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HIV-Associated Monoclonal Gammopathy: A Retrospective Analysis of 25 Patients

  1. Sashi Amara1,
  2. Bruce J. Dezube3,
  3. Timothy P. Cooley4,5,
  4. Liron Pantanowitz6, and
  5. David M. Aboulafia1,2
  1. 1Virginia Mason Medical Center and University of Washington School of Medicine, Seattle, Washington
  2. 2University of Washington School of Medicine, Seattle, Washington
  3. 3Beth Israel Deaconess Medical Center and Baystate Medical Center, Tufts School of Medicine, Springfield, Massachusetts
  4. 4Boston University School of Medicine, Boston, Baystate Medical Center, Tufts School of Medicine, Springfield, Massachusetts
  5. 5Lahey Clinic, Burlington, and Baystate Medical Center, Tufts School of Medicine, Springfield, Massachusetts
  6. 6Baystate Medical Center, Tufts School of Medicine, Springfield, Massachusetts
  1. Reprints or correspondence: Dr. David M. Aboulafia, Section of Hematology/Oncology, Virginia Mason Medical Center, 1100 Ninth Ave., P.O. Box 900 (H14-HEM), Seattle, WA 98111(hemdma{at}vmmc.org).
 
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Abstract

Background. Monoclonal gammopathy of undetermined significance (MGUS) is unusual in the general population aged <60 years. Various reports indicate a much higher incidence of monoclonal gammopathy among human immunodeficiency virus (HIV)–infected patients and a significantly younger age at diagnosis. We sought to describe the laboratory findings and clinical course of MGUS, including association with plasma cell disorders, other malignancies, and infections, in 25 HIV-infected patients with a detectable serum monoclonal protein.

Methods. We reviewed the patients' demographic characteristics, stage of HIV infection, and clinical course. Laboratory studies included determination of CD4+ T lymphocyte cell counts, HIV type 1 loads, and quantitative immunoglobulin levels; serum and urine protein immunoelectrophoresis; and determination of serum viscosity indices. Skeletal surveys and bone marrow biopsies were performed in selected cases.

Results. Twenty-four of 25 patients were male, and the median age of patients was 50 years (range, 21–69 years). The median CD4+ T lymphocyte count was 350 cells/µL (range, 40–1029 cells/µL; mean, 355 cells/µL), and the median HIV load was <75 copies/mL (range, <50 to 100,000 copies/mL; mean, 20,800 copies/mL). Thirteen of 25 patients had HIV viremia, despite receiving highly active antiretroviral therapy (HAART). After a mean follow-up duration of 21 months, 7 patients (28%) received a diagnosis of a malignancy (multiple myeloma, in 1 patient; non-Hodgkin lymphoma, in 1; Hodgkin lymphoma, in 1; Kaposi sarcoma, in 2; and plasmacytoma, in 2). Ten patients were coinfected with hepatitis B virus and/or hepatitis C virus; 6 were anemic. No patients developed renal failure or hypercalcemia. Nine (56%) of 19 evaluable patients had a decrease of serum monoclonal protein (mean, 0.5 g/dL) while receiving HAART.

Conclusions. Patients in our study were characterized by the detection of a monoclonal protein at a younger age and the increased presence of other viral infections (infection with hepatitis B or C virus or Kaposi sarcoma herpesvirus) than is typically seen in an HIV-uninfected cohort. CD4+ T lymphocyte counts were relatively robust. HAART appeared to have a favorable impact on the serum monoclonal protein level in 9 patients. Long-term follow-up is needed to better define the natural history of MGUS and the link to other possible contributing factors.

Monoclonal gammopathy of uncertain significance (MGUS) is defined by the presence of serum monoclonal protein (M-protein; whether IgA, IgG, or IgM) at a concentration typically <3 g/dL, a concentration of plasma cells in the bone marrow <10%, and absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to a plasma cell proliferative process [1]. The incidence of MGUS in the general population is low (2%–3%) among persons aged 50–70 years [2, 3]. Often an asymptomatic process, MGUS may herald more-serious diseases, such as multiple myeloma, plasmacytoma, non-Hodgkin lymphoma (NHL), Waldenström macroglobulinemia, chronic lymphocytic leukemia, or amyloidosis, at the rate of 1% per year [2].

