Demyelinating disease in monoclonal gammopathy of undetermined significance

We describe herein the case of a 57 year old man who, over the last five years, has presented ataxic and spastic gait on the right side, a reduction in fine motor movement of the fingers mainly on the right side, superficial right side brachiocrural hypoesthesia and a marked dysarthria associated with internuclear ophthalmoplegia. The neurological picture, after an initial progressive worsening which lasted some months, remained relatively stable over the years. Repeated magnetic resonance imaging (MRI) of the brain and spinal cord documented the presence of demyelinating plaques spread in the white matter of the periventricular region and the semioval centres, and a right side paramedian plaque at the C4-C5 level, none of which were in the active phase. Oligoclonal bands were revealed in the cerebrospinal fluid (CSF). Monoclonal IgM/lambda gammopathy with anti-myelin and anti-nucleo reactivity, found with serum immunofixation, were confirmed several times in successive annual controls, not associated to myeloproliferative pathology. The lack of progression in the clinical picture would seem to contradict the diagnosis of late Multiple Sclerosis. The presence of antibody activity against the myelin might support the hypothesis of a pathogenetic role of the immunoglobulins at the onset of the demyelinating disease in this patient. However, in the end, there is the possibility of casual association with a poorly functioning immune system connected to age.     

Prognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma.

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), Waldenstr?m'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.     

Prognostic factors and predictors of outcome of immunoglobulin M monoclonal gammopathy of undetermined significance

Monoclonal gammopathy of undetermined significance (MGUS) of the immunoglobulin M (IgM) class was diagnosed at our institution in 213 patients who resided in the 11 counties of southeastern Minnesota from 1960 to 1994. The median age at diagnosis was 74 years and the median concentration of serum M-protein was 1.2 g/dL. The 213 patients were monitored for 1567 person-years (median, 6.3 years), during which 71% died. During follow-up, non-Hodgkin's lymphoma (n = 17), Waldenstrom's macroglobulinemia (n = 6), primary amyloidosis (n = 3), and chronic lymphocytic leukemia (n = 3) developed in 29 patients (14%). The number of patients with progression to lymphoid neoplasms was 15.9 times that expected in the general population. The cumulative probabilities of progression to one of these disorders were 10% at 5 years, 18% at 10 years, and 24% at 15 years. The overall average risks for progression were approximately 1.5% per year. Rates of death resulting from other diseases (cardiovascular, cerebrovascular, etc.) were 31% at 5 years, 52% at 10 years, and 65% at 15 years. Multivariate analysis revealed that only the concentration of serum M-protein at diagnosis and the serum albumin value were independent predictors of progression. It was concluded that the patients with IgM MGUS should be followed indefinitely.     

Malignant transformation in IgM monoclonal gammopathy of undetermined significance

Monoclonal gammopathy of undetermined significance (MGUS) is a frequent disorder characterized by the presence of a small serum M-protein in individuals with no evidence of multiple myeloma (MM), Waldenstrom's macroglobulinemia (WM), or primary amyloidosis (AL). Although one fourth of these individuals will develop a malignant disease, there are no well-established predictors of outcome, particularly in the IgM type MGUS. Among 434 patients diagnosed with MGUS from 1970 to 2001 with a minimum follow-up of 1 year, 52 (27 men and 25 women; median age, 67 years) of IgM type were identified. After a median follow-up of 5 years, five patients (9.6%) have developed WM. The risk of transformation was 13.3% (95% confidence interval [CI], 0 to 27) and 27.7% (95% CI, 0.3 to 55.1) at 10 and 20 years, respectively. The variables significantly associated with transformation were the proportion of bone marrow plasma cells (BMPC) and the percentage of bone marrow lymphocytes (BML). No significant differences in the risk of transformation were found between IgM MGUS and the remaining MGUS types. Thus, in IgM MGUS the rate of transformation was similar to the risk observed in other MGUS types, the percentage of BMPC and BML being the features significantly associated with evolution into WM.     

