Correspondence
Monoclonal Gammopathy of Undetermined Significance
N Engl J Med 2002; 346:2087-2088June 27, 2002
- Article
To the Editor:
In their long-term follow-up study of patients with monoclonal gammopathy of undetermined significance (MGUS), Kyle et al. (Feb. 21 issue)1 did not include patients with pure Bence Jones proteinuria, resulting from a plasma-cell dyscrasia involving the excretion of monoclonal light chains into the urine. From a pathophysiological point of view, it is reasonable to include light-chain disease in MGUS, since it clearly also represents a gammopathy.2 Although the disorder is clinically relevant, there is astonishingly little information in the literature on the prognosis for patients with pure, idiopathic Bence Jones proteinuria.3,4 Before 1980, it was not recognized that there are indolent cases in which Bence Jones proteinuria remains stable for years,2 thus representing a benign counterpart of light-chain myeloma with its poor prognosis. In 1982, seven patients with idiopathic Bence Jones proteinuria, five of whom had progression to myeloma, were described in detail by Kyle and Greipp.3 Clinical information on a larger series of patients with pure Bence Jones proteinuria (which should certainly be available at the Mayo Clinic3) would permit a reliable estimate of the prognosis. Therefore, we wonder about the incidence of Bence Jones MGUS in the group of patients who were followed at the Mayo Clinic, the authors' approach to the treatment of these patients, and the natural course of the condition.
4 ReferencesMichael Fiegl, M.D.
Richard Greil, M.D.
University of Innsbruck, A-6020 Innsbruck, Austria
michael.fiegl@uibk. ac. at 1
Kyle RA ,Therneau TM ,Rajkumar SV , et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 2002;346:564-569
Full Text | Web of Science | Medline2
Paladini G ,Sala PG ,Santini PA . Benign Bence Jones gammopathy. Acta Haematol 1980;63:241-246
CrossRef | Web of Science | Medline3
Kyle RA ,Greipp PR . “Idiopathic“ Bence Jones proteinuria: long-term follow-up in seven patients. N Engl J Med 1982;306:564-567
Full Text | Web of Science | Medline4
Pezzoli A ,Pascali E . The clinical significance of pure Bence Jones proteinuria at low concentration. Am J Clin Pathol 1989;91:473-475
Web of Science | Medline
To the Editor:
Kyle et al. reported that the probability of progression of MGUS was 12 percent at 10 years and 25 percent at 20 years of follow-up. The initial concentration of the monoclonal protein was the most important predictor of progression. One concern regarding this type of analysis is its reproducibility. In our series of 434 patients who were followed for a median of 5.2 years (range, 1 to 29), the risk of malignant transformation was 15 percent at 10 years and 34 percent at 20 years. The likely explanation for the higher risk of malignant transformation in our study than in the study by Kyle et al. is our finding of a higher median serum monoclonal protein concentration (1.56 vs. 1.2 g per deciliter). Interestingly enough, in the original Mayo Clinic series,1 which included 241 patients with a median serum monoclonal protein concentration of 1.7 g per deciliter, the risk of malignant transformation was 16 percent at 10 years and 33 percent at 20 years. In our series, the variables associated with a higher risk of progression in the multivariate analysis were the kappa light chain (as compared with the lambda light chain, relative risk, 4.1), the serum monoclonal protein concentration (<1.5 vs. ≥1.5 g per deciliter, relative risk, 2.6), and the percentage of bone marrow plasma cells (<5 percent vs. ≥5 percent, relative risk, 2.2). These findings indicate that the initial plasma-cell burden, as reflected by the serum monoclonal protein concentration and the proportion of bone marrow plasma cells, is the critical risk factor for malignant transformation in MGUS.
1 ReferencesSilvia Montoto, M.D.
Joan Bladé, M.D.
Emili Montserrat, M.D.
Hospital Clínic Barcelona, 08036 Barcelona, Spain
30069sma@comb.es 1
Kyle RA . “Benign“ monoclonal gammopathy -- after 20 to 35 years of follow-up. Mayo Clin Proc 1993;68:26-36
Web of Science | Medline
To the Editor:
Kyle et al. offer no guidelines for the prevention or amelioration of pathologic fractures before the onset of multiple myeloma in patients with MGUS who are at risk. Do they routinely perform bone-densitometry scanning at base line in their patients with MGUS? Bisphosphonates represent the standard of care in the treatment of metastatic skeletal lesions1 and in the prevention of bone loss in men2 and postmenopausal women.3 Furthermore, thalidomide has been suggested as a single agent to ameliorate multiple myeloma in the early stages of the disease.4
In the light of their identification of a population at risk, can the authors explain their approach to patients at risk for pathological fractures who have asymptomatic MGUS?
