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.     

Angiogenesis in multiple myeloma.

Angiogenesis is the process of new blood vessel formation, and normally occurs during embryonal growth, wound healing, and the menstrual cycle. It is essential for the proliferation and metastases of most malignant neoplasms. There is now growing evidence that angiogenesis is increased and is likely important in multiple myeloma. Recent evidence suggests that angiogenesis is greater in multiple myeloma compared to monoclonal gammopathy of undetermined significance (MGUS). Angiogenic cytokines such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are expressed by neoplastic plasma cells, and may play a role in the increased angiogenesis seen in myeloma. In a study of 400 patients with plasma cell disorders, microvascular density (MVD) was significantly higher in smoldering myeloma, newly diagnosed myeloma, and relapsed myeloma compared to controls, MGUS, and primary amyloidosis. In another study involving 74 newly diagnosed patients with myeloma treated at the Mayo Clinic, overall survival was significantly longer in patients with low-grade angiogenesis compared to those with high-grade or intermediate-grade angiogenesis. The finding of increased angiogenesis in myeloma provides the rationale for the study of antiangiogenic therapy in this disease.     

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).     

14q32 translocations and monosomy 13 observed in monoclonal gammopathy of undetermined significance delineate a multistep process for the oncogenesis of multiple myeloma. Intergroupe Francophone du Myélome.

Clonal plasma cells in monoclonal gammopathy of undetermined significance (MGUS) have been shown to bear copy number chromosome changes. To extend our knowledge of MGUS to structural chromosomal abnormalities, we have performed fluorescence in situ hybridization experiments with probes directed to the 14q32 and 13q14 chromosomal regions in 100 patients with either MGUS or smoldering multiple myeloma (SMM). 14q32 abnormalities were observed in at least 46% of patients with MGUS/SMM, with these abnormalities being present in the majority of clonal plasma cells. Whereas t(11;14)(q13;q32) occurs in 15% of MGUS/SMM patients, an incidence similar to that of overt multiple myeloma (MM) patients, translocation t(4;14)(p16;q32) is observed in only 2% of these cases [P = 0.002 for difference with t(11;14)], as compared with 12% in MM patients (P = 0.013). Monoallelic deletions of the 13q14 region were found in 21% of patients, with two types of situations. In half of the evaluable patients, and especially in patients with SMM, the deletion is present in the majority of clonal plasma cells, as in MM, whereas in the other half of the evaluable patients (essentially in MGUS patients), it is observed in subclones only. These data enable us to elaborate a plasma cell oncogenesis model from MGUS to MM.     

High Dimensional Immune Profiling of Smoldering Multiple Myeloma Distinguishes Distinct Tumor Microenvironments

BackgroundMultiple myeloma (MM) is a malignancy of plasma cells that arises from premalignant Monoclonal Gammopathy of Undetermined Significance (MGUS) and often progresses through an asymptomatic Smoldering (SMM) phase. Understanding the interactions between abnormal clonal plasma cells and the tumor microenvironment (TME) in the early disease states (MGUS, SMM) may inform risk assessment and therapy.Patients and MethodsWe performed high dimensional immunologic analysis of bone marrow specimens from 73 subjects with SMM by mass cytometry and T cell receptor sequencing of CD138-depleted bone marrow (BM) mononuclear cells, and proteomics and seromic profiling of BM plasma. Analysis of individual assay data identified self-organizing subgroups of SMM patients. We then applied novel bioinformatic methods to integrate data from pairs, trios, and quartets of assays.ResultsMass cytometry, TCRSeq and proteomics identified three taxa (sing. taxon) of subjects that shared common characteristics across all three assays. Differential levels of BM plasma pleiotropin (PTN) and BM T cells and their productive clonality emerged as strong distinguishing factors among these taxa.ConclusionThese results suggest that the continuum from MGUS to MM does not consist of a single pathway in the TME, and that complex interactions between myeloma cells and the TME may ultimately determine progression and inform clinical management.     

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.     

A phase II trial of imatinib in patients with refractory/relapsed myeloma

Although imatinib was designed to specifically inhibit the bcr-abl gene product, it inhibits other receptor tyrosine kinases including c-kit. As pre-clinical data, 126 patients with plasma cell disorders and 19 controls were evaluated for c-kit expression. Patients were eligible for the treatment trial if they had relapsed/refractory myeloma. The primary end-point of the study was response. Of the 145 studied before the trial, c-kit expression was present on the bone marrow plasma cells of control (11%), AL amyloid (53%), MGUS (47%), SMM (67%) and MM (42%) patients. Twenty-three MM patients were enrolled on the therapeutic trial (imatinib 400 mg daily) and 52% had positive c-kit staining. There were no responses. The median duration of treatment was 48 days (range: 12-349). Patients ended treatment due to progressive disease (18 patients), death (3) and other (2). The data suggest that imantinib is not an active agent in patients with relapsed or refractory multiple myeloma.     