Long-term follow-up of IgM monoclonal gammopathy of undetermined significance

The current study was conducted to determine the risk of adverse outcomes among patients with monoclonal gammopathy of undetermined significance (MGUS) of the IgM class. Two hundred thirteen patients with IgM MGUS were identified in southeastern Minnesota from 1960 to 1994. The primary end point was progression to lymphoma or a related disorder assessed by the Kaplan-Meier method. Patients were followed for a total of 1,567 person-years (median, 6.3 years per subject). Seventeen patients developed lymphoma (relative risk [RR], 14.8) and six progressed to Waldenstrom's macroglobulinemia (RR, 262), while three developed primary amyloidosis (RR, 16.3) and three others had chronic lymphocytic leukemia (RR, 5.7). The relative risk of progression was 16-fold higher in the IgM MGUS patients compared to the white population of the Iowa Surveillance, Epidemiology, and End Results (SEER) program. The risk of progression of MGUS of IgM type to lymphoma or related disorders averaged 1.5% per year throughout the period of observation.     

Deletions of chromosome 13q in monoclonal gammopathy of undetermined significance.

Since deletion of chromosome 13q is a clinically relevant feature in multiple myeloma (MM), we analyzed bone marrow plasma cells from 29 patients with monoclonal gammopathy of undetermined significance (MGUS) to investigate the chromosome 13 status in MGUS. Studies were performed by interphase fluorescence in situ hybridization (FISH) with a panel of 13q14-specific probes (RB1, D13S319, D13S25, D13S31). Plasma cells with a deletion of at least one of the 13q14 loci were detected in 13 patients (44.8%) with MGUS. In five patients (17.2%), deletions of all four 13q14-specific probes were observed, and the additional deletion of a 13q telomeric region (D13S327) suggested loss of the entire 13q arm or monosomy 13. Loss of 13q14 was observed to be monoallelic and to occur in 11.0 to 35.0% of plasma cells (cut-off levels for a deletion <10% with all probes). Nine of 17 patients (52.9%) with MM progressing from a pre-existing MGUS had evidence for a deletion of 13q14 as determined by FISH with the RB1 probe. These results suggest that deletion of 13q14 is an early event in the development of monoclonal gammopathies, but its role for the eventual progression to MM remains to be determined prospectively.     

MICA expressed by multiple myeloma and monoclonal gammopathy of undetermined significance plasma cells Costimulates pamidronate-activated gammadelta lymphocytes

Amino-biphosphonates (like pamidronate) activate human Vgamma9/Vdelta2 T lymphocytes and promote their cytotoxicity against multiple myeloma cells. T-cell receptor (TCR)-mediated effector functions of gammadelta cells are enhanced upon triggering of the activating receptor NKG2D by MICA, a stress-inducible antigen expressed by epithelial and some hematopoietic tumors, including multiple myeloma. Here we show that MICA was expressed not only by myeloma cell lines and by 6 of 10 primary multiple myeloma cells from patients but also by bone marrow plasma cells from all (six of six) patients with preneoplastic gammopathy (monoclonal gammopathy of undetermined significance, MGUS), a direct precursor of multiple myeloma. Moreover, compared with multiple myeloma plasma cells, MICA was expressed by MGUS plasma cells at significantly (P < 0.05) higher levels. MICA expressed by myeloma cell lines contributed to killing and IFN-gamma production by Vgamma9/Vdelta2 cells only upon pamidronate treatment, suggesting a dual interaction between Vgamma9/Vdelta2 lymphocytes and multiple myeloma plasma cells involving both TCR triggering and NKG2D-mediated signals. Finally, MICA enhanced killing of freshly derived, pamidronate-treated multiple myeloma cells from patients by gammadelta cells, as indicated by the significantly (P < 0.05) higher gammadelta cytotoxicity against MICA-positive rather than MICA-negative multiple myeloma cells. Our results indicate that MICA expressed by monoclonal plasma cells is functional and correlates with disease stages, suggesting a role for the molecule in the immune surveillance against multiple myeloma. Moreover, pamidronate-activated Vgamma9/Vdelta2 lymphocytes can be exploited in the immune therapy of early stages multiple myeloma and possibly of premalignant disease.     

