Unusual Myelomas: A Review of IgD and IgE Variants
Unusual Myelomas: A Review of IgD and IgE Variants
ABSTRACT: Immunoglobulin D multiple myeloma (IgD MM) accounts for almost 2% of all myeloma cases. It is associated with an increased frequency of undetectable or small monoclonal (M)-protein levels on electrophoresis; osteolytic lesions; extramedullary involvement; amyloidosis; a lambda (?) light chain predilection; renal failure; hypercalcemia; and, often, advanced disease at diagnosis. Immunoglobulin E (IgE) MM is rare, with fewer than 50 cases reported in the literature. IgE MM presents with features similar to those of IgD MM, along with a higher incidence of plasma cell leukemia. The hallmark of IgE MM is t(11;14)(q13;q32). IgD and IgE levels are generally very low and hence may escape detection; thus, it is important that, when myeloma is suspected, patients be screened for the presence of IgD and IgE if they have an apparently free monoclonal immunoglobulin light chain in the serum. Although survival of patients with IgD MM or IgE MM is shorter in comparison to those with immunoglobulin G (IgG) MM or immunoglobulin A (IgA) MM, the outcome for patients with IgD and IgE subtypes is improving with the use of novel agents and autologous transplantation.
Multiple myeloma (MM) is a neoplastic condition whose hallmark is the proliferation of malignant plasma cells in the bone marrow, resulting in an increase in serum and/or urine monoclonal-(M) protein and end-organ damage, including hypercalcemia, renal failure, anemia and/or bone lesions, commonly described by the acronym CRAB. The interaction of stromal and plasma cells produces immunoglobulins (Igs), which are proteins synthesized by immunocompetent cells. These immunoglobulins form the body’s humoral defense against infections and allergens. There are five kinds of immunoglobulins and two types of polypeptides, known as the heavy and light chains. The structurally specific heavy chains in each class of Ig are referred to as gamma (G), alpha (A), mu (M), delta (D), and epsilon (E). The two light chains, kappa (κ) and lambda (λ), are immunologically distinct and common to all immunoglobulins. These immunoglobulins have a protective function in the human immune system, and a pathologic derangement leading to an increase in one type of immunoglobulin, resulting in a monoclonal gammopathy. In multiple myeloma, IgG, IgA, and light chains predominate, with a prevalence of 52%, 21%, and 16%, respectively, comprising almost 90% of all myeloma types. The remainder consists of IgD, IgE, IgM, and nonsecretory types. In this review, we will focus our discussion on IgD and IgE variants of myeloma.
IgD secreting plasma cells originate from germinal center B cells due to somatic hypermutation of IgV regions, while t(11;14)(q13;q32) translocation has been reported as a characteristic feature of IgE MM. IgG and IgA have a serum concentration of 1,020 mg/dL to 1,460 mg/dL and 210 mg/dL to 350 mg/dL, respectively; the level of IgD in serum is 0 to 10 mg/dL, whereas IgE may be present only in trace amounts. Thus, in IgD MM and IgE MM, there may only be a small or unrecognizable M-protein spike on electrophoresis. This may lead to diagnostic errors in identifying these patient subgroups.
Epidemiology, incidence, and presentation
After IgD MM was first reported by Rowe and Fahey in 1965, multiple studies have reported an IgD MM prevalence of approximately 1% to 2% of myeloma patients,[2,6-9] whereas IgE is rare, with fewer than 50 cases reported in the literature. Another study found an IgD MM incidence of 6% in myeloma patients younger than 40 years. Given their rarity, knowledge about these diseases is gained mostly from a few single-center case series and isolated case reports. Although the clinical features of IgD MM are similar to those of IgG MM, IgA MM, and light chain myeloma, IgD MM has been recognized as involving relatively younger patients, with a median age of 52 to 60 years at onset; occurring predominantly in males; and being characterized by a small or absent M-protein spike on electrophoresis, as previously noted, as well as extramedullary involvement, osteolytic lesions, presence of systemic amyloidosis, hypercalcemia, a λ light chain bias, Bence Jones proteinuria (BJP), renal failure, and a shorter survival time[6-9] (Table 1). Another feature of IgD MM is the presence of advanced disease at the time of diagnosis. Shimamoto et al reviewed 165 Japanese patients with IgD MM classified according to the Durie-Salmon (DS) staging system. They found 7% of patients to be DS stage I, 22% DS stage II, and 71% DS stage III. Similarly, a staging of 379 IgD patients in another study reported 6%, 17%, and 77% in DS stages I, II, and III, respectively. However, two studies found no significant relationship between DS stage and survival outcomes in patients with IgD MM.[12,13] Because of the limited number of patients, an attempt to create a prognostic system for IgD MM has not been successful. Jancelewicz et al reported that hemoglobin and serum albumin were important prognostic features; however, the methods for this analysis were not described, and only a limited number of parameters were analyzed. Similarly, Shimamoto et al proposed that light chain subtype and white blood cell count (WBC) were significant predictors of survival. In their study, patients were divided into four groups depending on the type of light chain (κ or λ) and WBC count above or below 7 × 109/L. The group with the κ subtype and WBC counts < 7 × 109/L was considered to be at low risk, with a 5-year overall survival (OS) of 66%, while OS in the intermediate group was 22.5% and in the high-risk group was 0%. In a series of 1,202 myeloma patients, including 12 (1%) with IgD MM, gene-expression profiles (GEPs) defining high-risk MM were found in all Ig isotypes. A total of 38% of the IgD myeloma patients, in comparison with 10% of the overall cohort, were included in the proliferation subgroup (P = .003). Other factors associated with IgD were more common occurrence of cytogenetic abnormalities, elevated serum lactate dehydrogenase (LDH), beta-2 microglobulin (B2M), and C-reactive protein (CRP) values; these features could account for an increased proliferation subtype, which might help to explain the shorter OS in IgD myeloma.
