Soluble and membrane levels of molecules involved in the interaction between clonal plasma cells and the immunological microenvironment in multiple myeloma and their association with the characteristics of the disease

Clonal plasma cells (PC) from different types of monoclonal gammopathies (MG) display distinct phenotypes consistent with an increased antigen‐presentation and T‐cell costimulation in MG of undetermined significance that deteriorates in malignant conditions. Expression of other cell surface and soluble molecules (e.g. adhesion/proliferation molecules) involved in the interaction between clonal PC and the bone marrow (BM) microenvironment has also been related to malignant PC, although the exact clinical significance of their expression remains largely unknown. Analysis of cell surface levels of several of these molecules in multiple myeloma (MM) patients shows an association between lower expression on BMPC of the HLA‐I and β2‐microglobulin antigen‐presenting molecules, the CD126 and CD130 IL6 receptor (IL6R) chains, and CD38, and adverse prognostic features of the disease. Likewise, patients showing higher soluble levels of antigen‐presenting molecules (HLA‐I and β2‐microglobulin), IL6R and CD95 tended to be associated with more aggressive disease behavior. In contrast, CD40, CD86, CD56, CD19, and CD45 were not associated with patients' outcome. Interestingly, upon considering the ratio between the soluble and PC membrane expression of each molecule, an increased adverse prognostic impact was observed for both HLA‐I and β2‐microglobulin, but not for the other molecules. Multivariate analysis confirmed the independent prognostic value of cell surface expression of CD126 on BMPC together with serum β2‐microglobulin and LDH. In summary, our results show an abnormal distribution of the cellular and soluble compartments of the HLA‐I, IL6R, and to a lower extent, CD95 molecules, in MM, associated with the clinical characteristics and behavior of the disease. © 2008 Wiley‐Liss, Inc.     

Peripheral blood dendritic cell subsets from patients with monoclonal gammopathies show an abnormal distribution and are functionally impaired

Objectives. The information currently available about dendritic cells (DCs) in patients with different types of monoclonal gammopathy (MG) is limited and frequently controversial. In the present study, we analyzed the ex vivo distribution as well as the phenotypic and functional characteristics of peripheral blood (PB) DCs from different types of MG. Methods. For this purpose, 61 untreated patients in total with MG were analyzed-MG of undetermined significance (MGUS), 29 cases; multiple myeloma (MM), 28 cases; and plasma cell leukemia (PCL), 4 cases-in comparison with a group of 10 healthy controls. Results. Our results show an absolute overall higher number of all subsets of PB DCs in PCL, together with lower numbers of myeloid DCs in MM patients. From a phenotypic point of view, PB DC subsets from all types of MG expressed significantly higher levels of HLA molecules and altered patterns of expression of the CD2, CD11c, CD16, CD22, CD62L, and CD86 molecules, in association with altered patterns of secretion of inflammatory cytokines. Conclusion. In summary, we show the existence of significant abnormalities in the distribution, phenotype, and pattern of secretion of inflammatory cytokines by different subsets of PB DCs from patients with MGs, which could reflect a potentially altered homing of DCs, together with a greater in vivo activation and lower responsiveness of PB DCs, which are already detectable in MGUS patients.     

Characterization of bone marrow T cells in monoclonal gammopathy of undetermined significance, multiple myeloma, and plasma cell leukemia demonstrates increased infiltration by cytotoxic/Th1 T cells demonstrating a squed TCR-Vbeta repertoire

