Case vignettes and other brain teasers of monoclonal gammopathies

Guido Fanconi first described the syndrome of glycosuria, aminoaciduria, hypophosphatemia, and vitamin D-resistant rickets. Defective renal tubular reabsorption of glucose, amino acids, calcium, and phosphate result in osteomalacia. Renal tubular dysfunction occurs because of the crystalline deposition of κ-Ig light chain in the proximal renal tubule.¹ 

The finding of κ-light chains in the urine may result in the misdiagnosis of Bence Jones myeloma. If these patients do not have multiple myeloma at presentation, development of multiple myeloma would be rare. These patients can present with lower extremity or migratory bone pain due to microfractures, increasing the risk of confusion with myeloma bone disease. The chronic loss of phosphorus in the urine results in secondary hyperparathyroidism, which causes microscopic bone fractures. The combination of κ-light chain proteinuria and bone pain can lead to inappropriate use of chemotherapy when, in fact, chemotherapy will not correct the proximal tubular defect and will not reduce the bone pain. Replacement of phosphorus orally will suppress the hyperparathyroidism and often result in complete resolution of bone pain. Clues to the diagnosis include the finding of glycosuria with a normal serum glucose level. Hypouricemia in the absence of aspirin or allopurinol use can be an important clue. Radiographs performed for the bone pain can show osteomalacia. The diagnostic test of choice is a 24-hour urine amino acid measurement, which will show an excess of all amino acids in the urine, reflecting profound proximal tubular dysfunction.

Fanconi syndrome is indolent, but the chronic loss of urinary protein can result in the gradual development of renal insufficiency. Preservation of renal function justifies therapy to eliminate the κ-light chain excretion. In asymptomatic patients, no treatment is indicated. Calcium, phosphorus, and calcitriol supplementation can manage the bone disease. Patients developing renal insufficiency or those few who actually develop overt multiple myeloma can benefit from chemotherapy. In the experience of the Mayo Clinic, the median serum creatinine at presentation is 2 mg/dL with evidence of osteomalacia in most. Only 1 of 14 patients with a measurable monoclonal protein transform to multiple myeloma. Two-thirds of the patients are male. Ninety percent have κ-light chain proteinuria as opposed to λ-light chain proteinuria. Hypouricemia was seen in two-thirds and glycosuria and aminoaciduria in all patients.² 

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a plasma cell disorder that is invariably characterized by the presence of progressive peripheral neuropathy and a monoclonal protein, which almost always has a λ-light chain isotype. The combination of these 2 things often results in the erroneous diagnosis of monoclonal gammopathy of undetermined significance (MGUS)–associated peripheral neuropathy. These patients frequently undergo high-dose steroid trials, Ig infusions, and total plasma exchange without benefit due to the failure of physicians to recognize the underlying etiology.

Practicing neurologists often fail to do bone imaging to look for diagnostic osteosclerotic lesions in patients presenting with a monoclonal gammopathy and a peripheral neuropathy. POEMS patients have a high prevalence of endocrinopathy, papilledema, and nonspecific pulmonary abnormalities that can be hard to integrate into a single unifying diagnosis if POEMS is not considered. A subtle clue to the diagnosis is the presence of thrombocythemia, which is normally not part of myeloma or amyloidosis. Patients often have erythrocytosis, and these patients have been mistakenly diagnosed as having polycythemia rubra vera.

Although the exact pathogenesis of POEMS is not well understood, most patients demonstrate high levels of VEGF.³  The BM will not be diagnostic of multiple myeloma, but will show a small percentage of clonal plasma cells with surface Ig expressing lambda. Unexplained weight loss is seen in greater than one-third of patients and can result in a fruitless search for an underlying malignancy. For patients who have a solitary sclerotic bone lesion and a BM that fails to show a significant clonal abnormality, localized radiation to the sclerotic lesion can be curative. For patients in whom radiation therapy has failed or who have widespread osteosclerotic lesions, systemic chemotherapy is required.

