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IgM multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM) are two distinct hematologic entities with the common finding of an IgM monoclonal gammopathy. Distinguishing these two diagnoses is critical as the approach to therapy and prognosis greatly differ [1, 2]. This importance will increase with the continued development of novel agents and combination therapies.
WM is a disorder of B-lymphocytes with plasmacytic differentiation, and first line therapy typically includes rituximab, a monoclonal antibody directed against the B-lymphocyte antigen CD20. In contrast, anti-CD20 immunotherapy has not shown benefit in MM, which is consistent with the infrequent expression of this antigen by mature plasma cells . Further, first line therapy in appropriate candidates with MM should include consideration of an early autologous stem cell transplant . In WM, autologous stem cell transplant may have a potential role, but it is currently reserved for refractory or relapsed disease with no first-line indication. These differences in treatment of patients with newly diagnosed disease are summarized in Table I. In general, the clinical course and prognosis of WM tends to be more indolent than MM. These disparities in treatment and prognosis create the need for an accurate diagnostic approach for these two disease processes.
Table I. Recommended Treatment Regimens for Multiple Myeloma and Waldenstrom's Macroglobulinemia for Newly Diagnosed Disease [1, 2]
SMM (smoldering multiple myeloma) or SWM (smoldering Waldenstrom's macroglobulinemia).
Induction with a nonalkylator-based regimen such as Lenalidomide plus Dexamethasone or Bortezomib plus Dexamethasone.
Rituximab, cyclophosphamide, dexamethasone (RCD); or rituximab alone
Induction followed by autologous stem cell transplantationb
Nontransplant candidate with good performance status
Rituximab, cyclophosphamide, dexamethasone (RCD); purine nucleoside analogues with or without rituximab; or rituximab alone
Melphalan, prednisone, thalidomide (MPT) or melphalan, prednisone, bortezomib (MPV)
Nontransplant candidate with poor performance status
Rituximab alone or chlorambucil alone
Melphalan and prednisone (MP)
Findings of IgM monoclonal gammopathy, plasma cell proliferation on bone marrow biopsy, and clinical findings consistent with myeloma, (hypercalcemia, renal impairment, anemia, and lytic bone lesions) classically distinguished the rare diagnosis of IgM MM from the more common WM. However, some patients may not have all of these findings, making the diagnosis difficult. Recent advances in cytogenetics can help further define the differences between IgM MM and WM. A recent study demonstrated the presence of t(11;14), leading to cyclin D1 dysregulation, in 7 of 8 patients with IgM MM, but it was absent in all 17 cases of WM . Another group demonstrated the association of 6q- deletion with WM, and proposed it to be able to distinguish WM from IgM monoclonal gammopathy of undetermined significance (MGUS) . These studies suggest that cytogenetic findings, in conjunction with clinical features, may be helpful in defining IgM MM.
We defined IgM MM as a symptomatic monoclonal plasma cell proliferative disorder characterized by a serum IgM monoclonal protein (regardless of size), 10% or more plasma cells on bone marrow biopsy, plus the presence of lytic bone lesions related to the underlying plasma cell disorder and/or t(11;14) on fluorescent in situ hybridization. The cases for the study were screened by a computerized database search for “IgM” and “Myeloma” of all patients seen at Mayo Clinic in the last 15 years at all three sites (Rochester, Arizona, and Florida). Patients identified on the computerized database were then reviewed to identify the study cohort.
Thirty-seven patients were identified on the initial screen. Of these, 21 patients met our definition of IgM MM (including presence of lytic lesions and/or t(11;14)). Two patients were considered to have clinical IgM MM but were excluded because they did not have t(11;14) or lytic bone lesions. In these two patients, the diagnosis of IgM MM had been entertained by their treating physician because of immunophenotype suggestive of MM and not WM (CD138+,CD20−). Of the remaining fourteen excluded patients, eight were excluded because they had IgM MGUS (less than 10% plasma cells on bone marrow biopsy), and five were excluded because they had WM based on clinical presentation (hyperviscosity, lymphadenopathy, and organomegaly) and biopsy findings of lymphoplasmacytic lymphoma. One case was excluded due to lack of information. None of the excluded patients had lytic bone lesions or t(11;14).
All 21 patients that fit our definition had lytic bone lesions. Of the 16 patients evaluated with FISH, 6 (38%) demonstrated the t(11;14) abnormality. Median overall survival by Kaplan-Meier analysis was 30 months represented in Fig. 1.