BACKGROUND: The majority of studies published to date regarding the role of the bone marrow (BM) microenvironment in the pathogenesis of monoclonal gammopathies (MG) have focused on the interaction between stroma cells and plasma cells, whereas information concerning the lymphocytes infiltrating the tumor microenvironment is scanty. METHODS: The authors measured the distribution, TCR-Vbeta repertoire, immunophenotype, and functional characteristics of different subsets of BM T lymphocytes from 61 nontreated patients with MG (30 patients with MG of undetermined significance [MGUS], 27 patients with multiple myeloma [MM], and 4 patients with plasma cell leukemia [PCL]). RESULTS: The authors found a significantly increased rate of BM infiltration by T cells in all patient groups, at the expense of CD4+CD8- and CD4-CD8- T lymphocytes and both CD4+CD28- and CD8+CD28- cytotoxic/effector T cell subsets, and associated with TCR-Vbeta expansions in both CD4+ and CD8+ BM T cells in the majority of patients with MGUS, MM, and PCL. Moreover, the percentage of T cells secreting interferon (IFN)-gamma was found to be increased (P < or = 0.05) both in CD4+ and CD8+ T cells in MGUS and MM patients, and a higher plasma concentration of IFN-gamma was found in patients with MM. It is interesting to note that a positive correlation was noted between the proportion of CD28- and both the percentage of IFN-gamma-secreting cells and the proportion of expanded TCR-Vbeta lymphocytes within the total BM CD4+ T cells. CONCLUSIONS: The results of the current study demonstrated an increased infiltration of BM by T cells associated with frequent TCR-Vbeta expansions and a more prominent cytotoxic/Th1 phenotype in all the patient groups studied.     

Fluorescence in situ hybridization analysis of aneuploidization patterns in monoclonal gammopathy of undetermined significance versus multiple myeloma and plasma cell leukemia

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) is a clonal plasma cell (PC) disorder usually characterized by a benign clinical course. However, in approximately 25% of patients, the disorder has been found to evolve into a multiple myeloma (MM). The mechanism leading to the evolution of MGUS remains unknown. The aim of the current study was, first, to assess by interphase fluorescence in situ hybridization (FISH) the incidence of numerical abnormalities of chromosomes 6, 9, 13, and 17 in MGUS patients and to compare it with that found in MM and PC leukemia (PCL) patients and, second, to explore the potential heterogeneity of the pathologic PC in MGUS as a way to identify unique cytogenetic patterns different from those frequently observed in MM and PCL. METHODS: Numerical abnormalities of chromosomes 6, 9, 13, and 17 were investigated by dual- and triple-color FISH in bone marrow PC from 208 patients corresponding to MGUS (n = 30), MM (n = 158), and PCL (n = 20) cases. In MGUS and MM patients with < 10% PC, both normal and phenotypically aberrant PC were discriminated by multiparameter flow cytometry, the latter subset being specifically sorted for FISH analysis with a purity of 93% +/- 6%. RESULTS: Overall, 57% of the MGUS patients displayed abnormalities for at least 1 of the 4 chromosomes analyzed compared with 75% of both MM and PCL cases. The most common single chromosome abnormalities detected in MGUS were gains of chromosomes 9 (23%) and/or 6 (21%) and loss of chromosomes 13 (21%) and/or 17 (17%). Compared with MM patients, MGUS patients were found to have both a lower incidence of gains of chromosome 9 (23% vs. 54%, P = 0.002) and monosomy 13/13q(-) deletions (21% vs. 38%, P = 0.07); with respect to PCL cases, MGUS patients were found to have a lower incidence of monosomy 13/13q(-) deletions (21% vs. 75%, P < 0.001) together with a slightly higher frequency of gains of both chromosomes 6 (21% vs. 0%, P = 0.05) and 9 (23% vs. 7%, P = 0.1). The simultaneous use of two or three different chromosome probes showed that within the purified compartment of phenotypically aberrant PC from most MGUS patients (67%), more than 1 PC clone could be identified. In contrast, the incidence of 2 or more PC clones was much lower in MM (19%, P < 0.001) and PCL (15%, P = 0.003). Interestingly, although some FISH patterns were shared by both groups of diseases (i.e., monosomy 13/13q(-) deletions alone, gains of chromosome 9 alone or together with trisomy 6), others were found almost exclusively in either MGUS (i.e., a clone with monosomy 6 and/or 17 together with nuclei displaying a normal chromosome number) or in MM (i.e., monosomy 13/13q(-) deletions together with gains of chromosome 6 and/or 9). CONCLUSIONS: In summary, the results of the current study showed that MGUS patients displayed a high incidence of numerical alterations, which are usually associated with the presence of more than one tumor cell clone. It is interesting to note that the cytogenetic patterns observed in the aneuploid PC clones from MGUS patients were frequently different from those observed in both MM and PCL.     