HIV-seropositive patients may have a higher incidence of MGUS than their HIV-seronegative counterparts. In various retrospective analyses, the incidence of MGUS ranged from 3% to 26% [4–6]. Much less common is the association between HIV infection and monoclonal gammopathy and the presence of an asymptomatic lymphoproliferative or plasma cell disorder [7, 8].

The etiology of HIV-associated MGUS is uncertain. A leading hypothesis holds that chronic antigenic stimulation leads to B cell hyperplasia [6, 7, 9–11]. B cell dysregulation in the context of impaired T cell responses, as well as an altered cytokine milieu, could also contribute to the clonal phenotype [12]. The role of viruses, such as Epstein-Barr virus (EBV), Kaposi sarcoma herpesvirus, and hepatitis B and C viruses (HBV and HCV, respectively), in this process is an area of active clinical investigation [13–15].

Herein, we describe the clinical and immunologic profile of our HIV-infected patients in whom serum or urine M-protein was identified. We also assess what percentage of patients developed symptomatic disease and what effect effective HAART might have on M-protein quantitation.

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Materials and Methods

We abstracted the medical records of 19 patients in whom M-protein was detected. They were identified from a database of >500 HIV-infected patients who were cared for at Virginia Mason Medical Center (Seattle, WA) during the period 1996–2005. An additional 6 cases of HIV-associated MGUS or symptomatic plasma cell disorder were identified and included in this analysis (4 from Beth Israel Deaconess Medical Center [Boston, MA] and 2 from Boston Medical Center).

We obtained medical record documentation of HIV serostatus, monoclonal gammopathy, hematologic malignancies, and AIDS-defining opportunistic infections. Demographic data included age, sex, race, and risk factors for HIV acquisition. Laboratory assessments routinely included complete blood cell counts, serum chemistries, and determination of hepatic transaminase levels, CD4+ T-lymphocyte cell counts, and HIV loads. Additional laboratory studies included urine and serum protein immunoelectrophoreses, determination of quantitative immunoglobulins, β2-microglobulin, serum viscosity index, and HBV and HCV serologic tests. We used Sebia split β gel electrophoresis hydrasis and phoresis systems for serum protein electrophoresis. If a monoclonal band or Bence Jones protein was identified, then further identification by immunofixation was performed. Selected patients were first evaluated by skeletal metastatic bone surveys and by posterior iliac crest bone marrow biopsy and aspirate. We followed guidelines for human experimentation of the US Department of Health and Human Services, Virginia Mason Medical Center, Beth Israel Deaconess Medical Center, and Boston Medical Center.

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Results

Demographic characteristics. Twenty-four patients were male, and 1 was female; the mean age was 44 years (range, 21–69 years). Thirteen patients (52%) were white, 8 (32%) were African or African American, 3 (12%) were Hispanic, and 1 (4%) was a Pacific Islander. Of the 25 patients, 19 identified unprotected sex with other men as their principal risk factor for HIV acquisition. Six also noted a history of injection drug use. The demographic characteristics of this patient population mirrored those of the general HIV-infected population seen in the medical centers (data not shown).

Initial clinical and hematologic findings. Clinical presentations leading to the finding of an M-protein included systemic symptoms of fatigue (21% of patients), weight loss (20%), and lymphadenopathy (20%) (table 1). Hematopoietic malignancy led to an assessment of M-protein in 5 patients. Laboratory findings leading to a serum protein electrophoresis assessment included elevated serum protein level (15% of patients), a hemoglobin level <12 g/dL (27%), and a platelet count <100,000 platelets/mm3 (27%). Anemia was characterized most often as hypoproliferative, with iron indices indicative of inflammatory block (in patients 1, 9, 10, 15, and 23). Patient 9 was pancytopenic, with HCV-induced cirrhotic liver disease and probable hypersplenism.

Table 1
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Table 1

Demographic characteristics, clinical presentation, and initial laboratory data for HIV-infected patients with monoclonal gammopathy of undetermined significance (MGUS).