With advanced disease, myeloma cells tend to become independent of the bone marrow microenvironment. This is at least partially responsible for the spread of plasma cells to the peripheral blood, thereby manifesting as plasma cell leukemia (PCL; defined as peripheral blood plasma cells > 2 × 109/L and/or > 20% plasma cells in the peripheral blood) or soft-tissue plasmacytomas. IgD MM has been reported to have a more aggressive course and a poor prognosis, with patients having a median survival of less than 2 years prior to the availability of novel agents and use of autologous transplantation. Interestingly, response to therapy both before and after autologous stem cell transplantation (ASCT) has been reported to be better in patients with IgD MM compared with other isotypes; however, this does not translate into increased survival. Morris et al reported complete response (CR) rates of 12% vs 20% after conditioning, and 28% vs 44% following transplantation in non-IgD vs IgD MM, respectively. The progression-free survival (PFS) was reported as 27 months vs 24 months (P = .017), while median OS was 62 months vs 43 months (P = .0001) in non-IgD vs IgD MM, respectively. This significant improvement in survival (eg, compared with the median OS of 21 months reported by Blad et al) is due to treatment with novel agents (thalidomide, bortezomib, lenalidomide) and ASCT. With use of novel agent therapy and ASCT, survival is improving, although it is still inferior to survival of IgG, IgA, and light chain MM.[6-9,13,16]
The most common presenting symptoms in IgD myeloma are similar to those of IgG and IgA myeloma, and include bone pain, weakness, fatigue, and weight loss. A higher frequency of skeletal involvement occurs in IgD MM, with more than 72% of patients reporting bone pain.[6,7] While one study reported the incidence of osteolytic lesions as 42%, Blad et al found that 77% had an abnormal skeletal survey.
While the incidences of hepatomegaly, splenomegaly, and lymphadenopathy were reported as 55% each by Jancelewicz et al, organomegaly was reported to occur in 13%, 6%, and 9% of patients, respectively, in another study. Shimamoto et al reported a 26% incidence of hepatomegaly, 12% splenomegaly, and 10% lymphadenopathy in IgD MM. Blad et al found no significant difference in the recognition of hepatomegaly and splenomegaly in comparison with IgG, IgA, and light chain MM, but lymphadenopathy was more common in IgD than in other isotypes. Symptoms attributable to amyloidosis, such as carpal tunnel syndrome and macroglossia, were reported in 19%. Other symptoms included higher rates of extramedullary plasmacytoma (EMP), which sometimes presented as an extradural tumor or nerve root compression.
Amyloidosis has been reported to commonly affect patients with IgD MM. As noted, Blad et al found amyloidosis in 19% of patients. In an autopsy series, 10 of 23 patients (44%) had amyloidosis. In another series of 53 patients with IgD and amyloidosis, fatigue; peripheral edema; carpal tunnel syndrome; macroglossia; cardiac, renal, or hepatic involvement; and peripheral neuropathy were reported as presenting complaints. These 53 cases of IgD-related amyloidosis were compared with 144 cases of non-IgD monoclonal protein–related amyloidosis. Cardiac amyloidosis was found in 45% vs 56% of patients with IgD vs non-IgD amyloidosis (P = .047), and renal amyloidosis was noted in 36% vs 58% of these two groups of patients (P = .005). Survival outcomes in patients with IgD amyloidosis were not different from those of patients with IgG, IgA, or light chain myeloma amyloidosis. In another study, t(11;14) was associated with poorer outcomes in light chain amyloidosis. There was a significant survival disadvantage (hazard ratio [HR] = 2.1; 95% confidence interval [CI], 1.04–6.39; P = .04) for patients with the t(11;14) translocation.