C-kit receptor (CD117) expression on plasma cells in monoclonal gammopathies

The surface expression of CD117 antigen (c-kit) on plasma cells from 158 multiple myeloma (MM), 12 plasma cell leukemia (PCL), 7 MGUS, 7 IgM lymphoplasmacytic lymphoma patients and 10 healthy subjects has been analyzed by flow cytometry using triple staining with the monoclonal antibodies CD138, CD117 and CD38. The antigen expression intensity was calculated as relative fluorescence intensity (RFI) and for direct quantitative analysis the QuantiBRITE test (Becton Dickinson) was applied. Antibody bounding capacity (ABC) was calculated using QuantiCALC software. CD117 antigen was present in 49/158 MM, 5/12 PCL and 5/7 MGUS patients. The RFI values ranged from 0.2 to 20.2 in particular MM patients (mean: 11.0 ± 5.3; median 11.5) while the number of CD117 binding sites (ABC) on MM plasma cells ranged from 637 to 6217 (mean: 3029 ± 1568; median 2946) (r = 0.8328). In responsive to chemotherapy c-kit positive MM patients the percentage of CD117⁺ plasma cells in the bone marrow decreased significantly while in c-kit negative MM patients the percentage of CD117⁺ cells in bone marrow did not change and remained in the normal limits. When comparing the clinical and biological disease characteristics (monoclonal protein isotype, albumin, β₂-microglobulin, lactate dehydrogenase, stage of disease, response to chemotherapy, survival time) of c-kit positive and c-kit negative cases, no significant differences were found. In CD117 positive PCL cases expression of CD117 was detected in bone marrow plasma cells as well as in peripheral blood plasma cells. Normal plasma cells and those in IgM lymphoplasmacytic lymphoma did not show reactivity for the CD117 antigen. We conclude that it may be rationale to consider usefulness of therapy with tyrosine kinase inhibitors in the management of c-kit positive plasma cell proliferations. In one third of MM and PCL patients c-kit antigen could be considered as a "tumor associated marker" and together with CD38 and CD138 it may be of value for the identification of the malignant clone in minimal residual disease as it was first suggested by Spanish authors.     

CD117 (c-kit) is aberrantly expressed in a subset of MGUS and multiple myeloma with unexpectedly good prognosis

CD117 (c-kit) was evaluated on normal plasma cells (PC) (n=10), PC of individuals with monoclonal gammopathy of undetermined significance (MGUS, n=12), malignant PC from patients with multiple myeloma (MM) either at diagnosis (n=83) or relapse (n=38) and on 23 human myeloma cell lines (HMCL). Whereas CD117 is never expressed in normal PC, it is expressed in 50% of MGUS (p=0.015). Furthermore, 33% of MM at diagnosis do express CD117, as opposed to 8% of those in relapse (p=0.003). Finally, CD117 was never found in HMCL. CD117 expression was associated with a better prognosis: overall survival was 93% at 4 years in CD117+ MM versus 64% in CD117- MM (p=0.05). Conversely, lack of CD117, but also high beta-2 microglobulin, t(4;14) and CD221 (IGF-1R) expression were associated with a poorer prognosis. Multivariate analysis revealed that CD117- patients were those with CD221 and t(4;14) and had the poorest prognosis. In conclusion, CD117 (c-kit) is aberrantly expressed on a subset of MGUS and MM with a more indolent presentation and is functionally antinomic to CD221 (IGF-1R). CD117 expression could be related to a specific oncogenic pathway in MM.     

