Paraproteinemia, Plasmacytoma, Myeloma and HIV Infection a S Fiorino1 and B Atac2,3

Home , Monoclonal gammopathy, Plasmacytoma

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 environmental 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 clinically 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 cell bility. However, these results do establish that the incidence lymphoma, but in combination with the constitutively of mono- and oligoclonal gammopathy in HIV-positive 44 expressed c-myc, it gives rise to plasmacytomas. These data patients is increased over that observed in the general popu- are consistent with a model in which transformation occurs lation. Similarly, the median age of HIV-negative patients with in B lymphocytes that have undergone somatic hypermutation MGUS is 64 years, with only 4% younger than 40 years, and but are still capable of class switching, and certain stimuli, a 10 year period before the development of plasma cell neo- such as T cell regulation and oncogene expression, are critical plasm in the subpopulation that progresses;12 Ishida and Dorf- in promoting differentiation of the transformed B cells into man77 found fewer than 25 well-documented reports in the malignant plasma cells, not lymphoma cells. literature of multiple myeloma occurring before the age of 30 The mechanism by which aberrant growth factor regulation years. Two recent reports from Kyle’s group have described and oncogene activation occur has not been elucidated. A patients with myeloma under the age of 40 (only 2% of mye- theory of antigen-driven expansion and selection has been loma patients)78 and under the age of 30 (only 0.3% of mye- applied to B cell neoplasms and has received some experi- loma patients).79 mental support.45–49 Chronic antigenic stimulation, which In contrast to the general population, the mean patient age might result from self-reactive lymphocytes, provides a selec- in the reported cases of MGUS, plasmacytoma and myeloma tive stimulus for a clonal subgroup of B cells. The expansion in AIDS patients is 33 years (34 years for MGUS, 32 years for of a clonal lymphocyte population increases the likelihood of documented neoplasms). Why the development and/or pro- sustaining mutations leading to neoplastic transformation. This gression of plasma cell neoplasms is accelerated in AIDS model can account for the development of multiple myeloma: patients has not been investigated, although the pathogenic a B lymphocyte population chronically exposed to antigen mechanisms may be similar to those proposed for lymphoma will proliferate and, if the environmental and genetic circum- development in AIDS patients. These mechanisms include stances are correct, one or more members of the proliferating genetic disturbances resulting in oncogene activation, HIV- B cell population might sustain a transforming mutation. In induced immunosuppression allowing expansion of Epstein– Barr virus (EBV)-infected/immortalized B cells, and chronic this way, a single or several clones escape from antigen- and 45 stimulus-dependent proliferation. These B lymphocytes may antigenic stimulation causing B cell proliferation. EBV and still respond to environmental differentiation cues, giving rise Kaposi sarcoma-associated herpes virus sequences and c-myc mutations have been identified in HIV-related lym- to an expanded population of clonal immunoglobulin- phomas,5,80,81 and an increased number of EBV-positive B secreting plasma cells (ie MGUS). Alternatively, the nature of cells are found in AIDS patients, perhaps due to a defect in T the transforming events might affect the differentiation of the cell-mediated suppression of EBV-positive B cells.4,82 The transformed cells.44 In either case, the antigen-independent B broad activation of B lymphocytes in HIV infection is well- cells would have an increased chance of sustaining a second characterized.3–5,7–9 This B cell activation, with the expansion transforming event that would render a clone malignant, of EBV-infected B cell populations, may be the initial steps in resulting in plasmacytoma or multiple myeloma. The identifi- B lineage tumorigenesis and may account for the high fre- cation in some MGUS patients of circulating lymphocytes quency of oligoclonal lymphoma observed in these patients.5 clonally related to the paraprotein-producing plasma Such a broad lymphocyte activation may predispose to the 36,50 cells, and the observation in some MGUS patients of generation of lymphoma even in the absence of EBV infection. ongoing somatic hypermutation in the clonally expanded cell Several additional factors may play a role. Elevated levels 38 population, support this model. of IL-6, important in the etiology of multiple myeloma, are found in the sera of AIDS patients,3,83–85 although this has not Plasma cell disorders and HIV infection AS Fiorino and B Atac 2152 Table 1 MGUS in HIV-positive patients