Combination chemotherapy has been used for POEMS as it is administered for multiple myeloma and is useful, but autologous stem cell transplantation has been shown to be particularly effective in the long-term management of this disorder. Confusion of POEMS with light-chain amyloidosis may occur because the clinical phenotype of the neuropathy is similar in both. Single-agent corticosteroids will not produce lasting benefit for these patients. Thalidomide and bortezomib have activity, but need to be administered cautiously because of the risk of aggravating the peripheral neuropathy.

For many years, there was doubt about the existence of IgM multiple myeloma. However, this is a distinct entity and comprises 1% of all patients seen with multiple myeloma. In IgM multiple myeloma, pure plasma cell dyscrasias characterized by lytic bone disease, anemia, and cast nephropathy are seen. The prognosis and survival is no different from typical multiple myeloma. The presence of a large IgM monoclonal protein can result in misdiagnosis as Waldenström macroglobulinemia and can result in inappropriate rituximab-based therapy or other lymphoma regimens including fludarabine or everolimus that are not active in multiple myeloma. Defining IgM multiple myeloma is a challenge. The BM demonstrates clear plasma cell morphology and does not show the lymphoplasmacytic features typically associated with Waldenström's macroglobulinemia. Many patients will have typical FISH cytogenetics for multiple myeloma such as t(11;14) and lack the characteristic 6q- genetic findings associated with Waldenström's macroglobulinemia. Patients with Waldenström's typically lack abnormalities of chromosome 14 where these genetic abnormalities are seen in as many as 88% of patients with IgM myeloma. The malignant cells demonstrate an aberrant plasma cell phenotype. Lytic bone disease is rare in Waldenström's macroglobulinemia. The presence of lytic bone lesions should raise suspicion of multiple myeloma. The plasma cells will express monotypic IgM.

Plasma cells in IgM multiple myeloma demonstrate bright CD38 expression, CD138 and CD56. In contrast, Waldenström's macroglobulinemia clonal B cells express CD19, CD20, CD45, and surface Igs instead of cytoplasmic Igs. Immunophenotypic profiles and flow cytometry of BM plasma cells in IgM myeloma show uniform expression of CD38 and a uniform failure to express CD20, which is a critical distinguishing feature of this disorder.

We have performed transplantations in 10 patients with IgM multiple myeloma and have not been able to demonstrate clinical differences between outcome for this group and those with non-IgM myeloma. In a Mayo Clinic report of 21 patients,⁴  there was no difference between presenting age, hemoglobin, creatinine, calcium, or β2 microglobulin compared with non-IgM multiple myeloma. IgM multiple myeloma should be kept in mind, and close collaboration with a hematopathologist is required to avoid misclassification.

Patients with Coombs-positive hemolytic anemia are often not further evaluated other than to exclude an underlying autoimmune disorder such as systemic lupus erythematosus. It is a diagnostic failure to not further characterize the autoantibody as being either warm or cold in origin. Unlike warm autoimmune hemolytic anemia, corticosteroids are less effective and are potentially toxic to patients with cold hemagglutinin disease. Recognizing a cold Ab should trigger a cascade of diagnostic studies to detect the presence of a small monoclonal IgM κ-protein, which may be associated with the presence of an underlying low-grade lymphoplasmacytic lymphoma. Patients with cold hemagglutinin disease as adults are characterized by a strongly positive Coombs test, the presence of a circulating IgM κ-monoclonal gammopathy, and diagnostic features consistent with extravascular hemolysis, including reticulocytosis, indirect hyperbilirubinemia, elevation of lactate dehydrogenase, and suppression of the plasma haptoglobin level.

