NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.

  • By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.
Cover of Holland-Frei Cancer Medicine

Holland-Frei Cancer Medicine. 6th edition.

Show details

Other Plasma Cell Dyscrasias

, MD, MB, BS, , MD, PhD, and , MD.


Clinical Characteristics

Plasmacytomas are collections of monoclonal plasma cells originating either in bone (solitary osseous plasmacytoma, SOP) or in soft tissue (extramedullary plasmacytoma, EMP). They comprise < 10% of plasma cell dyscrasias. MM must be excluded before the diagnosis of either SOP or EMP can be made. Magnetic resonance imaging can be useful to show additional marrow abnormalities consistent with MM.402 The median age of diagnosis of either SOP or EMP is approximately 50 years, nearly 10 years younger than that for MM.403–405Although patients with SOP and EMP can both progress to MM, persons with SOP progress in the majority of cases, in contrast to EMP, where only up to 50% eventually develop MM. The median survival of 86.4 months and 100.8 months for patients with SOP and EMP, respectively, is similar; however, progression-free survival is markedly different, 16% for SOP patients versus 71% for EMP patients. The persistence of stable monoclonal Ig in serum and/or urine after primary treatment for plasmacytoma does not necessitate additional therapy, since it does not influence survival or disease-free survival.403 In contrast, rising monoclonal Ig levels in a patient with a history of either SOP or EMP should trigger a work-up for either recurrent plasmacytoma or MM. It has been suggested, as is true for MM, that serum β2M has prognostic value in patients with SOP. Specifically, 17 of 19 patients with elevated serum β2M had transformation to MM and shorter survival (31 months) than those with normal serum β2M levels.406


Treatment for SOP and EMP is local therapy, primarily radiotherapy with surgery as needed for structural anatomic support.403–405 The benefit of chemotherapy, either alone or in combination with radiotherapy and surgery, as primary therapy for SOP or EMP has not been proven. Moreover, the benefit of adjuvant chemotherapy, given to prevent recurrent disease and/or progression to MM, is also undefined. Disappearance of protein after involved-field radiotherapy predicts for long-term disease-free survival and possible cure.407

Immunoglobulin-M (IgM) Monoclonal Gammopathy

Excess monoclonal IgM in the serum can occur in a variety of diseases. In a Mayo Clinic series of 430 patients in whom a monoclonal IgM protein was identified, 242 (56%) had MGUS, 71 (17%) had Waldenstrom macroglobulinemia, 28 (7%) had lymphoma, 21 (5%) had chronic lymphocytic leukemia, 6 (1%) had primary amyloidosis, and 62 (14%) had other malignant lymphoproliferative diseases.408 The duration of time from the recognition of the M protein to the development of a malignant lymphoid disease ranged from 4 to 9 years, suggesting that long-term follow-up of such patients is necessary.

Waldenstrom Macroglobulinemia

The diagnosis of Waldenstrom macroglobulinemia (WM) requires an IgM serum level of at least 3.0 gm/dL in association with an increase in lymphocytes or plasmacytoid lymphocytes in the marrow.408–410 WM corresponds most closely to the lymphoplasmacytic lymphoma (LPA) under the World Health Organization (WHO) classification of lymphoid tumors (LPL/immunocytoma of the Revised European-American [REAL] classification of lymphoma). WM accounts for approximately 2% of all hematologic malignancies and is more common in men than in women. Its incidence increases with age, and it is more common among whites than among African Americans.411, 412 Although the etiology of WM is unclear, genetic factors may contribute to the pathogenesis of this disease, since there are reports of families with WM in association with other lymphoproliferative and immunologic disorders.413 Cytogenetic abnormalities occur in 15% to 90% of cases, but none are specific for WM.414, 415 The WM B-cell clone demonstrates interclonal differentiation from small lymphocytes with large focal deposits of surface immunoglobulins, to lymphoplasmacytic cells and mature plasma cells that contain intracytoplasmic immunoglobulin. This morphologic heterogeneity is reflected by variable expression of phenotypic markers. All WM cells express monoclonal IgM and most cells are CD19, CD20, CD22, and FMC7 positive. High density of CD38 is also detected with variable intensity of the PCA-1 antigen. Predictably, CD45 isoform expression is heterogenous, probably reflecting ongoing monoclonal B-cell differentiation. In approximately 20% of cases, CD5 and CD23 expression are seen, but their coexpression is uncommon.416 Circulating clonal B-cells in WM increase in patients who fail to respond to therapy or who progress.417 Recent studies suggest that WM originates from a post-germinal center B cell that has undergone somatic mutations and antigenic selection in the lymphoid follicle and has the characteristics of an IgM-bearing memory B cell.418–420

