losartan-potassium and Multiple-Myeloma

The last decade has witnessed a dramatic progress in the treatment of multiple myeloma. Both the chemotherapy protocols and the supportive therapy options have improved significantly since the publication of the previous Hungarian national guideline. An increasing proportion of patients now reach a durable response and cure became a potential option for some. The aim of the authors was to adapt the international guidelines to the specific circumstances of the Hungarian healthcare system in the light of the most recent developments.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Protocols; Diphosphonates; Drug Administration Schedule; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Hungary; Multiple Myeloma; Practice Guidelines as Topic

Tumor associated macrophages (TAMs) are a rich source of pro-angiogenic cytokines and growth factors, and a relationship between the TAMs content, the rate of tumor growth and the extent of vascularization has been shown in several tumors. In this article, we have summarized the literature and our data concerning the involvement of TAMs in angiogenesis occurring in multiple myeloma. Finally, therapeutic aspects concerning the potential role of molecules which inhibit macrophage recruitment in the tumor side are also discussed.

Topics: Animals; Antineoplastic Agents; Erythropoietin; Humans; Macrophages; Multiple Myeloma; Neovascularization, Pathologic

Drug-induced liver injury (DILI) is a leading cause of liver failure and an important safety issue in drug development. Thalidomide is nowadays used for the treatment of several conditions including multiple myeloma (MM). Several adverse effects have been described but liver toxicity was seldom reported. We describe a case of thalidomide-induced hepatitis in a man treated for MM. The clinical setting and temporal association between the start of the drug and liver injury allowed the assumption of the causative role of thalidomide. As its clinical indications expand we wish to increase awareness of a new potential side effect of thalidomide. A short review on thalidomide-induced liver injury is also presented.

Topics: Acute Disease; Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Chemical and Drug Induced Liver Injury; Darbepoetin alfa; Diazepam; Erythropoietin; Fatal Outcome; Humans; Jaundice, Obstructive; Liver Function Tests; Male; Melphalan; Multiple Myeloma; Omeprazole; Pneumonia; Polypharmacy; Prednisolone; Thalidomide

In this chapter we want to give an overview on various supportive measures, which help to prevent or to fight complications of multiple myeloma, improve patient wellbeing and increase safety of administration of specific anti-myeloma therapy.

Topics: Anemia; Blood Transfusion; Bone Diseases; Calcitonin; Clodronic Acid; Diphosphonates; Erythropoietin; Fractures, Bone; Hematinics; Humans; Hypercalcemia; Imidazoles; Multiple Myeloma; Osteoporosis; Pamidronate; Recombinant Proteins; Renal Insufficiency; Zoledronic Acid

Heavy chain deposition disease (HCDD) is a comparatively recently described entity characterized by glomerular and tubular basement membrane deposition of monoclonal heavy chains without associated light chains. To our knowledge, review of the literature shows only 24 previously reported cases of HCDD with unequivocal evidence of monoclonal heavy chain deposition in the kidney using immunofluorescence microscopic and electron microscopic studies. The predominant heavy chain subtype was γ. There has been a single case of μ HCDD and 2 previously reported cases of α HCDD. In this report, we describe 3 additional cases of α HCDD, all with a crescentic pattern of injury and one of which was associated with cutis laxa. We compare their clinicopathologic features with all previously reported cases of HCDD.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cutis Laxa; Dexamethasone; Diabetic Nephropathies; Erythropoietin; Fatal Outcome; Female; Heavy Chain Disease; Hematuria; Humans; Hypertension, Renal; Immunoglobulin alpha-Chains; Immunoglobulin gamma-Chains; Immunoglobulin mu-Chains; Kidney Glomerulus; Male; Multiple Myeloma; Paraproteinemias; Proteinuria; Pyrazines; Thalidomide; Urticaria; Vasculitis, Leukocytoclastic, Cutaneous

Topics: Adrenal Cortex Hormones; Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials as Topic; Erythropoietin; Female; Humans; Models, Biological; Multiple Myeloma; Myeloproliferative Disorders; Neoplasms; Recombinant Proteins; Risk; Thrombophilia; Thrombosis; Venous Thromboembolism

The effectiveness of erythropoiesis-stimulating agents (ESAs) for the treatment of anemia in patients with non-myeloid hematological malignancies needs to be assessed as the response to their administration is not uniform and their cost is high. We conducted a systematic review (SR) of the literature to identify reports of the effect of ESAs on survival, quality of life (QOL), transfusion requirements, and anemia. The entries to MEDLINE, EMBASE, and the Cochrane Library databases, and abstracts published in the proceedings of the annual meetings of the American Society of Clinical Oncology and the American Society of Hematology were searched. Seventeen reports and five abstracts of randomized trials fulfilled prospective criteria for inclusion. Five trials reported on survival; three failed to detect differences between groups and two demonstrated inferior survival in patients allocated to an ESA. Seven trials and three abstracts reported on QOL with four articles and three abstracts describing improvements in patients allocated to erythropoietin. However, important methodologic limitations were identified in these reports. Seven randomized controlled trials reported a reduction in the proportion of patients transfused. The absolute risk reduction in transfusions ranged from 15% to 24%. This is the only SR that assesses the use of erythropoiesis-stimulating agents specifically in patients with hematological malignancies. We conclude that available data evaluating ESAs in patients with hematologic malignancies demonstrate that these agents reduce transfusion requirements. Limitations of these data preclude conclusions that these agents improve QOL. More data are required to confirm the inferior survival associated with ESAs.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Lymphoma; Multiple Myeloma; Randomized Controlled Trials as Topic; Recombinant Proteins; Survival Analysis

Recombinant human erythropoietin (epoetin) has become the standard of care in the treatment of anaemia resulting from cancer and its treatment, and chronic kidney disease. The discovery that erythropoietin and its receptor are located in regions outside the erythropoietic system has led to interest in the potential role of epoetin in other tissues, such as the central nervous system. Animal studies have shown that systemically applied epoetin can cross the blood-brain barrier, where it reduces tissue injury associated with stroke, blunt trauma and experimental autoimmune encephalomyelitis. Pilot studies in humans have shown that epoetin treatment given within 8 h of stroke reduces infarct size and results in a significantly better outcome when compared with placebo treatment. Studies also suggest that epoetin has the potential to improve cognitive impairment associated with adjuvant chemotherapy in patients with cancer. Anaemia is a major factor causing tumour hypoxia, a condition that can promote changes within neoplastic cells that further tumour survival and malignant progression and also reduces the effectiveness of several anticancer therapies including radiotherapy and oxygen-dependent cytotoxic agents. Use of epoetin to prevent or correct anaemia has the potential to reduce tumour hypoxia and improve treatment outcome. Several therapeutic studies in anaemic animals with experimental tumours have shown a beneficial effect of epoetin on delaying tumour growth. Furthermore, clinical observations in patients with multiple myeloma and animal studies have suggested that epoetin has an antimyeloma effect, mediated via the immune system through activation of CD8+ T cells. Therefore, the role of epoetin may go well beyond that of increasing haemoglobin levels in anaemic patients, although additional studies are required to confirm these promising results.

