Is urine immunofixation electrophoresis necessary for monitoring myeloma patients who have undergone hematopoietic stem cell transplantation?

INTRODUCTION: To investigate the role of urine immunofixation electrophoresis in detecting relapse in patients with myeloma who have undergone autologous and allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: The study included a total of 78 patients, comprising 49 males and 29 females, with progressive disease or relapse after HSCT. Serum protein electrophoresis (sPE), serum immunofixation electrophoresis (sIFE) and serum free light chain κ/λ ratio in addition to urine immunofixation (uIFE) were studied. RESULTS: sPE, sIFE and κ/λ ratio demonstrated relapse in 65.3%, 88.3% and 58.9% of the cases by theirselves respectively. The combination panel of sPE and sIFE demonstrated relapse in 88.3% of patients whereas sPE, sIFE and κ/λ ratio all together demonstrated relapse in 95.8% of the patients. In relapsed patients, urine immunofixation was found to be positive in 16.2% of the patients. No patients with relapsed disease were missed by omitting uIFE from serum studies (sPE, sIFE and sFLC). CONCLUSION: For evaluation of relapse in MM patients after HSCT, uIFE had no additional diagnostic capability compared to serum studies (sPE, sIFE, and sFLC). Therefore, urine studies should be performed more selectively.

Early Prognostic Value of Monitoring Serum Free Light Chain in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation.

We hypothesized the levels of free light chains obtained before and after autologous stem cell transplantation can be useful in predicting transplantation outcome. We analyzed 70 multiple myeloma patients. Abnormal free light chain ratios before stem cell transplantation were found to be associated early progression, although without any impact on overall survival. At day +30, the normalization of levels of involved free light chain related with early progression. According to these results almost one-third reduction of free light chain levels can predict favorable prognosis after autologous stem cell transplantation.

A Randomized Study Comparing the Efficacy of Three Hepatitis B Vaccine Induction Regimens in Adult Patients with Hematological Malignancies.

OBJECTIVE: Non-responsiveness to hepatitis B virus (HBV) vaccines is not rare in hemato-oncological patients due to disease-associated or treatment-induced immune suppression. Although different strategies have been employed to improve the response rates, to date there is not an approved schedule for HBV immunization in patients with hematological malignancies. We designed a prospective randomized study to evaluate the efficacy of 3 different induction regimens for HBV vaccination. MATERIALS AND METHODS: In the standard-dose (SD) group, total vaccine dose delivered was 40 µg and patients were vaccinated with 20 µg at weeks 0 and 4. In the high-dose dose-intensive (HDDI) group, total vaccine dose delivered was 80 µg and patients were vaccinated with 40 µg at weeks 0 and 4. In the high-dose time-intensive (HDTI) group, total vaccine dose delivered was 80 µg and patients were vaccinated with 20 µg at weeks 0, 2, 4, and 6. RESULTS: In a cohort of 114 patients, 38.6% responded to HBV vaccination. The response rate in the SD arm, HDDI arm, and HDTI arm was 26.2%, 29.7%, and 44.4%, respectively (p>0.05). Age was the only variable identified as having a negative impact on response. CONCLUSION: Short of achieving statistical significance, a higher response rate was observed in the HDTI arm. Therefore, this study supports a high-dose, time-intensive HBV vaccine induction regimen in patients with hematological malignancies who are not on chemotherapy.

Serum free light chain response after 2 courses of induction chemotherapy predicts prognosis in myeloma patients.

BACKGROUND: The aim of this study was to investigate the prognostic effect of serum free light chain (sFLC) response after 2 cycles of first-line chemotherapy (CT) in multiple myeloma (MM) patients. MATERIALS AND METHODS: The data of 78 newly diagnosed MM patients who had sFLC levels at diagnosis and after 2 cycles of first-line CT were included in the study. The prognostic effect of sFLCs were evaluated with normalization of sFLC κ/λ ratio after 2 cycles of CT and involved/uninvolved (i/u) sFLCs. RESULTS: At the end of follow-up the probability of overall survival (OS) was 95.7% versus 68.5% in patients with and without normalized sFLC κ/λ ratio, respectively (P = .072). The probability of OS with i/u sFLC assessment was 97.4% versus 55.8% with regard to i/u sFLC ≤ 10 and > 10, respectively (P = .001). In univariate and multivariate analysis including sFLC ratio, age, sex, and International Staging System, i/u sFLC ratio > 10 after 2 cycles of CT was identified as an independent risk factor for OS (P = .015; hazard ratio [HR], 13.2; 95% confidence interval [CI], 1.668-104.65 vs. P = .011; HR, 15.17; 95% CI, 1.85-123.89). CONCLUSION: Early response assessment in terms of sFLC after 2 courses of induction CT seems to have a prognostic effect in MM patients. The methodology and timing of the evaluation based on sFLCs needs to be validated in prospective studies.