The median age of onset of WM is 61 years. Symptoms are characteristically vague and nonspecific, with the most common being weakness, anorexia, and weight loss. Symptoms due to peripheral neuropathy and Raynaud phenomenon can precede more serious manifestations. Lymphadenopathy, splenomegaly, and/or hepatomegaly are present in 30% to 40% of cases, and at least 20% to 25% lymphoplasmacytoid cells are usually present in the marrow. Visceral involvement of small bowel and peripheral nerves can cause the clinical sequelae of malabsorption and neuropathy, respectively. Hemorrhagic complications are common, attributable to abnormal bleeding times, decreased platelet adhesiveness, or direct interference by the IgM protein with the release of platelet factor 3 and with coagulation factors. An important part of the differential diagnosis is to exclude the less common entity of IgM MM, which is characterized by lytic bone disease and an absence of organomegaly and/or lymphocytic involvement; rarely, WM can itself progress to IgM MM.421 Amyloidosis occurs rarely in Waldenstrom macroglobulinemia.422 Hyperviscosity syndrome, described earlier as a rare complication in MM, occurs more commonly in the setting of excess IgM and is characterized by mucosal bleeding and neurologic, ocular, and cardiovascular abnormalities.237 Therapy with plasmapheresis is more useful to remove excess IgM than it is in the setting of excess IgG monoclonal proteins and related hyperviscosity in MM.

Plasmapheresis can be considered as only an adjunctive therapy. Treatment regimens utilized are similar to those used to treat low-grade lymphomas and MM, including chlorambucil, cyclophosphamide, melphalan, and corticosteroids, either as single agents or in combinations.409 Just as for MM, there is no evidence that combined drug regimens are superior to single therapies. The median survival is approximately 50 months, not that dissimilar from the best reported series of patients with MM. In contrast to persons with MM, however, many individuals with WM have indolent disease requiring no therapy for long periods of time, with survivals in excess of 20 years. Pretreatment parameters, including older age, male gender, general symptoms, and cytopenias, define a high-risk population that could perhaps benefit from newer therapeutic approaches.423, 424 Acute leukemia has developed in patients with WM, emphasizing a potential complication of premature and prolonged low-dose therapy with alkylating agents.425 Nucleoside analogs, including fludarabine and 2-chlorodeoxyadenosine, have been shown to be effective in newly diagnosed as well as in refractory patients with WM and may achieve more rapid cytoreduction than oral chlorambucil.409, 426–428 Prospective randomized trials are needed to assess the effect of nucleoside analogs on survival.429 In a recent multicenter trial, 92 patients with WM resistant to first-line treatment were treated with fludarabine or combination chemotherapy including cyclophosphamide, doxorubicin, and prednisone.430 Although response rates and EFS were significantly higher in patients treated with fludarabine, no survival difference was noted.

Several reports describe responses in patients with WM using recombinant interferon-α or -γ. 431, 432 Interestingly, patients who had been treated with prior chemotherapy had an equivalent response rate to those who had not. Future studies are needed to assess its affect as a remission therapy or as part of other strategies.433 Although high-dose therapy with autologous stem cell support has been shown to be effective in many patients with MM or with low grade lymphoma, relatively few patients with WM have undergone transplant. Nonetheless, preliminary data suggest that high-dose therapy is associated with a high complete response rate and acceptable toxicity, and this approach therefore warrants further investigation, particularly in younger patients with poor prognostic features.434 Splenectomy has been reported to be effective in chemotherapy-resistant patients with WM and results in a major decrease in monoclonal protein concentration and durable remission.435, 436 Monoclonal antibody therapy with rituximab, a chimeric anti-CD20 monoclonal antibody, produces responses in both treated and untreated patients with low-grade lymphoma. Given that the CD20 antigen is typically present in WM, rituximab has been given to patients and a clinical response was seen in about one-third of previously treated patients in early studies.437, 438 Ongoing studies are looking at combining rituximab with fludarabine in the treatment of WM.