Serum bone sialoprotein as a marker of tumour burden and neoplastic bone involvement and as a prognostic factor in multiple myeloma

To test the potential of immunoreactive BSP, a non-collagenous bone matrix component, as a clinical guide in patients with plasma cell dyscrasias, serum BSP concentrations were measured in 62 patients with newly diagnosed multiple myeloma (MM) followed over a period of 4 years, in 46 patients with monoclonal gammopathy of undetermined significance (MGUS), in 71 patients with untreated benign vertebral osteoporosis (OPO), and in 139 healthy adults. Results were compared with clinical and laboratory data, including serum osteocalcin (OC), and urinary pyridinoline (PYD) and deoxypyridinoline (DPD) as markers of bone turnover. In MM, serum BSP, and urinary PYD and DPD were higher than in healthy controls and in MGUS or OPO (P< 0.001). BSP levels correlated with the bone marrow plasma cell content (r = 0.40, P< 0.001), and serum beta2-microglobulin (r = 0.31, P < 0.01). The differentiation of MM from healthy controls and from MGUS or OPO was highest for BSP. After chemotherapy, BSP reflected the response to treatment and correlated with the change in monoclonal protein (r = 0.55, P< 0.001). MM patients with normal baseline BSP levels survived longer than patients with initially elevated BSP values (P< 0.001, log rank test). Only serum monoclonal protein and BSP were independent predictors of survival. We conclude that in MM, BSP levels are associated with skeletal involvement and tumour cell burden. The quantification of serum BSP may be a non-invasive method for the diagnosis and follow-up, and may improve the prognostic value of conventional staging in MM.     

Genetic aberrations including chromosome 1 abnormalities and clinical features of plasma cell leukemia

Plasma cell leukemia (PCL) is a rare form of plasma cell malignancy, few large series reported underlying genetic abnormalities. We systematically evaluated the genomic aberrations in 41 PCL patients by combining fluorescence in situ hybridization with cytoplasmic light chain immunofluorescence and correlated with their clinical outcome. The genomic aberrations in the 15 primary PCL (pPCL) and 26 secondary PCL (sPCL) were compared with 220 newly diagnosed multiple myeloma (MM) patients. There was no significant difference in the prevalence of genetic abnormalities in pPCL and sPCL but del(13q), t(4;14), 1q21 amplification and del(1p21) were more common in PCL than MM. Patients with pPCL had higher creatinine and beta(2)-microglobulin levels and tended to have a longer overall survival than patients with sPCL. In univariant analysis, PCL patients with t(4;14) (p=0.006) and del(1p21) (p=0.003) had shorter overall survivals. In multivariant analysis adjusting for all tested genetic factors as well as clinico-biologically relevant factors including C-reactive protein, calcium and beta(2)-microglobulin, t(4;14) remained a significant predictor for adverse overall survival in PCL (p=0.008).     

Clinicopathological correlates of plasma cell CD56 (NCAM) expression in multiple myeloma

The aim of this prospective, long-term study was to define the flow cytometric characteristics of plasma cell CD56 expression as well as determine the clinical characteristics of 204 multiple myeloma (MM) patients and 26 plasma cell leukemia (PCL) patients with regard to CD56 expression. CD56 expression intensity was determined by measurement of antigen molecules on the cell defined as Antibodies Bound per Cell (ABC) and calculation of Relative Fluorescence Intensity (RFI). CD56 expression was found in 66% of MM and 54% of PCL cases. The RFI values for individual MM patients ranged from 7.6 to 27.4 while ABC values on MM plasma cells from 2255 to 58469. There was a correlation between the proportion of all bone marrow CD38⁺⁺/CD138⁺ cells with CD56 expression and ABC and RFI indices. With regard to CD56 expression positive patients, the CD56^- MM patients presented lower frequency of osteolysis (p = 0.01). The median survival was 48 months in CD56⁺ patients and 43 months (p = 0.84) in CD56^- cases. In conclusion, CD56 expression carries no distinct adverse prognosis and the lack of CD56 expression does not define a unique clinicopathological or prognostic entity in MM. A remarkable heterogeneity of CD56 expression intensity in CD56⁺ patients imposes the necessity of determining CD56 expression intensity in candidates to antibody-based therapy.     