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.     

组织因子在多发性骨髓瘤中的表达及其与血管新生的关系

 目的　研究多发性骨髓瘤（MM）患者骨髓组织中组织因子（TF）的表达及其与血管内皮生长因子（VEGF）和骨髓血管新生程度的关系。方法　采用免疫组织化学法对试验组32例初治／复发的MM患者、对照组32例缺铁性贫血患者和健康者骨髓组织的TF、VEGF表达水平和微血管密度（MVD）进行测定。结果　试验组与对照组的TF、VEGF阳性率分别为88 %、78 %;60 %、10 %。试验组与对照组TF、VEGF中位表达水平分别为（++） 、（++）;（-）、（-）;试验组与对照组中位MVD分别为4、0。试验组TF表达水平与血管新生程度等级相关性分析结果显示TF表达水平与血管新生程度呈等级正相关（rs＝0.568,P＜0.001）。结论　MM患者骨髓组织中的TF表达水平与VEGF表达水平高于对照组,与血管新生程度呈等级正相关。     

Monoclonal Gammopathies After Renal Transplantation: A Single-center Study

IntroductionPlasma cell disorders (PCDs) are clonal plasma cell disorders that include conditions such as monoclonal gammopathy of undetermined significance (MGUS), monoclonal gammopathy of renal significance (MGRS), multiple myeloma (MM), smoldering MM (SMM), solitary plasmacytoma, and light-chain (AL) amyloidosis. The risk factors associated with and the clinical course of PCDs after renal transplantation is not well established although immunosuppressive protocols may impact the incidence and natural history of PCDs posttransplant.Patients and MethodsThis single-center retrospective study evaluated patients with a history of renal transplant who developed a PCD between January 1, 2014-December 31, 2018.ResultA total of 41 patients met the inclusion criteria including 29 with MGUS and 12 with symptomatic PCD (4 with MM, 2 with SMM, 4 with MGRS, 1 with AL amyloidosis, and 1 with solitary plasmacytoma). The median follow-up of survivors was 41.6 months. Three patients (1 with MGUS and 2 with MGRS) progressed to MM during the follow-up period. There was a male preponderance in both groups. There was no correlation between the donor and immunosuppressive regimen and the development of a PCD. Patients with symptomatic PCD had higher serum creatinine and M-protein levels at diagnosis and higher free light chain ratio and plasma cell burden. There was also a higher percentage of allograft failure noted in the symptomatic PCD subset 50% (n = 6), whereas only 23% (n = 7) of patients had allograft failure in the MGUS group.ConclusionThis study shows the importance of considering monoclonal gammopathy in the differential of renal dysfunction after kidney transplant and the need to follow these patients closely to monitor for progression to symptomatic PCD.     

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.     

Angiogenesis in multiple myeloma: correlation between in vitro endothelial colonies growth (CFU-En) and clinical-biological features.

Mouse models and studies performed on fixed bone marrow (BM) specimens obtained from patients with multiple myeloma (MM) suggest that plasma cell growth is dependent on endothelial cell (EC) proliferation within the BM microenvironment. In order to assess whether EC overgrowth in MM reflects a spontaneous in vitro angiogenesis, BM mononucleated cells from 13 untreated (UT) MM, 20 treated (11 with melphalan and nine with DAV schedule) MM, eight patients with monoclonal gammopathy of uncertain significance (MGUS) and eight controls were seeded in an unselective medium to assess EC proliferation. Furthermore, the influence of IL6 on the EC growth was investigated. Endothelial colonies (CFU-En) appeared as small clusters, formed by at least 100 slightly elongated and sometimes bi-nucleated cells expressing factor VIII, CD31 and CD105 (endoglin). The CFU-En mean number/10(6) BM mononucleated cells in untreated MM samples (2.07 s.d. +/- 1.3) was significantly higher than in normal BM (0.28 +/- 0.48), while no difference was seen between normal BM and MGUS (0.28 +/- 0.54). Interestingly, the mean number of CFU-En in the DAV group (1.88 +/- 1.6) did not differ from the UT, while it was found to be lower in the melphalan group (0.31 +/- 0.63). The addition of anti-IL6 monoclonal antibody induced a reduction of both the plasma cells in the supernatant and the CFU-En number. This study describes a rapid and feasible assay providing support for the association between EC and plasma cells further suggesting that the in vitro angiogenesis process may parallel that observed in vivo.     

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.     

