Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant plasma cell proliferative disorder with a lifelong risk of progression to multiple myeloma or another plasma cell dyscrasia (1). It is defined by the presence of a serum monoclonal M-protein less than 3 g/dL, less than 10% plasma cells in the bone marrow, and the absence of CRAB (hypercalcemia, renal failure, anemia, and lytic bone lesions) features that can be directly attributed to the underlying monoclonal gammopathy (2–5). MGUS arises from a clonal proliferation of differentiated plasma cells and is a necessary precursor to development of multiple myeloma and some other B-cell malignancies (6). In longitudinal surveys, the risk of malignant transformation from MGUS to a more serious malignancy is approximately 1.5% per year in the absence of immunosuppression (7). The risk of progression can be better defined by quantifying the monoclonal protein, examining the serum free light chain ratio, and immunoglobulin isotype. Despite a high incidence in the general population (1%–2% of adults in the sixth and seventh decades) (8) and an increased relative risk for later malignancy, there are few reports about the clinical course and prognosis of MGUS in long-term immunosuppressed patients (9). We aimed to evaluate the significance of MGUS in patients undergoing solid transplants in terms of clinical outcomes and rate of transformation to secondary B-cell malignancy.
Between January 1999 and July 2009, 1199 serum protein electrophoreses (SPEPs) were performed on 1593 consecutive adult solid organ transplant patients and in follow-up. The study group had a median age of 55 years (range 7–84 years) and encompassed a variety of solid organ transplant types including kidney (living donor related, living donor unrelated, and deceased donor), liver, and pancreatic. The clinical characteristics of patients are presented in Table 1.
SPEP Abnormalities and Outcomes
The most common findings detected by SPEP in all 1199 patients in which test results were available included a normal pattern (70%), polyclonal elevation pattern (16.8%), hypoalbuminemia (8%), hypogammaglobulinemia (2.4%), and the presence of M-spike (2.8%). Overall survival was compared, and no significant changes were detected among the different groups of abnormalities detected by SPEP.
To examine the impact of polyclonal hypergammaglobulinemia, we examined in more detail the group with the highest incidence. From June 1999 through March 2006, 302 patients (96 women and 206 men) underwent liver transplantation. Mean age at transplantation was 52.3 years. The causative factors of liver disease were hepatitis C virus (HCV; n=162), alcoholic liver disease (n=38), cryptogenic and nonalcoholic steatohepatitis (n=35), primary sclerosing cholangitis and primary biliary cirrhosis (n=31), miscellaneous (n=21), autoimmune hepatitis (n=10), and hepatitis B (n=5).
Before transplantation, 75.5% of these patients had evidence of hypergammaglobulinemia. This number declined to 9.4% at the 4-month posttransplant evaluation but increased again thereafter: 22.5% at 1 year, 29.8% at 2 years, 31.2% at 3 years, 36.7% at 4 years, and 43.8% at 5 years after liver transplantation. Polyclonal gammopathy occurred at similar frequency in all causative factors of liver disease. An increase in globulin levels likely reflects reduction in immunesuppression over time. After transplantation, recurrence of polyclonal gammopathy occurred with similar frequency in all groups except for cryptogenic cirrhosis and nonalcoholic steatohepatitis (Table 2). After transplantation, no relationship was found between the recurrence of polyclonal gammopathy and fibrosis or inflammation based on protocol liver biopsy.
We next focused on the potentially more serious clinical dilemma of MGUS identified before or after transplant. Immunofixation revealed the presence of a monoclonal immunoglobulin in 34 patients: monoclonal IgG band in 27 patients (79%), IgM alone in 2 patients (6%) an IgA spike in 1 patient (3%), and biclonal disease in 4 patients (11.7%). In 16% of patients, a small monoclonal band was seen on electropheresis, and immunofixation was not performed. The median age at diagnosis of MGUS was 60 years (mean 60.5 years; range 46–84 years) and included 63.7% of men. In liver transplants, 5.9% (22/368) of patients had MGUS at baseline, whereas only 1.7% (14/823) of kidney recipients had MGUS. The clinical characteristics of the MGUS cases are presented in Table 3.
