By Maryann Kwa, MD
Faculty Peer Reviewed
Clinical Case:
A.D. is a healthy 65-year-old African American male with no prior medical history who presents to his primary care physician for an annual check up. He feels well and has no complaints. Physical exam is normal. Common laboratory tests are ordered which are significant for an elevated total serum protein with normal albumin. A serum protein electrophoresis (SPEP) is then performed. The patient is found to have a monoclonal protein (M protein) of 12 g/L, IgG type, and normal free light chain ratio. All other lab results including hemoglobin, creatinine, and calcium are within their normal ranges. A skeletal survey is done which is negative for lytic lesions. A bone marrow biopsy is also performed which reveals <10% plasma cells. The patient is referred to a hematologist who informs him that he has monoclonal gammopathy of undetermined significance (MGUS). The patient inquires about whether any treatment is recommended.
Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell dyscrasia that is defined as a serum M protein <30 g/L, clonal plasma cells <10% in the bone marrow, and the absence of end-organ damage that can be attributed to a plasma cell proliferative disorder (see table) [1]. End-organ damage is defined by the presence of hypercalcemia, renal insufficiency, anemia, and bony lesions (which can be remembered by the acronym CRAB). MGUS is usually discovered incidentally in the blood during routine laboratory tests. It affects approximately 3% of individuals older than 50 years [2]. Prevalence is twice as high among African Americans and is lower in Asians. Older age, male sex, family history, and immunosuppression are also factors that increase the risk of MGUS [3]. So why do we worry about MGUS? It is important to clinicians because it is associated with a 1% annual risk of progression to multiple myeloma or related malignancy [4]. According to the International Myeloma Working Group (IMWG), the diagnostic criteria for multiple myeloma involves clonal plasma cells >10% in bone marrow biopsy, presence of monoclonal protein in either serum or urine, and evidence of end organ damage related to the plasma cell disorder. A prospective study by Landgren et al. (2009) demonstrated that multiple myeloma is consistently preceded by MGUS [5]. Of the approximately 77,400 healthy adults in the United States who were observed for up to ten years, 71 developed multiple myeloma. Prior evidence of MGUS was demonstrated in all these patients by assays for protein abnormalities in prediagnostic serum samples.
The pathophysiology of the transition from normal plasma cells to MGUS to multiple myeloma involves many overlapping oncogenic events [6]. The first step in the pathogenesis is usually an abnormal response to antigenic stimulation, possibly mediated by overexpression of interleukin (IL)-6 receptors and dysregulation of the cyclin D gene. These changes result in the development of primary cytogenetic abnormalities, either hyperdiploidy or immunoglobulin heavy chain translocation (the most common are t(4;14), t(14;16), t(6;14), t(11;14), and t(14;20)). The progression of MGUS to multiple myeloma is likely secondary to a random second hit, the manner of which is unknown. Mutations with Ras and p53, methylation of p16, myc abnormalities, and induction of angiogenesis have also been associated with progression.
Since MGUS was first described approximately thirty years ago, there have been new concepts and advances concerning classification and management. There are currently three distinct clinical types of MGUS: 1) non-IgM (IgG or IgA); 2) IgM; and 3) light chain. Non-IgM MGUS is the most common type and its more advanced premalignant stage of plasma cell proliferation is called smoldering (asymptomatic) multiple myeloma which is characterized by a higher risk of progression to multiple myeloma. Smoldering myeloma is defined by a serum monoclonal protein (IgG or IgA) ≥30 g/L and/or clonal plasma cells ≥10% in bone marrow with absence of end organ damage [7]. It is associated with a 10% annual risk of progression to multiple myeloma. On the other hand, the IgM subtype of MGUS is mainly associated with predisposition to Waldenström macroglobulinemia and less frequently to IgM multiple myeloma. Finally, the light chain type comprises approximately 20% of new cases of multiple myeloma.
In terms of outcome of MGUS, Kyle et al. (2002) published a cohort study of 1384 patients from Minnesota with MGUS who were followed for up to 35 years (median, 15.4 years) [8]. Results showed that eight percent developed multiple myeloma (n=75), IgM lymphoma (7), AL amyloidosis (10), leukemia (3), and plasmacytosis (1). The cumulative probability of progression was 12% at 10 years, 25% at 20 years, and 30% at 25 years. The overall risk of progression was about 1% per year.