Cold-reactive Abs are prevalent in the general population. However, Abs with a thermal amplitude to produce in vivo hemolysis are quite rare. Immunological characteristics of this form of extravascular hemolysis include the finding of complement proteins on the RBC surface. Monospecific direct Ab testing will often fail to demonstrate the presence of Ig on the surface. At 37°C, IgM proteins do not adhere to the RBC surface membrane but do fix complement. The entire complement cascade is not activated, as it would be with paroxysmal nocturnal hemoglobinuria. These patients have surface complement, but never develop late complement factor activation that would lead to RBC membrane perforation. Specialized receptors in the liver, spleen, lymph nodes, and lungs are able to remove fragments of the RBC membrane, leading to microspherocytosis in the peripheral blood. When a cold-reactive Ab develops in a viral setting, it is polyclonal and self-limited and supportive care is all that is required. Cold hemolysis in the presence of a monoclonal IgM protein leads to a sustained chronic hemolytic state. The density of complement on the RBC surface renders these patients insensitive to traditional treatments such as corticosteroids and splenectomy. Some will have overt lymphoplasmacytic lymphoma that can serve as a target for therapy.

Diagnostic error can occur when a patient is seen with a monoclonal IgM protein in the serum with associated anemia. It could be inferred that anemia is due to Waldenström macroglobulinemia if a screening for a hemolytic process is not performed.

Patients with anemia as the sole manifestation of Waldenström macroglobulinemia should be screened with a reticulocyte count and a Coombs test. Patients who have a stable hemoglobin level that does not lead to significant reduction in quality of life are best observed without therapeutic intervention, because many are capable of tolerating relatively low levels of hemoglobin with minimal symptomatology. All available treatments for cold agglutinin disease are potentially toxic and carry risks. The age of onset of cold agglutinin disease tends to be substantially higher than other patients with autoimmune hemolytic anemia and likely reflects the population most at risk of developing IgM monoclonal gammopathies.

Rituximab has been demonstrated to be an effective therapy in the treatment of Cold hemagglutinin disease, with approximately half of patients showing responses. The combination of rituximab and fludarabine has also been reported to be effective. The myelosuppressive effect of fludarabine in patients who have significant RBC hyperplasia in the BM can result in a significant transfusion dependency for months while waiting for the fludarabine to take effect. Raynaud phenomenon is seen in patients who have cold agglutinin disease, but otherwise, patients lack any other cryopathic syndrome and there is no association between cold agglutinin disease and type II cryoglobulinemia. BM examination will usually detect a lymphoplasmacytic clone that is monoclonal for κ-Ig, although the fraction of clonal cells is often less than 5%. Naturally occurring cold agglutinins are seen in many patients with cold hemagglutinin disease, but the diagnosis should not be considered unless the cold agglutinin titer is > 1:64 at 4°C. As in all patients with chronic hemolysis, folate supplementation is warranted. Steroids and splenectomy should not be considered early in the course until other, more effective therapies have been exhausted. The use of erythropoietin is unlikely to be of benefit, because these patients have an expanded RBC production in the BM and a high level of peripheral blood reticulocytosis.

Amyloidosis is associated with Ig light chains. The recognition that IgM monoclonal proteins can be associated with amyloidosis is not well appreciated. In addition, unlike multiple myeloma, in which the frequency of IgM monoclonal proteins is 1%, and MGUS, in which the frequency is 16%, in light-chain amyloidosis, IgM accounts for approximately 5% of all patients seen. Patients with IgM amyloidosis share many of the characteristics of other patients with systemic amyloidosis, including cardiomyopathy and nephrotic range proteinuria, but there appears to be a higher incidence of pulmonary involvement with amyloid and peripheral neuropathy than in non-IgM forms of amyloidosis. When a patient with an IgM monoclonal protein is seen, amyloidosis must always be kept in the differential diagnosis. Patients have been reported in whom the presence of an IgM monoclonal protein and proteinuria has led to an incorrect diagnosis of renal Waldenström macroglobulinemia. Patients with amyloid peripheral neuropathy and an IgM monoclonal protein can be confused with chronic inflammatory demyelinating polyneuropathy with an IgM monoclonal protein and be inappropriately treated with steroids, IV infusions of Ig, and plasma exchange. Histologic studies are required, up to and including sural nerve biopsy, to exclude amyloidosis from the differential diagnosis.

One important distinguishing feature between IgM amyloidosis and Waldenström macroglobulinemia is that the majority of patients with the former have an associated λ-light chain isotype, whereas in the latter, a majority have the κ-light chain isotope.

