MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS) WITH SEVERAL APPARENT CLONES.
Classically, a MGUS is discovered by chance during a work-up for an unrelated medical problem. The serum monoclonal protein that defines MGUS, referred to as the M-protein, is typically less than 3 g/dL. The M-protein by definition is clinically stable, i.e. present for a prolonged period of time and unaccompanied by other findings of myeloma or macroglobulinemia. Typically, the M-protein is absent from the urine, or present only in small amounts. If present in the urine, the monoclonal light-chain protein is referred to as a Bence Jones protein. An excellent review of MGUS has recently been published. (1)
The frequency of MGUS in the general population increases with age and is seen in about 1% of patients older than 50 years of age and reaches approximately 3% in those older than 70 years (1). There is some evidence that the incidence of MGUS may be higher in African-American populations (2) but lower in Japanese populations (3). A retrospective case-control study found an increase in frequency of MGUS in individuals with exposures to various chemicals, such as farmers and workers in industrial settings, as well as in those individuals with chronic inflammatory conditions. (4)
Mayo Clinic Study
The Mayo Clinic has studied a cohort of 241 patients with MGUS with a follow-up period ranging from 24 to 38 years. (1) The median age at diagnosis was 64 years in this group of 140 males and 101 females. The level of M-protein at diagnosis ranged from 0.3 to 3.2 g/dL and was IgG (73%), IgM (14%), and IgA (11%). Interestingly, the heavy chain was biclonal in 2% of patients. The light chain was typically kappa (62%). Bence Jones proteins were present in 6.2% of patients at presentation.
In 12% of these patients, the clinical course has been benign with no substantial increase in the serum or urine monoclonal protein. In 10% of the patients, the serum protien increased to greater than 3 g/dL, but myeloma did not develop. In 26%, frank myeloma, macroglobulinemia, amyloidosis, or a malignant lymphoproliferative disorder developed. The remaining 52% of patients died from unrelated processes.
A wide variety of factors present at the time of presentation were investigated by the Mayo Clinic, but none predicted whether the clinical course would be benign or one of progression. The following factors were examined: age, sex, presence of organomegaly, initial hemoglobulin level, level of serum M-protein, serum albumin level, IgG subclasses, number of plasma cells in bone marrow, presence of small amounts of Bence Jones proteins in the urine.
Molecular biology of progression from MGUS to myeloma
Numerous studies have attempted to determine the steps in progression from MGUS to myeloma. One study has shown that patients with MGUS slowly accumulate cytogenetic abnormalities and that various clones coexist within the same patient (5). Studies of several oncogenes have shown that p53 does not appear to play any significant role (6) while bcl-2 over-expression may contribute by preventing apoptosis (7). Cytokine production may be important and autocrine production of IL-6 and aberrant expression of IL1-beta may predict progression to myeloma. (8, 9) Low levels of soluble CD16 may also indicate a more rapid progression to myeloma (9)
This patient was diagnosed with a MGUS while being worked up for pleural and pericardial effusions. He had several risk factors including a history of chronic inflammatory conditions and possible work-related exposure to chemicals. His serum gammopathy was at a low level and he had small amounts of Bence Jones proteins in the urine. Interestingly, there was evidence for multiple clones, a finding also seen in a small number of patients in the Mayo Clinic study and in the previously cited cytogenetics study.
Contributed by Michael Torbenson, MD and Robert Kelly, PhD