Smoldering multiple myeloma (SMM)

SMOLDERING MULTIPLE MYELOMA (SMM)

Epidemiology : SMM accounts for approximately 8-15% 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. 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 women^ref
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 :

serum M protein >= 3 g/dL : the serum monoclonal protein level at the time of diagnosis ranged from 0.5 to 5.4 g per deciliter (median, 2.9). The levels for 11% of the patients were 4 g/dl or more (including 1% with > 5 g/dl), those for 37% were 3 to 3.9 g/dl, and those for 52% were < 3 g/dl. The monoclonal protein level in the 27 patients in group 3 (with a monoclonal protein spike of 3 g/dl and <10% plasma cells) ranged from 3.0 to 3.9 g/dl (median, 3.1). Of these 27 patients, 26 had monoclonal IgG present in serum, whereas only 2 had a urinary monoclonal protein level of more than 200 mg per 24 hours (240 and 450 mg per 24 hours). Of the 276 patients, 74% had monoclonal IgG, 22.5% had IgA, 0.5% had IgD, and 3% had biclonal immunoglobulins. The light-chain type was k in 67% and l in 33%. Concentrations of uninvolved (normal, polyclonal, or background) immunoglobulins were reduced in 83% of 230 patients whose immunoglobulin levels were determined quantitatively. A single reduction in immunoglobulin was found in 31% of patients, whereas 52% had a reduction of both uninvolved immunoglobulins (e.g., reduced IgM and IgA in a patient with a monoclonal IgG). Immunoelectrophoresis or immunofixation was performed on urine samples from 259 of the patients (94%). Of those patients, 92 (36%) had a monoclonal k light chain, 43 (17%) had a l light chain, and 123 (47%) had negative results for monoclonal light chain. A urinary monoclonal protein level < 0.1 g per 24 hours was found in 84%; only 4 patients (1.5%) had a level of > 1.0 g per 24 hours

AND/OR

bone marrow plasma cells >= 10% : the most common proportion was 15 to 19%. Of the 276 patients, 10% had less than 10% plasma cells in the marrow, and 10% had 50% or more plasma cells. Cyclin D1 was expressed by the plasma cells in 18% of the bone marrow specimens.

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 myeloma^ref1,
ref2.

2 small randomized trials with alkylating agents showed similar overall survival with early therapy compared to therapy at the time of symptomatic progression
bisphosphonates
thalidomide : a recent phase II clinical trial demonstrated significant paraprotein responses, and prolongation of time to progression compared to historical controls^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
interleukin-1 inhibitors
clarithromycin
dehydroepiandrosterone

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); 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 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).
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 MGUS^ref. 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 findings^{ref1,
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 MM^ref. However, other findings, such as a reduction in the level of uninvolved immunoglobulins^ref1,
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 :

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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