Topics: Anemia, Hypochromic; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Hypoxia; Central Nervous System Diseases; Chemotherapy, Adjuvant; Cognition; Erythropoietin; Humans; Multiple Myeloma; Neoplasms; Pilot Projects; Recombinant Proteins

Topics: Anemia; Autoimmune Diseases; Cell Hypoxia; Disease-Free Survival; Double-Blind Method; Erythropoietin; Heart Failure; Humans; Kidney; Kidney Diseases; Lymphoma, Non-Hodgkin; Multiple Myeloma; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins

Within the past decade, clinical trials have shown that the presence of anemia can diminish the physical status, functional abilities, and overall quality of life (QOL) of cancer patients and can negatively influence the outcome of their treatment. However, recent preclinical and clinical studies have also shown that increasing hemoglobin levels by administering recombinant human erythropoietin (rHuEPO, epoetin alfa) may ameliorate anemia and, in doing so, improve QOL and possibly result in better treatment outcomes following radiotherapy, chemotherapy, or a combination of these modalities. Several mechanisms by which rHuEPO may improve treatment outcome have been proposed, including correction of tumor hypoxia, increased sensitivity of tumor cells to radiotherapy and chemotherapy, correction of anemia and its associated symptoms (particularly fatigue), and immune-modulated effects of rHuEPO on tumor growth. Improvement of tumor oxygenation by rHuEPO could affect treatment outcome in two ways. First, correction of hypoxia results in the downregulation of hypoxia-inducible factor 1 (HIF-1), a key regulator of cellular adaptive responses to hypoxia (e.g., angiogenesis), including many pathways that are important for tumor growth and metastasis. Interruption of the HIF-1 pathway not only limits growth of the primary tumor but also reduces the potential for the development of more aggressive tumors and metastatic spread, which could ultimately improve treatment outcome. Second, within the tumor, it is the hypoxic cells that are resistant to oxygen-dependent radiotherapy and chemotherapy, and improvement in their oxygenation would increase their sensitivity to the cytotoxic effects of such treatment. Correction of anemia and its associated symptoms, particularly fatigue, can have a beneficial effect on patient QOL, and this in turn may translate into greater tolerance of radiotherapy and chemotherapy, allowing patients to receive full doses and on-schedule dosing, and thus have an increased likelihood of a therapeutic response. Lastly, results of a study using a murine model of multiple myeloma have indicated that rHuEPO may induce an immune-mediated antitumor effect. Therefore, additional research is warranted to further explore the biologic actions of rHuEPO and to determine their relevance to therapeutic outcome.

Topics: Anemia; Animals; Cell Hypoxia; Clinical Trials as Topic; Combined Modality Therapy; Disease Models, Animal; Drug Interactions; Drug Resistance, Neoplasm; Erythropoietin; Fatigue; Humans; Mice; Multiple Myeloma; Neoplasms; Quality of Life; Radiation Tolerance; Recombinant Proteins; T-Lymphocytes; Treatment Outcome

Anemia is a common complication in patients with multiple myeloma (MM) and occurs in more than two thirds of all patients. The most frequent underlying pathophysiological mechanism is anemia of chronic disease (ACD), relative erythropoietin (EPO) deficiency (due partly to renal impairment) and myelosuppressive effects of chemotherapy, but many other factors may account for or contribute to anemia in myeloma. In patients who achieve complete remission after chemotherapy, anemia usually normalizes. Nonresponders and relapsing myeloma patients often continue to suffer from anemia. Treatment options for anemic myeloma patients include red blood cell (RBC) transfusions and recombinant human erythropoietin (rHuEPO). Red blood cell transfusions convey an immediate effect and rapidly increase the patient's hemoglobin level. Unfortunately, effects of RBC transfusions are only transient and can be associated with several risks, including infections and mild to even life-threatening immunologic reactions. rHuEPO is biologically equivalent to the human endogenous hormone EPO, and its application leads to an increase of hemoglobin levels over an extended time without the risks of blood transfusions. Several studies reported a significant improvement of erythropoiesis, reduction in transfusion need, and improved quality of life by using rHuEPO as long-term treatment of myeloma-associated anemia. Recently, an international expert panel recommended the use of rHuEPO for anemic myeloma patients where other possible causes of anemia have been eliminated.

Topics: Anemia; Cell Hypoxia; Clinical Trials as Topic; Erythropoietin; Fatigue; Humans; Models, Biological; Multiple Myeloma; Neovascularization, Pathologic; Recombinant Proteins; Transfusion Reaction; Treatment Outcome

The prevalence of tumour anaemia in patients with multiple myeloma is greater than 80%. At the time of diagnosis 20% of these patients are already anaemic. In about 70% of patients with multiple myeloma, recombinant human erythropoietin (r-HuEPO) leads to a reduction in transfusion frequency, resulting in a drop in transfusion- related side-effects like infections and immune reactions, iron overload and hyperviscosity which often negatively influence the course of disease. A further reason for the use of erythropoietin is to achieve and maintain high haemoglobin levels (11-12 g/dl), which are of considerable prognostic significance in patients with multiple myeloma. Increasing Hb levels with r-HuEPO also improve the quality of life of patients, thus leading to better therapy compliance. The trade-off between high costs of an erythropoietin treatment and lower indirect costs (infusion material, personal equipment, patient transport costs, etc.) should be evaluated. Nevertheless, an exact definition of patients for whom the use of erythropoietin is beneficial is warranted. The pathogenesis of anaemia and the clinical experiences of erythropoietin in patients with multiple myeloma are discussed.