Ref. Year Age CD4 Ratio Paraprotein Urine Diagnosis ␣-HIV

52 1985 34 214 0.2 IgG ␬␬ MGUS 53 1985 47 321 0.6 IgG, ␬, IgG ␭, IgA ␭␬, ␭ MGUS with shifting components 55 1986 20 IgG ␬ MGUS 55 1986 23 IgG ␬ MGUS 55 1986 26 IgG ␬ MGUS 56 1986 50 inverted IgM ␬, IgG ␬, IgG ␭ MGUS, hyperviscosity 57 1987 41 IgG3 ␭ MGUS none 58 1987 297 0.3 IgG ␬ − MGUS yes 58 1987 312 0.9 IgG ␬ − MGUS 58 1987 514 0.7 IgG ␬ − MGUS 58 1987 371 0.9 IgG ␬ − MGUS 58 1987 331 0.7 IgG ␭ − MGUS 58 1987 443 0.8 IgG ␭ − MGUS 59 1987 42 1610 1.5 IgM ␬ MGUS 59 1987 21 530 1.0 IgG ␬ MGUS 59 1987 33 548 0.7 IgG ␬ MGUS 59 1987 26 520 0.5 IgM ␬ MGUS 59 1987 38 760 1.4 oligoclonal MGUS 59 1987 40 490 0.7 oligoclonal MGUS 61 1988 20 IgG ␬, trace IgG ␭␬ MGUS gag, pol 63 1989 IgG1 ␬ MGUS gag, pol 63 1989 IgG1 ␬ MGUS gag, pol 63 1989 IgG1 ␬ MGUS gag, pol 63 1989 IgG1 ␬ MGUS gag, pol 63 1989 IgA ␭ MGUS none 66 1990 50 0.1 IgG ␬ − MGUS 67 1993 30 IgG ␬ IgG ␬ MGUS vs myeloma gag 68 1993 298 IgG ␬ − transient MGUS 68 1993 311 IgG ␬ − transient MGUS 68 1993 270 IgG ␭ − transient MGUS 68 1993 200 IgG ␬ − MGUS 68 1993 350 IgG ␬, IgG ␭ − MGUS 68 1993 470 IgG ␬ − transient myeloma 68 1993 332 IgG ␬ − MGUS 68 1993 410 IgG ␬ − transient MGUS 68 1993 640 IgG ␭ − MGUS 68 1993 670 IgG ␬ − transient MGUS 68 1993 611 IgG ␬ − transient MGUS

CD4, CD4-positive lymphocyte count (cells/␮l); Ratio, ratio of CD4 to CD8 lymphocytes; Paraprotein, type of serum paraprotein(s); Urine, type of globulin found in urine; Diagnosis, clinical status; ␣-HIV, presence of anti-HIV antibodies and reactivity, if reported; −, reported as negative; blank entries indicate the information was not reported.

Table 2 Plasmacytoma and multiple myeloma in HIV-positive patients

Ref. Year Age CD4 Ratio Paraprotein Urine Diagnosis

51 1983 39 188 1.1 IgG ␬␬ plasmacytoma 54 1986 29 1180 2.4 IgA ␬␬ myeloma 60 1987 44 3 0.1 ␭␭ myeloma 62 1989 31 inverted IgG ␬␬non-secreting IgM ␭ myeloma + MGUS 64 1989 23 − non-secreting plasmacytomas, ␬ then IgG ␭ 65 1990 33 −−non-secreting IgM ␬ plasmacytoma 65 1990 22 − non-secreting Ig-free plasmacytoma 69 1994 43 −by SPEP ␬ plasmacytoma 69 1994 30 −by SPEP non-secreting ␬ plasmacytoma, EBV+ 69 1994 34 −by SPEP ␭ plasmacytoma, EBV+ 70 1994 32 81 0.1 IgG ␬ plasmacytoma 71 1995 38 10 IgG ␬␬ myeloma, EBV+