TCTP/HRF pathway and angiogenesis: a feasible intercourse in chronic lymphocytic leukemia.

This prospective study was planned to determine the intercourse between translationally controlled tumor protein (TCTP)/histamine releasing factor (HRF)/histamine pathway and angiogenesis in chronic lymphocytic leukemia (CLL). A total of 153 CLL patients were included. Serum histamine levels were higher in CLL patients. A positive correlation was found between microvessel density (MVD)-mast cell (MC) count; MVD-TCTP/HRF and MC count-TCTP/HRF. Microvessel density, MC and ZAP 70 were significantly higher in TCTP/HRF-positive group. Time to first treatment was shorter in patients with increased MVD and TCTP/HRF. Further data is essential to ascertain the role of TCTP/HRF pathway in tumor angiogenesis and CLL prognosis.

Tumor-associated macrophages as a prognostic parameter in multiple myeloma.

The interaction between multiple myeloma (MM) cells and the bone marrow stroma constitutes the basis of myeloma pathogenesis and has led the way for the corresponding therapeutic strategies. The aim of this study is to evaluate tumor-associated macrophages (TAMs) which is an important element of bone marrow stroma and its prognostic relevance in newly diagnosed MM patients. We also wanted to determine the association between TAMs and microvessel density (MVD). Sixty-eight patients, who were diagnosed with MM at the Department of Hematology, Gazi University Hospital, between January 2000 and January 2011, were reviewed retrospectively. Tumor-associated macrophages were evaluated by staining with anti-CD68 and anti-CD163 monoclonal antibodies, and MVD was evaluated by factor VIII staining. Median age was 60 (range, 40-84) years with 36 males and 32 females. The number of both CD 68+ and CD 163+ cells had a negative impact on OS at 6 years (p = 0.013 vs. 0.036; p = 0.015 vs. 0.039) in univariate and multivariate analysis in which age, sex, ISS, the induction treatment, and response to induction treatment are included as variables. High-grade MVD was found to be associated with increased CD163+ cell count. In conclusion, TAMs seems to be a promising prognostic histopathological marker in newly diagnosed MM patients.

A new target for myeloma therapy.

In this issue of Blood, Azab and colleagues demonstrate that PSGL-1 expressed on myeloma cells is involved with regulating tumor cell extravasation, homing, disease progression, and drug resistance.

Evaluation of multiple myeloma patients presenting with renal failure in a university hospital in the year 2010.

BACKGROUND: The aim of this cross-sectional study was to evaluate multiple myeloma patients presenting with renal failure in a University hospital. METHODS: The records of all the patients diagnosed with multiple myeloma in the departments of hematology and nephrology at Gazi University Hospital between January 2010 and January 2011 were reviewed retrospectively. Renal failure was defined as a serum creatinine level of ≥2 mg/dL. Median age was 63 (range 37-80) years, with 13 male and 17 female patients. RESULTS: Eight (26.7%) of the 30 patients had renal failure and 4 (50%) patients with renal failure required renal replacement therapy with hemodialysis after admission. Renal functions recovered in four (50%) of the eight patients after treatment. In one of the eight patients (12.5%) creatinine levels improved, but did not reach the level defined as reversal of renal failure. The renal functions of the three (37.5%) patients did not improve and they remained on chronic hemodialysis program during which one of them died due to a cerebrovascular accident and one other patient was lost due to follow-up. CONCLUSION: A substantial proportion of myeloma patients referred with renal failure might enjoy a disease-free survival and could be saved from chronic renal replacement therapy with prompt diagnosis and treatment in the era of new-generation anti-myeloma agents which provide fast and effective responses. Multiple myeloma should be considered in the differential diagnosis of acute renal failure even in the absence of hyperglobulinemia and hypercalcemia.

TSH-induced gene expression involves regulation of self-renewal and differentiation-related genes in human bone marrow-derived mesenchymal stem cells.

