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Biomedical subjects

S Vincent Rajkumar

Publications and source records attributed to S Vincent Rajkumar.

At least 73 records · Page 4Linked to original sources
PubMed2004

Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myeloma.

Adult-acquired Fanconi syndrome (FS) is a rare complication of monoclonal gammopathy. We retrospectively reviewed 32 patients diagnosed with adult-acquired FS between April 1968 and June 2002 at Mayo Clinic (Rochester, MN). At diagnosis, most patients had monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM), with a median creatinine level of 176.8 microM (2.0 mg/dL; range, 79.56-327.08 microM [0.9-3.7 mg/dL]) and evidence of osteomalacia. During the average 65 months (range, 2-238 months) of follow-up, 5 patients developed end-stage renal disease (ESRD) and only 1 of 14 patients with MGUS transformed to multiple myeloma (MM). Also, 14 deaths occurred, with only 1 from ESRD but 4 from alkylator-related leukemia or myelodysplastic syndrome. Chemotherapy offered little benefit on renal functions of MGUS or SMM patients. In conclusion, FS associated with monoclonal gammopathy does not appear to confer an additional risk of subsequent evolution to MM. ESRD occurs late in the disease process.

Adult↗
PubMed2004

Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study.

Primary systemic amyloidosis (AL) is a plasma cell dyscrasia resulting in multisystem failure and death. High-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) has been associated with higher response rates and seemingly higher overall survival than standard chemotherapy. Selection bias, however, confounds interpretation of these results. We performed a case-match-control study comparing overall survival of 63 AL patients undergoing transplantation with 63 patients not undergoing transplantation. Matching criteria included age, sex, time to presentation, left ventricular ejection fraction, serum creatinine, septal thickness, nerve involvement, 24-hour urine protein, and serum alkaline phosphatase. According to design, there was no difference between the groups with respect to sex (57% males), age (median, 53 years), left ventricular ejection fraction (65%), number of patients with peripheral nerve involvement (17%), cardiac interventricular septal wall thickness (12 mm), serum creatinine (1.1 mg/dL [97.24 micromol/L]), and bone marrow plasmacytosis (8%). Sixty-six patients have died (16 cases and 50 controls). For PBSCT and control groups, respectively, the 1-, 2-, and 4-year overall survival rates are 89% and 71%; 81% and 55%; and 71% and 41%. Outside a randomized clinical trial, these results present the strongest data supporting the role of PBSCT in selected patients with AL.

Adult↗
PubMed2004

Cell proliferation of myeloma plasma cells: comparison of the blood and marrow compartments.

The plasma cell labeling Index (PCLI), a measure of marrow plasma cells in S phase of the cell cycle, provides a good estimate of the proliferative capacity of the malignant clonal plasma cells. Multiple studies have also demonstrated its prognostic value in multiple myeloma (MM). Clonal plasma cells have been demonstrated in the peripheral blood of patients with multiple myeloma. The labeling index of these circulating cells can also be determined by a method similar to that employed for marrow plasma cells. The goal of this study was to compare the proliferation kinetics of plasma cells in the marrow to that in the circulation. The PCLI was estimated on peripheral blood (PBLI) and bone marrow aspirates (BMLI) using a slide-based bromodeoxyuridine (BrdU) immunofluorescence microscopy technique. One hundred seventeen patients who had simultaneous estimation of the PBLI and BMLI and who had > or =90% of the blood cIg+ cells identified as monoclonal plasma cells were studied. The PBLI was generally lower than the BMLI (median difference 0.4) and correlated with the BMLI (rho = 0.491, P < 0.0001). Twenty-seven patients with PBLI higher than BMLI had a poorer prognosis, with median survival of 2 months from the time of the labeling index determination, compared to 12 months for the remaining 90 patients (P = 0.01). Myeloma plasma cells circulating in the peripheral blood are capable of proliferation, albeit at a slower rate compared to those in the marrow. These differences reflect a more favorable microenvironment in the marrow likely resulting from the differences in the cytokine levels and supporting stromal cells in the marrow.

Adult↗
PubMed2004

Presence of monoclonal free light chains in the serum predicts risk of progression in monoclonal gammopathy of undetermined significance.