When evaluating a patient for the first time, a complete history and physical examination should be done with emphasis on symptoms and findings that may suggest multiple myeloma. A complete blood count, serum creatinine, serum calcium, and a qualitative test for urine protein should also be performed. If serum abnormalities or proteinuria is found, electrophoresis and immunofixation is indicated. Predicting which patients with MGUS will remain stable compared to those who will progress is very difficult at the time of diagnosis. Those patients with non-IgG type, high serum M protein level (≥15 g/L), and an abnormal serum free light chain ratio (i.e., the ratio of free immunoglobulin kappa to lambda light chains in the serum) are associated with increased risk for progression to smoldering myeloma and then to multiple myeloma.
In June 2010, the IMWG released consensus guidelines for monitoring and managing patients with MGUS and smoldering myeloma. Patients with MGUS are divided into different categories based on low risk, intermediate risk, and high risk. If the serum monoclonal protein is <15 g/L, IgG type, and the free light chain ratio is normal, then the risk of eventual progression to multiple myeloma or related malignancy is low. In this low-risk setting, a baseline bone marrow examination or skeletal survey is not routinely indicated if the clinical evaluation and laboratory values suggest MGUS. Patients should be followed with SPEP 6 months after diagnosis and if stable can be followed every 2-3 years (or sooner if symptoms suggestive of disease progression arise).
However, patients that fall in the intermediate and high risk MGUS category are managed differently. They usually have a serum monoclonal protein >15 g/L, IgA or IgM type, and/or an abnormal free light chain ratio. In this situation, a bone marrow biopsy should be carried out at baseline. Both conventional cytogenetics and fluorescence in situ hybridization should be performed. These patients are followed with SPEP, complete blood count, serum calcium and creatinine levels 6 months after diagnosis and then yearly for life. It is important to note, however, that a bone marrow biopsy and skeletal survey is always indicated if a patient with presumed MGUS has unexplained anemia, renal insufficiency, hypercalcemia, or skeletal lesions.
And finally, those patients with smoldering (asymptomatic) multiple myeloma always receive a baseline bone marrow biopsy and mandatory skeletal survey. An MRI of the spine and pelvis is also recommended because it can detect occult lesions which predict a more rapid progression to multiple myeloma. Wang et al. (2003) estimated the risk of progression in 72 patients with smoldering myeloma in which an MRI of the spine was also performed at baseline [9]. The median time to progression was significantly shorter with an abnormal MRI compared with a normal MRI (1.5 years versus 5 years). Nonetheless, if laboratory values, bone marrow biopsy, and MRI results are stable, then these studies should be repeated every 4-6 months for one year with the interval afterward being every 6 to 12 months if stable.
An estimated 20,580 new cases of multiple myeloma were diagnosed in the United States in 2009. Median survival is about 3 to 4 years following diagnosis, although survival has improved with newer therapies such as autologous stem cell transplantation, immunomodulatory drugs (thalidomide and lenalidomide), and proteosome inhibitors (bortezomib) [10]. Given this finding, should patients with the precursor diseases of MGUS and smoldering myeloma also be treated? According to the current IMWG guidelines, MGUS and smoldering myeloma should not be treated outside of clinical trials. Patients with MGUS are relatively healthy and have a low lifetime risk of progression.
On the other hand, patients with smoldering myeloma have a relatively high rate of progression to multiple myeloma at 10% yearly. Prior to the advent of novel therapies, a 1993 randomized controlled trial of melphalan-prednisone given initially or at progression to multiple myeloma did not show a significant difference in response rate or overall survival [11]. A single-group trial in 2008 using thalidomide in 76 patients with smoldering myeloma failed to show a clear benefit for treatment [12]. Currently, a study by Mateos et al. (2009) that randomized patients with smoldering myeloma to lenalidomide-dexamethasone versus active surveillance is ongoing [13]. At 19 months of follow-up, interim analysis showed that approximately 50% of patients in the surveillance group progressed to multiple myeloma while none of the patients in the treatment group progressed. In general, it still remains unknown whether treating patients with smoldering myeloma improves overall survival.
