Bone marrow angiogenesis in 400 patients with monoclonal gammopathy of undetermined significance, multiple myeloma, and primary amyloidosis.

PURPOSE: To determine whether bone marrow (BM) angiogenesis progressively increases along the spectrum of plasma cell disorders ranging from monoclonal gammopathy of undetermined significance (MGUS) to advanced myeloma. EXPERIMENTAL DESIGN: Four hundred patients with the following disorders were studied: MGUS (76 patients); smoldering (indolent; early-stage) multiple myeloma (SMM; 112 patients); newly diagnosed, active multiple myeloma (MM; 99 patients); relapsed (advanced) multiple myeloma (RMM; 26 patients); and primary amyloidosis (AL; 87 patients). Forty-two normal control BM samples were studied for comparison. BM angiogenesis was studied in a blinded manner by immunohistochemical staining for CD34 to identify microvessels. RESULTS: The median (range) microvessel density (MVD) per x400 high power field was 1.3 (0-11) in the controls, 1.7 (0-10) in AL, 3 (0-23) in MGUS, 4 (1-30) in SMM, 11 (1-48) in newly diagnosed MM, and 20 (6-47) in RMM; P < 0.001. MVD was significantly higher in MGUS, SMM, newly diagnosed MM, and RMM compared with controls and AL; P < 0.001. MVD was not significantly different between controls and AL. By grading, high-grade angiogenesis was present in 0% of controls and AL, 1% of MGUS, 3% of SMM, 29% of newly diagnosed MM, and 42% of RMM; P < 0.001. MVD correlated with the BM plasma cell labeling index (rho = 0.46, P < 0.001) and BM plasma cell percentage (rho 0.5, P < 0.001). Survival was 28 months in SMM and newly diagnosed MM with high-grade angiogenesis, compared with 53 months for those with low- and intermediate-grade angiogenesis; P = 0.02. CONCLUSIONS: BM angiogenesis progressively increases along the spectrum of plasma cell disorders, from the more benign MGUS stage to advanced myeloma, indicating that angiogenesis may be related to disease progression.     

Elevated level of plasma basic fibroblast growth factor in multiple myeloma correlates with increased disease activity.

Recent reports that bone marrow angiogenesis is increased in multiple myeloma prompted us to examine plasma concentrations of angiogenic growth factors and to elucidate their clinical and biological significance. In 45 cases including 36 cases of multiple myeloma and 9 cases of monoclonal gammopathies of undetermined significance (MGUS), plasma concentrations of basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF) were evaluated. FGF-2 was significantly elevated in 25 out of 45 (56%) of the patients with multiple myeloma compared with control subjects (median 9.01 pg ml vs. 1.58 pg/ml, P < 0.0001). The 25 cases were all active multiple myeloma, and none of the non-active myeloma and MGUS patients showed a high FGF-2 level. VEGF level was also elevated in 26 out of 45 patients (58%) compared with control subjects (median 42.0 pg/ml vs. 15.8 pg/ml, P < 0.0001 for VEGF). VEGF concentration was high in 20 active myelomas, but also in one non-active myeloma and five MGUS. Elevation of FGF-2 level was associated with beta2-microglobulin level, anemia and bone marrow plasma cell percentage, which represent disease activity. Interestingly, none of five Bence-Jones type myelomas, including four clinically active cases, revealed a high plasma FGF-2 level, while all of them showed a high VEGF level. In all five responders, the plasma FGF-2 levels were significantly decreased after chemotherapy. FGF-2 was immunohistochemically detected in the bone marrow myeloma cells of the patients with high plasma FGF-2 level. We conclude that plasma concentration of FGF-2 can be a useful indicator of disease activity.     