意义未明的单克隆免疫球蛋白病血栓栓塞并发症的研究进展

意义未明的单克隆免疫球蛋白病（MGUS）患者静脉血栓栓塞（VTE）的过度危险已有报道。群体研究MGUS 1年-、5年-和10年-静脉血栓形成（VT）的危险性。深静脉血栓形成（DVT）和肺栓塞（PE）危险、动脉血栓形成、冠状动脉和脑血管事件的危险均增加。IgM MGUS患者并无血栓形成增加的危险,而IgG/IgA MGUS患者静脉血栓形成的危险增加4倍。血栓形成的危险不随诊断时M-蛋白浓度（〉10.0g/L或〈10.0g/L）而变动。伴/不伴血栓形成的MGUS患者血栓形成的危险未超过MM或原发性巨球蛋白血症（WM）。伴比不伴血栓形成的MGUS患者其5年和10年生存率差。     

意义未明的单克隆免疫球蛋白病血栓栓塞并发症的研究进展

意义未明的单克隆免疫球蛋白病(MGUS)患者静脉血栓栓塞(VTE)的过度危险已有报道。群体研究MGUS 1年-、5年-和10年-静脉血栓形成(VT)的危险性。深静脉血栓形成(DVT)和肺栓塞(PE)危险、动脉血栓形成、冠状动脉和脑血管事件的危险均增加。IgM MGUS患者并无血栓形成增加的危险,而IgG/IgA MGUS患者静脉血栓形成的危险增加4倍。血栓形成的危险不随诊断时M-蛋白浓度(>10.0g/L或<10.0g/L)而变动。伴/不伴血栓形成的MGUS患者血栓形成的危险未超过MM或原发性巨球蛋白血症(WM)。伴比不伴血栓形成的MGUS患者其5年和10年生存率差。     

T-cell subsets defined by monoclonal antibodies in monoclonal gammopathy of undetermined significance (MGUS)

Peripheral T lymphocytes from 31 patients with monoclonal gammopathy of undetermined significance (MGUS), and from a group of controls of the same age range, were stained using monoclonal antibodies of the OKT series. The absolute number and the percentage of OKT3+ cells did not differ in patients compared with the controls. The percentage and absolute number of T-cell subsets with helper/inducer OKT4+ and suppressor/cytotoxic OKT8+ phenotype were not different from those of the controls, thus the OKT4/OKT8 ratio in the patients with MGUS was normal (1.60 versus 1.57 in normal controls). These results suggest that MGUS is a B-cell disorder without imbalance of peripheral T-cell subsets unlike B-cell malignancies such as multiple myeloma and B-cell chronic lymphocytic leukemia.     

The risk of venous thromboembolic disease in patients with monoclonal gammopathy of undetermined significance.

BACKGROUND: Recent evidence indicates that patients with multiple myeloma receiving combination chemotherapy containing thalidomide are at a significantly high risk for venous thromboembolic disease (VTD). However, information on the occurrence of VTD in a related disorder, benign monoclonal gammopathy of undetermined significance (MGUS), is limited. PATIENTS AND METHODS: We prospectively investigated patients with MGUS for the occurrence of VTD. The diagnosis of MGUS was based on well known criteria for the disorder. The variables examined were sex, age, race, presence of underlying conditions, level and type of immunoglobulin [serum monoclonal (M)-protein] platelet counts and level of fibrinogen. RESULTS: Of a total of 310 patients with MGUS, 19 (6.1%) developed VTD after a median follow-up of 44 months (range 12-67 months). In a univariate analysis, age >/=65 years (P=0.01), M-protein >/=16 g/l (P=0.001) and progression to plasma cell or lymphoproliferative disorders (28 of 310 patients; P=0.001) were significant risk factors for VTD. In multivariate analysis, M-spike >/=16 g/l [risk ratio (RR)=6.3; 95% confidence interval (CI) 2.25-17.6; P=0.001] and future development of plasma cell or lymphoproliferative disorder (RR = 4.2; 95% CI 1.64-10.7; P=0.003) were variables strongly associated with the occurrence of VTD. A total of 46 patients (14.8%) died during the follow-up period of the study. CONCLUSION: This study demonstrates that patients with MGUS are at increased risk for VTD. Although a clear reason for the pre-thrombotic state in these patients is not currently evident, few risk factors were identified in the group of patients examined.     

