Clinical Presentation and Gene Expression Profiling of Immunoglobulin M Multiple Myeloma Compared With Other Myeloma Subtypes and Waldenström Macroglobulinemia

Abstract

PurposeMultiple myeloma (MM) is a clonal bone marrow disease characterized by the neoplastic transformation of differentiated postgerminal B cells. It is a heterogeneous disease both at the genetic level and in terms of clinical outcome. Immunoglobulin M (IgM) MM is a rare subtype of myeloma. Similar to Waldenström macroglobulinemia (WM), patients with MM experience IgM monoclonal gammopathy; however, both diseases are distinct in terms of treatment and clinical behavior.Materials and MethodsTo shed light on the presentation of IgM MM, its prognosis, and its gene expression profiling, we identified and characterized 21 patients with IgM MM from our database.ResultsOne of these patients presented with a rare IgM monoclonal gammopathy of undetermined significance that progressed to smoldering myeloma. The median survival of the 21 patients was 4.9 years, which was comparable to a matched group of patients with non-IgM MM with similar myeloma prognostic factors (age, gender, albumin, creatinine, anemia, lactate dehydrogenase, β2-microglobulin, cytogenetics abnormalities), but much less than the median survival reported for patients with WM (9 years). We identified a cluster of genes that differ in their expression profile between MM and WM and found that the patients with IgM MM displayed a gene expression profile most similar to patients with non-IgM MM, confirming that IgM MM is a subtype of MM that should be differentiated from WM.ConclusionBecause the prognosis of IgM MM and WM differ significantly, an accurate diagnosis is essential. Our gene expression model can assist with the differential diagnosis in controversial cases.

Mouse models of human multiple myeloma subgroups

“…An expansion of IgM-expressing plasma cells is usually associated with Waldenström’s macroglobulinemia (WM), an indolent lymphoplasmacytic lymphoma ( 46 ). However, the occurrence of IgM MM has also been described, differing from WM in gene expression ( 47 ) and clinical manifestation ( 48 ). In line with this, Ccnd1/Ikk2ca and MMSET/Ikk2ca BM plasma cells were clearly distinguished from WM cells by GSEA using MM- and WM-specific gene sets ( 49 ) ( SI Appendix , Fig.…”

Preclinical models of human multiple myeloma subgroups

“…An expansion of IgM-expressing plasma cells is usually associated with Waldenström’s macroglobulinemia (WM), an indolent lymphoplasmacytic lymphoma (( 31 )). However, the occurrence of IgM MM has also been described, differing from WM in gene expression (( 32 )) and clinical manifestation (( 33 )). In line with this observation, Ccnd1/Ikk2ca and MMSET/Ikk2ca BM plasma cells were clearly distinguished from WM cells by GSEA using MM- and WM-specific gene sets (( 34 )) (Fig.…”

Immunoglobulin M Paraproteinaemias

“…Paraprotein-related neuropathies can occur in a proportion of patients while organomegaly and lymphadenopathy may be found on physical examination in 15–30% of cases [ 19 ]. Immunoparesis also occurs in WM, though is generally milder than in MM [ 23 ]. Although recurrent infections have been reported in WM, the degree of immunoparesis does not predict the incidence of infection [ 24 ].…”

“…Although not specific for IgM MM, this translocation has not been described in WM and hence has clinical utility in distinguishing the two conditions [ 32 ]. Gene expression profiling (GEP) has also shown promise as a means for distinguishing these entities and further studies are required to validate this [ 23 ]. Treatment for IgM MM is currently similar to that for other subtypes of MM, however given the emergence of venetoclax as a means to target t(11;14), clinical trials evaluating this agent in IgM MM are called for [ 33 ].…”

“…MALT: mucosa-associated lymphoid tissue. References: [ 23 , 24 , 32 , 38 , 40 , 45 , 48 , 49 , 50 ].…”