CD45 expression by bone marrow plasma cells in multiple myeloma: clinical and biological correlations.

Multiple myeloma (MM) is characterized by accumulation of clonal plasma cells (PCs). CD45, a key regulator of antigen-mediated signaling and activation in lymphocytes, is present in early stages of PCs development. We studied CD45 expression on MM PCs by flow cytometry, correlating it to important biological disease characteristics. Additionally, we examined the expression of various adhesion molecules on PCs. A total of 75 patients with untreated MM (29), relapsed MM (17), smoldering MM (12), and monoclonal gammopathy of undetermined significance (MGUS) (17) were studied. The proportion of PCs expressing CD45 was higher among those with early disease (MGUS or smoldering MM) compared to those with advanced disease (new or relapsed MM) (43 vs 22%; P=0.005). Among those with advanced disease, patients with bone lesions had a lower percentage of CD45-positive (CD45+) PCs; 14 vs 34% (P=0.02). Patients with high-grade angiogenesis had a lower percentage of CD45+ PCs; 13 vs 31% (P=0.03). The median overall survival for the CD45+ group (>20% PCs positive) was 39 vs 18 months for the CD45-negative (CD45-) group (P=0.07). The expression of CD138, CD56 and CD54 were higher among the CD45- PCs. This study demonstrates important biological correlates of CD45 expression on myeloma cells.     

Analysis of chromosome 12p deletion in plasma cell dyscrasias

The prognostic relevance of 12p deletion is controversial in multiple myeloma (MM) and the status of 12p deletion is unknown in other plasma cell disorders. We investigated 12p deletion in 88 patients with MM, 19 patients with monoclonal gammopathy of undetermined significance (MGUS), and 17 patients with plasma cell leukemia (PCL). Cytoplasmic immunoglobulin light chain immunofluorescence with simultaneous FISH analysis (cIg-FISH) detected hemizygous 12p deletion in 8% of MM and 24% of PCL, respectively, but in none of the MGUS cases (p = 0.0366). 12p deletions were found in 5 of 7 (71%) MM patients at diagnosis with stage III disease (Durie-Salmon), 2 of 7 (28%) with stage I or II. Of 11 cases with 12p deletions, 6 (55%) had coexistence of p53 deletions, including 3 of 7 (42%) MM, and 3 of 4 (75%) PCL cases. There were no significant differences in progression free or overall survivals in MM patients with or without 12p deletions. Our results do not support the use of 12p deletion as a prognostic marker in MM, rather, it tends to occur in advanced disease, may represent a secondary change associated with the disease progression.     

Flow cytometric differentiation of abnormal and normal plasma cells in the bone marrow in patients with multiple myeloma and its precursor diseases

Flow cytometric (FC) enumeration of abnormal plasma cells (APCs) for diagnosis and prognostication of plasma cell dyscrasias (PCD) is challenging. We studied antigen expression in normal plasma cells (NPC) (N = 34) and APC in a series of unselected PCD (N = 59). NPC subpopulations often demonstrated CD19(−), CD20(+), CD45(−) or dim and CD56(+), an immunophenotype observed in PCD. However abnormal CD81 was only observed in APCs (APC detection sensitivity 95%; specificity 100%). We evaluated differences in antigen expression patterns among MGUS (N = 14), SMM (N = 35) and MM (N = 10), finding the combination of CD45 and CD56 helpful in differentiating MGUS from SMM and MM (p = 0.0002).     