Heavy-Chain Diseases

Since the original description by Franklin and coworkers of a patient with malignant lymphoma whose serum and urine contained large amounts of the Fc fragment of IgG, the clinical and immunochemical scope of gamma-heavy-chain disease (γHCD) has broadened.439 These diseases are characterized by the presence of a portion of the Ig heavy chain in the serum or urine or both. The median age at diagnosis is similar to that for MM, approximately 60 years.440 The clinical and laboratory features can be heterogeneous. Most common presenting symptoms are weakness, fatigue, and fever, associated with lymphadenopathy and hepatosplenomegaly. In addition to Ig heavy chain in serum or urine, a lymphoplasmacytic marrow infiltrate is noted in most cases. The clinical course can be fulminant and rapidly progressive; alternatively, the monoclonal heavy chain can persist for years in otherwise asymptomatic patients. Thus, survival is variable, but the median is only 12 months. Treatment options for patients with active disease are similar to those used for lymphoma or MM, whereas patients with indolent disease should be followed expectantly without therapy. Cases of αHCD, μHCD, and δHCD have also been described. HCD is typically associated with non-Hodgkin lymphoma in the gastrointestinal tract, beginning with plasma cells that produce a heavy chain and aggregate in the intestinal tract and subsequent transformation into a malignant non-Hodgkin lymphoma of the immunoblastic type, probably arising from the more mature plasma cells.441 The ideal therapy for heavy-chain disease is not known because of its rarity, but intensive chemotherapy including intravenous cyclophosphamide, doxorubicin, vincristine, and oral prednisone appears to offer some patients long-term remissions.


Amyloidosis is relatively rare as a clinically significant disease. It has been classified into five categories. These include (1) primary, with or without plasma cell and lymphoid neoplasms; (2) secondary, associated with chronic infections or autoimmune disease; (3) hereditary, associated with familial Mediterranean fever, Portuguese lower limb neuropathy, and others; (4) amyloidosis associated with aging; and (5) amyloidosis of endocrine glands, with medullary thyroid carcinoma and multiple endocrine neoplasia, type 2.422, 442 The amyloid found in most cases of amyloidosis can be assigned to one of two types, according to whether the fibrils consist mainly of the variable region of Ig light chains (AL, or primary amyloidosis) or protein A (AA, or secondary amyloidosis). Protein A has a molecular weight of 8,500 daltons and consists of 76 amino acids; it is not related to any known immunoglobulin. In AL, amyloid primarily involves the heart, tongue, gastrointestinal tract, and skin, whereas AA primarily results in fibril deposition in liver, kidney, and spleen. A review of 229 patients with AL documented MM in 47 (21%) patients.442 Initial presenting symptoms were fatigue and weight loss, with pain more common in those who also had MM. Hepatomegaly and macroglossia were present in up to one-third of patients with AL; renal insufficiency was present in one-half of patients, and proteinuria (defined as albuminuria with immune globulin seen, only in MM) was documented in 82% of patients. Nephrotic syndrome, congestive heart failure, orthostatic hypotension, carpal tunnel syndrome, and peripheral neuropathy were all more common in those without MM (30 to 70% of patients studied) than in persons with (< 20%) MM. Overall median survival was 12 months, 5 months for those with MM in contrast to 13 months for individuals without MM. Although it has been difficult to monitor the distribution and progression of disease, it has been shown that radiolabeled serum amyloid P component, which has specific binding affinity for amyloid fibrils, can be given intravenously and localizes rapidly and specifically in amyloid deposits.443 This technique may therefore facilitate diagnosis and monitoring of the extent of systemic amyloidosis, including the effects of therapeutic interventions.

Treatment for AL is unsatisfactory. Only 27 of 153 (18%) patients responded to MP, although median survival for responders was prolonged at 89.4 months; only 5% of patients with primary AL survive ≥ 10 years.422, 444 A prospective randomized trial has concluded that MP was superior to colchicine when analyzed from time of entry into the study to time of death or progression of disease.445 Other retrospective studies suggest that colchicine is superior to placebo for patients with AL.446 Alkylating agent-based chemotherapy may therefore be beneficial for a subset of patients and result in prolonged survival. One randomized trial of colchicine, MP, or a combination of the three drugs in patients with primary amyloidosis found that therapy with MP results in objective responses and prolonged survival as compared to colchicine.447 However, therapy with multiple alkylating agents did not achieve either higher response rate or longer survival time than MP.448 Early reports suggest that dose-intensive melphalan with blood stem cell support can achieve CRs, with improvement in performance status and clinical remission of organ-specific disease.449 Guidelines have been developed for patient selection to maximize benefit and minimize treatment-related mortality.450, 451 As in MM, a randomized trial is required to assess the true efficacy of high-dose therapy, since those patients eligible for high-dose treatments may also do well with chemotherapy.452 Attempts to improve outcomes for patients with symptomatic and advanced multisystem disease may require both solid and stem cell transplantation, as well as the use of less intensive conditioning regimens. 453 Novel drugs with promise in the treatment of MM, including Thal, IMiDs, and PS-341, are also being tested in patients with amyloidosis.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2003, BC Decker Inc.
Bookshelf ID: NBK12766


  • Cite this Page

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...