Leukemia (1997) 11, 2150–2156 1997 Stockton Press All rights reserved 0887-6924/97 $12.00 Paraproteinemia, plasmacytoma, myeloma and HIV infection A S Fiorino1 and B Atac2,3 1Medical Scientist Training Program and 2Department of Medicine, Albert Einstein College of Medicine; and 3Department of Medicine, Jacobi Medical Center, Bronx, NY, USA We have identified by MEDLINE search the cases of gammaglo- Monoclonal gammopathy and the progression to myeloma binopathy and plasma cell malignancy in HIV-positive patients reported in the English language literature. The average age The natural history of MGUS in the general population has at presentation among HIV-positive patients with plasma cell 12 disorders is 33 years, far younger than the average age of pres- been extensively studied by Kyle. MGUS is found in entation in the general population. Some of these patients approximately 1% of those older than 50 years and 3% of present with transient paraproteinemias, while others have per- those over 70 years. Kyle has followed a group of 241 patients sistent paraproteins, which may or may not be associated with with MGUS for 20 to 35 years,12–15 and categorized their clini- true plasma cell malignancies. In most cases in which it has cal course: 19% had no significant change, 10% had an been examined, the paraprotein contains high-titer anti-HIV activity. The presence of high-titer anti-HIV activity in the para- increase in monoclonal gammopathy to over 3.0 g/dl without proteins of AIDS patients suggests that an antigen-driven pro- an associated disorder, 47% died of unrelated disease and cess in response to HIV infection may contribute to the early 24% went on to develop a plasma cell disorder. Of these development of plasma cell disorders in these patients. Recent patients, 66% developed multiple myeloma, 12% macroglobi- work in plasma cell tumorigenesis has indicated that trans- nemia, 14% amyloidosis and 8% other lymphoproliferative formation at a single point in the B lymphocyte lineage can give disease after a median follow-up of 10 years from the recog- rise to either lymphoma or myeloma, dependent upon environ- mental factors such as T cell function, which may be required nition of the gammopathy. These data might indicate that for directing transformed lymphocytes from lymphoma and there are two sets of patients with MGUS – those in whom it towards plasma cell differentiation. This may explain why B lin- represents a benign condition, and those in whom it rep- eage oncogenesis in AIDS patients favors the development of resents a precursor lesion to a plasma cell neoplasm. How- lymphoma over that of myeloma. ever, no clinical or laboratory markers have been shown to Keywords: HIV; paraproteins; plasmacytoma; multiple myeloma distinguish between these two proposed groups of patients. Alternatively, and more likely, MGUS may represent a stage in the development of a plasma cell neoplasm, with only a Introduction fraction of MGUS patients living long enough to develop clini- cally apparent malignancy. In this model, a monoclonal gam- An increased globulin fraction is a common incidental labora- mopathy, reflecting a clonal expansion of plasma cells, is the tory finding in patients infected with HIV; in these cases, plasma cell equivalent to the solid tumor carcinoma in situ, serum protein electrophoresis usually reveals a polyclonal representing a pre-malignant lesion at risk for further trans- gammaglobinopathy.1–4 Although HIV-infected individuals formation and evolution into a full blown malignancy. Such have deficiencies in CD4-positive T helper cells, and thus models of epithelial tumor progression are well established.16–18 might be expected to have problems with B cell activation Thus, multiple factors including genetic susceptibility and and immunoglobulin secretion, experimental studies of B lym- environmental exposure, determine if an individual will phocytes in HIV infection have revealed polyclonal B cell develop monoclonal gammopathy, and then if that premalig- activation.3,5 B cells exposed to HIV in vitro may proliferate6 nant lesion will develop into a plasma cell neoplasm. or become activated and begin secreting immunoglobulin.4,7,8 Some of the factors responsible for the progression to mye- HIV-infected T cells can induce contact-dependent but anti- loma have recently been identified, and include growth factor gen-independent polyclonal activation of B cells.9 Bone mar- stimulation, oncogene activation, tumor suppressor gene inac- row biopsy of HIV-infected patients commonly reveals a plas- tivation, altered expression of cell adhesion molecules, and macytosis, even in the absence of any plasma cell disorder.1,10 disrupted immunoregulation; paracrine and perhaps autocrine A distinct but related phenomenon