Elevated Level of Plasma Basic Fibroblast Growth Factor in Multiple Myeloma Correlates with Increased Disease Activity

Recent reports that bone marrow angiogenesis is increased in multiple myeloma prompted us to examine plasma concentrations of angiogenic growth factors and to elucidate their clinical and biological significance. In 45 cases including 36 cases of multiple myeloma and 9 cases of monoclonal gammopathies of undetermined significance (MGUS), plasma concentrations of basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF) were evaluated. FGF-2 was significantly elevated in 25 out of 45 (56%) of the patients with multiple myeloma compared with control subjects (median 9.01 pg/ml vs. 1.58 pg/ml, P <0.0001). The 25 cases were all active multiple myeloma, and none of the non-active myeloma and MGUS patients showed a high FGF-2 level. VEGF level was also elevated in 26 out of 45 patients (58%) compared with control subjects (median 42.0 pg/ml vs. 15.8 pg/ml, P <0.0001 for VEGF). VEGF concentration was high in 20 active myelomas, but also in one non-active myeloma and five MGUS. Elevation of FGF-2 level was associated with β2-microglobulin level, anemia and bone marrow plasma cell percentage, which represent disease activity. Interestingly, none of five Bence-Jones type myelomas, including four clinically active cases, revealed a high plasma FGF-2 level, while all of them showed a high VEGF level. In all five responders, the plasma FGF-2 levels were significantly decreased after chemotherapy. FGF-2 was immunohistochemically detected in the bone marrow myeloma cells of the patients with high plasma FGF-2 level. We conclude that plasma concentration of FGF-2 can be a useful indicator of disease activity.     

Prognostic value of bone marrow angiogenesis in multiple myeloma.

We studied the prognostic value of angiogenesis grading and microvessel density estimation in newly diagnosed multiple myeloma. Seventy-five patients with newly diagnosed myeloma, treated on Eastern Cooperative Oncology Protocol E9486 and Intergroup study 0141 (S9321) at the Mayo Clinic, were studied. Bone marrow microvessels were examined using immunohistochemical staining for von Willebrand factor. Determination of microvessel density and angiogenesis grading was done in a blinded manner. There was a strong correlation between microvessel density and the plasma cell labeling index, rho 0.42, P < 0.001. Angiogenesis grade was also significantly associated with the plasma cell labeling index. Fifteen % of patients with low-grade angiogenesis had a high labeling index (>1%). In contrast, 47% of patients with intermediate or high-grade angiogenesis had high labeling indices (P = 0.02). Overall survival was significantly different among those with high-, intermediate-, and low-grade angiogenesis, with median times of 2, 4, and 4.4 years, respectively (P = 0.02). Similarly, patients with microvessel density >50/x400 field had poorer survival compared with those with 50 or fewer microvessels/field, median survival 2.6 versus 5.1 years, respectively (P = 0.004). There was a strong association between angiogenesis grade and microvessel density (P < 0.001). We conclude that bone marrow angiogenesis is a predictor of poor survival in newly diagnosed myeloma. Angiogenesis is correlated with the plasma cell labeling index but not the bone marrow plasma cell percentage. A simple visual grading of angiogenesis is an efficient alternative to microvessel density estimation.     

Human myeloma cells express the bone regulating gene Runx2/Cbfa1 and produce osteopontin that is involved in angiogenesis in multiple myeloma patients.

Osteopontin (OPN) is a multifunctional bone matrix glycoprotein that is involved in angiogenesis, cell survival and tumor progression. In this study we show that human myeloma cells directly produce OPN and express its major regulating gene Runx2/Cbfa1. The activity of Runx2/Cbfa1 protein in human myeloma cells has also been demonstrated. Moreover, using small interfering RNA (siRNA) to silent Runx2 in myeloma cells, we suppressed OPN mRNA and protein expression. OPN production in myeloma cells was stimulated by growth factors as IL-6 and IFG-1 and in turn OPN stimulated myeloma cell proliferation. In an 'in vitro' angiogenesis system we showed that OPN production by myeloma cells is critical for the proangiogenic effect of myeloma cells. The expression of OPN by purified bone marrow (BM) CD138(+) cells has also been investigated in 60 newly diagnosed multiple myeloma (MM) patients, finding that 40% of MM patients tested expressed OPN. Higher OPN levels have been detected in the BM plasma of MM patients positive for OPN as compared to controls. Moreover, significantly higher BM angiogenesis has been observed in MM patients positive for OPN as compared to those negative. Our data highlight that human myeloma cells with active Runx2/Cbfa1 protein directly produce OPN that is involved in the pathophysiology of MM-induced angiogenesis.     