Protein electrophoresis. Serum and urine protein immunoelectrophoreses results were determined using standard laboratory methods (using the HYDRASYS electrophoresis agar gel system; Sebia). Serum M-protein levels ranged from 0.2 to 6.0 g/dL, with a median monoclonal concentration of 0.3 g/dL and a mean concentration of 1.5 g/dL (table 1). For patients with malignancy, the mean M-protein level was 2.1 g/dL, compared with 1.1 g/dL for patients without malignancy. All patients experienced an IgG M-protein spike, except for patient 13, who had a spike in the IgA M-protein concentration.

Patient 3 presented with fatigue and weight loss; bone marrow biopsy revealed multiple myeloma. Patient 1 presented with progressive adenopathy and a serum IgG κ light chain of 1.7 g/dL; a cervical node biopsy indicated marginal zone NHL. Patients 2 and 4, who had biopsy-proven Kaposi sarcoma, had spikes in the serum M-protein level of 3.5 and 3.9 g/dL, respectively. Patient 5, whose M-protein level spiked to 2.2 g/dL, presented with generalized lymphadenopathy; an inguinal lymph node biopsy revealed evidence of soft-tissue plasmacytoma composed of IgG light chain–staining plasma cells. In contrast, patients who were not identified with malignancies had relatively low serum M-protein values (median level, 0.6 g/dL; range, 0.1–1.5 g/dL). Malignancy rates were much higher in this population (28%) than in the general HIV-infected population [24]. Patient 14 developed a second spike in the M-protein level of 0.6 g/dL. Patients 19, 20, and 22 had high spikes in the serum M-protein level (3.5, 6, and 5 g/dL, respectively), with hypergammaglobulinemia and elevated serum protein levels but no hematological malignancies (table 1).

Urine protein immunoelectrophoreses results were available for 20 (80%) of 25 patients. Only 3 patients (patient 1, who had marginal zone NHL; patient 3, who had multiple myeloma; and patient 22, who had a spike in the M-protein level of 5 g/dL) secreted small quantities of Bence Jones protein in the urine.

Serum immunoglobulin measurements. Serum immunoglobulin measurements were available for 23 of the 25 patients. Seven (28%) of the 23 assessable patients had normal immunoglobulin levels, 14 had IgG hypergammaglobulinemia, and 2 had hypogammaglobulinemia (table 1). Patient 3, who had multiple myeloma, had reciprocal IgA and IgM hypogammaglobulinemia in conjunction with a IgG M-protein level of 4.7 g/dL.

β2-microglobulin and serum viscosity index. The serum β2-microglobulin level was measured using a quantitative nephelometer. Of 14 patients with a β2-microglobulin level, 9 had values >2.0 mg/L (range, 2.2–6.8 mg/L), which is the normal cutoff value (table 1). Patient 1, who had marginal zone NHL, had the highest β2-microglobulin level (6.8 mg/L), and the level in patient 20, who had plasmacytoma, was 3.4 mg/L. Patient 14 had an increased β2-microglobulin level that ranged from 2.5 to 5.0 mg/L. Patient 7, who had Hodgkin lymphoma, had a β2-microglobulin level of 2.5 mg/L, which normalized after administration of chemotherapy.

Serum viscosity index data were available for 11 of 25 patients. For 8 patients, the serum viscosity index was within normal limits; for patients 3 and 4, the serum viscosity index was elevated, at 2.5 millipascal second (m PAS) units (normal level, <2 m PAS units). Only patient 4 required plasmapheresis to ameliorate hyperviscosity symptoms (lethargy, confusion, and diffuse ischemic colonic bleeding).

HIV status and the effect of HAART on HIV load. The median CD4+ T lymphocyte count of the 25 patients was 350 cells/µL (range, 40–1029 cells/µL); the mean CD8+ cell count was 677 cells/µL (table 1). The CD4+ T lymphocyte count was <200 cells/µL in 9 patients, 200–350 cells/µL in 7 patients, and >350 cells/µL in 9 patients. The mean CD4+ T lymphocyte count in patients with malignancy (330 cells/µL) was similar to that in patients without malignancy (355 cells/µL). At the time of M-protein assessment, 16 (68%) of 25 patients had detectable HIV loads, but only 2 (8%) of 25 had HIV loads >60,000 copies/mL (table 1). Patients were assigned Centers for Disease Control and Prevention HIV statuses: A1, 2 patients; A2, 5 patients; A3, 3 patients; B1, 3 patients; B2, 3 patients; B3, 3 patients; C2, 2 patients; and C3, 4 patients. There was no correlation between patients' Centers for Disease Control and Prevention HIV stage and the M-protein amplitude.

