By William B. Ershler, MD, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC. Dr. Ershler reports no financial relationships relevant to this field of study.
An 84-year-old community-dwelling retired physician who maintains an active lifestyle and regularly attends community hospital meetings and lectures is seen for advice regarding management. He has a longstanding history of mild hypertension currently controlled by diet and hydrochlorothiazide. He has had a total left knee replacement and cataract surgery bilaterally. Otherwise, he has been well and other than minor, stable arthritic symptoms, he has no physical complaints. When he was seen in his primary care physician's office for an annual physical exam, a chemistry survey revealed a total serum protein of 9.2 g/dL, with a globulin fraction of 4.8 g/dL. Total serum protein the year before was 7.9 g/dL. His physician requested serum protein electrophoresis and this revealed a monoclonal spike.
Immunofixation identified the spike to be IgGk and quantitative immunoglobulin measurement revealed 4.2 g/dL IgG, with low normal levels of IgA and IgM. Beta-2 microglobulin was 4.0 mg/L. The remainder of his chemistries were normal, including a creatinine of 0.9 mg/dL. Hemoglobin was 12.5 g/dL, white blood count was 4,500/cu mm with a normal appearing differential, and the platelet count was 215,000/cu mm. A full-bone radiographic survey revealed arthritic changes without evident lytic disease. A bone marrow aspirate and biopsy was slightly hypercellular (for age) with normal trilinear hematopoiesis but with increased numbers of normal appearing plasma cells (14%).
Smoldering Myeloma Criteria for Diagnosis
Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic disorder characterized by the presence of serum M-protein of < 3 g/dL with fewer than 10% monoclonal plasma cells in the bone marrow.1 Under normal circumstances, post-germinal center B cells, having undergone several rounds of somatic hypermutation and antigen selection in germinal centers and then immunoglobulin heavy chain (IgH) recombination, finally differentiate into plasmablasts, and these typically migrate back to the bone marrow and become terminally differentiated long-lived plasma cells.2 Originally considered a benign reflection of age-associated immune dysregulation (hence the term "benign monoclonal gammopathy"), it is now believed that MGUS is a clonal disorder derived from those terminally differentiated plasma cells and is a precursor to multiple myeloma (MM). This is supported by large cohort observational studies in which stored serum from those individuals who developed myeloma was found to be positive for monoclonal protein many years in advance of the myeloma diagnosis.
As mentioned, the rate of progression to myeloma is approximately 1-2% per year, but there are some features of MGUS that would indicate a greater likelihood of more rapid progression, including a higher M protein level, IgA rather than IgG paraprotein, a higher percentage of marrow plasma cells (e.g., > 10%), unbalanced serum light chain ratio, or a beta-2 microglobulin level of greater than 3.5 mg/L. The diagnosis of MM hinges on these criteria, but also includes the presence of end organ damage (e.g., lytic bone disease, anemia, hypercalcemia, renal failure). In asymptomatic patients who meet criteria for MM but without these clinical manifestations, an intermediate category of smoldering multiple myeloma (SMM) has gained clinical recognition.3 Although the prevalence of SMM is not yet established, progression to overt myeloma has been estimated to be on the order of 10% per year or more.4
SMM is thus a premalignant condition with a very high likelihood of progression to clinically important and debilitating disease. As such, despite the asymptomatic nature of the disorder, rationale has been forwarded for therapeutic intervention and several trials have been completed or are underway. The reports to date have been mixed. For example, a trial published in 1993 comparing early treatment with melphalan/prednisone vs treatment at the time of progression to clinical myeloma demonstrated no difference in response rates or overall survival.5 More recent studies have included the use of immunomodulatory drugs such as thalidomide and lenalidomide or drugs targeting the bone microenvironment, such as pamidronate.6,7 On a positive note, the PETHEMA Phase 3 trial is currently investigating treatment with lenalidomide/dexamethasone vs surveillance in high-risk SMM patients. An interim analysis showed that at 19 months of follow-up, about 50% of patients in the surveillance arm progressed to MM whereas no treated patients progressed.8 Yet, as pointed out by Korde in a review of this topic,4 it remains unknown whether treating SMM patients improves overall survival or quality of life, as such data are not yet available.
Accordingly, the current standard of care for patients with SMM is either enrollment on clinical trial or careful surveillance, with the introduction of appropriate myeloma treatment once the diagnosis is apparent. The recommended surveillance includes a serum protein electrophoresis test and physician visit every 2-3 months for the first year, followed by gradual extension of visit intervals if all remains stable.1 Furthermore, guidelines currently recommend an MRI of the spine and pelvis as this may detect occult lesions and, if present, predict for a more rapid progression to multiple myeloma.9
For the patient referred to above, a thoughtful discussion about the disorder and likelihood of progression to overt myeloma is warranted. As a physician himself, he may recognize the value of participating on a clinical trial, and indeed he would be an excellent candidate.
1. Kyle RA, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia 2010;24:1121-1127.
2. Shapiro-Shelef M, Calame K. Regulation of plasma-cell development. Nature reviews. Immunol 2005;5:230-242.
3. Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med 1980;302:1347-1349.
4. Korde N, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): Novel biological insights and development of early treatment strategies. Blood 2011;117:5573-5581.
5. Hjorth M, et al. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I A randomized study. Myeloma Group of Western Sweden. Eur J Haematol 1993;50:95-102.
6. Barlogie B, 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;112:3122-3125.
7. Musto P, et al. A multicenter, randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma. Cancer 2008;113:1588-1595.
8. Mateos MV, et al. Multicenter, randomized, open-label, phase III trila of lenalidomide-dexamethasone (len/dex) vs therapeutic abstension in smoldering mutiple myeloma at high risk of progression to symptomatic MM: Results of the first interim analysis. Blood 2009;114:614a.
9. Hillengass J, et al. Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 2010;28:1606-1610.