BONE MARROW INVOLVEMENT BY BLASTIC MULTIPLE MYELOMA WITH SERUM AND URINE DETECTION OF A MONOCLONAL IgD/LAMBDA PARAPROTEIN
Multiple myeloma of the IgD isotype is relatively uncommon in the realm of plasma cell malignancies, comprising anywhere from 1% to 2% of all reported myeloma cases in the literature (1,2,3,6). Due to this low frequency, the characteristic features of this disorder have been essentially compiled from case reports, or from somewhat larger case series such as the 165 IgD myeloma patients reviewed in Japan (2). Classically, IgD myeloma predominantly affects men, with approximately 67% of patients presenting prior to the age of 60 years. The age at presentation is believed, overall, to be earlier than with IgG or IgA multiple myeloma (2,4). Clinical features include anemia, hepatosplenomegaly, lymphadenopathy, extraosseous lesions, amyloidosis, and a high incidence of renal failure frequently associated with Bence Jones proteinuria (4,5). The increased incidence of renal failure and lymphadenopathy also appears to be associated with the IgD isotype when compared to IgG or IgA multiple myeloma, with the IgD variant showing significantly higher urinary monoclonal (M)-protein excretion, serum creatinine, and serum calcium (1). In addition, one study noted significant clinical symptoms of bone pain, fatigue, and weight loss; and hypercalcemia was a significant finding in 22% of those patients (1). It is also generally accepted that the IgD variant of multiple myeloma is associated with a relatively short survival time, with 21 months a reported median time of survival from diagnosis (1,4), and 60% of patients dying within one year of diagnosis (6). The results of therapeutic trials have shown similar response rates, however, as those seen with the more common IgG or IgA multiple myeloma (1,4). Some reports of long-term survival have been documented in the literature (4). Prognostic indicators IgD myeloma, although difficult to accurately determine based on the small patient population available for study, appear to be related to the WBC count at diagnosis and the kappa or lambda subtype. A WBC count < 7.0 10x9/L at diagnosis, and monoclonal IgD/kappa are both associated with longer survival (3). In light of these findings, a new staging system specifically for IgD myeloma has recently been proposed since conventional myeloma staging systems in use, do not account for the IgD isotype (2,3).
Laboratory analysis of IgD multiple myeloma cases by serum protein electrophoresis (SPE) usually demonstrates a minimally detectable M-protein spike, often in the beta, gamma, or beta-gamma region. A large percentage of cases can actually show hypogammaglobulinemia or a normal serum electrophoretic pattern making detection of the paraprotein difficult (1,2,4). This can apparently occur despite very high levels of IgD in the patient's serum, with some cases mistakenly diagnosed solely as light chain disease (6). One study has addressed this issue of frequent small or non-detectable M-protein by SPE, and specifically analyzed the serum from four female IgD myeloma patients by two-dimensional (2D) gel electrophoresis. The reported results show an expected higher resolution of the protein components than conventional electrophoresis, with demonstration of both size and charge differences between the various monoclonal immunoglobulins examined. Based on the 2D-gel electrophoresis and specialized silver staining, the authors claim the highest sensitivity and resolution of the IgD paraproteins (6). Once detected by SPE, classification of the paraprotein by standard immunoelectrophoresis will often demonstrate a predominance of lambda IgD monoclonality, with 60% to 91% lambda-restricted cases seen in various studies (1,2,3). Interestingly, a study contrasting Western and Japanese IgD myeloma cases showed a similar 90% and 82% lambda IgD monoclonality in the respective population (2). Urine total protein electrophoresis also appears to have a significantly higher detection rate of the IgD myeloma paraproteins than SPE, with up to 96% of cases showing a detectable paraprotein in one study (1). This finding should reinforce the need for both serum and urine protein electrophoretic analysis as standard parallel testing in all myeloma patients.