Ras oncogene expression and DNA content in plasma cell dyscrasias: a flow cytofluorimetric study

Using bivariate flow cytofluorometry, we have determined the nuclear DNA distribution and the expression of the p21 protein (coded by the Ha-ras oncogene) in the bone marrow (BM) cells of five solid tumour patients having histologically normal BM and in those of 57 patients with plasma cell dyscrasia (28 with monoclonal gammopathies of undertermined significance, MGUS, and 29 with multiple myeloma, MM). All normal and MGUS and 21/29 (72.4%) MM BM had diploid modal DNA content and 8/29 (27.6%) MM BM had both diploid and hyperdiploid cell populations. In normal and MGUS BM, the level of the p21 oncoprotein was low and uniform in all G0/G1, S and G2 cells (median fluorescence values in arbitrary units were 6.1 and 7.5, respectively). The level of p21 was increased both in different aliquots of G0/G1 cells and in the S and G2 cells in diploid MM (median value for G0/G1 cells was 20), and especially in MM with hyperdiploid clones (median value for hyperdiploid cells was 40.5, P less than 0.005 with respect to normal and MGUS BM and less than 0.005 with respect to diploid MM BM). The p21 expression was greater in patients with advanced (stage III) than in earlier MM (stages I + II) (P less than 0.005), and it was directly related to the BMPC infiltration (r = 0.7; P less than 0.005). Since p21 expression is greater in MM than in both normal and MGUS BM, Ha-ras could be involved in the malignant plasma cell transformation that distinguishes MM from MGUS.     

Argonaute 2与多发性骨髓瘤血管生成临床关系研究

目的 了解Argonaute 2(Ago2)在多发性骨髓瘤(MM)骨髓组织中的表达水平,探讨其与骨髓内血管生成的关系.方法 应用改良的甲基丙烯酸甲酯(MMA)单体塑料包埋法对59例MM患者及16例正常对照进行骨髓活组织检查的组织制片,采用EnVision免疫组织化学二步法检测MM患者及正常对照骨髓组织中Ago2蛋白表达水平及微血管密度(MVD),并用Western blot方法检测8例MM患者和3例正常对照Ago2蛋白表达水平.结果 Western blot检测显示,Ago2蛋白在MM患者骨髓组织中表达高于正常对照(1.35±0.19比0.15±0.03,t=-19.883,P＜0.001).免疫组织化学结果表明,59例MM患者骨髓组织中Ago2蛋白阴性和阳性分别为9例和50例,对照组16例均为阴性,两组差异有统计学意义(x2=42.586,P＜ 0.001).MM患者中,Ago2阳性组β2-微球蛋白高于阴性组,差异有统计学意义(Z=-2.014,P=0.042).MM患者骨髓组织中MVD为7.89±4.88,正常对照组为2.16±1.32,两组之间差异有统计学意义(t=4.63,P＜0.001).MM患者骨髓组织中Ago2蛋白表达水平与MVD具有相关性(r=0.461,P=0.023).Ago2蛋白阳性组MVD较阴性组增高,差异有统计学意义(t=2.71,P=0.009).结论 Ago2在MM患者骨髓组织中表达水平明显升高,可能参与了MM患者的病理发生,并对骨髓内异常新生血管生成起一定的调节作用.     

Serum BCMA levels predict outcomes in MGUS and smoldering myeloma patients

Soluble BCMA (sBCMA) levels are elevated in monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). However, the association between sBCMA levels and prognosis in MGUS and SMM has not been studied. We retrospectively analyzed sBCMA levels in stored samples from 99 MGUS and 184 SMM patients. Baseline sBCMA levels were significantly higher in MGUS and SMM patients progressing to MM during clinical follow up. When stratified according to the median baseline sBCMA level for each cohort, higher levels were associated with a shorter PFS for MGUS (HR 3.44 comparing sBCMA ≥77 vs <77 ng/mL [95% CI 2.07–5.73, p < 0.001] and SMM (HR 2.0 comparing sBCMA ≥128 vs <128 ng/mL, 95% 1.45–2.76, p < 0.001) patients. The effect of sBCMA on PFS was similar even after adjusting for the baseline MGUS or SMM risk stratification. We evaluated paired serum samples and found that sBCMA increased significantly in MGUS and SMM patients who eventually progressed to MM, whereas among MGUS non-progressors the sBCMA level remained stable. While our results require independent validation, they suggest that sBCMA may be a useful biomarker to identify MGUS and SMM patients at increased risk of progression to MM independent of the established risk models.Subject terms: Myeloma, Tumour immunology, Prognosis     

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.     

