Smoldering multiple myeloma (SMM)

SMOLDERING MULTIPLE MYELOMA (SMM)

Epidemiology : SMM accounts for approximately 15% of all cases with newly diagnosed MM^ref (Kyle RA, Rajkumar SV: Plasma cell disorders. In Goldman L, Ausiello D, eds. Cecil Textbook of Medicine, 22nd ed. Philadelphia: W. B. Saunders; 2004:1184–1195). The prevalence estimates for SMM are distorted since many reports include asymptomatic patients with small lytic bone lesions on skeletal survey. Others exclude patients with bone lesions on skeletal survey, but include patients who have lytic lesions by MRI. A true prevalence using strict symptoms & laboratory findings as defined below is not available.
Aetiology : as or multiple myeloma
Symptoms & signs : absence of anemia, hypercalcemia, lytic bone lesions, or renal failure attributable to the plasma cell proliferative disorder.
Laboratory examinations :

serum M protein >= 3 g/dL
bone marrow plasma cells >= 10%
plus

Therapy : no specific therapy is recommended for SMM, but patients require more frequent follow-up than MGUS, at least once every 3–4 months. In addition to follow-up studies recommended for MGUS, a skeletal survey should be repeated at least once every year. In addition if the patient has evidence of baseline urinary paraprotein excretion, a 24-hour urine protein electrophoresis should also be done periodically during follow-up. So far there is no evidence to support early therapy prior to development of symptomatic MM. 2 small randomized trials with alkylating agents showed similar overall survival with early therapy compared to therapy at the time of symptomatic progression. However, clinical trials are now underway to determine if newer agents and bisphosphonates

can delay progression. A recent phase II clinical trial demonstrated significant paraprotein responses, and prolongation of time to progression compared to historical controls with thalidomide

^ref. However, thalidomide has significant nonhematologic side-effects and confirmatory data from randomized trials are needed before such therapy can be recommended for patients with SMM. A randomized phase III trial at Mayo Clinic is currently testing thalidomide plus zoledronic acid versus zoledronic acid in patients with SMM and the results of this study will shed light on the utility of thalidomide in this setting. Outside of a clinical trial, therapy with bisphosphonates is not recommended
Prognosis : risk of progression to MM = 10-20% per year^{ref1,
ref2,
ref3} (Wang M, Alexanian R, Delasalle K, Weber D. Abnormal MRI of spine is the dominant risk factor for early progression of asymptomatic multiple myeloma. Blood. 2003;102:687a). Most patients with SMM progress eventually to symptomatic disease, and the risk of progression is substantially higher than with MGUS^ref. However, as illustrated in the first description of the entity, some patients can remain free of progression for a number of years^ref. The time to progression (TTP) to symptomatic disease is approximately 3–4 years, but differs greatly depending on the definition used for SMM (Wang M, Alexanian R, Delasalle K, Weber D. Abnormal MRI of spine is the dominant risk factor for early progression of asymptomatic multiple myeloma. Blood. 2003;102:687a). In SMM patients having bone marrow plasma cells >= 10%, the median time to progression is approximately 2–3 years^ref. In another study, the risk of progression was only 20% at 6 years^ref. However, this study considered patients to have SMM only if patients demonstrated no disease progression after one year of follow up. Preliminary data from a large study by Kyle and colleagues using the current criteria for SMM indicate a risk of progression of approximately 10% per year, a rate much higher than observed with MGUS (Kyle RA, Therneau TM, Rajkumar SV, et al. Update on smoldering multiple myeloma. Haematologica. 2005;90 (Suppl 1):12). Although most patients with SMM are candidates for clinical trials evaluating preventive strategies, using selected risk factors it may be possible to identify a cohort of patients who may benefit the most and in whom the risks of chronic therapy are acceptable :

abnormal peripheral blood monoclonal plasma cell studies, defined as an increase in the number or proliferative rate of circulating plasma cells by immunofluorescent assays, have been shown to indicate a higher risk of progression in SMM^ref. This test is, however, not widely available.
Weber and colleagues have shown, in a study of 109 patients, that the size and type of immunoglobulin are important predictors of progression^ref. Patients with a serum M protein <= 3 gm/dL and IgG type (comprising about 45% of patients) had a median TTP of over 4 years. Patients with either serum M protein > 3 gm/dL or IgA type (about 45% of patients) had a median TTP of approximately 2 years, while a small subset of patients with > 3 gm/dL IgA SMM had a median TTP of 9 months.
in patients determined to have SMM by using standard clinical, laboratory and roentgenographic studies, the presence of occult bone lesions on MRI greatly increases the risk of progression in asymptomatic MM^ref. In a recent study, Wang and colleagues estimated risk of progression in 72 patients with SMM in whom an MRI of the spine was also performed (Wang M, Alexanian R, Delasalle K, Weber D. Abnormal MRI of spine is the dominant risk factor for early progression of asymptomatic multiple myeloma. Blood. 2003;102:687a). The median TTP was significantly shorter with an abnormal MRI compared to normal MRI, 1.5 years versus 5 years, respectively
there are no data on the use of the serum FLC assay to predict risk of progression in SMM at present.

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