Topics: Anemia; Contraindications; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Hemoglobinometry; Humans; Multiple Myeloma; Recombinant Proteins; Treatment Outcome

We have done a systematic review of all randomised studies in myeloma, identified through a comprehensive search. Our aim was to investigate and critically examine the effects of various treatment modalities on outcome in patients with multiple myeloma and address 22 specific clinical questions in the management of this disease. As a result of our analysis we identified two therapeutic advances in the management of myeloma that, according to the evidence, are most important for improving outcome. These advances were: introduction of high dose chemotherapy, which appears to be superior to conventional chemotherapy, and the use of bisphosphonates, which decrease the probability of pathological vertebral fractures. However, the overall quality of the body of evidence for myeloma management was poor. Many trials were done with small sample sizes, and did not include reporting power analysis. The majority of studies had inadequate allocation concealment, and few were analysed according to intention to treat principle. We conclude that the quality of total evidence supporting treatment recommendations in myeloma is modest at best and has an ample scope for improvement.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Boronic Acids; Bortezomib; Diphosphonates; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Hematinics; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Neoplasm Staging; Pyrazines; Randomized Controlled Trials as Topic; Recombinant Proteins; Salvage Therapy; Survival Analysis; Time Factors; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome

Multiple myeloma (MM) is characterized by infiltration of bone marrow with a clone of neoplastic plasma cells. Impaired hematopoiesis and reduced production of functional immunoglobulins, as well as the induction of pathognomonic osteolytic lesions primarily contribute to the morbidity of patients with MM. Conventional chemotherapy is the treatment of choice for older patients, whereas those under 60 years benefit significantly from high-dose therapy followed by stem-cell rescue. The use of tandem transplantation, developed to further escalate the conditioning dose, has achieved additional improvement in survival. Interferon-alpha and glucocorticoids are effective as maintenance measures in MM but remain controversial because of their associated high costs and considerable toxicity. The resurrection of an old drug, thalidomide, for the therapy of MM and the development of potent immunomodulatory derivatives are highly promising new treatments that target MM cell-host interactions and the bone-marrow microenvironment, as well as the myeloma cell itself. The importance of the use of bisphosphonates for the prevention or amelioration of skeletal complications and hypercalcemia is well established. New generations of bisphosphonates show potent antitumor activity, again emphasising the importance of targeting the microenvironment of the plasma-cell clone.

Topics: Adjuvants, Immunologic; Aged; Angiogenesis Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Bone Marrow Transplantation; Boronic Acids; Bortezomib; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Dexamethasone; Diphosphonates; Drug Therapy, Combination; Erythropoietin; Glucocorticoids; Growth Inhibitors; Humans; Immunosuppressive Agents; Middle Aged; Multiple Myeloma; Oxides; Peripheral Blood Stem Cell Transplantation; Protease Inhibitors; Pyrazines; Randomized Controlled Trials as Topic; Stem Cell Transplantation; Thalidomide; Time Factors; Transplantation, Autologous; Transplantation, Homologous

Multiple Myeloma (MM) is a B cell neoplasia affecting approximately 14,400 new individuals in the United States each year. Although MM remains an incurable disease, encouraging advances have been made in its therapy in the recent past. High dose chemotherapy with autologous stem cell transplantation has been shown in randomized controlled trials to improve survival in MM and is currently considered the first line treatment for all patients except those with advanced age of co-morbidities. For such patients, conventional chemotherapy with melphalan and steroids continue to be the treatment of choice. The use of tandem stem cell transplants and the use of both myeloablative and nonmyeloablative allogeneic stem cell transplantation remains investigational. Thalidomide is a new therapeutic option with promising results; however, it is associated with significant side effects including deep venous thrombosis and peripheral neuropathy. Its use in combination with other chemotherapy agents is still under investigation. Novel promising agents are currently under clinical trials including Proteosome Inhibitors and much more potent thalidomide analogs or immunomodulators. This review summarizes recent developments in the therapy and supportive care of MM and introduces the newer drugs in preclinical and early clinical trials.

Topics: Adjuvants, Immunologic; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Bone Marrow Transplantation; Clinical Trials as Topic; Cysteine Endopeptidases; Diphosphonates; Doxorubicin; Erythropoietin; Etoposide; Forecasting; Humans; Interferons; Multienzyme Complexes; Multiple Myeloma; Organometallic Compounds; Organophosphorus Compounds; Oxides; Peripheral Blood Stem Cell Transplantation; Proteasome Endopeptidase Complex; Thalidomide; Tissue Extracts

Anemia has been reported in approximately 40%-70% of patients with hematologic malignancies, with severity depending on the type and stage of disease and whether the patient has received myelosuppressive chemotherapy. Growing evidence supports the role of epoetin alfa in correcting anemia and improving quality of life (QOL) in patients with hematologic malignancies. Clinical practice guidelines recommend the use of epoetin alfa in patients with cancer-related anemia (including patients with hematologic malignancies) and hemoglobin levels < or =10 g/dL. Epoetin alfa treatment is optional for patients with cancer-related anemia and hemoglobin levels>10 g/dL and <12 g/dL, depending on clinical circumstances. A prospective, open-label, randomized trial evaluating hematologic response, transfusion use, and QOL after immediate or delayed epoetin alfa treatment in mildly anemic patients (hemoglobin< or =12 g/dL) undergoing chemotherapy for chronic lymphocytic leukemia, multiple myeloma, or lymphoma was recently completed. Study objectives included determining any correlation between changes in hemoglobin level and QOL and assessing any correlation between QOL measures and health care resource use. Interim results suggest that epoetin alfa treatment in patients with hematologic cancers and hemoglobin< or =12 g/dL who are receiving chemotherapy increases hemoglobin, functional capacity, well-being, work and productivity, and health resource use. Further evaluation of alternative epoetin alfa dosing schedules and use of epoetin alfa in treating anemia in patients with specific hematologic malignancies is ongoing.

Topics: Anemia; Clinical Trials as Topic; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Hematinics; Hematologic Neoplasms; Hemoglobins; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Linear Models; Multiple Myeloma; Myelodysplastic Syndromes; Quality of Life; Random Allocation; Recombinant Proteins