Blood-based risk stratification for pre-malignant and symptomatic plasma cell neoplasms to improve patient management

Standard risk stratification (sRisk) guides clinical management in monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and multiple myeloma (MM). Nonetheless, clinical results are considerably heterogeneous among patients with similar risk status. Blood and bone marrow samples from 276 MGUS, 56 SMM and 242 MM in regular clinical practice were analyzed at diagnosis by flow cytometry. Higher levels of aberrant circulating plasma cells (cPC) (> 0.0035% of leukocytes), combined with albumin, beta2-microglobuline and lactate-dehydrogenase levels, offered minimally-invasive risk stratification (RcPC) with results comparable to sRisk. RcPC and sRisk 10-year progression-free-survival (10y-PFS) rates were: 93.8% vs. 95.1% for low-risk, 78.4% vs. 81.7% for intermediate-risk and 50.0% vs. 47.8% for high-risk MGUS; 58.3% vs. 57.8% low-risk, 44.4% vs. 45.8% intermediate-risk and 8.9% vs. 15.0% high-risk SMM; and 44.4% vs. 44.4% low-risk, 36.1% vs. 36.8% intermediate-risk, and 13.3% vs. 16.2% high-risk MM. Circulating-PC > 0.0035% vs. cPC<0.0035% was an independent prognostic factor for PFS (HR=4.389, P=1.2×10^-15, Harrell C-statistic =0.7705±0.0190) and over-all survival (OS, HR=4.286, 2.3×10^-9, Harrell C-statistic =0.8225±0.0197) that complemented sRisk in patients with low-sRisk (10y-PFS rates 48.1% vs. 87.3%, P=1.2×10^-8) and intermediate-sRisk (10y-PFS rates 28.9% vs. 74.1%, P=8.6×10^-12). Patients with high cPCs values are associated with higher proliferation and lower apoptosis rates of PC. Circulating-PC > 0.0035% identified MGUS, SMM and MM patients at higher risk of progression or death and predicted a cohort of patients that after relapse from stringent complete response showed shorter OS. These patients could benefit from early consolidation therapy, tandem ASCT or intensive maintenance.     

Prognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma.

PURPOSE: To evaluate the natural history of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), identify early predictors of evolution, and assess whether associated conditions correlate with disease progression. PATIENTS AND METHODS: A total of 1,231 consecutive patients with either MGUS (n = 1,104) or SMM (n = 127) diagnosed from July 1975 to March 1998 were included in the study. Cumulative survival probability and cumulative probability of transformation into lymphoproliferative disease were calculated by means of the Kaplan-Meier estimator. Univariate and multivariate Cox models were used to identify possible predictors of malignant evolution. RESULTS: Cumulative transformation probability at 10 and 15 years was 14% and 30%, respectively. At a median follow-up of 65 months (range, 12 to 239 months), 64 MGUS cases (5.8%) evolved to multiple myeloma (MM) (n = 43), extramedullary plasmacytoma (n = 1), primary amyloidosis (n = 1), Waldenstr?m's macroglobulinemia (n = 12), non-Hodgkin's lymphoma (n = 6), and B-chronic lymphocytic leukemia (n = 1). At a median follow-up of 72 months (range, 12 to 247 months), 25 SMMs (19.7%) evolved to overt MM. A lower evolution risk was observed in MGUS than in SMM (P <.0001). Greater than 5% marrow plasmacytosis, detectable Bence Jones proteinuria, polyclonal serum immunoglobulin reduction, and high erythrocyte sedimentation rate (ESR) were independent factors influencing MGUS transformation. SMM progression correlated with greater than 10% marrow plasma cells, detectable Bence Jones proteinuria, and immunoglobulin (Ig) A isotype. Neither concomitant diseases nor immunosuppression correlated with progression. CONCLUSION: Careful evaluation of marrow plasmacytosis, urinary paraprotein, background immunoglobulins, ESR, and paraprotein isotype might help identify at presentation patients with benign monoclonal gammopathies requiring stricter monitoring.     

Thalidomide for previously untreated indolent or smoldering multiple myeloma.

We conducted a clinical trial of thalidomide as initial therapy for asymptomatic smoldering (SMM) or indolent multiple myeloma (IMM). Sixteen patients were studied. Thalidomide was given orally at a dose of 200 mg/day for 2 weeks, and then increased as tolerated by 200 mg/day every 2 weeks to a maximum dose of 800 mg/day. Bone marrow microvessel density (MVD) and angiogenesis grading were estimated using CD34 immunostaining. Six patients had a confirmed response to therapy with at least 50% or greater reduction in serum and urine monoclonal (M) protein. When minor responses (25-49%) decrease in M protein concentration) were included, 11 of 16 patients (69%) responded to therapy. Major grade 3-4 toxicities included two patients with somnolence, and one patient each with syncope and neutropenia. Pre-treatment MVD was not a significant predictor of response to therapy, median MVD 4 and 12 in responders and non-responders respectively, P = 0.09. We conclude that thalidomide has significant activity in the treatment of newly diagnosed SMM/IMM. However, we do not recommend treatment with thalidomide at this stage since some patients with SMM/IMM can be stable for several months or years without any therapy. Additional randomized trials are needed to determine if thalidomide will delay progression to active multiple myeloma.