Other Prognostic Markers With Biological Importance

Numerous other prognostic factors have been identified, many of which are of major biological importance, as they shed light on the mechanisms of disease progression in myeloma. However, their impact on outcome is minimal once the major independent factors described above are known, thus limiting their clinical utility as prognostic tools.

Microvessel density

Studies in myeloma indicate that bone marrow angio-genesis is increased in myeloma (Figure 86.3).89-92 There is also evidence that bone marrow angiogenesis correlates with the proliferation of neoplastic plasma cells and may be important in disease progression and activ-ity.89 90 Several studies now show that increased angio-genesis measured by microvessel density is a significant adverse prognostic factor in myeloma.93-96 In the ECOG study, OS was significantly longer in patients with low-grade angiogenesis (53 months), compared to those with high-grade (24 months) or intermediate-grade angiogenesis (48 months) (P = 0.18).97

Interleukin 6

Although IL-6 is an important growth factor in the differentiation of normal B lymphocytes to plasma cells,98 99 it does not generally induce proliferation of normal B lymphocytes or plasma cells.100 In contrast, IL-6 can induce a significant proliferative response in myeloma cells.98 It appears to have both an autocrine and paracrine role in the growth and proliferation of

Figure 86.3 Increased bone marrow microvessels in myeloma bone marrow as visualized by immunohistochemi-cal staining for CD34

myeloma cells.98,101 The proliferative response of myeloma cells to IL-6 is a major factor that distinguishes malignant proliferating from normal nonpro-liferating plasma cells.100

Serum IL-6 levels are elevated in about one-third of myeloma patients, and are more frequently elevated in plasma cell leukemia. IL-6 levels correlate with bone marrow plasmacytosis, serum LDH, p2M , and calcium.102,103

Soluble IL-6 receptors

The activity of IL-6 in myeloma appears to be modulated by the expression of soluble IL-6 receptors (slL-6R).100,104,105 In the presence of IL-6, sIL-6R associates with glycoprotein 130 (gp130), and leads to signal transduction and augmentation of the IL-6 proliferation effect.106 sIL-6R potentiates the proliferative effect of IL-6 on myeloma cells up to 10-fold.104105

An elevated sIL-6R level has independent poor prognostic value in myeloma.2833 A multivariate analysis of 388 patients showed independent prognostic significance for a sIL-6R >300.33 The sIL-6R level did not correlate with PCLI or other prognostic variables. Adding sIL-6R to PCLI and p2M allowed improved prognostic classification, doubling the proportion identified as high risk.

Immunophenotyping

Certain immunophenotypic features have been suggested to have prognostic value. CD20+ plasma cells in myeloma have been associated with a more aggressive course of disease.107 Initial reports suggested that the presence or coexpression of CD 10 or surface immunoglobulin may represent poor prognostic features in myeloma. However, the prognostic value of CD10 in myeloma is unclear, as others have reported conflicting results.107-109 Further, only 15% of myeloma cells are positive for CD10, limiting its role as a prognostic factor. The presence of surface immunoglobulin may be indicative of more immature plasma cell clone. It does not appear that any of these immunopheno-typic characteristics of plasma cells have independent prognostic value in myeloma.

Oncogenes and tumor suppressor genes

Mutations in the ras oncogene have been noted in plasma cells of myeloma, more commonly in the advanced phase of the disease.110111 Liu and colleagues examined the mutational status of the N- and K-ras genes in 160 newly diagnosed multiple myeloma patients enrolled on the ECOG phase III clinical trial E9486.112 The incidence of ras mutations was 39%. Patients with K-ras, but not N-ras, mutations had a significantly shorter median survival, 2.0 years versus 3.7 years, P < 0.02.112

Mutations of the tumor suppressor gene p53 have also been studied. The incidence of p53 point mutations in myeloma in one study was 13%.113 Mutations were more common (43%) in the more advanced and clinically aggressive forms of the myeloma.

Alternative measures of plasma cell proliferation

Besides the PCLI and S-phase estimations, other methods are available to evaluate the proliferative activity of the plasma cells. Immunohistochemical staining of bone marrow using the Ki-67 antibody has been proposed as a surrogate marker for the PCLI, because it identifies plasma cells undergoing active cell division.114 The correlation between the results of this assay and disease activity is good, but comparisons suggest a wider variation of results and lack of correlation with the PCLI.115

Similarly, the use of the proliferating cell nuclear antigen (PCNA) monoclonal antibody has been proposed as a surrogate marker of cell proliferation.116 The results of PCNA correlate more closely with PCLI than with the Ki-67 assay.

T- and B-cell levels

Several studies have shown that baseline and posttreat-ment levels of T and B lymphocytes may be important to outcome in myeloma. San Miguel and colleagues demonstrated that loss of CD4+ T cells is associated with a worse prognosis in myeloma patients.117 Similarly, an elevated level of T cells with activation markers or plasma cell markers has been associated with an unfavorable outcome.118 Kay and colleagues showed that approximately 20% of patients with myeloma have increased levels of circulating CD19+ B cells.119 Low numbers of circulating CD19+ B-cell level (< 125 ^L) were associated with more advanced disease (clinical stage III, P = 0.033). Survival was better in patients with higher levels of circulating CD 19 cells (>125 |L, P < 0.0001). CD19 was found to be an independent prognostic factor.

Recently, Kay and colleagues have confirmed the above findings in an ECOG phase III trial involving 504 newly diagnosed patients with myeloma treated with standard-dose chemotherapy.120 Higher baseline levels of CD3(+), CD4(+), CD8(+), and CD19(+) cells were each associated with improved survival. Porrata and colleagues have demonstrated that early lymphocyte recovery is important for survival, postautologous transplanatation in myeloma.121

Other novel factors

An association between high serum levels of the carboxy terminal of telopeptide of type I collagen (ICTP) and survival has been suggested in newly diagnosed myeloma patients.122 In one study, patients with high serum level of ICTP had poorer OS compared to those with low levels with a median survival of 3.5 years versus 4.1 years, respectively (P = 0.001).123

Serum levels of thymidine kinase also have prognostic value in myeloma.124 Thymidine kinase may identify a small subset of patients with a high PCLI. An elevated IL-2 level is associated with a better prognosis.125

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