Clonal plasma cells from monoclonal gammopathy of undetermined significance, multiple myeloma and plasma cell leukemia show different expression profiles of molecules involved in the interaction with the immunological bone marrow microenvironment.

The immunological bone marrow (BM) microenvironment plays a major role in controlling growth and survival of clonal plasma cells (PC); this might translate into different patterns of expression of molecules involved in immune responses on PC from different types of monoclonal gammopathies (MG). We have studied the expression of a group of nine such molecules on both BMPC and the plasma of 61 newly diagnosed MG patients (30 MG of undetermined significance (MGUS), 27 multiple myeloma (MM) and four plasma cell leukemia (PCL)) and five normal individuals. Clonal PC from all MG displayed significantly increased levels of CD56, CD86 and CD126, and decreased amounts of CD38 (P<0.001). Additionally, HLA-I and beta2-microglobulin were abnormally highly expressed in MGUS, while CD40 expression was decreased in MM and PCL (P<0.05). Interestingly, a progressive increase in the soluble levels of beta2-microglobulin was found from MGUS to MM and PCL patients (P=0.03). In contrast, all groups showed similar surface and soluble amounts of CD126, CD130 and CD95, except for increased soluble levels of CD95 observed in PCL. Overall, those phenotypic differences are consistent with increased antigen presentation and costimulatory capacities in MGUS, which progressively deteriorate in malignant MG (MM and PCL).     

Cytokine and chemokine profiles in multiple myeloma; significance of stromal interaction and correlation of IL-8 production with disease progression

Multiple myeloma (MM) is a product of interactions between tumor plasma cells and multiple cell types native to the bone marrow (BM). We have used antibody array technology to examine the proteins produced by BM stromal cells in response to stimulation by BM taken from patients diagnosed with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and MM. We observed increased production of the chemokine IL-8 by stromal cells co-cultured with supernatants from bone marrow cells of patients with active myeloma. IL-8 production is correlated with active disease and is dependent upon IL-1beta and NF-kappaB signaling. Consistent with the pro-angiogenic activity of IL-8, increased BM microvessel density (MVD) correlated with stimulation of stromal cell IL-8 production. In addition, the majority of MM cell lines and MM patient plasma cells were found to express IL-8 receptors CXCR1 and CXCR2. We conclude that stromal cell IL-8 production parallels MM disease activity, is IL-1beta induced, and correlates with bone marrow angiogenesis.     

Total soluble HLA class I and soluble HLA-G in multiple myeloma and monoclonal gammopathy of undetermined significance.

Serum beta2-microglobulin, the light chain of the HLA class I molecular complex, remains one of the best survival prognostic factors in multiple myeloma, but other HLA class I molecules might be of interest in monoclonal gammopathies. In this study, we evaluate total soluble HLA class I (HLA-Is) and soluble HLA-G (HLA-Gs) in 103 patients with newly diagnosed multiple myeloma, 30 patients with monoclonal gammopathy of undetermined significance (MGUS), and 30 healthy subjects, studying their prognostic value in multiple myeloma. In multiple myeloma patients, HLA-Is and HLA-Gs median values were 0.8 microg/mL and 28 ng/mL, respectively. Median HLA-Is concentration was higher in stage II and III multiple myeloma patients than in stage I multiple myeloma, MGUS, and control patients. Median HLA-Gs was significantly lower in healthy controls than in MGUS and multiple myeloma patients. A high level of HLA-Is (> or =2.1 microg/mL) was predictive of short survival (P = 0.017). For each given level of beta2-microglobulin, the relative risk of death was higher for patients with HLA-Is > or = 2.1 microg/mL than in patients with a lower level (P = 0.047). HLA-Gs, a marker of monoclonal gammopathy, was of no prognostic value, but the addition of HLA-Is to beta2-microglobulin produced an efficient prognostic score (P < 0.0001). HLA-Is is a new marker of multiple myeloma tumor load and provides additional survival prognostic information to beta2-microglobulin.     