Bone marrow-derived mesenchymal stem cells are pluripotent cells that are capable of differentiating into a variety of cell types including neuronal cells, osteoblasts, chondrocytes, myocytes, and adipocytes. Despite recent advances in stem cell biology, neuroendocrine relations, particularly TSH interactions remain elusive. In this study, we investigated expression and biological consequence of TSH receptor (TSHR) interactions in mesenchymal stem cells of cultured human bone marrow. To the best of our knowledge, we demonstrated for the first time that human bone marrow-derived mesenchymal stem cells expressed a functional thyrotropin receptor that was capable of transducing signals through cAMP. We extended this study to explore possible pathways that could be associated directly or indirectly with the TSHR function in mesenchymal stem cells. Expression of 80 genes was studied by real-time PCR array profiles. Our investigation indicated involvements of interactions between TSH and its receptor in novel regulatory pathways, which could be the important mediators of self-renewal, maintenance, development, and differentiation in bone marrow-derived mesenchymal stem cells. TSH enhanced differentiation to the chondrogenic cell lineage; however, further work is required to determine whether osteoblastic differentiation is also promoted. Our results presented in this study have opened an era of regulatory events associated with novel neuroendocrine interactions of hypothalamic-pituitary axis in mesenchymal stem cell biology and differentiation.

Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials.

The role of thalidomide for previously untreated elderly patients with multiple myeloma remains unclear. Six randomized controlled trials, launched in or after 2000, compared melphalan and prednisone alone (MP) and with thalidomide (MPT). The effect on overall survival (OS) varied across trials. We carried out a meta-analysis of the 1685 individual patients in these trials. The primary endpoint was OS, and progression-free survival (PFS) and 1-year response rates were secondary endpoints. There was a highly significant benefit to OS from adding thalidomide to MP (hazard ratio = 0.83; 95% confidence interval 0.73-0.94, P = .004), representing increased median OS time of 6.6 months, from 32.7 months (MP) to 39.3 months (MPT). The thalidomide regimen was also associated with superior PFS (hazard ratio = 0.68, 95% confidence interval 0.61-0.76, P < .0001) and better 1-year response rates (partial response or better was 59% on MPT and 37% on MP). Although the trials differed in terms of patient baseline characteristics and thalidomide regimens, there was no evidence that treatment affected OS differently according to levels of the prognostic factors. We conclude that thalidomide added to MP improves OS and PFS in previously untreated elderly patients with multiple myeloma, extending the median survival time by on average 20%.

Prognostic value of bone marrow microvessel density and angiogenic cytokines in patients with multiple myeloma undergoing autologous stem cell transplant.

Angiogenesis is important for the proliferation and metastasis of most malignant neoplasms including multiple myeloma (MM). The aim of this study was to evaluate the role of bone marrow angiogenesis and angiogenic cytokines in patients with MM prior to and after autologous stem cell transplant (ASCT). Twenty-nine patients with MM who underwent ASCT had serial samples of serum and bone marrow biopsies at diagnosis, prior to ASCT, and at the 3rd and 6th months post-transplant. Besides bone marrow microvessel density (MVD), serum angiogenic cytokines including vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) and markers of disease activity such as interleukin-6 (IL-6), IL-1ß, C-reactive protein (CRP), ß(2)-microglobulin, and bone marrow plasma cells (BMPCs) were also determined. Bone marrow MVD, serum levels of IL-6, CRP, and ß(2)-microglobulin, and BMPCs decreased significantly from diagnosis to the 6th month post-transplant (p < 0.05). Serum FGF and IL-1ß levels decreased significantly until 3 months post-transplant, however lost this significance at the 6th month. Serum VEGF levels did not vary significantly during follow-up. MVD, serum angiogenic cytokine levels, and parameters reflecting disease activity were similar in responders and non-responders to induction chemotherapy. Cytokines and MVD both at diagnosis and prior to transplant did not show any correlation with overall survival (OS) and progression-free survival (PFS) after a median follow-up of 55 months after transplant (p > 0.05). Our findings suggest that bone marrow MVD decreases significantly with ASCT in MM, however without an impact on OS and PFS.

Value of 18F-fluorodeoxyglucose uptake in positron emission tomography/computed tomography in predicting survival in multiple myeloma.