less frequently observed stimulation by interleukin-6 (IL-6) and activation of the c-myc in AIDS patients is mono- or oligoclonal gammaglobinopathy. oncogene have been strongly implicated.19–24 Comparison of Briault and co-workers11 observed mono- or oligoclonal anti- myelomatous and normal plasma cells has revealed activation bodies in the sera of 26% of 62 HIV-positive patients at vari- of various oncogenes,19,24 disruption of tumor suppressor ous stages of infection. As in non-HIV-infected individuals, a genes,19,24 mutations in the IL-6 transducer protein gp130,22 monoclonal gammopathy may be associated with no other and altered expression of cell differentiation (CD) anti- disorders and thus be characterized as a monoclonal gammo- gens.25,26 Further progression of multiple myeloma, charac- pathy of undetermined significance (MGUS), or may be asso- terized clinically by escape from the plateau phase, may be ciated with plasma cell disorders including multiple myeloma, ¨ mediated by these factors as well as additional mechanisms plasmacytoma, Waldenstrom’s macroglobinemia or primary such as enhanced nucleoside transport and multidrug resist- amyloidosis. ance.21 Recent investigations have begun to elucidate from where in the B cell lineage the malignant myeloma clones originate.27 On the basis of immunoglobulin and other gene sequences, B lymphocytes clonally related to malignant plasma cells have been identified in the bone marrow28–31 and Correspondence: A Fiorino, at his current address: Department of Der- 28,30,32–37 matology, University of Pennsylvania Medical Center, 2 Rhoads Pav- peripheral blood of myeloma patients. Myeloma ilion, Philadelphia, PA 19104, USA; Fax: 215 349 8339 cells, as well as these clonally related lymphocytes, express Received 11 March 1997; accepted 2 September 1997 immunoglobulin genes that have undergone somatic hyper- Plasma cell disorders and HIV infection AS Fiorino and B Atac 2151 mutation, reflecting antigen exposure.27,30,31,36,38,39 Ongoing Gammopathy and plasma cell tumors in AIDS hypermutation does not occur during tumor progression.39 Thus, transformation occurs after somatic hypermutation, and A number of cases of mono- and oligoclonal gammopathy, the lack of subsequent mutation indicates that the malignant, plasmacytoma, and multiple myeloma occurring in HIV- clonal lymphocyte–plasma cell population has escaped the infected patients have been reported in the English literature; antigen selection process. Lymphocyte populations clonally these are summarized in Tables 1 and 2.51–74 The diagnosis of related to myeloma cells undergo class switching,30,31,36,41 multiple myeloma can be difficult to make in an AIDS patient indicating that transformation occurs prior to class switching because these patients often have renal failure, anemia, 1 and leaves intact either the switching mechanisms or a prepro- thrombocytopenia and bone marrow plasmacytosis simply as grammed switch. The transformed population in myeloma a consequence of HIV infection, opportunistic pathogens, thus appears to be restricted to the myelomatous plasma cells and/or medications. Thus we have considered the presence of and clonally related, hypermutated, pre-switched B lympho- lytic bone lesions, hypercalcemia, or documented mono- cyte populations found in the bone marrow or periphery. clonal plasma cell expansion necessary to classify a case as These lymphocytes may comprise a non-malignant population multiple myeloma. related to the myeloma clone, or may be the true malignant HIV-positive patients with plasma cell disorders are dis- tinguishable from non-infected patients both by the number cell population, driven by genetic and environmental cues to of patients and by the age at presentation. While the overall differentiate into plasma cells.35 CD34-positive stem cells do incidence of monoclonal gammopathy in the general popu- not appear to contain cells related to the malignant clone.29,42 lation is 0.15%,75 the incidence of monoclonal or mono- and The differentiation stimuli needed to drive a transformed B oligoclonal gammopathy in AIDS patients has been reported cell to a plasma cell phenotype have also been studied. In as 2.5% (monoclonal only),58 3.2%,68 9%,59 12%,55 26%,11 nude mice, a retrovirus containing c-myc and c-raf gives rise 28%,1 29%73 and 56%.72 Using isoelectric focusing, Sinclair to non-immunoglobulin secreting B cell lymphomas, whereas and co-workers76 reported an incidence of 61% for oligo- the same retrovirus gives rise to plasmacytomas in both nor- clonal gammopathy. These studies have been of relatively 43 mal mice and nude mice that have had T cell reconstitution. small patient populations, perhaps accounting for the varia- The Abelson murine leukemia virus alone induces a pre-B