The Value of the Bone Marrow Plasma Cell Cytoplasmic Light Chain Ratio in Differentiating Between Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance

We compared the plasma cell light chain ratios in the bone marrows of 13 patients with multiple myeloma (MM), with those of 13 patients with monoclonal gammopathy of undetermined significance (MGUS). The mean light chain ratio in favour of the paraprotein isotype in the myeloma group was 51.83 (95% confidence limits (CL) 29.52-74.14) while in the MGUS group it was 5.30 (CL 2.07-8.52). The difference between the MGUS and MM groups was significant (p = 0.0005). Neither the bone marrow plasma cell count nor the paraprotein level were significantly correlated with the light chain ratio in either of these two groups. We found a cut-off ratio of 8 to be the most useful in differentiating between myeloma and MGUS. Only one patient with myeloma had a ratio below 8, and one MGUS patient had a ratio above this cut-off point. We conclude that determination of the bone marrow plasma cell light chain ratio is a simple and useful test in differentiating between myeloma and MGUS in difficult cases.     

Clinical features and outcome of multiple myeloma arising from the transformation of a monoclonal gammapathy of undetermined significance.

Patients with a monoclonal gammapathy of undetermined significance (MGUS) are usually submitted to a periodical clinical follow-up, but it is not known if this surveillance can ameliorate the prognosis of a plasma cell malignancy that will be eventually detected. We compared the clinical and laboratory characteristics at onset, the response to chemotherapy and the survival, of 21 cases of newly diagnosed multiple myeloma (MM) arising from the malignant transformation of MGUS and 41 cases without a previous history of MGUS, recruited to the same first-line treatments over a 3-years period. The former group showed a significant lower frequency of advanced stages as well as other several prognostic factors of high risk including anemia, renal failure, bone lesions and increase of beta2 microglobulin and C-reactive protein levels. Despite a similar response to treatment of the two groups, MM arising from MGUS showed a significantly longer median survival than MM without prior MGUS. This was particularly true for stage I, while stages II and III behaved similarly. We conclude that the regular clinical monitoring of MGUS patients allowed the identification of earlier malignant transformation, when tumor burden is lower, as indicated by lower beta2 microglobulin levels and marrow plasmacytosis of stage I MM arising from MGUS. Moreover, a slower proliferation rate of myeloma cells, as suggested by lower C-reactive protein levels, may be considered so as to explain the longer survival of these patients.     

The relationship between soluble receptor of interleukin-6 with angiogenic cytokines and proliferation markers in multiple myeloma

Soluble interleukin-6 receptor (sIL-6R) is part of IL-6 receptor that may stimulate cells that do not express the whole molecule. It may enhance myeloma cell proliferation and furthermore angiogenesis. The aim of the study was to evaluate the clinical significance and the relationship between serum levels of sIL-6R, with various stimulators of angiogenesis, such as hepatocyte growth factor (HGF) and interleukin-18 (IL-18) and with markers of proliferation, such as beta-2 microglobulin (B2M) levels and plasma cell Ki-67 proliferation index in the bone marrow, in patients with multiple myeloma (MM). We studied 45 newly diagnosed MM patients. Serum levels of sIL-6R, HGF, IL-18, and B2M and Ki-67 proliferation index (Ki-67 PI) in bone marrow’s plasma cells were determined. The mean concentrations of sIL-6R, HGF, IL-18, and B2M and the value of Ki-67 were significantly higher in the patients compared to controls and with increasing disease stage. sIL-6R was strongly positively correlated with HGF, IL-18, B2M, and Ki-67 PI. There is a positive correlation between plasma cell growth, as determined by Ki-67 PI, and different angiogenic cytokines, such as HGF and IL-18, with sIL-6R. This relationship suggests the significant role of these cytokines in the proliferation and disease activity in MM patients.     

