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Progression Risk for Smoldering Myeloma
Abstract & Commentary
By Andrew Artz, MD, MS, Division of Hematology/Oncology, University of Chicago, Chicago, IL. Dr. Artz reports no financial relationship to this field of study.
Synopsis: Information on prognostic factors and progression rates from smoldering (ie, asymptomatic) myeloma to multiple myeloma and amyloidosis are limited. In this observational study from the Mayo Clinic database, the risk of progression was 73% at 15 years in 276 patients. In the first 5 years, the annual progression rate was 10% per year, 3% per year in the following 5 years, and only 1% per year thereafter. The progression risk was greatest in those having > 10% plasma cells at diagnosis. Smoldering myeloma frequently progresses, and the greatest risk occurs in the first 5 years after diagnosis.
Source: Robert Kyle, et al. Clinical Course and Prognosis of Smoldering (Asymptomatic) Multiple Myeloma. N. Eng. J. Med. 2007. Vol 356:2582-2590.
Monoclonal gammopathies encompass a spectrum of disorders related to a clonal proliferation of plasma cells. Although not necessarily distinct entities, diagnostic criteria separate monoclonal gammopathy of unknown significance, smoldering multiple myeloma, and multiple myeloma. To diagnose multiple myeloma (as opposed to smoldering), The International Working Group requires a monoclonal gammopathy (without defining a concentration), clonal bone marrow or plasma cells, and organ impairment (ie, hypercalcemia, renal insufficiency, anemia, lytic lesions of the bone, and/or bacterial infections).1 Multiple myeloma absent organ manifestations has been termed smoldering multiple myeloma, usually categorized as ≥ 3 g/dL serum monoclonal or ≥ 10% marrow plasma cells without myeloma related signs or symptoms. The risk of progression and prognostic factors has not been well characterized.
Investigators at the Mayo Clinic retrospectively reviewed the institutional records for evidence of an IgA or IgG monoclonal gammopathy ≥ 3 g/dL and/or ≥ 10% or more plasma cells from 1970 to 1995. Active myeloma or amyloidosis or having received chemotherapy were exclusion criteria. The time to progression to active multiple myeloma (ie, anemia, hypercalcemia, renal insufficiency or bone lesions) or amyloidosis with either one requiring therapy was determined. Among 3549 patients diagnosed with myeloma, 276 (8%) met criteria for smoldering myeloma. The median age was 64 years and 62% were men. The serum monoclonal protein at diagnosis ranged from 0.5 to 5.4 g/dL and 52% had a concentration < 3 g/dL.
In the follow-up period, 85% of smoldering myeloma patients died. The probability of progression to amyloidosis or active myeloma was 51% at 5 years and 66% at 10 years, almost always to active myeloma (97%) rather then amyloidosis. Risk factors for progression in the unadjusted analysis included monoclonal protein concentration, IgA isotype (as opposed to IgG), presence of urinary light chain, > 20% bone marrow involvement by plasma cells, reciprocal reduction in other immunoglobulins, and pattern of marrow involvement. Serum monoclonal and plasma cell marrow involvement predicted progression in multivariate analysis. They constructed a scoring system to stratify progression risk. Thus, progression was 87% for those having ≥ 10% plasma cells and ≥ 3 g/dL monoclonal protein, 70% for those having ≥ 10% plasma cells and < 3 g/dL monoclonal protein, and 39% in the 27 patients having < 10% plasma cells but ≥ 3 g/dL monoclonal protein. Median time to progression was 2 years, 8 years, and 19 years, in the respective groups (P < 0.001).
Smoldering multiple myeloma may be defined as meeting criteria for multiple myeloma but absent symptoms. The authors report on the risk of progression to myeloma and amyloidosis from smoldering myeloma defined as > 3 g/dL monoclonal protein in the serum and/or > 10% bone marrow plasma cells but lacking anemia, renal insufficiency, skeletal lesions, or recurrent infections.
Defining risk can help determine monitoring strategies and allow appropriate patient counseling. While the progression rate of smoldering myeloma to active multiple myeloma or amyloidosis is high, variable definitions and study populations contribute to imprecise estimates. In one study, for those without progression after one year, the rate of evolution was reported to be 3.3% per year2 and are considerably higher than that of monoclonal gammopathy of unknown significance.3
The authors suggest a time-dependent impact of disease progression such that the risk of progression is greatest within the 5 years of diagnosis at 10% per year, 3% per year for the following 3 years, and then approximately 1% annually. The data are instructive and confirm the high progression rate of smoldering myeloma.
Methodological limitations present a major obstacle to applying the data to clinical practice. The bias of this observational study is particularly problematic and not properly discussed. Patients were not prospectively or uniformly followed which impairs accurately determining progression rates. More problematic is not addressing the actual time of diagnosis. Patients may have been identified and/or referred because of recent symptoms (fatigue) or worsening laboratory findings (rising monoclonal gammopathy). Thus, they may have been diagnosed with MGUS of smoldering myeloma before and this could easily account for a high progression rate after the Mayo Clinic diagnosis. It would be very useful to know when the first diagnosis of a monoclonal protein was identified clinically. A population-based survey would be very helpful in this regard to better understand the biology and true progression rate of from smoldering myeloma. Referral bias may also hinder generalizability. Do these patients represent the routine patient in non-academic clinical practice?
The diagnostic criteria for smoldering myeloma, although standard, require comment. Diagnostic thresholds are essential to establish prognosis, guide treatment, and enable comparisons across studies. The World Health Organization (WHO) criteria for active myeloma differ somewhat, incorporating plasma cell number and monoclonal protein concentration but not mandating symptoms. By WHO criteria, many patients may have met criteria for active myeloma.
The three prognostic groups created used plasma cells ≥ 10% and monoclonal protein ≥ 3 g/dL as cut points. The very small numbers (26/276) in the "best risk group" where bone marrow plasma cells were < 10% prevents precise estimates or conclusions. These risk groups should be validated in other studies. Established prognostic markers for myeloma were not available but could prove more useful in stratifying patients. For example, the International Staging System accurately stratifies active myeloma by serum albumin and beta-2 microglobulin.4 FISH analysis, MRI and other modalities may better define risk groups although these are high-cost tests that may not be available everywhere.
To the extent the patients in this study represent those who oncologists see in clinical practice, the data are highly relevant. Patients presenting with smoldering myeloma to the oncologist probably do have a high progression rate in the first 5 years. This suggests focusing follow-up testing early in the disease course, especially for patients having > 10% marrow plasma cells. Alternatively, for those who have been followed for 5 years, a less aggressive monitoring strategy could be considered.
The therapeutic armamentarium for multiple myeloma continues to increase and suggests intriguing possibilities. Will treatment of smoldering myeloma prevent progression or prolong survival? Would early treatment lead to cures in some patients? Might bisphosphonates prevent progression of skeletal lesions?
1. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 121:749-57, 2003.
2. Cesana C, et al. J Clin Oncol. 2002;20:1625-1634.
3. Kyle RA, et al. N Engl J Med. 2002;346:564-569.
4. Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420.