The effect of HAART on HIV load and M-protein level is reviewed in table 2. Nine (56%; patients 1, 2, 3, 8, 11, 12, 15, 17, and 25) of 16 evaluable patients experienced a decrease in serum M-protein level (mean, 0.5 g/dL; range, 0.1–2.3 g/dL) after receiving HAART. For 6 of these patients (patients 1, 2, 8, 11, 17, and 25), the decrease in the M-protein level was associated with a significant decrease in the IgG level. Notably, patient 19, who had a high M-protein spike (3.5 g/dL) and an IgG level of 5403 g/dL, had a nondetectable HIV load, even though the patient was not taking HAART. Patient 25 had a complete resolution of M-protein spikes and a concomitant resolution of HBV viremia. Four patients (patients 7, 21, 23, and 24) had MGUS newly diagnosed, and the duration of follow-up was limited to <6 months.

Table 2
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Table 2

Antiretroviral therapy received and selected outcomes.

Coinfection. Seven (28%) of the 25 patients were coinfected with HCV (patients 6, 9, 11, 12, 14, 15, and 23), 2 (patients 4 and 19) had chronic active HBV infection, and 1 (patient 25) had chronic active HBV infection and cleared the virus. HCV genotypes included 1A (in patients 6, 14, and 15), 3A (in patients 9 and 23), and 2B (in patients 11 and 12). Two of the HCV-infected patients received IFN-α and ribavirin-based antiviral therapy. Although patient 9 had a nondetectable HIV load and resolution of HCV viremia, the M-protein level remained unchanged, at 0.6 g/dL, over a 28-month follow-up period. The other 3 patients were not candidates for HCV therapy because of issues of compliance with treatment, psychiatric concerns, or the presence of another comorbid illness. The HCV infection rate for these patients (28%) was greater than the rate in our general HIV-infected population (10%).

Renal status. In all instances, patients had normal serum creatinine levels (0.1–1.3 g/dL). No patient had persistent hematuria.

Bone marrow and skeletal survey findings. Bone marrow aspirate and biopsy specimens were obtained from 10 patients. Indications for bone marrow assessments included urine light chains, lytic or sclerotic bone lesions on skeletal survey, anemia, and to complete NHL and myeloma staging evaluation (for patients 1 and 3, respectively). Patient 1, who had marginal zone NHL, had lymphomatous marrow involvement. The patient with multiple myeloma (patient 3) had a hypercellular marrow, with >60% malignant plasma cells. Patient 20 had a normocellular marrow but a λ-staining plasma cell concentration of >20%. The remaining 6 patients (including patients 5 and 6, who had soft-tissue plasmacytoma) had a marrow plasma cell concentration of <10%. The marrow iron level was adequate in all patients, and no chromosomal anomalies were identified by conventional culture and banding techniques.

Metastatic skeletal surveys were performed for 16 (64%) of 25 patients during the course of their medical care to evaluate for overt lytic or sclerotic bone lesions. In all but 3 instances, radiograph findings returned within normal limits. Patient 3, who had multiple myeloma, had lytic lesions of the spine, and MRI of the spine, hip, and femurs also revealed a marrow infiltrative pattern. Patient 17 had several questionable tiny lytic skull lesions that were determined to be nonpathologic. Patient 21 had ill-defined sacral alae lucencies, which were also considered nonpathologic after MRI of the spine, sacrum, and bilateral femurs yielded unremarkable findings.

Selected outcomes. With mean and median durations of follow-up of 21 and 12 months, respectively (range, 1–48 months), from the time of identification of M-protein to the most recent clinic visit, 22 of 25 patients are alive (table 2). Three patients died, and 2 are no longer observed at our clinics. Patient 3 initially responded favorably to thalidomide-based therapy but later died of complications of chemotherapy-refractory myeloma. At time of death, his CD4+ T lymphocyte count was >500 cells/µL, and his HIV load was <50 copies/mL. His complete clinical course has been described elsewhere [16].