PURPOSE: We assessed the role of the maximum standardized uptake value (SUV(max)) of bone marrow and the extramedullary lesion with the highest SUV(max) in positron emission tomography/computed tomography (PET/CT) of newly diagnosed multiple myeloma (MM) patients in predicting overall survival (OS). METHODS: A total of 61 newly diagnosed patients (55 MM and 6 plasmacytoma) were enrolled in the study [37 men and 24 women with a median age of 57 years (range 28-80 years)]. The SUV(max) of bone marrow and the extramedullary lesion in PET/CT was correlated with the levels of ß(2)-microglobulin, C-reactive protein (CRP), albumin, creatinine, per cent of bone marrow plasma cells, serum free light chain (FLC) ratio, International Staging System (ISS) score and Durie-Salmon stage. RESULTS: The extramedullary lesion with the highest SUV(max) showed significant correlation with bone marrow fluorodeoxyglucose (FDG) uptake (p = 0.027) and near significant correlation with ISS (p = 0.048). Bone marrow SUV(max) correlated significantly with the per cent of bone marrow plasma cell count (p = 0.024), CRP (p = 0.012) and ISS (p = 0.013). In stage III MM the mean values of SUV(max) in extramedullary lesions were significantly higher than stages I and II (6.23 ± 6.32 vs 2.85 ± 3.44, p = 0.023). The serum FLC ratio did not show any correlation with SUV(max) of lesions and bone marrow (p > 0.05). Forty-four MM patients with FDG-positive lesions in PET/CT showed inferior 5-year estimated survival (61.73%) when compared to 11 patients without FDG-positive lesions, all of whom were alive (p = 0.01). In multivariate analysis an extramedullary lesion with the highest SUV(max) was the only independent predictor of OS (p = 0.03). CONCLUSION: PET/CT allows identification of high-risk myeloma patients, and extramedullary lesions with the highest SUV(max) independently predict inferior OS.

Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group.

The combination of melphalan-prednisone-thalidomide (MPT) has been investigated in several clinical studies that differed significantly with regard to patient characteristics and treatment schedules. This prospective trial differs from previous melphalan-prednisone (MP) vs. MPT trials by treatment dosing, duration, routine anticoagulation, and permission for a crossover. Newly diagnosed patients with multiple myeloma (MM) (n=122) aged greater than 55 yr, not eligible for transplantation were randomized to receive 8 cycles of M (9 mg/m(2) /d) and P (60 mg/m(2) /d) for 4d every 6 wk (n=62) or MP and thalidomide (100 mg/d) continuously (n=60). Primary endpoint was treatment response and toxicities following 4 and 8 cycles of therapy. Secondary endpoints were disease-free (DFS) and overall survival (OS). Overall, MPT-treated patients were younger (median 69 yr vs. 72 yr; P=0.016) and had a higher incidence of renal impairment (RI, 19% vs. 7%, respectively; P=0.057). After 4 cycles of treatment (n=115), there were more partial responses or better in the MPT arm than in the MP arm (57.9% vs. 37.5%; P=0.030). However, DFS and OS were not significantly different between the arms after a median of 23 months follow-up (median OS 26.0 vs. 28.0 months, P=0.655; DFS 21.0 vs. 14.0 months, P=0.342, respectively). Crossover to MPT was required in 11 patients, 57% of whom responded to treatment. A higher rate of grade 3-4 infections was observed in the MPT arm compared with the MP arm (22.4% vs. 7.0%; P=0.033). However, none of these infections were associated with febrile neutropenia. Death within the first 3 months was observed more frequently in the MP arm (n=8, 14.0%) than in the MPT arm (n=2, 3.4%; P=0.053). Long-term discontinuation and dose reduction rates were also analyzed (MPT: 15.5% vs. MP: 5.3%; P=0.072). Although patients treated with MPT were relatively younger and had more frequent RI, better responses and less early mortality were observed in all age groups despite more frequent discontinuation.

Hepatitus B virus reactivation in HBV-DNA negative and positive patients with hematological malignancies.

Reactivation of hepatitis B virus (HBV) is a frequent complication of chemotherapy (CT) in patients with HBsAg carriers. In this prospective study, we documented CT induced HBV reactivation risk in patients with hematological malignancies. HBV reactivation risk is influenced by baseline viral load. Therefore, we divided our study population into two groups according to HBV-DNA status. HBV-DNA negative patients (n=18) were treated with nucleoside analogues once HBV reactivation was observed. HBV-DNA positive patients (n=12) commenced lamivudine before the initiation of the CT. In HBV-DNA negative patients HBV reactivation was found in 10 patients (55.5%). HBV reactivation was significantly more frequent in chronic lymphocytic leukemia (CLL) patients (P=0.008) and in patients receiving rituximab containing chemotherapy regimens (P=0.06). Eight patients (80.0%) responded to antiviral treatment after HBV reactivation. Two CLL patients experienced a flare-up after the withdrawal of antiviral therapy. In HBV-DNA positive patients, HBV reactivation was observed in four patients (33.3%) during lamivudine treatment and in two patients after lamivudine withdrawal. This study demonstrated the increased risk of CT-induced HBV reactivation in CLL patients, for the first time.

Thrombopoietic cytokines and platelet count in multiple myeloma.