Malignant transformation of monoclonal gammopathy of undetermined significance: cumulative incidence and prognostic factors.

The cumulative incidence of malignant transformation was studied in 88 patients with monoclonal gammopathy of undetermined significance (MGUS) that had a complete prospective follow-up. At a median follow-up of 6.75 years, 10 patients developed multiple myeloma (MM) (11.4%) and 2 developed immunocytoma (2.3%). The cumulative incidence of malignant transformation was 9.1, 21.3, 38 and 48.3% at 5, 10, 15 and 20 years, respectively. In univariate analysis on 102 MGUS patients, M-component level, bone marrow plasma cell percentage and kappa light chain correlated significantly with the development of a malignancy (p=0.0289, 0.0265 and 0.0013, respectively). In multivariate analysis, light chain type of M-component and plasma cell percentage had independent prognostic significance. A high-risk (M-component level > 10 g/l and/or plasma cell percentage > 2%) and a low-risk group ( M-component level < 10 g/l and/or plasma cell percentage < 2%) of MGUS patients was identified, which differed significantly in the cumulative incidence of developing a malignancy (p<0.001 for M-component level and p=0.007 for plasma cell percentage). These results imply that high-risk patients should receive a more frequent follow-up, in comparison to low-risk patients.     

Fluorescence in situ hybridization analysis of aneuploidization patterns in monoclonal gammopathy of undetermined significance versus multiple myeloma and plasma cell leukemia

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) is a clonal plasma cell (PC) disorder usually characterized by a benign clinical course. However, in approximately 25% of patients, the disorder has been found to evolve into a multiple myeloma (MM). The mechanism leading to the evolution of MGUS remains unknown. The aim of the current study was, first, to assess by interphase fluorescence in situ hybridization (FISH) the incidence of numerical abnormalities of chromosomes 6, 9, 13, and 17 in MGUS patients and to compare it with that found in MM and PC leukemia (PCL) patients and, second, to explore the potential heterogeneity of the pathologic PC in MGUS as a way to identify unique cytogenetic patterns different from those frequently observed in MM and PCL. METHODS: Numerical abnormalities of chromosomes 6, 9, 13, and 17 were investigated by dual- and triple-color FISH in bone marrow PC from 208 patients corresponding to MGUS (n = 30), MM (n = 158), and PCL (n = 20) cases. In MGUS and MM patients with < 10% PC, both normal and phenotypically aberrant PC were discriminated by multiparameter flow cytometry, the latter subset being specifically sorted for FISH analysis with a purity of 93% +/- 6%. RESULTS: Overall, 57% of the MGUS patients displayed abnormalities for at least 1 of the 4 chromosomes analyzed compared with 75% of both MM and PCL cases. The most common single chromosome abnormalities detected in MGUS were gains of chromosomes 9 (23%) and/or 6 (21%) and loss of chromosomes 13 (21%) and/or 17 (17%). Compared with MM patients, MGUS patients were found to have both a lower incidence of gains of chromosome 9 (23% vs. 54%, P = 0.002) and monosomy 13/13q(-) deletions (21% vs. 38%, P = 0.07); with respect to PCL cases, MGUS patients were found to have a lower incidence of monosomy 13/13q(-) deletions (21% vs. 75%, P < 0.001) together with a slightly higher frequency of gains of both chromosomes 6 (21% vs. 0%, P = 0.05) and 9 (23% vs. 7%, P = 0.1). The simultaneous use of two or three different chromosome probes showed that within the purified compartment of phenotypically aberrant PC from most MGUS patients (67%), more than 1 PC clone could be identified. In contrast, the incidence of 2 or more PC clones was much lower in MM (19%, P < 0.001) and PCL (15%, P = 0.003). Interestingly, although some FISH patterns were shared by both groups of diseases (i.e., monosomy 13/13q(-) deletions alone, gains of chromosome 9 alone or together with trisomy 6), others were found almost exclusively in either MGUS (i.e., a clone with monosomy 6 and/or 17 together with nuclei displaying a normal chromosome number) or in MM (i.e., monosomy 13/13q(-) deletions together with gains of chromosome 6 and/or 9). CONCLUSIONS: In summary, the results of the current study showed that MGUS patients displayed a high incidence of numerical alterations, which are usually associated with the presence of more than one tumor cell clone. It is interesting to note that the cytogenetic patterns observed in the aneuploid PC clones from MGUS patients were frequently different from those observed in both MM and PCL.     