Patient 10 died of encephalopathy and cholestatic jaundice in the context of AIDS-associated cholangitis. Five years earlier, in the absence of a serum M-protein, he received chemotherapy after stage IV diffuse large B cell NHL had been diagnosed. At time of death, he did not have recurrent NHL. His CD4+ T lymphocyte count was <50 cells/mL, and he was infected with multidrug-resistant HIV (HIV load, >100,000 copies/mL).

Patient 6 presented with a nasal plasmacytoma. Serum protein electrophoresis revealed an M-protein level of 0.8 g/dL. The findings of a bone marrow biopsy were unremarkable. The patient subsequently developed several additional soft-tissue plasmacytomas confined to the head and neck; these were treated with surgical resections and adjuvant external beam radiotherapy. He also received thalidomide and pulsed-dose dexamethasone. He tolerated this latter treatment poorly, experiencing substantial nausea, vomiting, and skin rash. In the context of progressive disease, he received bortezomib chemotherapy. He died of complications of intrathoracic plasmacytoma.

Patient 14 had severe hemophilia A and a distant history of testicular cancer. He was identified with a second spike in the M-protein level of 0.6 g/dL in the context of a 2-log increase in the HIV load.

Patient 5, the study's lone woman, presented with AIDS and generalized lymphadenopathy. An incisional biopsy of an enlarging cervical node demonstrated plasmacytoma. External beam radiotherapy was administered to her tumor. Three years after she started receiving HAART, her CD4+ T lymphocyte count has increased from 40 cells/µL to 212 cells/µL, and her HIV load has remained undetectable.

In total, 7 (28%) of 25 patients presented with or later received a diagnosis of a malignancy. This incidence of malignancy is higher than that for Virginia Mason Medical Center's general HIV-infected population (8%) and higher than that reported elsewhere [24]. Patient 3 had multiple myeloma, and patient 1 had marginal zone lymphoma. Patients 2 and 4 had Kaposi sarcoma, and patients 5 and 6 had plasmacytoma. Most recently, patient 7 presented with progressive left axillary lymphadenopathy. Lymph node biopsy and staging evaluation revealed stage IIIB nodular sclerosis Hodgkin lymphoma. This patient is receiving systemic chemotherapy, consisting of doxorubicin, vinblastine, and dacarbazine.

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Discussion

Individuals with MGUS may, at a rate of 1% per year, progress to more-severe disorders, including multiple myeloma, NHL, and primary amyloidosis [1, 2]. Consequently, only after several decades may we begin to expect a significant number of patients to develop symptomatic illness [1]. Given that most patients in whom M-proteins are present are aged >60 years, and the vast majority are far more likely to die of unrelated illnesses. In contrast, we find that patients with HIV/AIDS at our clinics are more likely to have a serum M-protein present while still in their fifth decade of life. This is consistent with studies suggesting HIV-associated monoclonal gammopathy occurs at a much younger age than in the general population [3–6]. For example, Pantanowitz et al. [3] screened serum samples from 322 HIV-infected patients. Thirteen unique samples (4%) contained an M-protein, and the mean age of patients with an M-protein present was 43 years. In a literature review of HIV-associated MGUS spanning 1985–1993, Fiorino and Atac [7] identified 12 separate reports involving 38 patients. The incidence of HIV-associated MGUS was disparate, ranging from a low of 2.5% to 29%, with a reported mean age of 34 years at diagnosis.

In the HAART era, there is uncertainty regarding the incidence and the natural history of M-proteins in HIV-infected individuals. The drivers of M-protein development are multifaceted and may be related [17]. Other viral infections also may be important [6]. For example, serum immunoglobulins specific to HIV p24 antigen have been described in HIV-infected patients, and Kaposi sarcoma herpesvirus DNA sequences have been identified in bone marrow stromal cells obtained from some patients with MGUS [12, 13]. The importance of EBV-induced activation of B lymphocytes in HIV-infected patients has also been well described [6]. It is noteworthy that, in our study, 2 patients with Kaposi sarcoma and 10 patients with either HBV infection (n = 3) and or HCV infection (n = 7) possessed monoclonal gammopathies. Perhaps these viral processes also contribute to B cell expansion and, ultimately, to monoclonal paraproteinemia [18].