CD4, CD4-positive lymphocyte count (cell/␮l); Ratio, ratio of CD4 to CD8 lymphocytes; Paraprotein, type of serum paraprotein(s); Urine, type of globulin found in urine; Diagnosis, clinical status; −, reported as negative; blank entries indicate the information was not reported.

been universally observed.86,87 B cells isolated from AIDS increased incidence of gammopathy in HIV infection. Another patients spontaneously secrete IL-6,88 while in vitro, IL-6 is factor in AIDS patients is antigen-driven tumorigenesis. In produced by monocytes exposed to HIV83 and B cells exposed HIV-negative patients, this model postulates chronic antigenic to HIV and IL-4.6 Elevated IL-6 levels would result in stimu- stimulation of self-reactive B lymphocyte populations. In AIDS lation of plasma cells and certainly could contribute to the patients, the antigenic stimulus is postulated to be not an auto- Plasma cell disorders and HIV infection AS Fiorino and B Atac 2153 antigen, but rather the viral proteins of HIV. The induction in nancy, this may be true only for low concentration, transient ` nude mice exposed to a transforming virus of plasmacytoma paraproteins as described by Lefrere.68 The presence of such only in the presence of T cells43 provides a possible expla- immunoglobulins may indeed reflect a temporary expansion nation for the high frequency of lymphoma compared to myel- of a clonal population in response to an antigenic challenge, oma in AIDS patients: the disrupted T cells in AIDS patients be it from HIV or from an opportunistic infection. Alterna- may be unable to provide the appropriate stimuli to drive the tively, small, transient monoclonal gammopathies might sim- differentiation of tumorigenic lymphocytes into plasma cells. ply reflect the fluctuating ability of the HIV-infected immune Thus, multiple mechanisms can account for the early develop- system to control a monoclonal expansion, even a truly pre- ment of MGUS, plasmacytoma, and multiple myeloma in malignant one. Moreover, the follow-up time of these studies HIV-infected individuals: direct activating effects of the virus is much less than the median of 10 years between detection on B cells, altered T cell regulation of B cells, infection with of paraproteinemia and onset of plasma cell neoplasm seen EBV, increased levels of IL-6, and chronic exposure to HIV in the general population. The high concentration, persistent ` antigens all may contribute to the increased incidence of B paraproteins reported by Lefrere68 and others (paraprotein lineage neoplasms, while severely deranged T cell function concentrations of 65,52 64,67 4363 and 3761 g/l have been might explain why the vast majority of these lymphocytic described) are much more likely to represent pre-malignant malignancies are lymphoma and not plasmacytoma or myel- states, similar to MGUS in the general population. Conclusive oma. proof, however, must come from long-term follow-up of If plasma cell malignancy in AIDS patients is indeed driven MGUS-positive AIDS patients who are carefully screened for by HIV antigens, then the antibodies secreted by these clonal signs of B lineage neoplasms, particularly plasma cell malig- or oligoclonal plasma cell populations should be, in most nancies. A limiting factor is that many patients with AIDS suc- ` cases, specific for HIV antigens. Lefrere and colleagues58 cumb to infections or other processes before developing reported that half of one patient’s anti-HIV activity could be plasma cell malignancies. accounted for by the monoclonal paraprotein. Papadopoulos and coworkers74 demonstrated that oligoclonal paraproteins from an HIV-positive patient reacted strongly with HIV antigens, whereas gammaglobulin from an HIV-positive patient Conclusions with polyclonal gammopathy reacted only weakly. Ng and co-workers61,63 purified paraproteins from the sera of HIV- infected patients. In five of seven cases, they found that the In the context of recent advances in understanding the patho- monoclonal paraproteins actually consisted of multiple co- genesis of MGUS and myeloma, we have reviewed the litera- migrating IgG1 ␬ antibodies with specificities for different HIV ture describing plasma cell disorders (paraproteinemia, antigens. In