Any patient with an IgM monoclonal protein and associated albuminuria, cardiomyopathy, unexplained hepatomegaly, or peripheral neuropathy should have a BM or subcutaneous fat aspirate biopsy or another noninvasive biopsy as fits institutional experience stained for amyloid deposits. Noninvasive biopsies such as BM and fat are less sensitive in amyloid peripheral neuropathy. In a patient with peripheral neuropathy associated with an IgM monoclonal protein with or without anti-myelin–associated glycoprotein Abs, sural nerve biopsy should be considered.⁵  The treatment of IgM amyloidosis resembles that for other forms of amyloidosis. However, because the cells responsible for the protein production are CD20⁺, rituximab may be added. The effectiveness of rituximab, bortezomib, and dexamethasone has been described previously.⁶  The median size of the monoclonal IgM protein is only 0.8 g/dL, although 88% have an abnormal free light chain ratio. There appeared to be a greater response to combination regimens and single-agent oral alkylators.⁷  When lymph node involvement is present, their size will not change after therapy. Stem cell transplantation has been used quite successfully for the treatment of IgM amyloidosis. There is no information on whether these patients should be conditioned with a melphalan-based regimen or with carmustine, etoposide, cytarabine, and melphalan.

Scleromyxedema is a rare, chronic fibromucinous disorder that can be disfiguring and cosmetically challenging. The clinical manifestations include skin sclerosis, but the disorder can produce life-threatening complications such as pharyngeal and upper airway involvement. Death occurs due to respiratory complications.⁸  To make the diagnosis of scleromyxedema, there must be 4 criteria met: (1) generalized papular and sclerodermoid eruption, (2) mucin deposition and fibroblast proliferation with fibrosis, (3) an IgG monoclonal gammopathy, and (4) the absence of thyroid disease, which would indicate myxedema. The most common monoclonal protein is IgG-λ. Ig deposits are never found on skin biopsy, but all cases are associated with a serum monoclonal Ig protein. Multiple therapies have been used for the treatment of scleromyxedema, all of which have been reported to be effective, but responses are frequently not durable. Stem cell transplantation has been reported to be highly effective, but skin relapses occur at a median of 37 months. Thalidomide-based regimens have recently been reported to be highly effective and are amenable to long-term administration.

Patients with papular skin diseases need to be screened for a monoclonal gammopathy. Patients referred from a dermatologist will virtually never fulfill the criteria for multiple myeloma. The average percentage of BM plasma cells is approximately 5%. It would be rare for the M-spike to exceed 2 g/dL. Clinical evaluation by the hematologist should focus on the presence of extracutaneous manifestations, including gastrointestinal dysmotility, and pulmonary complications, including obstructive lung disease and pulmonary hypertension. Although Ig deposits are not found in the skin, a hematologic response as measured by reduction in the monoclonal gammopathy is associated with clinical regression of the skin disorder. Control of the disease is compromised by the lack of durable response and is reflected by the multiplicity of available regimens. Although the Ig does not appear to be causative, the presence of scleromyxedema and a monoclonal protein is not an incidental MGUS finding and can be successfully treated by the hematologist because these patients fail to respond to topical therapies. Reports of successful treatment also have included bortezomib and dexamethasone, IV infusions of Ig, thalidomide, and dexamethasone.

There are several rare monoclonal gammopathies that can be overlooked if the diagnosis is not considered by the evaluating hematologist. Small monoclonal proteins may not simply represent MGUS. Consideration of the 6 rare plasma cell dyscrasias described herein is important in the care and management of these patients.

Conflict-of-interest disclosure: M.G. has received honoraria from Millennium and Binding Site; F.K.B. declares no competing financial interests. Off-label drug use: None disclosed.

Morie Gertz, Department of Hematology, Mayo Clinic, 200 SW First St, Rochester, MN 55905; Phone: 507-284-3725; Fax: 507-266-4972; e-mail: gertm@mayo.edu.