The importance of an M-protein in the setting of HIV infection is also uncertain. Among 340 HIV-infected patients, 11 (3%) developed a serum M-protein over a 6-year period [5]; none subsequently developed NHL or an overt plasma cell malignancy. Ng et al. [17] monitored 7 HIV-infected patients with IgG M-protein, and none of the patient's cases progressed to NHL or plasma cell malignancy over a 2–4-year period. In our study, malignancies were diagnosed in 7 patients (2 patients with Kaposi sarcoma, 1 with NHL, 1 with Hodgkin disease, and 3 with plasmacytoma or multiple myeloma). We continue monitoring our patient cohort for neoplastic diagnoses.

What salutary role HAART may play in reducing M-protein production in HIV-infected individuals is unclear [19]. If HAART results in a truly nondetectable HIV load, then perhaps reduced HIV p24 antigenic stimulation of B lymphocytes would lead to a reduction in M-protein level. On the other hand, low-level HIV viremia continues to occur in patients who receive HAART, including those who develop “blips” or spikes in the HIV load [19]. Experience is limited, but several reports suggest that a good response to HAART will lead to M-protein reduction in some HIV-infected patients [20]. Nine of our patients had a decrease in serum M-protein level while receiving HAART. This finding was not, however, uniform, and the persistence of M-protein in the context of effective HAART may reflect other processes driving M-protein production, including lymphoplasmacytic disorder and a history of HCV, HBV, or Kaposi sarcoma herpesvirus coinfection.

Our study has a number of flaws that make it difficult to reach firm conclusions regarding HIV-associated monoclonal gammopathy. Weaknesses include our small sample size and, for a process requiring decades to define, a relatively short follow-up period. Also worth noting is the study's retrospective nature. At Virginia Mason Medical Center, we identified 19 patients with M-paraproteinemia out of a clinic population of ∼500 patients. This certainly represents an underestimated prevalence of this condition in our clinic population, because serum protein electrophoresis testing is only performed in the event of a clinical suspicion. Reasons for assessing serum M-protein included unexplained anemia, rouleaux formation on peripheral blood smear, presence of hypergammaglobulinemia, and hematologic malignancy. Furthermore, we did not routinely collect information regarding EBV or cytomegalovirus serostatus. EBV loads were not determined, and cytomegalovirus DNA detection assays were performed only if retinal examination findings were disconcerting or if there was a clinical suspicion of active cytomegalovirus disease. In no instance did we identify a patient with active cytomegalovirus disease.

Although the patients in whom we identified with M-proteinemia were younger and had a higher incidence of certain viral infections than did HIV-uninfected patients with MGUS, it is worth emphasizing that this relationship may be spurious, because the precondition of being included in this analysis was enrollment in one of our HIV clinics. These clinic populations are younger and have a higher incidence of viral infection than do patients with MGUS in the general population.

Although it remains unclear whether monitoring monoclonal gammopathies in asymptomatic HIV-infected patients allows early diagnosis of hematological malignancies, reassessments made a minimum of once per year seem to be prudent, given this population's higher incidence of plasma cell malignancies [21] and NHL [22]. Improvements in the rate of survival among patients with HIV infection or AIDS, coupled with the long natural history associated with MGUS, mandate additional long-term follow-up. Recently, Rajkumar et al. [23] showed that an abnormal free light chain ratio (κ-λ ratio <0.26 or >1.65), non-IgG MGUS, and high serum M-protein level (>1.5 g/dL) are statistically significant predictors of disease progression in non–HIV-associated MGUS. It remains to be explored whether these findings might also apply to those with HIV-associated MGUS.

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Acknowledgments

We thank Denise Bundow for assistance with patient clinical care, Elizabeth Blanchard for providing a case abstraction, and Bonnie Marston for manuscript preparation.

Potential conflicts of interest. All authors: no conflicts.

  • Received January 25, 2005.
  • Accepted June 13, 2006.
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  1. Clin Infect Dis. (2006) 43 (9): 1198-1205. doi: 10.1086/508351
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