Characteristics and Prognosis Of IgM Multiple Myeloma
Authors: Atrash Shebli , Zhang Qing , Papanikolaou Xenofon , Heuck Christoph , Bakhous Aziz , Muzaffar Jameel , Abdallah Al-Ola , Barlogie Bart 
Published: October 2019

Abstract

Introduction
Multiple Myeloma (MM) is considered a malignancy of post germinal center long-lived plasma cells. Nevertheless T-cell independent antigen stimulation before the exposure of the B-cell to the germinal center can happen and results to IgM secreting short lived plasma cells and lymphoplasmacytes representing thus a potential alternative normal counterpart for IgM plasma cell dyscrasias. IgM myeloma is an infrequent subtytpe of MM with an estimated prevalence of 0.5%. Due to its rarity little is known about its characteristics and prognosis in comparison with Waldestrom’s macroglobulinemia (WM) and the other MM subtypes.

Purpose
To identify the characteristics and the prognosis of IgM MM, and compare it predominantly with WM and subsequently with the rest of the MM subtypes.

Methods
We interogatted our Multiple Myeloma Data Base for cases of IgM MM and their respective Overall Survival (OS), Progression Free Survival (PFS), bone disease as defined by x-Rays, PET-CT and MRI, Gene Expression Profile (GEP), and common disease characteristics (anemia,calcium, creatinine) and compare it to the prognosis of WM and non-IgM MM. Diagnosis was based on the morphological and immunophenotypical findings of pathologically examined biopsy specimens along with the presence or not of typical clinical characteristics of MM (lytic bone lesions, hypercalcemia, renal failure) or typical clinical characteristics of WM (organomegaly, lymphadenopathy).

Results
There were 22 confirmed IgM MM cases. 14 of them presented at MIRT at initial diagnosis while 8 had previously been treated elsewhere. Osteolytic bone lesions and/or pathological fractures by x-ray and CT examination were evident in 16 cases. For the remaining 6 cases active bone focal lesions by either MRI or PET were identified in three. There was no organomegaly evident in cases with an available PET/CT at baseline, while only one had evidence of hilar and mediastinal lymphadenopathy along with calcified lung nodules. Elevated creatinine levels (>2.0 mg/dl) were evident in 4 cases at initial diagnosis. Their disease characteristics are depicted in the table 1. Median OS for IgM MM was 4.9 years while PFS could not be accurately estimated due to lack of data on patients treated elsewhere. Median OS for a historical control of 158 WM cases in MIRT was 9.2 years (Clin Lymphoma Myeloma Leuk. 11(1):139-42). Median OS of the WM group remained largely unaffected, even when the subgroup of the WM cases requiring treatment was analyzed (9.0 years).To further clarify if the IgM MM differs in terms of OS from the other isotypes of MM, we compared the IgM group to a group of 61 non-IgM MM cases which were matched by important prognostic clinical factors (age, creatinine> 2mg/dl, LDH>190u/L, b-2M >5.5mg/dl and Albumin<3.5gr/dl). No statistical difference was found for OS (p=0.846). Out of 22 cases, 14 of them had available GEP data on initial diagnosis. In 6 of these cases the cyclin D1 gene expression was high enough to be consistent with a t(11;14) translocation at FISH analysis, one case was consistent with a t(14;16) translocation, one with a t(4;14) translocation and two more were classified as belonging to the hyperdiploid subgroup. A comparative genomic analysis was performed on the IgM MM, the non-IgM MM and WM cases with available GEP data at initial diagnosis (14, 61 and 42 cases respectively). 1155 probesets that had expression level significantly different between WM and non IgM MM (FDR<3E-06) were identified. Then, the expression values of these 1155 probesets in all GEP samples, including WM, non IgM MM, and IgM MM, were used to build a clustering tree. We found that IgM MM mainly clustered with non IgM MM, supporting the findings of the clinical data.

Conclusion
IgM MM is a discrete clinical entity that should be distinguished from WM. Bone disease is evident in the majority of the cases, especially when specialized radiological techniques are incorporated at the initial work up. It holds a distinct prognosis from WM, while when balanced for prognostic factors that hold importance in MM it does not differ from the other MM isotypes. Finally analysis of the genetic data further supports the resemblance between IgM MM and the non IgM MM, and the difference with WM.

Disclosures:
Zhang: University of Arkansas for Medical Sciences: Co-inventor of the DNA probes for FISH of IGHC/IGHV (14q32), MMSET/FGFR3 (4p16), CCND3 (6p21), CCND1 (11q13), MAF (16q23), and MAFB (20q12) loci, sub. to the US Patent & Trademark Office as Prov. App# 61/726,327: Methods of Detecting 14q32 Translocations, Co-inventor of the DNA probes for FISH of IGHC/IGHV (14q32), MMSET/FGFR3 (4p16), CCND3 (6p21), CCND1 (11q13), MAF (16q23), and MAFB (20q12) loci, sub. to the US Patent & Trademark Office as Prov. App# 61/726,327: Methods of Detecting 14q32 Translocations Patents & Royalties.