Total soluble HLA class I and soluble HLA-G in multiple myeloma and monoclonal gammopathy of undetermined significance.

Serum beta2-microglobulin, the light chain of the HLA class I molecular complex, remains one of the best survival prognostic factors in multiple myeloma, but other HLA class I molecules might be of interest in monoclonal gammopathies. In this study, we evaluate total soluble HLA class I (HLA-Is) and soluble HLA-G (HLA-Gs) in 103 patients with newly diagnosed multiple myeloma, 30 patients with monoclonal gammopathy of undetermined significance (MGUS), and 30 healthy subjects, studying their prognostic value in multiple myeloma. In multiple myeloma patients, HLA-Is and HLA-Gs median values were 0.8 microg/mL and 28 ng/mL, respectively. Median HLA-Is concentration was higher in stage II and III multiple myeloma patients than in stage I multiple myeloma, MGUS, and control patients. Median HLA-Gs was significantly lower in healthy controls than in MGUS and multiple myeloma patients. A high level of HLA-Is (> or =2.1 microg/mL) was predictive of short survival (P = 0.017). For each given level of beta2-microglobulin, the relative risk of death was higher for patients with HLA-Is > or = 2.1 microg/mL than in patients with a lower level (P = 0.047). HLA-Gs, a marker of monoclonal gammopathy, was of no prognostic value, but the addition of HLA-Is to beta2-microglobulin produced an efficient prognostic score (P < 0.0001). HLA-Is is a new marker of multiple myeloma tumor load and provides additional survival prognostic information to beta2-microglobulin.     

Immunoglobulin heavy chain sequence analysis in Waldenstrom's macroglobulinemia and immunoglobulin M monoclonal gammopathy of undetermined significance

In this study, we used IGH sequence analysis to assess the maturational status of Waldenstrom's (WM) macroglobulinemia and its putative precursor immunoglobulin (Ig)-M monoclonal gammopathy of undetermined significance (MGUS). IGH sequence analysis was performed using standard methods in 23 cases (20 WM and 3 IgM MGUS as defined by consensus panel criteria). Waldenstrom's macroglobulinemia cases were characterized by heavily mutated IGH genes (median, 6.3%; range, 3.8%-13.9%) but without intraclonal variation (ICV). IgM MGUS was similarly characterized by somatic hypermutation (median, 7.5%; range, 7%-7.7%), but ICV was evident in 1 of the 3 cases. We would therefore conclude that WM is characterized by somatic hypermutation without ICV, which supports a derivation from postgerminal center/memory B cells. IgM MGUS is also characterized by somatic hypermutation but, in a manner similar to IgA/IgG MGUS, can be associated with ICV, although the significance of this remains unclear.     

Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma

In 1978, the term "monoclonal gammopathy of undetermined significance" (MGUS) was introduced. MGUS is defined as a serum monoclonal (M) protein less than 3.0 g/dL; less than 10% plasma cells in the bone marrow, if done; little or no M protein in the urine; and absence of lytic bone lesions, anemia, hypercalcemia or renal insufficiency. This article discusses the recognition, prevalence, natural history, and progression of MGUS. Management of the disease is discussed along with its association with other disorders. Information on smoldering multiple myeloma is included.     

Clonal plasma cells from monoclonal gammopathy of undetermined significance, multiple myeloma and plasma cell leukemia show different expression profiles of molecules involved in the interaction with the immunological bone marrow microenvironment.