CD29 expressed on plasma cells is activated by divalent cations and soluble CD106 contained in the bone marrow plasma: refractory activation is associated with enhanced proliferation and exit of clonal plasma cells to circulation in multiple myeloma patients

Malignant plasma cells (PC) in human multiple myeloma (MM) are retained in the bone marrow (BM) microenvironment. Using HUTS21 monoclonal antibody that reacts with active CD29 integrin, we demonstrate that this active form is tightly regulated by divalent cations and soluble CD106 (sCD106) contained in the BM plasma. Moreover, we also show that in vivo expression of the active CD29 on PC was clearly diminished in a minority of MM cases (HUTS21(-) patients). HUTS21(-) cells were refractory to the addition of either normal allogeneic BM plasma or optimal concentrations of exogenous divalent cations and recombinant sCD106. Furthermore, a lower binding to fibronectin was detected in comparison with HUTS21(+) PC. On the other hand, although HUTS21(-) PC showed a reduced amount of total (active+inactive) CD29, western-blot assays demonstrated that these clonal PC contained the two species of CD29, with molecular masses of 110 and 130?kDa, which were expressed on normal or HUTS21(+) PC. Finally, we detected a clear association between the presence of HUTS21(-) PC in the BM and an increased percentage of circulating PC with a high proliferative index, emphasizing the essential role of CD29 in the pathogenesis and progression of this disease.     

CD44 isoforms are differentially regulated in plasma cell dyscrasias and CD44v9 represents a new independent prognostic parameter in multiple myeloma

To evaluate the role of CD44 variant isoforms (CD44v) in plasma cell dyscrasias, CD44v expression was analysed in bone marrow (BM) biopsies of multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) patients, in biopsies of soft tissue infiltration by MM and in extramedullary plasmacytoma samples. Expression of CD44 isoforms containing the 3v, 4v, 6v or 10v domain was observed in 15, 7, 13 and 5% of 87 samples from 49 consecutive MM cases, but could not be detected in ten normal persons or 11 MGUS patients. In contrast, CD44v9 revealed a broader pattern of expression and was observed in plasma cells in three out of ten normal persons and in three out of 11 MGUS cases. In MM, CD44v9 was detected in 32 out of 87 samples (37%) of BM infiltrates and was associated with an advanced Durie and Salmon stage (P<0.03), a progressive disease (P<0.01) and an IgA subtype (P<0.01). Furthermore, CD44v9 expression was observed in three out of five cases of MM soft tissue infiltrates, was often upregulated during disease progression, was significantly correlated with a shorter overall survival (P<0.03) and emerged as an independent prognostic factor in multivariate analysis (stage: relative risk 1.36, P<0.02; CD44v9 expression: relative risk 1.45, P<0.04). These results substantiate the clinical relevance of CD44v domains in plasma cell disorders and establish CD44v9 as a new independent prognostic parameter in MM.     

Flow cytometric immunophenotypic characteristics of 36 cases of plasma cell leukemia

Prospective flow cytometric analysis of antigens expression on bone marrow and peripheral blood plasma cells of 36 plasma cell leukemia (PCL) patients enabled to establish the following immunophenotype of leukemic plasma cell: CD38⁺⁺, CD138⁺, CD54⁺, CD49d⁺, CD29⁺, CD44⁺, CD126⁺, CD19⁻, CD45⁻. In one-third of patients PCL cells express CD56, CD71 and CD117. Expression of CD54 on plasma cells was higher as compared to expression of adhesion molecules CD11a, CD18 and CD11b (p < 0.01). Expression of CD18, CD11a, CD11b was lower on bone marrow and higher on peripheral blood cells. In conclusion, impaired expression of adhesion molecules such as CD11a/CD18 or CD56 may explain hematogenic dissemination characterizing PCL.     