Some debate exists as to the nature and source of the B-lymphocyte that ultimately evolves into the IgD-restricted malignant plasma cell. Current theories favor that the putative myeloma stem cell originates from either a na´ve B-cell, a memory B-cell, or a plasmablast (7,8). Some recent evidence derived from molecular studies of IgD and IgM myelomas suggests that these myeloma clones have a high number of somatic mutations based on molecular analysis of the immunoglobulin heavy chain V-region. The extensive mutations identified in these cases are attributed to the process of somatic mutation known to occur in na´ve B-cells trafficking within the germinal center. The authors of this study concluded that the myeloma cells most likely represent B-cells that have already passed through the germinal center; and, therefore, represent either memory B-cells or migrating plasmablasts (8). In addition, the study cites that similar findings of heavy mutation rates have also been reported in investigations of IgG and IgA multiple myeloma, suggesting a common point of origin between the various myeloma isotypes (8).
Another recent study has focused on the investigation of the molecular mechanism resulting in the exclusive expression of IgD. The cell populations studied included Epstein-Barr virus (EBV) transformed germinal center B-cells that were surface IgM-, IgD+, and CD38+; and normal IgD-secreting plasma cells derived from human tonsillar tissue (7). Analysis of genomic DNA from both cell types by polymerase-chain reaction (PCR) assays and cDNA sequencing, demonstrated a putative "sigma-delta" region located upstream of the C-delta exons that code for the IgD heavy chain. Based on the recombination events detected and sequenced, this "sigma-delta" sequence apparently has the ability to function as a switch-site (S-x), with recombination allowed to occur in conjunction with the IgM (S-mu) switch-site located 5' to the IgM heavy chain C-mu exons. This combination functionally splices out the C-mu exons only, as opposed to both the C-mu and C-delta exon splicing that normally occurs with the cytokine directed recombination between IgM and IgG class switch-sites. Therefore, a C-mu to C-delta "class switch" appears to be possible secondary to this "sigma-delta" sequence, leading to preferential expression of a secreted IgD product (7). This "class-switch" mechanism at the DNA level also appears to functionally delete a known transcription polyadenylation stop sequence, pA1, located between the C-mu and C-delta exons (9). This would also presumably eliminate a natural regulatory function that directs preferential transcription and expression of the IgM heavy chain under normal circumstances. This study also demonstrated that the germinal center B-cells will differentiate preferentially into IgD-secreting plasma cells, but not memory B-cells. Therefore, the authors suggest that both the myeloma cells and the IgD-secreting plasma cells normally found in tonsillar tissue are likely derived from these germinal center B-cells (7).
In the current case, the clinical impression for the acute cause of death was adult respiratory distress syndrome most likely secondary to acute renal failure. The acute renal failure was felt to be primarily related to the blastic IgD myeloma, as indicated by the 1.2 g/dL IgD paraprotein level, a 60 mg/dL lambda light chain proteinuria, uric acid nephropathy, and the tubular pattern of injury seen on urinary protein electrophoresis. The characteristics of a tubular proteinuria generally result from decreased reabsorptive capacity of the renal tubules for most of the low molecular weight proteins (< 20,000 kD) (10). Of note, one large case series in Japan reported a decrease in IgG, IgA, and IgM, associated with a marked increase in IgD up to >12 g/L in 50% of patients (3). The relative changes of the other immunoglobulins were not analyzed during the work-up of the current case. However, it did show an estimated 1.2 g/dL serum paraprotein level, which is very similar to a median level of 1.1 g/dL seen in a number of patients from a large Western-based case series (1). This high paraprotein level suggests a tremendous load on the kidneys, and likely contributed a great deal to the renal failure observed clinically in the current case. The patient also demonstrated significant hypercalcemia, and lytic bone lesions were later confirmed on radiographs indicating the extensive amount of disease present. In the same large case series previously mentioned, lytic bone lesions were detected in 42% of patients with IgD myeloma (3).