Monday, April 30, 2007

Malignant transformation of monoclonal gammopathy

Rosinol L. et al.  Mayo Clin Proc 2007;82:428-434.
The authors cite a NEJM article (2006) showing a prevalence of 3.2 % and 5.7 % in patients greater than 50 and 70, respectively.  The patients can transform after years of stability.  To determine the rate of transformation, the authors took into account both the presenting clinical finding and the evolutionary pattern of the M protein.  They excluded patients diagnosed in the first 3 years, or with smoldering myeloma.  537 were diagnosed with MGUS, 178 were lost to followup or were followed les than three years, 359 were followed more than 3 years.  Patients received a SPEP, UPEP and bonemarrow aspirate.  On followup they got an M protein measurement on pep yearly. Evolving type was defined as patients with an increase in the M protein size on electropheresis in each annual visit over three years.  330 patients were nonevolving and 29 were evolving.  32 developed malignancies.  Risk factors were the evolving typeand M protein concentration.  Of the 32 malignancies, 20 had multiple myeloma and 2 had Waldenstrom's macroglobulinemia after a median followup of 93 months (7 and a half years, just under ten percent).  However, 14/29 with evolving MGUS (48 %) developed symptomatic disease, and 18 (5%) on nonevolving progressed.  The rate of transformation in the evolving and nonevolving groups after ten and twenty years, respectively, were, 55 and 10, and 80 and 13, respectively. 
Initial factors associated with transformation were M protein size greaterthn 15 g/L, proportion of BMPCs (bonemarrow plasma cells) greater than 5 %; higher incidence of IgA v. IgG, and evolving MGUS. No nonevolving patients transformed after twelve years. 
The actuarial rate of progression is 1.5 % per year, 17 % at 10 years, 34 % at 20 years, 39 % at 25 years (Kyle et al., different paper).  Baldini et al. (Blood, 1996) emphasizes BMPC's as an important risk factor with followup of patients with BMPC ranging from 10-30 percent (normal was around 4) having a 5-6 year followup, having a rate of malignant transformation of 37 v. 7 percent.  Cesana et al.  (J Clin Oncol 2002) found bm plasmacytosis greater than 5 percent, presence of light chains proteinuria, polyclonal serum immunoglobulin reduction and high ESR as independent factors affecting transformation.  Kyle et al. found thatM protein size and non IgG type were the most important predictors of progression.  (Kappa v. lambda had relative risk of 4.1).  Rajkumar et al.(Blood 2005)found non IgG MGUS, M protein > 15 g/L, abnormal k/l light chain ratio had an actuarial probability of transforming of 58 % at 20 years, whereas patients who lacked all of the above risk factors had a rate of transformation at 20 years of only 6 percent. 
Kyle and Greipp(NEJM 1980) described SMM (smouldering multiple myeloma), defined as M protein > 30 and BMPC> 10 % without end organ impairment.  Patients with the evolving SMM type show a progressive increase in M protein until myeloma develops,  whereas nonevolving types have stable M protein until the onset of disease with a longer time till disease develops.  59 % of SMM patients who were evolving previously had an evolving MGUS, whereas only 4 % of nonevolving SMM had a previously noted MGUS .  This is due to genomic hybridization, with high chromosomal losses and iq gains in the evolving patients.
The authors hypothesize that there are two types oo MGUS evolving and nonevolving, and all patients with the evolving type will eventially get disease. 

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