The definition of IgM multiple myeloma
Authors: Steven R. Schuster, S. Vincent Rajkumar, Angela Dispenzieri, William Morice, Alvaro Moreno Aspitia, Stephen Ansell, Robert Kyle, Joseph Mikhael
Journal: American Journal of Hematology (2011)

In our original paper, we provided a strict definition of IgM multiple myeloma (IgM MM) based on clinical presentation and cytogenetic analysis to be certain to differentiate this rare subtype from the more common Waldenstrom's macroglobulinemia (WM) [1]. We described 21 patients characterized by (1) IgM monoclonal gammopathy, (2) ≥10% plasma cells on marrow biopsy, and (3) presence of lytic lesions and/or t(11;14). All the 21 patients had evidence of lytic lesions in bone, which is a unique feature of MM and not WM [2]. Of those tested with fluorescent in situ hybridization (FISH) analysis, six of 16 patients (38%) demonstrated a t(11;14) abnormality. Median overall survival was 30 months, which is typical for MM at the time of diagnosis of these patients. This is considerably less than the overall survival expected for WM. The principles we used to define this entity are similar to those we have used in the past to define monoclonal gammopathy of undetermined significance (MGUS), light chain MGUS, and smoldering MM [3]. When defining a disease entity, it is critical that the disease definition be highly specific, such that the definition can reliably differentiate it from closely-related disorders. More importantly, the next step is to outline the natural history of the disease defined as such. The steps we took with IgM myeloma are as follows. We used lytic bone lesions in the definition as evidence of end organ damage that is highly specific to MM, and it can therefore be used to distinguish IgM MM from WM [2]. Similarly, multiple studies demonstrate the specific association of t(11;14) with IgM MM but not WM [4]. Sensitivity was not of importance at this stage as our primary goals were to develop a definition of high specificity and to determine the natural history using the specified definition. We recognize that this definition will not capture every patient with IgM MM but will serve as the best starting point for the clinician to discriminate it from WM [5]. We agree that immunophenotype analysis is almost certain to represent an important element in the diagnostic evaluation of IgM MM. However, recent studies have demonstrated that there can be significant overlap between the immunophenotype of WM and MM, particularly when focusing on the plasmacytic component of WM. When examining the expression of a single antigen, the results can be confusing as illustrated by the expression of CD20 by five of the 15 IgM MM cases in our study. To use immunophenotypic markers, we need to know not only just the existence of differential expression of the markers between MM and WM but also whether the differentiation of IgM disorders into WM and IgM MM using such markers had specific clinical implications. More importantly, we need follow-up data on the natural history of patients distinguished by such markers. If such data are available, we would be able to expand our definition. If validated, immunophenotyping as proposed will require multiparametric flow cytometry studies and we hope to study this further through prospective analysis. We agree with the statement by Owen et al. that it would be ideal to define IgM MM in an identical way to non-IgM MM. However, IgM MM is a rare subset of MM, and it is frequently misdiagnosed and treated as WM. For example, 50% of patients in our study were treated initially as WM. Treatment recommendations for MM and WM are diverging. Clinically, the only useful reasons to split IgM plasma cell malignancies into two categories (IgM MM and WM) will be if the presentations vary considerably and if the prognosis and treatments varied as well. The definition we chose meets these requirements. There is no question that patients meeting our definition will present differently and behave differently. In their correspondence, Owen et al. suggest that patients with IgM dyscrasia and (t(4;14) or t(14;16)) should be considered as IgM MM since those cytogenetic abnormalities are not a feature of WM, and we agree. In our study involving 21 patients, we found one patient with t(4;14) and one with t(14;16), but these patients had lytic bone lesions, and ended up classified as IgM MM even though our disease definition did not use these cytogenetic abnormalities as disease-defining lesions. The definition of IgM MM will evolve as more progress is made in the study of the cytogenetics of MM, and we agree that it may include other switch-region translocations involving chromosome 14q32. In our retrospective analysis, two excluded patients had clinical presentations consistent with IgM MM including the usual phenotype (CD138+,CD20−) similar to the two case reports presented by Cabrera et al., but they would not meet our definition of IgM MM due to lack of lytic bone lesions or t(11;14). A limitation of our strict definition is that it may exclude patients with less advanced disease or atypical clinical features such as absence of lytic bone lesions. However, we strongly believe that it is imperative to begin with a strict definition of the entity to determine the natural history and treatment options and then make modifications based on a better understanding of IgM MM. Steven R. Schuster*, S. Vincent Rajkumar , Angela Dispenzieri , William Morice , Alvaro Moreno Aspitia , Stephen Ansell , Robert Kyle , Joseph Mikhael*, * Division of Hematology, Mayo Clinic, AZ 85259, Division of Hematology, Mayo Clinic, MN 55905, Division of Hematology, Mayo Clinic, FL 32224.