Monoclonal proteins measuring from 0.2 to 2.3 g/dL were diagnosed pretransplant. Further breakdown of the protein electrophoresis results are summarized in Table 4. Fifty-three percent of the time the report described a polyclonal pattern with a small monoclonal spike present. This pattern was observed in 3.8% (14/368) of liver and 0.48% (4/823) of renal transplants. Only four patients were on immunesuppression when the monoclonal protein was discovered. Two MGUS patients were diagnosed only after the transplant was performed (338 and 1082 days, respectively).
Six patients developed posttransplant lymphoproliferative disorders (PTLPDs), but none of these patients had MGUS. Seven of the 34 patients in the MGUS group died (20%), but the event was not related to progression of the monoclonal clone or development of a PTLPD or other malignancy in any case. A diagnosis of MGUS did not impact transplant outcomes or graft failure. After a median of 88 months, no MGUS patient developed transformation to active myeloma or a related disorder. Because no patient developed a plasma cell dyscrasia, no associations between electropheretic patterns, monoclonal protein levels, or isotypes were discerned.
Overall survival after transplantation was not significantly different among MGUS and non-MGUS cases (6.48 vs. 8.36 years, P>0.05; Fig. 1). Bone marrows and serum-free light chain assays were only intermittently obtained, and thus, data on genetic subsets or free light chain ratio is available in only a minority of patients and could not be analyzed further.
An increased incidence of monoclonal gammopathy in patients with autoimmune disease and in older nontransplant populations suggests that impaired immunity might lead to development of MGUS and later monoclonal B-cell malignancies. Indeed, MGUS has been reported at higher than expected frequency in patients with connective tissue disorders such as rheumatoid arthritis (10), systemic lupus erythematosus, scleroderma, polymyositis, and ankylosing spondylitis. A number of skin disorders have been described in association with plasma cell dyscrasias and neoplasms (11). The prevalence of polyclonal gammopathy and monoclonal gammopathies in patients with HCV-related chronic liver disease is striking (12) and may be accompanied by mixed cryoglobulinemia and has been reported to be more prevalent in the context of HIV infection than would be expected in HIV-negative individuals (13). All these examples suggest that failure of immune control systems is related to the development or emergence of MGUS. Despite the frequency of MGUS in the general population and concerns about the impact of immune suppression, there are few studies that have assessed the significance of MGUS in solid organ transplant patients (9, 14). However, MGUS is frequent after autologous blood stem-cell transplantation (15) (likely reflecting oligoclonal immune reconstitution), and a higher prevalence of MGUS has been noted after solid organ transplantation (14, 16, 17). Radl et al. (14) reported a 10 times higher than expected incidence of MGUS after kidney transplants than that in a control group of patients with chronic renal failure on dialysis treatment. The increase in the frequency of homogeneous immunoglobulins in the renal transplant recipients was related to the age of the patients but not to the duration of the immunosuppressive treatment. In a different study on heart transplant recipients, using the sensitive capillary electrophoresis, Caforio et al. (17) reported a higher frequency (25%) of MGUS than a normal age-matched population (1%). These studies demonstrate that MGUS is more common than in the general population after immune suppression is introduced but do not ask the clinically relevant question of what to do with a patient with MGUS diagnosed before solid organ transplant.
In this series, we report on the incidence and follow-up of MGUS in patients screened before transplantation. The primary outcome for transplant recipients is unaffected by the presence of MGUS. The incidence of 3% is perhaps higher than expected given the median age of the population and likely reflects the presence of HCV infection in prospective liver transplant patients in whom 5.4% patients had a monoclonal serum protein at baseline. Patients with MGUS do not appear in this series to be at increased risk for progression because of chronic immunosuppression. Although it is possible that plasma cell dyscrasias may emerge with longer follow-up, the median follow-up of this series is 7 years and thus would seem to play concerns that immunesuppression would accelerate disease progression.