Interleukin-18 in multiple myeloma patients: serum levels in relation to response to treatment and survival

Interleukin-18 (IL-18) plays a role in the host's response to tumours and angiogenesis. We determined serum levels of IL-18, vascular endothelial growth factor (VEGF), angiogenin (ANG), tumor necrosis factor (TNF-alpha) and CRP in 65 newly diagnosed myeloma patients. IL-18, VEGF, angiogenin, TNF-alpha and CRP were significantly higher at stage III in comparison to stages II and I. These cytokines (measured in 27 patients) significantly decreased after treatment. In survival analysis, higher levels of IL-18 were associated with a poorer prognosis. We conclude that increased serum IL-18 in myeloma patients correlates with advanced disease, increased levels of angiogenic cytokines and worse survival.     

Increased expression of vascular endothelial growth factor (VEGF) in bone marrow of patients with myeloproliferative disorders (MPD)

Angiogenesis is a multistep process of the development of capillaries from established blood vessels. Angiogenesis probably plays a significant role in the development and progression of hematopoietic malignancies. Higher microvascular density and increased serum levels of proangiogenic factors such as vascular endothelial growth factor (VEGF) or basic fibroblasts growth factor (bFGF) have been reported in acute and chronic leukemias, myeloproliferative and myelodysplastic disorders, multiple myeloma and lymphomas. The microvessel density of bone marrow stroma in myeloproliferative disorders is increased and VEGF is considered as the most potent endothelial cell activator. The purpose of this study was to examine the expression of VEGF in bone marrow of patients with MPD. 60 paraffinembedded bone marrow core biopsy specimens from newly diagnosed patients with MPD were evaluated. In addition 10 bone marrow core biopsy specimens from adult patients without evidence of malignancy were used as controls. Bone marrow sections were stained immunohistochemically for VEGF (PharMingen, USA). Obtained data show that MPD are associated with an increased expression of VEGF in the bone marrow. This observation support previous studies suggesting that angiogenesis may play a role in the pathophysiology of myeloproliferative disorders. Clinical significance of this phenomenon needs further investigation however thus provides rationale for use of angiogenesis inhibitors in MPD therapy.     

Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symptomatic myeloma: reduction post-bortezomib monotherapy

Sclerostin is a Wingless and Int-1 inhibitor, which is produced by osteocytes and inhibits osteoblast-driven bone formation. Sclerostin is implicated in the pathogenesis of bone loss in metabolic bone disorders but there is no information for its effect on multiple myeloma (MM)-related osteolytic disease. We evaluated circulating sclerostin in 157 newly diagnosed patients with symptomatic myeloma, in 25 with relapsed myeloma who received bortezomib monotherapy, in 21 patients with monoclonal gammopathy of undetermined significance (MGUS), and in 21 healthy controls. Patients with active myeloma had elevated circulating sclerostin compared to MGUS patients and controls (p < 0.01). MM patients who presented with fractures at diagnosis (n = 34) had very high levels of circulating sclerostin compared with all others (p < 0.01), whereas sclerostin correlated negatively with bone specific alkaline phosphatase (a bone formation marker; r = -0.541, p < 0.0001) and positively with C-telopeptide of collagen type-1 (a bone resorption marker; r = 0.524, p < 0.0001). Patients with International Staging System (ISS)-3 disease had higher circulating sclerostin compared to ISS-1 and ISS-2 MM (p = 0.001). Furthermore, patients with high sclerostin (upper quartile, n = 40) had a median survival of 27 months versus 98 months of all others (p = 0.031). Relapsed MM patients had higher levels of circulating sclerostin even compared to newly diagnosed patients (p < 0.01). Bortezomib monotherapy resulted in a reduction of sclerostin by almost 50% in both responders and non-responders. These results suggest that patients with active myeloma have elevated circulating sclerostin, which correlated with advanced disease features including severe bone disease. Our study indicates sclerostin as a possible target for the development of novel therapies to enhance osteoblast function in myeloma.     