The immunological bone marrow (BM) microenvironment plays a major role in controlling growth and survival of clonal plasma cells (PC); this might translate into different patterns of expression of molecules involved in immune responses on PC from different types of monoclonal gammopathies (MG). We have studied the expression of a group of nine such molecules on both BMPC and the plasma of 61 newly diagnosed MG patients (30 MG of undetermined significance (MGUS), 27 multiple myeloma (MM) and four plasma cell leukemia (PCL)) and five normal individuals. Clonal PC from all MG displayed significantly increased levels of CD56, CD86 and CD126, and decreased amounts of CD38 (P<0.001). Additionally, HLA-I and beta2-microglobulin were abnormally highly expressed in MGUS, while CD40 expression was decreased in MM and PCL (P<0.05). Interestingly, a progressive increase in the soluble levels of beta2-microglobulin was found from MGUS to MM and PCL patients (P=0.03). In contrast, all groups showed similar surface and soluble amounts of CD126, CD130 and CD95, except for increased soluble levels of CD95 observed in PCL. Overall, those phenotypic differences are consistent with increased antigen presentation and costimulatory capacities in MGUS, which progressively deteriorate in malignant MG (MM and PCL).     

Bone marrow angiogenesis in 400 patients with monoclonal gammopathy of undetermined significance, multiple myeloma, and primary amyloidosis.

PURPOSE: To determine whether bone marrow (BM) angiogenesis progressively increases along the spectrum of plasma cell disorders ranging from monoclonal gammopathy of undetermined significance (MGUS) to advanced myeloma. EXPERIMENTAL DESIGN: Four hundred patients with the following disorders were studied: MGUS (76 patients); smoldering (indolent; early-stage) multiple myeloma (SMM; 112 patients); newly diagnosed, active multiple myeloma (MM; 99 patients); relapsed (advanced) multiple myeloma (RMM; 26 patients); and primary amyloidosis (AL; 87 patients). Forty-two normal control BM samples were studied for comparison. BM angiogenesis was studied in a blinded manner by immunohistochemical staining for CD34 to identify microvessels. RESULTS: The median (range) microvessel density (MVD) per x400 high power field was 1.3 (0-11) in the controls, 1.7 (0-10) in AL, 3 (0-23) in MGUS, 4 (1-30) in SMM, 11 (1-48) in newly diagnosed MM, and 20 (6-47) in RMM; P < 0.001. MVD was significantly higher in MGUS, SMM, newly diagnosed MM, and RMM compared with controls and AL; P < 0.001. MVD was not significantly different between controls and AL. By grading, high-grade angiogenesis was present in 0% of controls and AL, 1% of MGUS, 3% of SMM, 29% of newly diagnosed MM, and 42% of RMM; P < 0.001. MVD correlated with the BM plasma cell labeling index (rho = 0.46, P < 0.001) and BM plasma cell percentage (rho 0.5, P < 0.001). Survival was 28 months in SMM and newly diagnosed MM with high-grade angiogenesis, compared with 53 months for those with low- and intermediate-grade angiogenesis; P = 0.02. CONCLUSIONS: BM angiogenesis progressively increases along the spectrum of plasma cell disorders, from the more benign MGUS stage to advanced myeloma, indicating that angiogenesis may be related to disease progression.     

Management of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM)

Monoclonal gammopathy of undetermined significance (MGUS) is defined as a serum M protein level of less than 3 g/dL, less than 10% clonal plasma cells in the bone marrow, and the absence of end-organ damage. The prevalence of MGUS is 3.2% in the white population but is approximately twice that high in the black population. MGUS may progress to multiple myeloma, AL amyloidosis, Waldenstr?m macroglobulinemia, or lymphoma. The risk of progression is approximately 1% per year, but the risk continues even after more than 25 years of observation. Risk factors for progression include the size of the serum M protein, the type of serum M protein, the number of plasma cells in the bone marrow, and the serum free light chain ratio. Smoldering (asymptomatic) multiple myeloma (SMM) is characterized by the presence of an M protein level of 3 g/dL or higher and/or 10% or more monoclonal plasma cells in the bone marrow but no evidence of end-organ damage. The overall risk of progression to a malignant condition is 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% to 2% per year for the following 10 years. Patients with both MGUS and SMM must be followed up for their lifetime.