Returning to patient A.D. in the clinical case, he is diagnosed with MGUS (low-risk type). Of note, he underwent a bone marrow biopsy and skeletal survey which are not routinely indicated. His hematologist advised him to repeat a SPEP in 6 months. If he remains stable at that time, then he can be followed every two to three years. Any treatment at this stage is not indicated.¬
Table: Diagnostic criteria for the plasma cell disorders
| Disorder | Disease definition |
| Monoclonal gammopathy of undetermined significance (MGUS) |
|
| Smoldering (asymptomatic) multiple myeloma |
|
| Multiple myeloma |
– hypercalcemia: serum calcium ≥11.5 mg/dL or – renal insufficiency: serum creatinine >2mg/dL or estimated creatinine clearance <40 mL/min – anemia: normochromic, normocytic with hemoglobin >2 gm/dL below lower limit of normal or <10gm/dL – bone lesions: lytic lesions, severe osteopenia, or pathological fractures
|
Table adapted from Kyle RA, et al. Leukemia. 2010;24:1121-1127.
Dr. Maryann Kwa is a 3rd year resident at NYU Langone Medical Center
Peer reviewed by Harold Ballard, MD Clinical Professor of Medicine, Division of Hematology and Oncology, NYU Langone Medical Center
Image courtesy of Wikimedia Commons
References:
[1] Kyle RA, Durie BG, Rajkumar SV, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: International Myeloma Working Group (IMWG) consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia. 2010;24(6):1121-1127. Available from: http://www.nature.com/leu/journal/v24/n6/full/leu201060a.html
[2] Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354(13):1362-1369. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa054494
[3] Rajkumar SV, Kyle RA, Buadi FK. Advances in the diagnosis, classification, risk stratification, and management of monoclonal gammopathy of undetermined significance: implication for recategorizing disease entities in the presence of evolving scientific evidence. Mayo Clin Proc. 2010;85(10):945-948. Available from: http://www.mayoclinicproceedings.com/content/85/10/945.full
[4] Landgren O, Waxman AJ. Multiple myeloma precursor disease. JAMA. 2010;304(21):2397-2404. Available from: http://jama.ama-assn.org/content/304/21/2397.full
[5] Landgren O, Kyle RA, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 2009;113(22):5412-5417. Available from: http://bloodjournal.hematologylibrary.org/cgi/content/full/113/22/5412
[6] Chng WJ, Glebov O, Bergsagel PD, Kuehl WM. Genetic events in the pathogenesis of multiple myeloma. Best Pract Res Clin Haematol. 2007;20(4): 571-596. Available from: http://www.bprch.com/article/S1521-6926(07)00064-3/fulltext
[7] Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007;356(25):2582-2590. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa070389
[8] 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(8):564-569. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa01133202
[9] Wang M, Alexanian R, Delasalle K, Weber D. Abnormal MRI of spine is the dominant risk factor for abnormal progression of asymptomatic multiple myeloma. Blood. 2003;102:687a (abstract). Available from: http://bloodjournal.hematologylibrary.org/archive/2003.dtl
[10] Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516-2520. Available from: http://bloodjournal.hematologylibrary.org/cgi/content/full/111/5/2516
[11] Hjorth M, Hellquist L, Holmberg E, et al. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I—a randomized study. Eur J Haematol. 1993;50(2):95-102. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0609.1993.tb00148.x/abstract
[12] Barlogie B, van Rhee F, Shaughnessy JD Jr., et al. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008;112(8):3122-3125. Available from: http://bloodjournal.hematologylibrary.org/cgi/content/full/112/8/3122
[13] Mateos MV, Lopez-Corral L, Hernandez MT, et al. Multicenter, randomized, open-label, phase III trial of lenalidomide-dexamethasone vs therapeutic abstention in smoldering multiple myeloma at high risk of progression to symptomatic multiple myeloma: results of the first interim analysis. In: 51st American Society of Hematology Annual Meeting and Exposition; December 5-8; New Orleans, LA. Abstract 614. Available from: http://ash.confex.com/ash/2009/webprogram/Paper21268.html