Bone marrow angiogenesis in patients with active multiple myeloma.

Factor VIII-related antigen (FVIII-RA)-positive microvessel areas were measured by both immunohistochemistry and computerized image analysis in patients with active multiple myeloma (MM), nonactive MM, and monoclonal gammopathies of undetermined significance (MGUS). A five-to sixfold larger area was found in patients with active MM compared to the other two groups. Aquaporin 1 (AQP1)-positive microvessel areas, measured with the same techniques on adjacent tissue sections, were also increased in active MM, and tended to be larger than and closely correlated with the FVIII-RA areas. Numerous mast cells were found in the bone marrow of active MM patients, and counts were strictly correlated with the microvessel density. The conditioned medium (CM) of bone marrow plasma cells from active MM patients stimulated endothelial cell proliferation and chemotaxis, monocyte chemotaxis, and angiogenesis in vivo (assessed by the chick embryo chorioallantoic membrane [CAM] system) more strongly and frequently than the CM of patients with nonactive MM and MGUS. Immunoassay of plasma cell lysates gave significantly higher levels of fibroblast growth factor-2 (FGF-2) in patients with active MM than in the other two groups, and a neutralizing anti-FGF-2 antibody inhibited by 46% to 68% the biological activity exerted by the CM in vitro and in the CAM. In situ hybridization of bone marrow plasma cells and zymography of CM showed that patients with active MM express higher levels of matrix metalloproteinase-2 (MMP-2) mRNA and protein than those with nonactive MM and MGUS, whereas MMP-9 expression and secretion overlapped in all groups. Overall data indicate that patients with active MM represent the vascular phase of plasma cell tumors that is induced, at least partly, through FGF-2 and MMP-2. Mast cells possibly contribute to the vascular phase via angiogenic factors in their secretory granules. Both angiogenesis and MMP-2 secretion can account for intramedullary and extramedullary spreading of plasma cells in patients with active MM.     

MICA expressed by multiple myeloma and monoclonal gammopathy of undetermined significance plasma cells Costimulates pamidronate-activated gammadelta lymphocytes

Amino-biphosphonates (like pamidronate) activate human Vgamma9/Vdelta2 T lymphocytes and promote their cytotoxicity against multiple myeloma cells. T-cell receptor (TCR)-mediated effector functions of gammadelta cells are enhanced upon triggering of the activating receptor NKG2D by MICA, a stress-inducible antigen expressed by epithelial and some hematopoietic tumors, including multiple myeloma. Here we show that MICA was expressed not only by myeloma cell lines and by 6 of 10 primary multiple myeloma cells from patients but also by bone marrow plasma cells from all (six of six) patients with preneoplastic gammopathy (monoclonal gammopathy of undetermined significance, MGUS), a direct precursor of multiple myeloma. Moreover, compared with multiple myeloma plasma cells, MICA was expressed by MGUS plasma cells at significantly (P < 0.05) higher levels. MICA expressed by myeloma cell lines contributed to killing and IFN-gamma production by Vgamma9/Vdelta2 cells only upon pamidronate treatment, suggesting a dual interaction between Vgamma9/Vdelta2 lymphocytes and multiple myeloma plasma cells involving both TCR triggering and NKG2D-mediated signals. Finally, MICA enhanced killing of freshly derived, pamidronate-treated multiple myeloma cells from patients by gammadelta cells, as indicated by the significantly (P < 0.05) higher gammadelta cytotoxicity against MICA-positive rather than MICA-negative multiple myeloma cells. Our results indicate that MICA expressed by monoclonal plasma cells is functional and correlates with disease stages, suggesting a role for the molecule in the immune surveillance against multiple myeloma. Moreover, pamidronate-activated Vgamma9/Vdelta2 lymphocytes can be exploited in the immune therapy of early stages multiple myeloma and possibly of premalignant disease.     