EMP may be palpable or observed radiographically as masses around bones or in soft tissue. EMP is reported to occur in 13% to 19% of myeloma patients[2,6,20]; however, a 19% to 63% prevalence of EMP associated with IgD MM in particular has been reported.[6,12,16] Usmani et al evaluated extramedullary disease (EMD) in 1,965 patients in whom a baseline positron emission tomography (PET)-CT and subsequent PET-CT at relapse were available. Patients were grouped as EMD-1 (EMD at diagnosis) or EMD-2 (EMD at subsequent relapse). EMD-1 was found in 3.3% of patients (66 of 1,965) with the most common sites of involvement in the chest wall, liver, lymph nodes, skin, soft tissue, and paraspinal areas. The incidence of EMD-2 was reported in 1.8% of patients at relapse or disease progression, with the liver as the most common site of involvement. The OS was 31% at 5 years (P < .001) in EMD-1 compared with 59% in those without EMD. The PFS was 21% vs 50% at 5 years (P < .001) in patients with EMD-1 compared with those without EMD. A combined cumulative incidence of EMD (both 1 and 2) 5 years post-transplant was higher in those with GEP-defined high-risk features (11% vs 2%; P < .001), pre-transplant cytogenetic abnormalities (7% vs 4%; P = .004), anemia (9% vs 3%, P < .001), and thrombocytopenia (9% vs 3%; P < .001).
A study looking at the outcome of EMD reported a significantly shortened PFS (18 months vs 30 months; P = .003) but no statistically significant difference in OS (36 months vs 43 months; P = .36) in those who had EMD at diagnosis compared with those who did not. Hobbs and Corbett suggested that EMPs be classified as (1) those breaking the cortex of the bone and growing locally or (2) those developing within soft tissue. They also noted that EMP was more common in those with increased BJP (93%) and λ light chain expression (90%). Blad et al reported that 10 of 53 patients (19%) with IgD myeloma had EMP. Extradural tumors were found in 7 of the 10 patients. Eight additional patients developed an EMP later in the course of disease. There have also been reports of spinal and nerve root compressions resulting in neurological deficits. Patients with IgD MM presenting as a testicular tumor who subsequently developed abdominal masses and ascites have been described. Chromosomal analysis of cells obtained from the ascitic fluid revealed aneuploidy and complex abnormalities, including 1q+, 2p+, and 14q+.
PCL is a rare extramedullary manifestation of myeloma and has a poor clinical outcome. As previously noted, it is defined by the presence of > 2 × 109/L circulating plasma cells and/or circulating plasma cells > 20%.[23,24] PCL is present in 2% to 5% of patients with IgD myeloma and can present de novo (primary PCL) or as secondary disease that develops in patients with advanced myeloma. Prognosis is very poor in secondary PCL. Noel and Kyle reported that patients with secondary PCL were usually elderly, with a higher incidence of lytic lesions and thrombocytopenia and a median survival of only 1.3 months. Some reports suggest that PCL is associated with IgD myeloma,[24,25] while others show an association with IgE. A higher incidence of t(11;14)(q13;q32) was reported to be associated with PCL, while another study reported t(11;14) as the hallmark feature of IgE myeloma.
Pertinent laboratory values reported in IgD myeloma include a higher frequency of anemia (Hb < 10 g/dL)[6,9,13]; hypercalcemia (> 11 mg/dL in 22% to 30%)[6,7]; elevated creatinine levels (> 2 mg/dL in 33% to 54%)[6,12]; a bias for λ light chain over κ[6-9,12]; the common occurrence of cytogenetic abnormalities; and, as previously mentioned, elevated levels of serum LDH, B2M, and CRP. While platelet counts were usually within normal limits, occurrence of thrombocytosis was associated with amyloidosis in one study. A serum M-spike of > 2 g/dL was noted in only 14% of IgD MM patients, while a urine light chain M component on electrophoresis of > 4 g/day was observed in 28% of patients. The same study also reported a urinary M-protein level of > 1 g/d in more than 60% of patients. Urinary light chain at diagnosis was reported in 61% of patients by Reece et al. A lower M-protein level, and higher serum albumin and B2M levels, were reported in another study.
The bias for λ light chain expression with a reversed light chain ratio is a characteristic feature of IgD MM.[6-8,12,13] Blad et al reported λ light chain expression in 60% of patients with IgD MM, Shimamoto et al reported it in 82%, Jancelewicz et al reported it in 90%, and Morris et al reported λ light chains in 75% of patients. Median survival of patients with κ vs λ light chains was 20 months and 29 months, respectively (P = .99). Renal failure is more common at presentation in IgD MM. An increase in serum creatinine (> 2 mg/dL) has been reported in various series of IgD MM.[6,7,12] Blad et al found an elevated creatinine level (> 2 mg/dL) in 33% of patients with IgD MM, and Reece et al reported elevated creatinine in 36% of patients with this variant. BJP was noted in more than 90% of IgD MM patients.[6,7] The combination of increased creatinine levels, hypercalcemia, hyperuricemia, and light chain excretion is often associated with renal insufficiency in IgD MM. In performing quantitative measurements of individual immunoglobulins, Shimamoto et al saw a decrease in serum levels of IgG (in 52% of patients), of IgA (in 53%), and of IgM (in 46%), along with an increase in IgD (> 12 g/dL). Similar results were reported by Blad et al, in that 84% of IgD MM patients had a reduction in one or more uninvolved immunoglobulin levels on quantitative measurements.