PTLPD is frequently associated with Epstein-Barr virus infection and occurs in the setting of pharmacologic immunosuppression used after organ transplantation. It has been reported that patients with MGUS developed PTLPD more frequently than those without (18). There have also been reports of a higher frequency of PTLPD in patients with MGUS after organ transplantation (19, 20).
In contrast with previous reports, PTLPD was not associated with the presence of MGUS in this series. To screen for patients at risk of PTLPD, SPEP has been suggested as a routine study to monitor for MGUS after organ transplantation (21). In contrast, our data show that there is a low frequency of MGUS in solid transplant recipients. The majority of MGUS patients have detectable M-component at the time of transplant, and only two cases were diagnosed after transplantation. The SPEP does not seem to have prognostic value because we did not detect any correlations with transplantation success rates or survival. In conclusion, testing for MGUS before transplantation is not cost efficient and therefore would not be recommended. To our knowledge, this is the largest series reporting on MGUS and transplant outcomes.
MATERIALS AND METHODS
We reviewed the medical records of patients in whom kidney (living donor related, living donor unrelated, and deceased donor), liver, and pancreatic transplants were performed at Mayo Clinic Arizona, between January 1, 1999, and July 31, 2009, to determine the incidence of MGUS and to further evaluate long-term follow-up.
We next reviewed in more detail the medical records of all liver transplant recipients from June 1, 1999, to March 31, 2006. The patients were evaluated for age, gender, and causative factor of liver disease. SPEP was performed on all patients as a part of a pretransplantation workup. As per protocol, SPEP was reviewed posttransplant at 4 months and then annually thereafter. Posttransplant protocol biopsies were obtained at 4 months, 1 year, and annually thereafter and were reviewed for fibrosis and inflammation. Fibrosis was measured using the Batts-Ludwig Staging system (22). Disease activity grade was measured using the histologic activity index (HAI) system (23) (formulation and application of a numerical scoring system for assessing histologic activity in asymptomatic chronic active hepatitis) and rejection activity index (RAI) for rejection (24). Patient age, causative factor of liver disease, and comorbid medical conditions were also reviewed.
An International Working Group has recently recommended a new classification of monoclonal gammopathies based on the level/concentration of serum M-protein, percentage of bone marrow plasma cells, and the presence or absence of myeloma-related organ or tissue impairment (25). MGUS is characterized by the presence of M-protein in serum less than 3 g/dL, less than 10% bone marrow clonal plasma cells, and low level of plasma cell infiltration in a trephine biopsy (if done), no myeloma-related organ or tissue impairment including bone lesions or symptoms, and no evidence of other B-cell lymphoproliferative disorder (LPD), or light chain–associated amyloidosis or other light chain, heavy chain, or immunoglobulin-associated tissue damage. Patients who had anemia unrelated to their plasma cell proliferative disorder (PCPD) were included in this study.
Laboratory Testing for MGUS
At Mayo Clinic Arizona transplants, recipient evaluation includes testing for monoclonal proteins using SPEP, and immunofixation is required for all cases where a monoclonal band is suspected. Electrophoresis was performed on agarose gel to test for monoclonal protein. Any serum with a discrete band or a suspect localized band was subjected to immunofixation. On the basis of SPEP and immunofixation, MGUS cases were assessed to evaluate definite diagnosis.
Patients were observed until death or, for those still alive, until July 2009. The major goal of the study was to assess the impact of MGUS on transplant outcomes and progression to active myeloma or related disorders. Patients who did not experience progression were censored at the time of last follow-up. Nominal variables were compared using Fisher's exact test. A two-tailed P value less than 0.05 was considered significant.
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