The potential diagnostic power of CD138+ microparticles from the plasma analysis for multiple myeloma clinical monitoring

Multiple myeloma (MM) is malignant tumor with abnormal proliferation of bone marrow plasma cells. The existing clinical tools used to determine treatment response and tumor relapse are limited in sensitivity. We investigated the CD138+ microparticles (MPs) of MM patients to find out whether MPs could provide a novel means to monitor the malignant cells in MM patients. Our study showed that the levels of MPs were significantly elevated in MM patients. The MP counts in peripheral blood from new diagnosed MM patients were significantly higher than patients in CR and HD. Consist with the total MPs, the number of the PC‐derived MPs (CD138+) increased in BM from MM patients compared with CR and HD. The ratio of the PC‐derived MPs (CD138+) in BM increased in MM patients compared with CR and HD. The correlation test revealed that the CD138+ MPs in BM and PB were all positively correlated with the plasmacyte ratio in bone marrow (BMPC) and the β₂‐MG. New diagnosed MM patients and controls were compared, and ROC curves were used to identify cutoff points with optimal sensitivity and specificity concerning the ratios and counts of CD138+ MPs in BM and PB. The AUC of the CD138+ MP counts in BM was 0.767, and in PB was 0.680. The AUC of the CD138+ MP ratios in BM was 0.714, and in PB was 0.666. According to this, the counts of CD138+ MPs in BM showed to be a powerful marker of diagnosis. We demonstrated that CD138+ MPs from the plasma provide support for a potential monitoring biomarker of MM.     

Serum beta 2-microglobulin in the initial staging and subsequent monitoring of monoclonal plasma cell disorders

Serum beta 2-microglobulin (beta 2-M) measurements were carried out in 97 patients with monoclonal plasma cell disorders. Twenty-six (87%) of 30 patients with monoclonal gammopathy of undetermined significance (MGUS) had increased beta 2-M levels and serial follow-up in seven patients showed a progressive increase with time. Of the 63 patients with active myeloma, pretreatment serum beta 2-M values were available in 25 for correlation with pretreatment stage. Stage III beta 2-M levels were significantly higher than stages I and II (p less than 0.001). Four patients with smoldering myeloma had beta 2-M values similar to stage I disease. There was, therefore, excellent correlation between beta 2-M and myeloma tumor burden. Levels of beta 2-M decreased with response to chemotherapy induction and low levels in stable remission (plateau phase) were associated with unusually good prognosis. Median survival for stage III patients in stable remission with low serum beta 2-M was greater than 48 months. Conversely, at relapse very high beta 2-M levels were associated with a very fulminant and refractory course. Serum beta 2-M, therefore, appears to be an extremely useful marker in initial stratification and follow-up of myeloma patients.     

SAMSN1 Is a Tumor Suppressor Gene in Multiple Myeloma

Multiple myeloma (MM), a hematological malignancy characterized by the clonal growth of malignant plasma cells (PCs) in the bone marrow, is preceded by the benign asymptomatic condition, monoclonal gammopathy of undetermined significance (MGUS). Several genetic abnormalities have been identified as critical for the development of MM; however, a number of these abnormalities are also found in patients with MGUS, indicating that there are other, as yet unidentified, factors that contribute to the onset of MM disease. In this study, we identify a Samsn1 gene deletion in the 5TGM1/C57BL/KaLwRij murine model of myeloma. In addition, SAMSN1 expression is reduced in the malignant CD138 + PCs of patients with MM and this reduced expression correlates to total PC burden. We identify promoter methylation as a potential mechanism through which SAMSN1 expression is modulated in human myeloma cell lines. Notably, re-expression of Samsn1 in the 5TGM1 murine PC line resulted in complete inhibition of MM disease development in vivo and decreased proliferation in stromal cell–PC co-cultures in vitro. This is the first study to identify deletion of a key gene in the C57BL/KaLwRij mice that also displays reduced gene expression in patients with MM and is therefore likely to play an integral role in MM disease development.