SMOLDERING MULTIPLE MYELOMA (SMM)

Epidemiology : SMM accounts for approximately 8-15% of all cases with newly diagnosed MMref (Kyle RA, Rajkumar SV: Plasma cell disorders. In Goldman L, Ausiello D, eds. Cecil Textbook of Medicine, 22nd ed. Philadelphia: W. B. Saunders; 2004:11841195). 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. The median age at diagnosis is 64 years (range, 26 to 90), and only 3% patients are younger than 40 years of age. 62% are men, and 38% are womenref
Aetiology : as or multiple myeloma
Symptoms & signs : absence of end-organ damage defined as hypercalcemia, renal insufficiency, anemia, lytic bone lesions, or recurrent bacterial infections attributable to the plasma cell proliferative disorder.
Laboratory examinations :

AND/OR Therapy : physicians should repeat the pertinent laboratory tests 2 to 3 months after the initial recognition of the disease to rule out an early active form; if the results are stable, the studies should initially be repeated every 4 to 6 months. However, given the high risk of progression among patients in prognostic groups 2 and 3 (see below), along with the availability of new active agents for the treatment of active MM, investigational approaches may be considered for selected patients in appropriate clinical trials. 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. Ongoing trials are testing the use of bisphosphonates, interleukin-1 inhibitors, clarithromycin, dehydroepiandrosterone, and thalidomide in the treatment of smoldering multiple myeloma in an attempt to delay progression to active multiple myelomaref1, ref2. Prognosis : risk of progression to MM = 10-20% per yearref1, 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); risk of progression to active MM or amyloidosis at 20 years (a 78% probability for smoldering multiple myeloma vs. 21% for MGUS)ref. Most patients with SMM progress eventually to symptomatic disease, and the risk of progression is substantially higher than with MGUSref. However, as illustrated in the first description of the entity, some patients can remain free of progression for a number of yearsref. The time to progression (TTP) to symptomatic disease is approximately 34 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 23 yearsref. In another study, the risk of progression was only 20% at 6 yearsref. 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).
The cumulative probability of progression to active multiple myeloma or amyloidosis was 51% at 5 years, 66% at 10 years, and 73% at 15 years; the median time to progression was 4.8 years (Figure 2). The overall risk of progression was 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% per year for the last 10 years. No such time-dependent reduction in risk occurs with MGUSref. The RR for MM was 522 and for amyloidosis was 50. In the 128 patients who did not have progression to active disease after more than 10 years after diagnosis, the disease was of the IgG subtype in 81%, the baseline median level of plasma cells in the bone marrow was 16%, the median spike in the serum monoclonal protein level was 2.8 g per deciliter, and uninvolved immunoglobulins were reduced in 78%. Significant baseline risk factors for progression of smoldering multiple myeloma to active disease or amyloidosis in the univariate analysis included the level of serum monoclonal protein (P<0.001), the presence of IgA monoclonal protein (P=0.004), the presence of urinary light chain (P=0.04), the extent of bone marrow involvement (plasma cells, 20%; P<0.001), a reduction in levels of uninvolved immunoglobulins (P=0.001), and the pattern of plasma-cell involvement in bone marrow (sheets of cells spanning the interfatty marrow spaces) (P<0.001)ref.

The proportion of plasma cells in bone marrow and the serum monoclonal protein level were combined to create a risk-stratification model with three distinct prognostic groups. At 15 years, the cumulative probability of progression was 87% for patients in group 1 (bone marrow plasma cells, >= 10%; monoclonal protein level, >= 3 g per deciliter), 70% for patients in group 2 (plasma cells, > =10%; monoclonal protein level, <3 g per deciliter), and 39% for patients in group 3 (plasma cells, <10%; monoclonal protein level, > 3 g per deciliter).


In contrast to previous findingsref1, ref2, ref3, the presence of urinary monoclonal protein, although significant on univariate analysis in our study, did not achieve statistical significance in the multivariate analysis. The roles of the serum free light-chain ratio and magnetic resonance imaging in determining the outcome of smoldering multiple myeloma are unknown and require investigation. The age and sex of the patients in our study and the distribution of heavy-chain and light-chain types were similar to those in patients with active MMref. However, other findings, such as a reduction in the level of uninvolved immunoglobulinsref1, ref2 and the presence of monoclonal urinary light chains, were intermediate between those in patients with active multiple myeloma and those in patients with MGUS.
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 :
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