the other two cases, the paraproteins were mono- plasmacytoma and multiple myeloma) in HIV-infected indi- clonal, non-HIV reactive IgG3 ␭ and IgA ␭. Most recently, viduals. MGUS, a precursor lesion for multiple myeloma, may Konrad and co-workers67 described a monoclonal IgG ␬ para- result from a partial transformation that leaves a clonal B cell protein that reacts specifically with the HIV p24 gag protein. population expanded but antigen-responsive; further trans- These results are supportive of a role for chronic antigenic formation results in the malignant growth of a single clone. stimulation by viral proteins in the etiology of MGUS and Myeloma is believed to develop from such transformed B cells plasma cell malignancies in AIDS patients. An alternative that have undergone somatic hypermutation but are capable explanation is that the paraproteinemia seen in AIDS patients of isotype switching. Current models suggest that clonal, trans- is not MGUS at all, but rather part of the normal response to formed lymphocytic precursors to myeloma cells are antigen- HIV infection.63,74 However, even if the B cell lineages gener- independent but, under the influence of T cells, c-myc over- ating mono- and oligoclonal paraproteins in HIV-infected expression, and other factors, are able to differentiate into patients have not undergone partial transformation, the cells plasma cells. In HIV infection, multiple factors contribute to in those lineages are, nevertheless, hyperstimulated and there- the increased incidence of B cell neoplasms, including direct fore at increased risk for transformation. activating effects of the virus, activation and dysregulation of ` Lefrere and co-workers58,68,89 have followed HIV-positive B cells, EBV and Kaposi sarcoma-associated herpes virus patients with mono- and oligoclonal gammopathies for up to infections, increased levels of IL-6, and chronic antigen 69 months. They noted that a number of these patients experi- exposure. Paraproteins in AIDS patients have been identified enced transient gammopathies lasting for 1–2 years, whereas as HIV-specific, supporting the idea that exposure to viral anti- others had persistent gammopathy.68,89 The size of the mono- gens drives B lymphocyte and plasma cell expansions. T cell clonal component correlated with longevity: persistent mono- dysfunction and depletion in AIDS patients may direct the dif- clonal gammopathies averaged 14.3 g/l, and transient mono- ferentiation of transformed lymphocytes to lymphoma rather clonal gammopathies averaged 4.2 g/l.68 None of the patients than plasma cell malignancy, as T cells are crucial for the were reported to develop B lineage malignancies over the fol- induction of plasmacytoma in a mouse model.43 Although low-up periods (averages, 2 years89 and 4 years68); thus, the gammopathy, plasmacytoma and myeloma appear to occur authors conclude that monoclonal gammopathy is not a pre- far earlier in AIDS patients than in the general population, an lymphomatous state. However, they did not provide clinical increased risk of malignancy in AIDS patients with paraprote- or laboratory data to indicate whether any of these patients ins has not been documented. Few patients have been fol- might have developed a plasma cell neoplasm. Ng and col- lowed long term, and screening for plasma cell neoplasms has leagues63 followed several patients for 2–4 years and others not been undertaken. A study prospectively assessing the HIV for shorter periods without progression; one of these patients specificity of paraproteins in AIDS patients, with long-term presented with paraproteinemia and a lymphoma, and clinical follow-up and plasma cell malignancy screening, another lost his paraprotein after developing primary biliary would address many of these issues, including the question lymphoma.57,63 Although these cases suggest that paraprotei- of disrupted T cell function as a permissive condition for the nemia in AIDS patients is not a precursor lesion for malig- development of lymphoma, but not myeloma. Plasma cell disorders and HIV infection AS Fiorino and B Atac 2154 Acknowledgements the disease escape from plateau phase? 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