Multiple myeloma (MM) is commonly associated with anemia. Several causes have been implicated, but anemia of chronic disease with inadequate erythropoietin (EPO) production related to the inflammatory cytokines appears to be of utmost importance. Interleukin-1 and tumor necrosis factor are capable of suppressing erythropoiesis. Anemia has broad implications. First, the low hemoglobin and hematocrit are associated with poor quality of life and performance and affect daily activity. Second, anemia has an impact on the cardiovascular system. Considering that most MM patients are elderly, this may be even more important. Anemia has been shown to induce or aggravate hypoxia and ischemic complications. Third, anemia has been shown to be a poor prognostic factor in MM. Traditionally, patients with symptomatic anemia were treated with red blood cell transfusions as needed. The introduction of epoetin alfa and epoetin beta into clinical practice opened new avenues to these patients. The administration of epoetins to patients with MM and anemia have been shown to be very useful. Several studies in more than 1000 patients have demonstrated a high response rate (range, 25%-85%; mean, 60%). This response is characterized by a significant increase of hemoglobin, hematocrit, and the number of red blood cells together with a reduction in the blood transfusion requirements. This is also associated with an improved quality of life. Although there is no complete agreement about the role of pretreatment serum EPO levels, many investigators believe that relatively low levels may help in predicting response, thereby limiting the number of potential candidates to receive this expensive therapy. The epoetins are safe and well tolerated with minimal toxicity; however, some concern has been recently raised regarding several dozen patients who developed pure red cell aplasia while on epoetin therapy. However, this adverse effect appears to be extremely rare. Recent data suggest that EPO has additional biologic effects, such as longer-than-expected survival in patients with MM. This observation is further supported by animal studies, demonstrating an antimyeloma effect of EPO in mice models. This effect has been shown to be immune mediated. If these exciting data are confirmed in future clinical trials, this may have significant implications on the treatment of MM.

Topics: Anemia; Animals; Cytokines; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Hemoglobins; Humans; Hypoxia; Mice; Mice, Inbred BALB C; Multiple Myeloma; Prognosis; Quality of Life; Recombinant Proteins; Time Factors

Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients often develop anemia due to the disease process and effects from disease therapy. Blood transfusion, the established treatment, has an immediate effect in improving patients' hemoglobin levels. However, this effect is transient and transfusion is associated with several risks, including infections and mild to life-threatening immunologic reactions. A newer option is recombinant human erythropoietin (epoetin); a biological treatment that leads to increased hemoglobin levels over an extended time without the risks of blood transfusion. Extensive evidence has shown that epoetin is effective in the treatment of cancer-associated anemia. An international expert panel met to develop treatment recommendations for the use of epoetin in MM and CLL patients. Based on the available data, it is recommended that treatment be initiated only after other possible causes of anemia are eliminated. Epoetin should be administered to any patient with hemoglobin < or=10 g/dl. Patients with hemoglobin 10-12 g/dl should receive epoetin if they suffer from significant symptoms of anemia and/or have progressively decreasing hemoglobin values. Dosage should be initiated at 10 000 IU three times/week or 40 000 IU once/week and be titrated to maintain hemoglobin at 12 g/dl. Nonresponsive patients (<1 g/dl increase over four weeks) may have their dose increased to 20 000 IU three times/week or 60 000 IU once/week, respectively. Epoetin treatment should be discontinued if there is no response to the increased dosage, or hemoglobin >14 g/dl. Treatment should resume for patients who exceed 14 g/dl, at a reduced dosage, if their hemoglobin falls below 12 g/dl.

Topics: Anemia; Disease Management; Epoetin Alfa; Erythropoietin; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Multiple Myeloma; Practice Guidelines as Topic; Recombinant Proteins

Anemia is prevalent among cancer patients with hematologic malignancies, with fatigue and weakness, major symptoms of anemia, contributing to diminished quality of life (QOL). Data from several randomized, placebo-controlled clinical trials and three large community-based studies in patients with hematologic malignancies indicate that recombinant human erythropoietin (r-HuEPO, epoetin alfa) can correct anemia, reduce transfusion requirements, and improve QOL. Moreover, a positive relationship has been found between increased hemoglobin (Hb) levels and improvements in QOL assessments, regardless of disease state, with the greatest incremental improvement occurring when Hb increases from 11 g/dL to 12 g/dL (range, 11 to 13 g/dL). This suggests that patients with mild-to-moderate anemia may achieve the greatest QOL benefit from epoetin alfa therapy. Evidence from community-based studies suggests that epoetin alfa administered once weekly has a similar safety and efficacy profile as three-times-weekly administration. Further research is ongoing with less frequent dosing regimens. The beneficial effects of epoetin alfa therapy have been reported in studies involving patients with chronic lymphocytic leukemia (CLL), multiple myeloma, and lymphomas. Evidence also exists that epoetin alfa can benefit patients with myelodysplastic syndromes (MDS), although these results have not been as impressive. Combining epoetin alfa with other cytokine growth factors may confer some additional benefit in these patients, but more rigorous investigation is required.

Topics: Anemia; Epoetin Alfa; Erythropoietin; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Multiple Myeloma; Recombinant Proteins; Treatment Outcome

Chronic anemia of variable severity occurs in more than two-thirds of patients with multiple myeloma (MM) as a consequence of the B cell malignancy. Its pathogenesis is multifactorial. Besides the altered inflammatory cytokine network, other events are held responsible, namely persistent defect of erythropoietin due to the kidney failure, shortening of red cell survival, accumulation of the serum monoclonal component and platelet dysfunction. Our recent studies have demonstrated that excessive erythroblast apoptosis promoted by myeloma cells drives the appearance of anemia, in particular in patients with severely progressive disease. A number of clinical trials have provided evidence for the effectiveness of recombinant human erythropoietin (rHuEPO-alpha: epoetin alpha) in improving the deregulated erythropoiesis in MM, since it acts as a major erythroid growth factor by exerting a specific anti-apoptotic effect. In the majority of these studies, the long-term treatment of MM-associated anemia with rHuEPO-alpha induced a significant improvement of erythropoiesis, as shown by a stable increase of hemoglobin values (> or = 2g/dL) and reduction of transfusion requirements. In a recent trial which included both a double-blind and an open-label phase, we have documented that rHuEPO-alpha induces a stable improvement of anemia in more than 75% of patients and a significant decrease of fatigue, with an overall recovery of the quality of life. Patients receiving a placebo also achieved similar results in the open-label phase, when they were switched to rHuEPO-alpha.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blood Transfusion; Cell Differentiation; Chronic Disease; Clinical Trials as Topic; Cytokines; Epoetin Alfa; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Humans; Multiple Myeloma; Quality of Life; Recombinant Proteins; Treatment Outcome

Anemia of variable severity occurs in more than two-thirds of patients with multiple myeloma (MM). Besides the altered cytokine network, chronic erythropoietn deficiency, blood loss and hemolysis, we have shown that deregulated myeloma cell apoptosis contributes to progressive destruction of the erythroid matrix by inducing erythroblast cytotoxicity. To exert this effect, highly malignant plasma cells overexpress both Fas-L and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which efficiently trigger the death of immature erythroblasts. However, this Fas-L/TRAIL-based anemia occurs in particular in patients with severely progressive MM, thus suggesting that these apoptogen receptors may characterize a peculiar cytotoxic-apoptogenic phenotype of malignancy. Immunophenotyping of myeloma cells could help to identify patients with a higher risk of erythropoiesis exhaustion.