4 ReferencesDanny H.-Kauffmann Jokl, M.D.
New York Medical College, Bronxville, NY 107081
Brown DL ,Robbins R . Developments in the therapeutic applications of bisphosphonates. J Clin Pharmacol 1999;39:651-660
CrossRef | Web of Science | Medline2
Orwoll E ,Ettinger M ,Weiss S , et al. Alendronate for the treatment of osteoporosis in men. N Engl J Med 2000;343:604-610
Full Text | Web of Science | Medline3
Hosking D ,Chilvers CED ,Christiansen C , et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. N Engl J Med 1998;338:485-492
Full Text | Web of Science | Medline4
Raje N ,Anderson K . Thalidomide -- a revival story. N Engl J Med 1999;341:1606-1608
Full Text | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Fiegl and Greil have raised an important point concerning disorders involving monoclonal light chains (idiopathic Bence Jones proteinuria). We specifically excluded patients with this disorder from our cohort of patients with MGUS, since idiopathic Bence Jones proteinuria is traditionally considered a separate disorder with a different prevalence and method of detection and probably a higher risk of progression to cancer. We have, however, identified and followed a number of patients with idiopathic Bence Jones proteinuria, who will be the subject of a future article. Montoto et al. question the reproducibility of estimates of monoclonal protein concentrations. In our experience, there is some variability in the measurement of the monoclonal protein, but it is usually small (<0.5 g per deciliter). We agree with their observation that the percentage of bone marrow plasma cells is most likely an important risk factor for progression. In our study, bone marrow biopsy was performed in only a minority of patients because the monoclonal protein concentration was low. We believe that bone marrow biopsy is not routinely indicated in patients with low monoclonal protein concentrations (<1 g per deciliter) who have no other evidence of myeloma. We were unable to demonstrate that the presence of kappa light chains was a risk factor for progression.
We did not write guidelines for the prevention of pathologic fractures in MGUS, because it is not yet clear that the risk of fracture is increased, although this is the subject of a study that has just been started. We do not perform base-line bone-densitometry studies in patients with MGUS, but Bataille et al.1 have demonstrated that increased bone absorption occurs in early myeloma but not in MGUS. One must take into account the fact that myeloma develops in only a minority of patients, even after 25 years of follow-up. Patients who have asymptomatic multiple myeloma (smoldering multiple myeloma) are candidates for clinical trials of agents that may delay the need for chemotherapy and the progression to symptomatic disease.2 Thalidomide therapy has some activity in patients with smoldering multiple myeloma.3 We are also studying the effect of dehydroepiandrosterone and clarithromycin in high-risk patients with MGUS. In addition, interleukin-1β antagonists are potential therapeutic agents in such patients. Finally, randomized, prospective studies are necessary before any treatment can be recommended for patients with MGUS.
3 ReferencesRobert A. Kyle, M.D.
S. Vincent Rajkumar, M.D.
Joseph Melton, III, M.D.
Mayo Clinic, Rochester, MN 55905
kyle.robert@mayo. edu 1
Bataille R ,Chappard D ,Basle MF . Quantifiable excess of bone resorption in monoclonal gammopathy is an early symptom of malignancy: a prospective study of 87 bone biopsies. Blood 1996;87:4762-4769
Web of Science | Medline2
Kyle RA ,Greipp PR . Smoldering multiple myeloma. N Engl J Med 1980;302:1347-1349
Full Text | Web of Science | Medline3
Rajkumar SV ,Dispenzieri A ,Fonseca R , et al. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia 2001;15:1274-1276
CrossRef | Web of Science | Medline
- Citing Articles (7)
Citing Articles
1
Sumit Madan, Philip R. Greipp. (2009) The incidental monoclonal protein: Current approach to management of monoclonal gammopathy of undetermined significance (MGUS). Blood Reviews 23:6, 257-265
CrossRef2
L. Rosinol, M. T. Cibeira, S. Montoto, M. Rozman, J. Esteve, X. Filella, J. Blade. (2007) Monoclonal Gammopathy of Undetermined Significance: Predictors of Malignant Transformation and Recognition of an Evolving Type Characterized by a Progressive Increase in M Protein Size. Mayo Clinic Proceedings 82:4, 428-434
CrossRef3
Bladé, Joan, . (2006) Monoclonal Gammopathy of Undetermined Significance. New England Journal of Medicine 355:26, 2765-2770
Full Text4
Joan Bladé, Laura Rosiñol. (2006) Smoldering multiple myeloma and monoclonal gammopathy of undetermined significance. Current Treatment Options in Oncology 7:3, 237-245
CrossRef5
J. Blade. (2004) On the "Significance" of Monoclonal Gammopathy of Undetermined Significance. Mayo Clinic Proceedings 79:7, 855-856
CrossRef6
L. Rosiñol, J. Bladé, J. Esteve, M. Aymerich, M. Rozman, S. Montoto, E. Giné, E. Nadal, X. Filella, R. Queralt, A. Carrió, E. Montserrat. (2003) Smoldering multiple myeloma: natural history and recognition of an evolving type. British Journal of Haematology 123:4, 631-636
CrossRef7
Joan Bladé, Silvia Montoto, Laura Rosiñol, Emili Montserrat. (2003) Appropriateness of applying the response criteria for multiple myeloma to Waldenstrom's macroglobulinemia?. Seminars in Oncology 30:2, 329-331
CrossRef