There is inadequate information about treatment in four patients. One patient elected for hospice at the time of diagnosis. Of the 16 patients with known treatment plans, six patients (37.5%) received autologous bone marrow transplant for MM. In total, eight patients (50%) received initial therapy for MM, and eight patients (50%) received initial treatment with conventional chemotherapy regimens appropriate for WM. Novel agents (Thalidomide, Lenalidamine, and/or Bortezomib) were used in 14 patients (87.5%) at some point in the course of treatment.
IgM MM is a discrete clinical entity that should be distinguished from WM. The clinical characteristics of our patients are shown in Table II. However, many cases are difficult to distinguish based on biopsy and clinical features. For example, 25% (two of eight) of IgM MM patients studied by Avet-Loiseau et al. had organomegaly, a finding more generally associated with WM . In our study, the median serum viscosity score was elevated, indicating that hyperviscosity is not unique to WM and is related to the absolute level and structure of the IgM pentamer.
Table II. Clinical Characteristics of Patients with IgM Myeloma at Time of Diagnosis
Median value (range)
Percentage of patients with abnormal level
95.2% (Hgb < 13.2)
47.6% (Cr > 1.3)
Corrected Calcium, mg/dL
61.9% (Ca > 10.1)
IgM, quantitative, mg/dL
90.5% (IgM > 300)
47.6% (M-spike ≥ 3)
92.3% (level > 1.8)
85.0% (level ≥ 1.5)
Bone marrow plasma cell, %
In this article, the largest known series of patients with IgM MM, we show that patients defined as IgM MM have a median overall survival of 30 months, similar to non-IgM myeloma patients treated during this period and shorter than what would be expected for WM .
Previous studies stressed the association of IgM MM with t(11;14), but we show that this finding is not sensitive and will not capture all cases with this rare disease [4, 7]. However, its presence is a specific finding for IgM MM, and therefore, it is a useful component for disease definition. Lytic bone lesions are objective evidence of end organ damage, and can be considered specific to MM and are not a feature of WM. A study by Donovan et al. demonstrated the high expression of IL-1β, a potent osteoclast activating factor that also upregulates IL-6, in MM with no increased expression in WM . Based on review of these data, we utilized t(11;14) and lytic bone lesions in the disease definition of IgM MM.
Other clinical features, such as immunophenotype analysis and presence of anemia, hypercalcemia, and renal failure, are not specific enough to MM to be included as a clinical diagnostic criteria. Our goal in this study was to describe the clinical features and prognosis of IgM MM using a strict disease definition that allows for a clear separation from WM.
Of the 15 cases with known immunophenotype analysis, 10 demonstrated the usual immunophenotype for MM (CD138+,CD20−). Three cases were considered “CD20partial,” one case exhibited an unusual CD138+ CD20+ immunophenotype, and one case was CD20 positive. IgM MM is most often CD20 negative, but we do not believe it can be a stringent requirement for diagnosis based on this study.
One of the limitations in establishing a strict disease definition is that it may miss patients who have less advanced stages of the disease. A review of the literature reveals a case report of lytic bone lesions in WM, and this patient would be classified as IgM MM using our disease definition . However, it is important while describing the natural history of a disease, that the initial disease definition be stringent and nonoverlapping with closely related clinical conditions. We have employed this strategy successfully in prior natural history studies [10, 11].
No previous studies have investigated the association between IgM monoclonal gammopathy of undetermined significance (IgM MGUS) and IgM MM. Previous studies show that 17.2% of cases of MGUS have the IgM isotype . Before progression to MM, one patient met criteria for IgM MGUS, and a second patient met criteria for Smoldering IgM MM [10, 11]. Based on this finding, we conclude that IgM MGUS can be a precursor condition to IgM MM, similar to the well-documented progression seen in non-IgM MM. Nineteen patients had MM at the time of diagnosis. However, this may be confounded by the frequency of referrals from outside clinics resulting in inadequate access to records before diagnosis of MM and underestimation of the prevalence of IgM MGUS preceding MM in this study.
We recognize that there will be a subset of patients with IgM monoclonal gammopathy who do not meet these criteria, but have immunophenotypic features more suggestive of MM rather than WM. These patients need further study.
S. S. collected the data, analyzed the data, and wrote the paper. S.V.R., A.D., R.K., and J.M. designed the concept, analyzed the data, and wrote the paper. W.M. provided expert hematopathology review. S.A. and A.M.A. analyzed data and reviewed the paper.