Topics: Anemia; Apoptosis; Apoptosis Regulatory Proteins; Bone Marrow; Cell Communication; Cell Differentiation; Coculture Techniques; Cytokines; Disease Progression; Drug Resistance; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Fas Ligand Protein; Humans; Membrane Glycoproteins; Multiple Myeloma; Plasma Cells; Recombinant Proteins; TNF-Related Apoptosis-Inducing Ligand; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Anemia is a common complication in patients with hematologic malignancies, and is caused by a variety of mechanisms, including neoplastic cell infiltration into the bone marrow, hemolysis, nutritional deficiencies, and defects in erythropoiesis as a result of the disease itself or cytotoxic therapy. The anemia associated with multiple myeloma is caused by inadequate erythropoietin levels consequent to renal impairment and the effect of inflammatory cytokines. The degree of anemia can have prognostic importance, as is the case with multiple myeloma, or be a significant indicator of disease stage, as noted with chronic lymphocytic leukemia. Anemia results in fatigue, exhaustion, dizziness, headache, dyspnea, and decreased motivation, seriously affecting a patient's quality of life. Since anemia is so prevalent in hematologic malignancy patients, its treatment must be an integral part of disease management, to improve quality of life and to possibly increase potential survival. Clinical studies have shown that effectively treating anemia and increasing hemoglobin levels using recombinant human erythropoietin (rHuEPO, epoetin alfa) has a significant effect on transfusion requirements and quality of life.

Topics: Anemia; Epoetin Alfa; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Multiple Myeloma; Myelodysplastic Syndromes; Prognosis; Quality of Life; Recombinant Proteins; Survival Rate

Anemia is a common complication in patients with hematologic malignancies, with incidence rates ranging up to 63%. In myelodysplastic syndromes, anemia is an essential feature of the disease. The decrease in hemoglobin may lead to several symptoms such as fatigue, exhaustion, and impaired quality of life, and it may worsen prognosis. Before the introduction of recombinant human erythropoietin (rHuEPO, epoetin alfa), red blood cell transfusions were the traditional treatment for improvement of Hb levels. Transfusions, however, are associated with several adverse events and risks, have only transient effects, and have a limited capacity to ameliorate the symptoms of anemia. Epoetin alfa represents a physiologic treatment option, especially in the long-term treatment of cancer- and cancer treatment-associated anemia, and is well tolerated, with response rates as high as 80%. Epoetin alfa is less effective in the treatment of the anemia of myelodysplastic syndrome, but appears to be synergistic with granulocyte-colony stimulating factor. However, not every patient responds to epoetin alfa; to avoid unnecessary interventions and costs, predictors of response have been proposed. This article outlines the advantages and disadvantages of the two major treatment forms of anemia: transfusions and epoetin alfa. Representative studies on the efficacy of epoetin alfa in anemic patients with hematologic malignancies as well as models to predict response to epoetin alfa treatment are summarized.

Topics: Anemia; Blood Transfusion; Epoetin Alfa; Erythropoietin; Hematinics; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Multiple Myeloma; Myelodysplastic Syndromes; Prevalence; Recombinant Proteins

Topics: Anemia; Antineoplastic Agents; Diphosphonates; Erythropoietin; Humans; Kidney Failure, Chronic; Multiple Myeloma; Recombinant Proteins

Advances continue in erythropoietin biology, and additional data reviewed here have recently become available on complex feedback mechanisms describing the interrelations of hypoxia and its effects on anemia and tumor behavior (eg, apoptosis, angiogenesis). In addition to biology, other clinically relevant data in oncology are included and an attempt is made to identify patients who are most likely to benefit from treatment. The latter aspects will better define the profile of the target patient, probably prevent overtreatment, and improve cost-benefit ratios. Interesting data on radiotherapy results improved by increasing tissue hemoglobin have been published but will need further confirmation.

Topics: Anemia; Antineoplastic Agents; Erythropoietin; Humans; Multiple Myeloma; Practice Guidelines as Topic; Recombinant Proteins

Despite considerable progress in recent years in the understanding of the biology of multiple myeloma (MM), this disease remains incurable, although many new therapeutic approaches are under evaluation. The rapid development of recombinant technologies has permitted the production of large amounts of cytokines and growth factors, favoring the use of biotherapies also in this disease. Among these products, the interferons have been the most extensively used in clinical trials, giving the most promising results especially in the setting of minimal residual disease, as maintenance therapy after response to conventional therapies, or to high dose chemotherapies followed by bone marrow (BM) or peripheral blood stem cell (PBSC) transplantation. However, more recently, a large number of cytokines and growth factors have been introduced in the clinical practice. Data of the use of erythropoietin have consistently demonstrated the role of this growth factor in ameliorating the grade of anemia as well as the quality of life of those MM patients whose disease is complicated by the presence of a severe or moderate anemia. Using hematopoietic growth factor in the mobilization of PBSC, the quantity of progenitor cells in the peripheral blood increased and the hematological toxicity of chemotherapy could be reduced. Despite the large amount of experimental data indicating a role for interleukins, as IL-2 and IL-6, in controlling tumor growth, there are only few clinical studies dealing with their use in MM. Results show that they arrest tumor progression rather than aid tumor regression, for this reason it appears that IL-2 and anti IL-6 antibodies should be investigated as maintenance therapy, in MM patients responding to chemotherapy. In the future it will be necessary to clarify for MM patients the role of other cytokines such as IL-1 beta and TNF alpha. A possible strategy to improve the clinical outcome of MM patients is to prevent the regrowth of residual tumor cells by establishing adoptive immunity at the stages of minimal residual disease previous obtained using chemotherapy. To this end a possible strategy is to induce an immune response against residual tumor cells by passive (using monoclonal antibodies) or active (using the idiotype expressed by malignant cells) immunotherapy.

