monitoring, thus assuming a crucial clinical importance. Additional investigations and longer follow-up studies are necessary to draw definitive conclusions on the prognosis of SMM as well as to reveal all the possible complications related to immune system alterations in patients with MGUS.
1. Ritzmann SE, Loukas D, Sakai H, et al: Idiopathic (asymptomatic) monoclonal gammopathies. Arch Intern Med 135: 95-106, 1975 2. Kyle RA, Lust JA: Monoclonal gammopathies of undetermined significance. Blood 26: 176-200, 1989 3. Kyle RA: Monoclonal gammopathy of undetermined significance (MGUS). Baillieres Clin Haematol 8: 761-781, 1995[CrossRef][Medline] 4. Axelsson U, Bachmann R, Hällén J: Frequency of pathological proteins (M-components) in 6,995 sera from an adult population. Acta Med Scand 179: 235-247, 1966[Medline] 5. Sinclair D, Sheehan T, Parrott DMV, et al: The incidence of monoclonal gammopathy in a population over 45 years old determined by isoelectric focusing. Br J Haematol 64: 745-750, 1986[Medline] 6. Crawford J, Eye MK, Cohen HJ: Evaluation of monoclonal gammopathies in the "well" elderly. Am J Med 82: 39-45, 1987[CrossRef][Medline] 7. Kyle RA: Monoclonal gammopathy of undetermined significance: Natural history in 241 cases. Am J Med 64: 814-826, 1978[CrossRef][Medline] 8. Fine JM, Lambin P, Muller JY: The evolution of asymptomatic monoclonal gammopathies: A follow-up of 20 cases over periods of 3-14 years. Acta Med Scand 205: 339-341, 1979[Medline] 9. Carter A, Tatarsky I: The physiopathological significance of benign monoclonal gammopathy: A study of 64 cases. Br J Haematol 46: 565-574, 1980[Medline]
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Kyle RA: "Benign" monoclonal gammopathy: A misnomer? JAMA 251: 1849-1854, 1984 11. Axelsson U: A 20-year follow-up study of 64 subjects with M-components. Acta Med Scand 219: 519-522, 1986[Medline] 12. Paladini G, Fogher M, Mazzanti G, et al: Gammapatia monoclonale idiopatica: Studio a lungo termine di 313 casi. Recenti Prog Med 80: 123-132, 1989[Medline] 13. Blade J, Lopez-Guillermo A, Rozman C, et al: Malignant transformation and life expectancy in monoclonal gammopathy of undetermined significance. Br J Haematol 81: 391-394, 1992[Medline] 14. Kyle RA: "Benign" monoclonal gammopathy after 20 to 35 years of follow-up. Mayo Clin Proc 68: 26-36, 1993[Medline] 15. Van de Poel MHW, Coebergh JWW, Hillen HFP: Malignant transformation of monoclonal gammopathy of undetermined significance among out-patients of a community hospital of Southeastern Netherlands. Br J Haematol 91: 121-125, 1995[Medline]
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Baldini L, Guffanti A, Cesana BM, et al: Role of different hematologic variables in defining the risk of malignant transformation in monoclonal gammopathy. Blood 87: 912-918, 1996 17. Vuckovic J, Ilic A, Knezevic N, et al: Prognosis in monoclonal gammopathy of undetermined significance. Br J Haematol 97: 649-651, 1997[CrossRef][Medline] 18. Pasqualetti P, Casale R: Risk of malignant transformation in patients with monoclonal gammopathy of undetermined significance. Biomed Pharmacother 51: 74-78, 1997[CrossRef][Medline] 19. Kyle RA, Greipp PR: Smoldering multiple myeloma. N Engl J Med 302: 1347-1349, 1980[Medline] 20. Zulian GB: Multiple myeloma: Clinical evaluation of plasma cell lymphoproliferative disorders and initial management. Semin Hematol 34: 29-39, 1997[Medline] 21. Boccadoro M, Gavarotti P, Fossati G, et al: Low plasma cell 3(H) thymidine incorporation in monoclonal gammopathy of undetermined significance (MGUS), smouldering myeloma and remission phase myeloma: A reliable indicator of patients not requiring therapy. Br J Haematol 58: 689-696, 1984[Medline] 22. Isaksson E, Björkholm M, Holm G, et al: Blood clonal B-cell excess in patients with monoclonal gammopathy of undetermined significance (MGUS): Association with malignant transformation. Br J Haematol 92: 71-76, 1996[CrossRef][Medline]
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Ong F, Kaiser U, Seelen PJ, et al: Serum neural cell adhesion molecule differentiates multiple myeloma from paraproteinemias due to other causes. Blood 87: 712-716, 1996 24. Luoni R, Ucci G, Riccardi A, et al: Serum thymidine kinase in monoclonal gammopathies. Cancer 69: 1368-1372, 1992[CrossRef][Medline]
25.
Vande Berg BC, Michaux L, Lecouvet FE, et al: Nonmyelomatous monoclonal gammopathy: Correlation of bone marrow MR images with laboratory findings and spontaneous clinical outcome. Radiology 202: 247-251, 1997 26. Heer M, Joller-Jemelka H, Fontana A, et al: Monoclonal gammopathy in chronic active hepatitis. Liver 4: 255-263, 1984[Medline] 27. Peltonen S, Wasastjerna C, Wager O: Clinical features of patients with a serum M component. Acta Med Scand 203: 257-263, 1978[Medline] 28. Radl J, Valentijn RM, Haaijman JJ, et al: Monoclonal gammopathies in patients undergoing immunosuppressive treatment after renal transplantation. Clin Immunol Immunopathol 37: 98-102, 1985[CrossRef][Medline] 29. Pham H, Lemoine A, Sol O, et al: Monoclonal and oligoclonal gammopathies in liver transplant recipients. Transplantation 58: 253-257, 1994[Medline] 30. Peest D, Schaper B, Nashan B, et al: High incidence of monoclonal immunoglobulins in patients after liver or heart transplantation. Transplantation 46: 389-393, 1988[Medline]
31.
Mitus AJ, Stein R, Rappeport JM, et al: Monoclonal and oligoclonal gammopathy after bone marrow transplantation. Blood 74: 2764-2768, 1989 32. Durie BGM: Staging and kinetics of multiple myeloma. Semin Oncol 13: 300-309, 1986[Medline] 33. Kyle RA, Gertz MA: Primary systemic amyloidosis: Clinical and laboratory features in 474 cases. Semin Hematol 32: 45-59, 1995[Medline] 34. Kyle RA, Robinson RA, Katzmann JA: The clinical aspects of biclonal gammopathies. Am J Med 71: 999-1008, 1981[CrossRef][Medline] 35. Garewal H, Durie BGM, Kyle RA, et al: Serum beta2-microglobulin in the initial staging and subsequent monitoring of monoclonal plasma cell disorders. J Clin Oncol 2: 51-57, 1984[Abstract] 36. Dysseleer A, Michaux L, Cosyns JP, et al: Benign monoclonal gammopathy turning to AL amyloidosis after kidney transplantation. Am J Kidney Dis 34: 166-169, 1999[Medline] Submitted October 11, 2000; accepted November 20, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
(n = 6), IgGk/IgM
20%). Thus, the evaluation of more patients should be interesting to verify a possible MC isotype involvement in SMM evolution risk. 