We hypothesized that the presence of monoclonal free light chains (FLC) in the serum of patients with monoclonal gammopathy of undetermined significance (MGUS) is a marker of clonal evolution and a risk factor for progression. Forty-seven patients with MGUS and documented progression to myeloma or related malignancy were compared with 50 age- and gender-matched patients with MGUS and no evidence of progression after 5 or more years of follow-up. The presence of an abnormal kappa/lambda FLC ratio in the serum was associated with a higher risk of MGUS progression (relative risk 2.5; 95% confidence interval: 1.6-4.0; P < 0.001).

Biomarkers, Tumor↗
PubMed2004

Fracture risk in monoclonal gammopathy of undetermined significance.

UNLABELLED: To assess fractures in monoclonal gammopathy of undetermined significance (MGUS), the precursor of multiple myeloma, we followed 488 Olmsted County, MN, residents with MGUS in a retrospective cohort study. There was a 2.7-fold increase in the risk of axial fractures but no increase in limb fractures. The pathophysiologic basis for the increased axial fractures should be determined. INTRODUCTION: Multiple myeloma is often preceded by monoclonal gammopathy of undetermined significance (MGUS). Fractures are common in myeloma as a result of lytic bone lesions, generalized bone loss, and elevated bone turnover from excessive cytokine production. Whether fractures are also increased in MGUS is unknown. MATERIALS AND METHODS: In a population-based retrospective cohort study, 488 Olmsted County, MN, residents with MGUS first diagnosed in 1960-1994 (52% men; mean age, 71.4 +/- 12.8 years) were followed for 3901 person-years; follow-up was censored at progression to myeloma. The relative risk of fractures was assessed by standardized incidence ratios (SIRs), and risk factors were evaluated in proportional hazards models. RESULTS AND CONCLUSIONS: Altogether, 200 patients experienced 385 fractures. Compared with expected rates in the community, statistically significant increases were seen for fractures at most axial sites, for example, vertebrae (SIR, 6.3; 95% CI, 5.2-7.5). There was a slight increase in hip (SIR, 1.6; 95% CI, 1.2-2.2) but not distal forearm fractures (SIR, 0.8; 95% CI, 0.4-1.5). The relative risk (SIR) of any axial fracture was 2.7 (95% CI, 2.3-3.1) compared with only 1.1 (95% CI, 0.9-1.4) for all limb fractures combined. In a multivariate analysis, the independent predictors of any subsequent fracture were age (hazard ratio [HR] per 10-year increase, 1.4; 95% CI, 1.2-1.6) and corticosteroid use (HR, 1.8; 95% CI, 1.2-2.6); greater weight at diagnosis (HR per 10 kg, 0.8; 95% CI, 0.8-0.9), and IgG monoclonal protein (HR, 0.7; 95% CI, 0.5-0.97) were protective. Baseline monoclonal protein level, a determinant of myeloma progression, did not predict fracture risk. Thus, the risk of axial, but not peripheral, fractures is increased among MGUS patients even before progression to myeloma. The pathophysiologic basis for this should be determined because elevated bone turnover, for example, might be treatable.

Accidental Falls↗
PubMed2004

Long-term follow-up of 241 patients with monoclonal gammopathy of undetermined significance: the original Mayo Clinic series 25 years later.

OBJECTIVE: To determine the long-term outcome of patients with monoclonal gammopathy of undetermined significance (MGUS). PATIENTS AND METHODS: We reviewed the medical records of 241 patients with MGUS who were examined at the Mayo Clinic in Rochester, Minn, between January 1, 1956, and December 31, 1970. RESULTS: Follow-up was 3579 person-years (median, 13.7 years; range, 0-39 years). Only 14 patients (6%) were alive and had no substantial increase of M protein at last follow-up; 138 patients (57%) died without evidence of multiple myeloma or a related disorder; a malignant lymphoplasma cell proliferative disorder developed in 64 patients (27%). The interval from diagnosis of MGUS to diagnosis of multiple myeloma or related disorder ranged from 1 to 32 years (median, 10.4 years). CONCLUSIONS: The median survival rate of study patients with MGUS was only slightly shorter than that of a comparable US population. Risk of progression of MGUS to lymphoplasma cell malignancy is indefinite and persists even after more than 30 years of follow-up, with no reliable predictors of malignant evolution.