Cytokines like interleukin (IL)-6 and IL-1beta are both implicated in multiple myeloma (MM) pathogenesis and megakaryopoiesis. The dynamic interaction between thrombopoiesis and thrombopoietic cytokines in MM may affect platelet (PLT) counts. Sixty-eight patients with MM (30 female, 38 male; median age 58 (40-79), 38 newly diagnosed, 15 in plateau, and 15 relapse and/or refractory patients) and 21 controls were included in the study. Plasma levels of thrombopoietin (TPO), IL-1beta, IL-11 and IL-6 were measured by ELISA. PLT counts were not different between the control group and MM patients with various disease stages and activity. IL-6 and TPO levels were higher in MM patients than healthy subjects (p < 0.001). PLT counts were inversely correlated with TPO (r = -0.566; p < 0.001) and positively correlated with IL-6 (r = 0.263; p = 0.04) levels in MM patients. TPO and IL-6 levels were significantly correlated (r = 0.305; p < 0.001). Disease activity has no effect on plasma cytokine levels. TPO levels were higher in stage III than stage I (p = 0.05) and stage II (p = 0.03) patients in newly diagnosed MM. High TPO levels induced by IL-6 may sustain normal PLT counts despite bone marrow infiltration by plasma cells and decreased PLT half-life.

Thrombopoietic cytokine and P-selectin levels in patients with multiple myeloma undergoing autologous stem cell transplantation: decrease in posttransplantation P-selectin levels might predict the degree of maximum response.

PURPOSE: This study was designed to determine the pretransplantation levels of thrombopoietic cytokines, which have a fundamental role in both megakaryopoiesis and myeloma pathogenesis and P-selectin in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation (AHSCT) and to correlate the cytokine levels with time to platelet recovery. The effect of AHSCT on the levels of the cytokines and its correlation with maximum disease response was also investigated. PATIENTS AND METHODS: The levels of thrombopoietin, interleukin (IL)-6, IL-11, IL-1beta, and P-selectin was measured before and 30 days after AHSCT in 32 patients with a median age of 55 years. The median time to platelet recovery was day +11 (range, 0-14 days) without any significant correlation with pretransplantation cytokine levels. RESULTS: No significant change was observed in thrombopoietic cytokines after AHSCT, whereas serum P-selectin levels showed a significant decrease after AHSCT (P = .001). The decrease in P-selectin was found to be significant in patients who achieved complete remission (P1 = .008) and partial remission (P2 = .018) early after AHSCT. Our data suggest that the level of thrombopoietic cytokines does not have a role in time to platelet recovery. CONCLUSION: The change in P-selectin levels early after transplantation could be a surrogate marker in determining the maximum posttransplantation response.

Osteonecrosis of the jaw in patients with multiple myeloma treated with zoledronic acid.

Intravenous bisphosphonates-the potent inhibitors of osteoclast-mediated bone resorption are among the most commonly prescribed drugs in the management of multiple myeloma (MM). Zoledronic acid (ZA) is a new generation potent intravenous bisphosphonate that has been approved for the treatment and prevention of bone lesions, and/or hypercalcemia associated with MM. Osteonecrosis of the jaw (ONJ) is an emerging serious side effect of the new generation bisphosphonates with a growing number of reports related to this pathological entity. ONJ usually appears following oral surgical and dental procedures but sometimes occur spontaneously. These cases are mostly seen and treated by dentists and oral surgeons. The aim of this study was to discuss the frequency, characteristics, risk factors, management and histopathological features of ZA induced ONJ based on the literature and illustrated with five own cases. Thirty-two patients with MM who received ZA for a median period of 26.5 +/- 18.7 months (min: 5 months, max: 76 months) were evaluated. ONJ was detected in five patients and mean drug duration time was 34 months. The frequency was 15% and the patients were usually symptomatic. There was no significant difference in terms of the duration of ZA in patients with and without ONJ. Management of these established cases were performed with medical treatment, minor debridement, sequestrectomy, and combining bone resection with autologous platelet rich plasma. Our data indicate that ZA therapy has a major role in the development of ONJ a fact that should be considered by physicians treating MM patients.

Allogeneic stem cell transplantation for severe aplastic anemia: graft rejection remains a problem.

We reviewed the outcome in 15 consecutive patients with severe aplastic anemia with a median age of 23 years who received matched sibling peripheral blood stem cell transplantation. Conditioning regimen was cyclophosphamide (Cy)+anti-thymocyte globulin (ATG). Cumulative incidence of transplant related mortality, graft failure, acute and chronic GVHD were 20%, 33%, 25%, and 8.3%, respectively. Conditioning with Cy only, resulted in higher rejection rate compared to Cy plus ATG (75% versus 12.5%, p=0.03). Eighty percent of patients are alive with a median follow-up of 19.5 (4.6-35.6) months. Two of the three patients who were re-transplanted with fludarabine had sustained donor chimerism.