Correspondence
Smoldering Multiple Myeloma
N Engl J Med 2007; 357:1048-1050September 6, 2007
- Article
To the Editor:
Kyle et al. (June 21 issue)1 propose a clinically useful risk-stratification model of progression from smoldering multiple myeloma to overt multiple myeloma. Gene-expression–signature data might enhance their model.
Recent studies have shown that a 50-gene panel can distinguish monoclonal gammopathy of undetermined significance (MGUS)–like multiple myeloma (better prognosis) from non–MGUS-like multiple myeloma.2 Studies have also shown that multiple myeloma can be divided into eight distinct molecular subtypes with different prognoses.3 Smoldering multiple myeloma with gains of chromosome 1q21 is associated with an increased risk of conversion to multiple myeloma,4 and a gene-expression signature of high-risk disease, reflecting altered expression of genes mapping to chromosomes 1q and 1p, could distinguish new and acquired high-risk disease independently of other prognostic factors.5
We look forward to the day when molecular tests become a component of the clinical workup in patients with plasma-cell dyscrasias.
5 ReferencesH. Keshava Prasad, M.D.
University of Arkansas for Medical Sciences, Little Rock, AR 72205
hskeshavaprasad@uams.edu Fenghuang Zhan, M.D., Ph.D.
John Shaughnessy, Ph.D.
Myeloma Institute for Research and Therapy, Little Rock, AR 722051
Kyle RA ,Remstein ED ,Therneau TM , et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 2007;356:2582-2590
Full Text | Web of Science | Medline2
Zhan F ,Barlogie B ,Arzoumanian V , et al. Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis. Blood 2007;109:1692-1700
CrossRef | Web of Science | Medline3
Zhan F ,Huang Y ,Colla S , et al. The molecular classification of multiple myeloma. Blood 2006;108:2020-2028
CrossRef | Web of Science | Medline4
Hanamura I ,Stewart JP ,Huang Y , et al. Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation. Blood 2006;108:1724-1732
CrossRef | Web of Science | Medline5
Shaughnessy JD Jr ,Zhan F ,Burington BE , et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 2007;109:2276-2284
CrossRef | Web of Science | Medline
To the Editor:
Kyle et al. correctly state that the diagnosis of smoldering multiple myeloma requires the absence of anemia, but they also state that in the cohort they investigated, “the initial hemoglobin level ranged from 10.0 to 16.8 g per deciliter (median, 13.0)” and “the hemoglobin level was 12 g per deciliter or more in 76% of patients.” Since the World Health Organization defines anemia as a hemoglobin value below 12 g per deciliter (7.5 mmol per liter) in women and below 13 g per deciliter (8.1 mmol per liter) in men,1 I infer that at least 24% of patients did not fulfill the criteria for the diagnosis of smoldering multiple myeloma.
The authors also state that the prognostic role of magnetic resonance imaging (MRI) is unknown. In 72 patients with smoldering multiple myeloma, Wang and colleagues2 calculated that the median time to progression was significantly shorter in patients with an abnormal MRI scan as compared with a normal MRI scan (1.5 years vs. 5 years). It would seem that MRI of the spine should be performed at diagnosis.2
2 ReferencesDaniele Focosi, M.D.
University of Pisa, 56100 Pisa, Italy
dfocosi@tin.it 1
Nutritional anaemias: report of a WHO scientific group. World Health Organ Tech Rep Ser 1968;405:5-37
Medline2
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-687a
Web of Science
To the Editor:
Kyle et al. identify the type of immunoglobulin heavy chain as a risk factor for progression in smoldering myeloma. They report that IgA was more of a risk factor than IgG. However, the absolute values of monoclonal proteins for both IgG and IgA are both reported in reference to a serum monoclonal protein level of 3 g per deciliter or more. For IgG, that value is two to three times the normal value, but for IgA it is 20 to 30 times the normal value. Have the IgG and IgA levels ever been divided by a normal value and the resultant figure used in developing criteria for the classification and prognosis of myeloma?
A. Thomas Andrews, M.D.
Andrews & Patel Associates, Camp Hill, PA 17011
toandrews@aol.com Author/Editor Response
As Prasad et al. suggest, it is possible that molecular genetic studies such as gene-expression signatures may add to the risk factors described in our study. However, the data they refer to are mainly relevant for predicting the outcome in patients with active multiple myeloma. Neither method has been shown to have independent prognostic value in a uniformly defined cohort of patients with smoldering multiple myeloma or MGUS. Hanamura and colleagues studied 14 patients with MGUS, 31 with smoldering multiple myeloma, and 479 with active myeloma.1 It is not clear whether the prognostic effect seen with gains of chromosome 1q21 in smoldering multiple myeloma will persist after adjusting for the size and type of monoclonal protein and the extent of bone marrow involvement. These new strategies are of interest, but the studies are hampered by insufficient sample sizes and limited follow-up.
Focosi points out that 24% of our patients had anemia with a hemoglobin value of less than 12 g per deciliter. The diagnosis of smoldering multiple myeloma (and MGUS) requires that patients not have end-organ damage such as anemia, hypercalcemia, renal failure, or bone disease that is attributable to the underlying plasma-cell disorder.2,3 In our study, none of the patients had anemia related to the underlying plasma-cell disorder; all patients with hemoglobin levels of less than 12 g per deciliter had other known causes, including gastrointestinal bleeding, the myelodysplastic syndrome, thalassemia minor, pernicious anemia, polyarthritis, postoperative orthopedic procedures, or recent meningitis.
We recognize the potential value of MRI4,5 and have described its role elsewhere.3 MRI is helpful in identifying occult bone lesions that are not apparent on skeletal survey, but whether this finding should be considered as being indicative of active multiple myeloma or smoldering multiple myeloma is a matter of definition of these diseases. The MRI studies are limited by modest sample sizes, and validation is needed to show that MRI has independent prognostic significance.
Andrews raises an interesting point concerning the prognostic value of the IgA level relative to its normal range. We have not used a differential cutoff level for IgA in diagnostic or prognostic studies, since it adds complexity to the prognostic model. However, the Durie–Salmon staging system does assign a differential level of importance to the IgA level relative to the IgG level in terms of disease staging.
5 ReferencesRobert A. Kyle, M.D.
S. Vincent Rajkumar, M.D.
Mayo Clinic, Rochester, MN 55905
kyle.robert@mayo. edu 1
Hanamura I ,Stewart JP ,Huang Y , et al. Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation. Blood 2006;108:1724-1732
CrossRef | Web of Science | Medline2
International Myeloma Working Group
CrossRef | Web of Science | Medline3
Rajkumar SV ,Dispenzieri A ,Kyle RA . Monoclonal gammopathy of undetermined significance, Waldenström macroglobulinemia, AL amyloidosis, and related plasma cell disorders: diagnosis and treatment. Mayo Clin Proc 2006;81:693-703[Erratum, Mayo Clin Proc 2006;81:1509.]
CrossRef | Web of Science | Medline4
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-687a
Web of Science5
Weber D ,Wang LM ,Delasalle K ,Smith T ,Alexanian R . Risk factors for early progression of asymptomatic multiple myeloma. Hematol J 2003;4:Suppl 1:S31-S31
CrossRef