Disease Progression↗
PubMed2004

Clinical course of patients with relapsed multiple myeloma.

OBJECTIVE: To study the clinical course of patients with multiple myeloma (MM) that relapses after initial therapy. PATIENTS AND METHODS: Patients with MM, seen at the Mayo Clinic in Rochester, Minn, between January 1, 1985, and December 31, 1998, were identified from a prospectively maintained database. Our study population consisted of 578 patients with newly diagnosed MM who were followed up and monitored throughout their clinical course at our institution. RESULTS: The median age of the 578 patients with MM was 65 years (range, 26-92 years); 228 patients (39%) were women. The median follow-up of 71 surviving patients was 55 months (range, 0-202 months). The overall survival (OS) for the 578 patients at 1, 2, and 5 years was 72%, 55%, and 22%, respectively; the median OS from initial therapy was 28.4 months. The median OS of 355 patients who experienced relapse after initial treatment was 17.1 months from initiation of the second therapy, and 84% died within 5 years. The duration of response decreased consistently with each successive regimen. Patients with a high plasma cell labeling index (> or = 1.0%), low platelet count (< 150 x 10(9)/L), high creatinine level (> or = 2.0 mg/dL), and low albumin level (< 3.0 g/dL) had a poorer prognosis. CONCLUSIONS: Our study revealed decreasing response duration with increasing number of salvage regimens, probably reflecting acquired drug resistance and an increasing proliferative rate of the myeloma cells. Patients who experienced relapse after initial treatment and received salvage therapy had a median survival of nearly 1.5 years. This must be remembered when making treatment decisions for these patients and must be factored in when assessing the efficacy of new therapies.

Adult↗
PubMed2004

Effect of statins, smoking and obesity on progression of monoclonal gammopathy of undetermined significance: a case-control study.

Interleukin-6 (IL-6) and C-reactive protein (CRP, a surrogate marker for IL-6) are important in monoclonal gammopathy of undetermined significance (MGUS) and myeloma. Smoking and obesity may elevate CRP levels, while statins decrease CRP levels. A case-control study in 200 MGUS patients found that statin use, smoking history and obesity do not affect MGUS progression.

Adult↗
PubMed2003

Identification of genes modulated in multiple myeloma using genetically identical twin samples.

Genetic heterogeneity between individuals confounds the comparison of gene profiling of multiple myeloma (MM) cells versus normal plasma cells (PCs). To overcome this barrier, we compared the gene expression profile of CD138+ MM cells from a patient bone marrow (BM) sample with CD138+ PCs from a genetically identical twin BM sample using microarray profiling. Two hundred and ninety-six genes were up-regulated and 103 genes were down-regulated at least 2-fold in MM cells versus normal twin PCs. Highly expressed genes in MM cells included cell survival pathway genes such as mcl-1, dad-1, caspase 8, and FADD-like apoptosis regulator (FLIP); oncogenes/transcriptional factors such as Jun-D, Xbp-1, calmodulin, Calnexin, and FGFR-3; stress response and ubiquitin/proteasome pathway-related genes and various ribosomal genes reflecting increased metabolic and translational activity. Genes that were down-regulated in MM cells versus healthy twin PCs included RAD51, killer cell immunoglobulin-like receptor protein, and apoptotic protease activating factor. Microarray results were further confirmed by Western blot analyses, immunohistochemistry, fluorescent in situ hybridization (FISH), and functional assays of telomerase activity and bone marrow angiogenesis. This molecular profiling provides potential insights into mechanisms of malignant transformation in MM. For example, FGFR3, xbp-1, and both mcl-1 and dad-1 may mediate transformation, differentiation, and survival, respectively, and may have clinical implications. By identifying genes uniquely altered in MM cells compared with normal PCs in an identical genotypic background, the current study provides the framework to identify novel therapeutic targets.

Adult↗
PubMed2003

Long-term follow-up of IgM monoclonal gammopathy of undetermined significance.