Topics: Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Biological Factors; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interferons; Interleukin-2; Interleukin-6; Multiple Myeloma

Topics: Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Combined Modality Therapy; Diphosphonates; Erythropoietin; Humans; Interferons; Interleukin-2; Middle Aged; Multiple Myeloma; Plasmacytoma; Prospective Studies; Radiotherapy Dosage; Randomized Controlled Trials as Topic; Stem Cell Transplantation; Transplantation, Autologous

Anaemia, manifesting as fatigue, dizziness, dyspnoea and anorexia, is common among patients with cancer. A host of factors, such as neoplastic bone marrow infiltration, impaired haematopoiesis, autoimmune haemolysis, impaired endogenous erthropoietin production and treatment with cytotoxic agents contribute to the underlying pathology. Traditionally, blood transfusions have formed the mainstay of therapy for the treatment of cancer-related anaemia. Numerous clinical trials have subsequently confirmed the safety and therapeutic utility of recombinant human erythropoietin (rHuEPO) in anaemic cancer patients, including those with haematological malignancies, such as multiple myeloma and non-Hodgkin's lymphoma. Indeed, well over 50% of unselected patients treated with rHuEPO can be expected to respond with increases in haemoglobin level and/or elimination of transfusion need. In addition, a low baseline serum erythropoietin level can identify those patients with haematological malignancies having a very high likelihood of responding to rHuEPO therapy. These findings, in combination with the possibility of titrating to a lower, maintenance dose, have improved the cost-benefit relationship and thus support the use of rHuEPO as an appropriate alternative to blood transfusions for the management of anaemic patients with lymphoma and myeloma.

Topics: Anemia; Blood Transfusion; Cost-Benefit Analysis; Drug Costs; Erythropoietin; Humans; Leukemia; Lymphoma; Multiple Myeloma; Recombinant Proteins; Treatment Outcome

Of patients presenting with multiple myeloma, 5% to 15% satisfy criteria for the diagnosis of multiple myeloma but have no or minimal symptoms and do not require chemotherapy (NRC). These patients are classified as having smoldering, asymptomatic stage 1, or indolent multiple myeloma in order of their increasing risk of progression. We avoid chemotherapy, especially with alkylating agents in such patients, and we either closely monitor them or use a nonchemotherapeutic intervention. If significant bone lesions, renal failure, or hypercalcemia occur, chemotherapy or transplant is recommended. Patients with mild anemia or with small or isolated bone lesions who are asymptomatic or minimally symptomatic because of anemia may be monitored and are classified as having indolent multiple myeloma. Unnecessary treatment with melphalan or cyclophosphamide probably has no benefit in multiple myeloma NRC and can cause significant risk. In long-term follow up, 25% of patients receiving alkylating agents develop myelodysplastic syndrome or acute leukemia. Patients who do not receive chemotherapy must be monitored closely to avoid complications of overt multiple myeloma, including anemia, bone lesions, renal failure, and hypercalcemia. We and others have begun to take a more active approach with the use of nonchemotherapeutic agents in selected patients. We use bisphosphonates in patients with bone lesions or osteoporosis or when there is a progressive rise in M-protein. We use dexamethasone alone in NRC multiple myeloma to reduce tumor burden in selected patients who do not yet have overt multiple myeloma or who are not candidates for chemotherapy. We use bisphosphonates to prevent osteoporosis in such patients. We use erythropoietin to correct anemia, and dexamethasone and erythropoietin together in patients with higher tumor burden (eg, indolent multiple myeloma). Future progress in treating multiple myeloma NRC depends on better identification of new therapeutic targets that control progression from the stable asymptomatic to the progressive symptomatic phase of multiple myeloma. We need to better understand the biologic target of new agents like thalidomide to design more effective treatment for this early phase of multiple myeloma. Although these approaches may delay chemotherapy, it is not known whether survival is prolonged. Nonchemotherapeutic approaches must be systematically studied in clinical trials in order to be put to better use.

Topics: Alkylating Agents; Antineoplastic Agents; Clinical Trials as Topic; Dexamethasone; Diet Therapy; Diphosphonates; Erythropoietin; Humans; Multiple Myeloma; Neoplasm Staging; Pamidronate; Thalidomide; Treatment Outcome

The correction of anemia in patients with chronic renal failure (CRF) has become the most important application of recombinant human erythropoietin (rHuEpo). The merits of rHuEpo therapy in patients with CRF are overt. Firstly, patients with CRF have an absolute deficiency in endogenous erythropoietin production and a relatively low maintenance dose of rHuEpo (often less than 100 IU/kg body weight per week) is effective in avoiding regular transfusions in the majority of the patients with CRF. Secondly, rHuEpo is able to avoid long-term complications of frequent transfusions (hemochromatosis, transfusion-transmissible diseases). Thirdly, patients with uremia notice a considerable improvement in quality of life (QOL) after initiation of rHuEpo. These advantages justify administration of this costly drug in CRF patients. The use of rHuEpo outside the setting of uremia do, however, not cover the complete spectrum of beneficial effects as compared to its use in (pre)dialysis patients. The aim of this overview is to provide some annotations on recently approved (cisplatin-induced anemia, preoperative anemia, zidovudine-related anemia) and possibly future (several types of malignancy and inflammation) indications for rHuEpo in non-uremic patients, leaving out the correction of anemia due to relatively uncommon disorders in the Dutch population (such as sickle cell anemia and thalassemia).

Topics: Anemia; Anti-HIV Agents; Arthritis, Rheumatoid; Blood Transfusion, Autologous; Chemotherapy, Adjuvant; Erythropoietin; Female; Humans; Male; Multiple Myeloma; Myelodysplastic Syndromes; Recombinant Proteins; Uremia; Zidovudine

About 50% of patients with multiple myeloma are older than 65 years and are not eligible for high-dose therapy, which has proved to be more efficacious than standard-dose chemotherapy in young patients.. Apart from high-dose therapy, no clear therapeutic advance has been achieved in the past 20 years, and melphalan-prednisone combinations remain reference treatments for many patients with multiple myeloma. Despite a great number of clinical trials, the use of interferon alpha is still controversial. The role of high-dose dexamethasone has been recently established and we are currently comparing dexamethasone alone, melphalan-dexamethasone and dexamethasone-interferon alpha treatments in a multicenter randomized trial (IFM 95-01). Bisphosphonates have also emerged as an efficacious and well tolerated adjuvant treatment. Optimal use of recently released bisphosphonates at various stages of the disease will possibly lead to a clear therapeutic advantage.. Other drugs, such as erythropoietin or interferon gamma require further evaluation. The recent implication of metalloproteinases in multiple myeloma and the efficacy of metalloproteinase inhibitors in animal models and phase I/II clinical studies in solid tumors provide a strong rationale for the clinical evaluation of these agents in multiple myeloma.

