"MGUS" now = MULTIPLE MYELOMA

http://bloodjournal.hematologylibrary.org/content/113/22/5412.full

From BLOOD

Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study

1. Ola Landgren1,2,
2. Robert A. Kyle3,4,
3. Ruth M. Pfeiffer1,
4. Jerry A. Katzmann3,4,
5. Neil E. Caporaso1,
6. Richard B. Hayes1,
7. Angela Dispenzieri3,4,
8. Shaji Kumar3,
9. Raynell J. Clark4,
10. Dalsu Baris1,
11. Robert Hoover1, and
12. S. Vincent Rajkumar3

+ Author Affiliations

1. ¹Division of Cancer Epidemiology and Genetics, and
2. ²Center for Cancer Research, Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD;
3. ³Division of Hematology and Internal Medicine, and
4. ⁴Division of Clinical Biochemistry & Immunology and Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN

 

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Abstract

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma-cell proliferative disorder associated with a life-long risk of progression to multiple myeloma (MM). It is not known whether MM is always preceded by a premalignant asymptomatic MGUS stage. Among 77 469 healthy adults enrolled in the nationwide population-based prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, we identified 71 subjects who developed MM during the course of the study in whom serially collected (up to 6) prediagnostic serum samples obtained 2 to 9.8 years prior to MM diagnosis were available. Using assays for monoclonal (M)–proteins (electrophoresis/immunofixation) and kappa-lambda free light chains (FLCs), we determined longitudinally the prevalence of MGUS and characterized patterns of monoclonal immunoglobulin abnormalities prior to MM diagnosis. MGUS was present in 100.0% (87.2%-100.0%), 98.3% (90.8%-100.0%), 97.9% (88.9%-100.0%), 94.6% (81.8%-99.3%), 100.0% (86.3%-100.0%), 93.3% (68.1%-99.8%), and 82.4% (56.6%-96.2%) at 2, 3, 4, 5, 6, 7, and 8+ years prior to MM diagnosis, respectively. In approximately half the study population, the M-protein concentration and involved FLC-ratio levels showed a yearly increase prior to MM diagnosis. In the present study, an asymptomatic MGUS stage consistently preceded MM. Novel molecular markers are needed to better predict progression to MM in patients with MGUS.

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Introduction

Multiple myeloma (MM) is a clonal plasma-cell proliferative disorder with a median survival of approximately 4 years.¹ Almost 19 900 new MM cases and 10 700 MM deaths are expected in the United States during 2008.² Monoclonal gammopathy of undetermined significance (MGUS) is one of the most common premalignant disorders in Western countries, with a prevalence of 3.2% in the white general population 50 years of age or older.³ It is an asymptomatic condition characterized by the presence of a monoclonal immunoglobulin (M-protein) in the absence of any clinical signs or symptoms of MM or other lymphoproliferative malignancies.^4,5

Long-term follow-up studies of MGUS patients show an excess risk of developing MM.⁶ However, a key gap in our understanding is whether MM is always preceded by MGUS, or if MM typically arises de novo. This knowledge is critically important in understanding the pathogenesis of MM and to develop preventive strategies. We hypothesize that a premalignant plasma-cell proliferative stage characterized by asymptomatic M-protein production, clinically defined as MGUS, is present in all patients with MM years prior to the development of the malignancy. The confirmation of this hypothesis would emphasize the need to focus on identifying risk factors for MGUS and to improve our knowledge on underlying mechanisms of transformation from MGUS to MM, with the aim to define better predictive markers of progression and to develop chemopreventive approaches.

Thus far, it has been impossible to determine whether a protracted premalignant phase MGUS precedes MM in all patients. Taking advantage of the large nationwide US PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial,⁷ we used a unique study design to conduct the first prospective study to address this question. Among 77 469 persons in the screened arm who were cancer-free at baseline, we identified 71 subjects who developed MM during the course of the study in whom serially collected prediagnostic serum samples obtained at least 2 years (up to 9.8 years) prior to MM diagnosis were available. Using multiple prediagnostic blood samples (up to 6 samples) obtained annually in the same subject, we applied serum protein electrophoresis, immunofixation, and kappa-lambda free light chain (FLC) assays to define the prevalence of MGUS prior to the diagnosis of MM, and characterized longitudinally patterns of M-protein abnormalities prior to MM diagnosis.