Little effort has been made to quantitate adverse outcomes of monoclonal gammopathy of undetermined significance (MGUS) of the immunoglobulin M (IgM) class, which progresses to lymphoma or Waldenström macroglobulinemia, whereas IgA and IgG MGUS progress to multiple myeloma, primary amyloidosis (AL), or a related plasma cell disorder. From 1960 to 1994, IgM MGUS was diagnosed in 213 patients in southeastern Minnesota. The end point was progression to lymphoma or a related disorder, as assessed with the Kaplan-Meier method. The 213 patients were followed up for 1567 person-years (median, 6.3 years per patient). Lymphoma developed in 17 patients (relative risk [RR], 14.8), Waldenström macroglobulinemia in 6 (RR, 262), primary amyloidosis in 3 (RR, 16.3), and chronic lymphocytic leukemia in 3 (RR, 5.7). The relative risk of progression was 16-fold higher in the patients with IgM MGUS than in the white population of the Iowa Surveillance, Epidemiology, and End Results Program. Cumulative incidence of progression was 10% at 5 years, 18% at 10 years, and 24% at 15 years. On multivariate analysis, the serum monoclonal protein and serum albumin concentrations at diagnosis were the only risk factors for progression to lymphoma or a related disorder. Risk for progression to lymphoma or a related disorder at 10 years after the diagnosis of MGUS was 14% with an initial monoclonal protein concentration of 0.5 g/dL or less, 26% with 1.5 g/dL, 34% for 2.0 g/dL, and 41% for more than 2.5 g/dL.

Adult↗
PubMed2003

A phase 2 study of bortezomib in relapsed, refractory myeloma.

BACKGROUND: Bortezomib, a boronic acid dipeptide, is a novel proteasome inhibitor that has been shown in preclinical and phase 1 studies to have antimyeloma activity. METHODS: In this multicenter, open-label, nonrandomized, phase 2 trial, we enrolled 202 patients with relapsed myeloma that was refractory to the therapy they had received most recently. Patients received 1.3 mg of bortezomib per square meter of body-surface area twice weekly for 2 weeks, followed by 1 week without treatment, for up to eight cycles (24 weeks). In patients with a suboptimal response, oral dexamethasone (20 mg daily, on the day of and the day after bortezomib administration) was added to the regimen. The response was evaluated according to the criteria of the European Group for Blood and Marrow Transplantation and confirmed by an independent review committee. RESULTS: Of 193 patients who could be evaluated, 92 percent had been treated with three or more of the major classes of agents for myeloma, and in 91 percent, the myeloma was refractory to the therapy received most recently. The rate of response to bortezomib was 35 percent, and those with a response included 7 patients in whom myeloma protein became undetectable and 12 in whom myeloma protein was detectable only by immunofixation. The median overall survival was 16 months, with a median duration of response of 12 months. Grade 3 adverse events included thrombocytopenia (in 28 percent of patients), fatigue (in 12 percent), peripheral neuropathy (in 12 percent), and neutropenia (in 11 percent). Grade 4 events occurred in 14 percent of patients. CONCLUSIONS: Bortezomib, a member of a new class of anticancer drugs, is active in patients with relapsed multiple myeloma that is refractory to conventional chemotherapy.

Adult↗
PubMed2003

Monoclonal gammopathies of undetermined significance: a review.

Monoclonal gammopathy of undetermined significance (MGUS) denotes the presence of a monoclonal protein (M-protein) in patients without evidence of multiple myeloma (MM), macroglobulinemia, amyloidosis (AL), or a related plasma cell proliferative disorder. MGUS is found in approximately 3% of persons older than 70 years and in about 1% of those older than 50 years. In a series of 1384 patients from south-eastern Minnesota in whom MGUS was diagnosed at Mayo Clinic from 1960 through 1994, the risk of progression was 1% per year. Patients were at risk of progression even after 25 years or more of a stable monoclonal gammopathy. The risk of development of MM was increased by 25-fold, the risk of macroglobulinemia was 46-fold, and the risk of primary AL was 8.4-fold when compared with a similar population (Surveillance, Epidemiology and End Results). The concentration of the serum M-protein was the major independent predictor of progression. Patients with an immunoglobulin M (IgM) or an IgA monoclonal gammopathy had a higher risk of progression than those with an IgG monoclonal gammopathy. The presence of a urine M-protein or the reduction of one or more uninvolved Igs was not a risk factor for progression. MGUS may be associated with many different disorders, including lymphoproliferative diseases, leukemia, connective tissue disorders, dermatologic diseases, and neurologic disorders.