Topics: Anemia; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Erythropoietin; Humans; Interferon-alpha; Kidney Failure, Chronic; Multiple Myeloma

The key role of a blunted production of endogenous erythropoietin (EPO) in determining anemia of patients with multiple myeloma (MM) has been definitively established. Thus, several clinical trials have investigated the effects of recombinant EPO (r-EPO) in anemic MM patients. The results of these studies have demonstrated that r-EPO is a safe and effective drug, which results in an increase in Hb levels in the majority of treated patients. However, several factors, such as serum levels of endogenous EPO, severity of anemia, presence of normal erythroid progenitors, serum levels of some cytokines with inhibitory activity on erythroid function and previous treatments, may significantly affect the possibility of response, thereby suggesting the need for careful selection of MM patients for treatment with r-EPO.

Topics: Anemia; Clinical Trials as Topic; Erythropoietin; Humans; Multiple Myeloma; Recombinant Proteins

Recombinant human erythropoietin has been recently introduced as an important alternative for treatment of anaemia in multiple myeloma and non-Hodgkin's lymphoma. In the present paper we review the basis for its use in the anaemia of both entities, and the most relevant clinical trials showing the effect of erythropoietin. In MM patients the response rate (assessed by an increase of at least 2g/dl in the Hb level) ranges between 60%-80% while in NHL patients it ranges from 50% to 61%. The most appropriate EPO dose is around 5000 units per day, which is equivalent to 150 u/kg, three times per week. In addition, this review provides tools to decide the best candidates for this treatment and a guideline to monitor its efficacy.

Topics: Anemia; Clinical Trials as Topic; Erythropoietin; Humans; Lymphoma, Non-Hodgkin; Multiple Myeloma; Recombinant Proteins

Topics: Antineoplastic Agents; Diphosphonates; Erythropoietin; Humans; Immunoglobulin A; Immunoglobulin G; Interferon-alpha; Interleukin-6; Multiple Myeloma

Topics: Anemia; Anemia, Aplastic; Erythropoietin; Humans; Multiple Myeloma; Myelodysplastic Syndromes

The median of survival among patients with multiple myeloma (MM) is about 30 months from the onset of treatment. Tumour burden and a range of other parameters, such as C-reactive protein levels, the plasma cell labelling index and beta2-microglobulin levels, can be used to assign patients to favourable and unfavourable prognostic groups. Conventional chemotherapy consists of melphalan and prednisone, and is as effective as moderately intensive cytotoxic drug regimens. Although second-line chemotherapy is initially effective, all patients eventually die. Maintenance therapy will interferon-alpha prolongs the plateau phase of the disease, but its effects on overall survival are minimal. One of the promising developments in the treatment of MM has been the introduction of high dosage chemotherapy, which can now be safely administered when stem cells are used for haematological recovery. Autologous bone marrow transplantation has been shown to produce a significant improvement in survival compared with conventional therapy. Several studies are under way that are examining the effects of multiple courses of high dosage chemotherapy together with peripheral stem cell support. Purging of autologous stem cell harvests will be performed in the near future to minimise contamination with myeloma cells. It is now feasible to use high dosage chemotherapy, with the support of granulocyte colony-stimulating factor-stimulated whole blood, in selected elderly patients. Besides the promising development of intensive therapy, a number of other treatment strategies have emerged, including treatment with monoclonal antibodies against interleukin-6 and multidrug resistance-modulating agents. Better supportive care can be provided for some patients by using epoetin (recombinant human erythropoietin), and the sequelae of lytic bone lesions can be ameliorated through the use of bisphosphonates.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone and Bones; Bone Marrow Transplantation; Colony-Stimulating Factors; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Erythropoietin; Humans; Interferon-alpha; Interleukin-6; Multiple Myeloma; Prognosis

Topics: Anemia; Erythropoietin; Humans; Multiple Myeloma; Recombinant Proteins

A patient with advanced multiple myeloma (MM) and renal failure presented a severe chronic anemia requiring frequent blood transfusions. Treatment with recombinant human erythropoietin (rHuEPO) led to a rapid improvement of anemia, and further blood transfusions were not required. Pathophysiological studies about the erythropoiesis in patients with MM and trials with rHuEPO in myeloma-associated anemia are commented.

Topics: Aged; Anemia; Chronic Disease; Combined Modality Therapy; Erythropoietin; Fatal Outcome; Female; Humans; Immunoglobulin kappa-Chains; Kidney Failure, Chronic; Multiple Myeloma; Recombinant Proteins

Anemia and bleeding are commonly observed in patients with multiple myeloma (MM). Anemia in MM is multifactorial in origin. Three common causes are marrow replacement by the malignant cells, thereby reducing the available number of BFU-E, chronic renal failure and shortening of the half life of erythrocytes. Some patients with anemia but without renal failure show a good response to erythropoietin (Epo) with full correction of anemia. This indicates that human Epo is a promising therapeutic tool or treating myeloma-associated anemia. The incidence of severe bleeding complications is low, despite the diversity of abnormal hemostatic tests in patients with MM. These patients frequently show abnormal coagulation tests, including thrombin time, fibrin degeneration products, platelet aggregation tests and bleeding time. The most effective therapeutic approach to bleeding is to treat the underlying malignancy. Supplemental to this, plasma exchange is useful.

Topics: Anemia; Erythropoietin; Hemorrhage; Humans; Multiple Myeloma

The crucial first step in management of multiple myeloma is to be certain regarding the diagnosis. Multiple myeloma must be distinguished from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma. Therapy should be administered to patients with advanced and active myeloma involving anemia, osteolysis or renal failure. Chemotherapy with a single agent (melphalan) is the preferred initial treatment for overt, symptomatic multiple myeloma. Cytostatic drug combinations produce a higher response rate, but survival and remission during are the same compared with melphalan/prednisone therapy. However, in patients with renal failure and/or poor prognostic factors (advanced stage, elevated beta 2-microglobulin, high bone marrow plasma cell labeling index, high levels of C-reactive protein and lactate dehydrogenase and/or nodular pattern of bone marrow infiltration), combined treatment with adriamycin, vincristine and prednisone should be administered to prevent nephrotoxicity and attain a rapid paraprotein decrease. Alpha interferon treatment as maintenance seems to prolong the duration of the plateau state after response to chemotherapy, but apparently does not prolong survival. Allogeneic bone marrow transplantation involves significant early mortality (50%); the risk of graft versus host disease, infections and renal failure is a problem, and relapse is common. High dose chemotherapy followed by autologous bone marrow transplantation or peripheral blood stem cell reinfusion may prolong survival and free time to progression, but, to date, there are no indications of cure. This therapeutic procedure, therefore, should be considered for randomized trials for young patients with poor prognostic factors.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Diagnosis, Differential; Drug Therapy, Combination; Erythropoietin; Humans; Interferon-alpha; Melphalan; Middle Aged; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Prednisone; Prognosis