Monoclonal gammopathy of undetermined significance and multiple myeloma are associated with an increased incidence of venothromboembolic disease

BACKGROUND: Venous thromboembolic disease (VTD) is a recently recognized complication of thalidomide in combination therapy for patients with multiple myeloma (MM). The authors assessed the frequency of VTD and its risk factors in 612 consecutive patients with plasma cell dyscrasia (PCD) who were evaluated and followed from 1991 to 2001. METHODS: In the current study, 404 patients were diagnosed with multiple myeloma (MM), 174 with monoclonal gammopathy of undetermined significance (MGUS), and 34 with other forms (excluding amyloidosis). Univariable correlates of VTD were assessed using Kaplan-Meier analysis and Cox proportional hazards analysis. RESULTS: The authors identified several univariable correlates of VTD in patients with MGUS, including a family and medical history of VTD, immobility, low serum albumin level, and high leukocyte count. Patients with MGUS with immunoglobulin (Ig) G monoclonal immunoglobulin were found to be less prone to develop VTD. In patients with MM, a family and medical history of VTD and the presence of a hypercoagulable state were factors identified in univariable analysis to be associated with an increased risk of VTD. In patients with MM, for each unit increase in serum albumin, the risk of VTD was lower. The type of the treatment regimen did not appear to correlate with the development of VTD. CONCLUSIONS: In the current study, the risk for thromboembolic diseases among patients with PCD was increased compared with the risk in the general population. Further studies are necessary to define the mechanisms involved.     

Prognostic value of circulating plasma cells in monoclonal gammopathy of undetermined significance.

PURPOSE: Monoclonal gammopathy of undetermined significance (MGUS) progresses to multiple myeloma or another related plasma cell disorder (PCD) at a rate of approximately 1% per year. Identification of patients with MGUS at high risk of progression will allow development of preventive strategies. We studied the prognostic value of circulating plasma cells (PCs) in patients with MGUS to predict progression. PATIENTS AND METHODS: Patients were eligible for this retrospective analysis if they were seen at the Mayo Clinic between 1984 and 1997, were diagnosed with MGUS, and had an analysis of the peripheral blood for circulating PCs by the slide-based immunofluorescence method. Patients were observed for progression to another PCD. RESULTS: Three hundred twenty-five patients were eligible and 63 (19%) had circulating PCs. Patients with circulating PCs were twice as likely (hazard ratio, 2.1) to experience progression to another PCD (most commonly myeloma), compared with those without circulating PCs (95% CI, 1.1 to 4.3; P = .03). In patients with circulating PCs, the median progression-free survival was 138 months compared with a median not yet reached for those without circulating PCs (P = .028). The median overall survival also was shorter for those with circulating PCs. Other factors with prognostic value were high levels of M protein and non-immunoglobulin G heavy-chain type. CONCLUSION: The presence of circulating PCs, especially when combined with other known prognostic factors such as M protein concentration and immunoglobulin isotype, identify a group of individuals with MGUS at higher risk of progression to overt multiple myeloma.     

A review of angiogenesis and antiangiogenic therapy with thalidomide in multiple myeloma

Angiogenesis is the formation of new blood vessels and occurs physiologically during embryonal growth, wound healing and during the menstrual cycle. It is essential for the proliferation and metastases of most malignant neoplasms. Recent evidence suggests that angiogenesis is increased in multiple myeloma and has prognostic value in the disease. Angiogenic cytokines such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor are expressed by myeloma cells and appear to play a role in the increased angiogenesis seen in myeloma. In addition, VEGF may serve as a paracrine growth factor for myeloma cells.Based on the increased angiogenesis observed in myeloma, thalidomide has been studied as antiangiogenic therapy. Although its mechanism of action in myeloma is still unclear, thalidomide appears to be active in 25-30% of patients with refractory myeloma. Major toxicities include constipation, sedation, skin rash, fatigue, and peripheral neuropathy. Studies are ongoing to determine its role as initial treatment for myeloma. This paper reviews the available data on angiogenesis in myeloma, and summarizes the role of thalidomide therapy in this disease. The pharmacology and toxicity of thalidomide are also discussed.