Diagnosis, Differential↗
PubMed2003

Bone marrow angiogenesis and circulating plasma cells in multiple myeloma.

Bone marrow (BM) angiogenesis is increased in multiple myeloma (MM) and has prognostic significance. The presence of circulating plasma cells (PCs) in MM is associated with a poorer prognosis. We examined BM biopsies obtained at diagnosis of MM for angiogenesis, and correlated the microvessel density (MVD) with the presence of circulating PCs. There was a positive correlation between the absolute number of circulating PCs and the mean MVD. This relationship was independent of the disease activity and of the PC burden in the marrow. The increased angiogenesis may promote plasma cell proliferation and enable PC migration into the circulation.

Bone Marrow↗
PubMed2003

Plasma levels of tumour necrosis factor alpha and interleukin-6 predict progression-free survival following thalidomide therapy in patients with previously untreated multiple myeloma.

We studied marrow angiogenesis and plasma levels of angiogenic cytokines in 38 patients receiving thalidomide therapy for previously untreated myeloma. The effect of therapy and the relationship of cytokine levels to myeloma cell proliferation, bone marrow microvessel density and progression-free survival (PFS) were studied. High pretreatment tumour necrosis factor-alpha (TNFalpha) levels (> 11 pg/ml) and increased interleukin (IL)-6 of > 2 pg/ml predicted for poorer PFS (TNFalpha, 48% versus 74% at 2 years, P = 0.01; IL-6, 24% versus 70% at 2 years, P = 0.01). None of the other parameters predicted response or PFS, and no significant changes in cytokine levels occurred with therapy.

Adult↗
PubMed2003

Thalidomide in newly diagnosed multiple myeloma and overview of experience in smoldering/indolent disease.

Based on the activity of single-agent thalidomide demonstrated in relapsed or refractory multiple myeloma, investigators have evaluated the role of this agent in the treatment of earlier stage disease. Two key phase II trials of thalidomide plus dexamethasone in patients with previously untreated symptomatic multiple myeloma have yielded overall response rates of 64% to 73%. Comparable response rates, reduced toxicity, and increased patient convenience with oral administration suggest it may offer an alternative to standard infusional chemotherapies, such as vincristine/doxorubicin/dexamethasone (VAD), before stem cell mobilization and high-dose chemotherapy in patients with active disease; further study is warranted. Two key phase II trials of single-agent thalidomide in patients with smoldering/indolent (asymptomatic) disease have yielded overall response rates of approximately 35%, and further study of thalidomide in this setting is also indicated. The primary toxicities of thalidomide-based therapy are neuropathy, sedation/fatigue, constipation, and rash. Studies of thalidomide in combination with dexamethasone suggest toxicities of both agents may be increased due to the synergy of these agents. Phase III trials of thalidomide in newly diagnosed symptomatic multiple myeloma or smoldering/indolent disease are ongoing.

Adjuvants, Immunologic↗
PubMed2003

Angiogenesis in Waldenstrom's macroglobulinemia.

Angiogenesis has been associated with disease progression and poor prognosis in several hematologic malignancies including multiple myeloma. In this article, we summarize the rationale for studying angiogenesis in plasma cell disorders including Waldenstrom's macroglobulinemia (WM). We also discuss the results of a study of angiogenesis in WM conducted at the Mayo Clinic. Our study shows that only 30% of patients with WM had increased (intermediate- or high-grade) angiogenesis. A weak correlation was found between mean microvessel density (MVD) and marrow infiltration. Unlike multiple myeloma, MVD and angiogenesis grade were not predictive factors for survival. Although these findings suggest that angiogenesis may not be a major factor in WM, it does not exclude a paracrine role for angiogenic cytokines or the study of antiangiogenic agents in this disease.

Angiogenesis Inhibitors↗