In this review, the pathophysiology and treatment of the anemia of multiple myeloma will be examined. While the anemia of cancer has multiple causes, an important component is labeled the "anemia of chronic disease" which is characterized by the combination of a shortened erythrocyte survival with failure of the bone marrow to increase red cell production in compensation. Depressed erythropoiesis is itself related to a combination of factors, including impaired availability of storage iron, inadequate erythropoietin response to anemia, and overproduction of cytokines which are capable of inhibiting erythropoiesis. These cytokines are involved in the retention of iron in the reticuloendothelial system, gastrointestinal tract and hepatocytes, may interfere with erythropoietin production by the kidney, and may exert direct inhibitory effects on erythroid precursors. While overproduction of several such cytokines, including IL-6, IL-1 and TNF-alpha, has been definitely demonstrated in multiple myeloma patients, it is still unclear whether they are directly involved in the pathogenesis of the anemia which develops. Although several mechanisms, such as hemodilution, bleeding, and decreased red cell survival operate, the anemia is mostly caused by defective erythropoietic activity. This in turn is partly explained by inadequate erythropoietin (Epo) production even in some patients without renal impairment. Based on measurements of serum erythropoietin and transferrin receptor, the distinction between marrow unresponsiveness to normal Epo stimulation and deficient Epo production is important for the treatment of the anemia of multiple myeloma with recombinant human Epo. Higher doses would probably be necessary if adequate Epo production is present, whereas only replacement therapy with lower doses may be sufficient when Epo production has been shown to be inappropriate.

Topics: Anemia; Cytokines; Erythropoiesis; Erythropoietin; Humans; Iron; Multiple Myeloma

During the last decade, the availability of large numbers of cytokines and growth factors has greatly favoured the use of biotherapies in several haematological disease. For MM, the majority of clinical studies have dealt with the use of IFN-alpha. From these studies it appears that IFN-alpha has a definite role in the treatment of MM especially in the setting of minimal residual disease, as maintenance therapy after response to conventional therapies or HDC followed by BMT procedures or PBSCI. Data on the use of EPO have consistently demonstrated the role of this growth factor in ameliorating the grade of anaemia as well as the quality of life of those MM patients whose disease is complicated by the presence of a severe or moderate anemia. Despite the large amount of experimental data indicating a role for IL-2 and IL-6 in controlling tumour growth, there are only a few clinical studies dealing with their use in MM. From these, it appears that IL-2 and anti-IL-6 antibodies should be further investigated as therapeutic tools useful in maintaining responses, because results show that they arrest tumour progression rather than aid, tumour regression. Finally, in the next years, there will be a wider diffusion of biotherapies in MM that should take into account the roles that IL-1 beta and TNF alpha play in myeloma cell proliferation and bone destruction and the finding that retinoic acid is capable of inhibiting the growth of human myeloma cells in vitro through modulation of IL-6 and its receptor.

Topics: Antibodies, Monoclonal; Erythropoietin; Humans; Interferon-alpha; Interferons; Interleukin-2; Interleukin-6; Interleukins; Multiple Myeloma

Recombinant human erythropoietin (rHuEPO) improves chronic anemia of cancer, but the proportion of patients who respond favorably to the treatment varies depending on the type of neoplasia. Preliminary data of the two malignancies with the highest response rates, namely, multiple myeloma and squamous cell carcinoma, are reported. Twenty patients with multiple myeloma and 14 with squamous cell carcinoma, who had presented with hemoglobin levels < 11 g/dl, were treated with rHuEPO, 150 U/kg, three times/week. Response, defined as an increase of at least 2 g/dl hemoglobin within 12 weeks, was achieved by 15 myeloma patients (75%) and 11 patients with squamous cell carcinoma (79%). Tolerance of the treatment was excellent. The WHO performance status and quality of life improved in responders. The remarkably low levels of endogenous EPO in our patients with squamous cell carcinoma, most of whom had been treated with cisplatin-or carboplatin-containing regimens, suggest that anemia in these cases had been at least partly chemotherapy induced. In myeloma patients, the blunted EPO response to the anemic condition may have been partly caused by subclinical tubular insufficiency induced by toxic paraproteins. Future studies should aim to elucidate factors which are responsible for the inability of some patients to respond to rHuEPO treatment, even though in multiple myeloma and squamous cell carcinoma these non-responders are a small minority.

Topics: Anemia; Carcinoma, Squamous Cell; Erythropoietin; Esophageal Neoplasms; Head and Neck Neoplasms; Humans; Iron; Lung Neoplasms; Multiple Myeloma; Recombinant Proteins

The anemia of multiple myeloma (MM) is multifactorial, including physical replacement of normal hemopoiesis by tumor cells, renal failure and cytokines which contribute to the blunted erythropoietin (EPO) response observed in anemias of chronic disease. Recombinant EPO has been evaluated in anemic patients with stable multiple myeloma (< or = 10g% hemoglobin). Responses (> or = 2g% hemoglobin increase) were observed in 78% of 41 patients in two separate studies. Responses were associated with an increase in bone marrow erythropoietic cell compartment and reticulocytosis. Evaluation of potential parameters affecting response identified prolonged cytotoxic therapy for > 12 months, especially with alkylating agents and pre-treatment EPO levels > 100 U/L, both of which seemed to decrease the likelihood of EPO response. EPO is a safe and effective treatment for the anemia associated with MM.

Topics: Anemia; Animals; Erythropoietin; Humans; Multiple Myeloma; Recombinant Proteins

Before proceeding to treatment selection for multiple myeloma, it is important to exclude monoclonal gammopathy of unknown significance or any similar smouldering or indolent type of myeloma not requiring immediate chemotherapy. In patients with active myeloma, pretreatment prognostic classification is important for appropriate balancing of the risks and benefits of particular treatment options. For example, conventional chemotherapy such as melphalan/prednisone may be appropriate for an elderly patient with active stage III myeloma, whereas high dose chemotherapy with or without bone marrow transplantation or cytokine support may be considered for the patient under age 45 with even earlier stage disease. A variety of options are now available for patients with relapsing or resistant disease, particularly using agents with potential for reversal of multi-drug resistance. The use of interferon-alpha as maintenance following initial response to chemotherapy is important for prolongation of remission, duration and potentially survival. A variety of supportive measures are also helpful including the use of epoetin (erythropoietin) to improve refractory anaemia and bisphosphonates for the inhibition of ongoing bone resorption. With the availability of various treatment options, it has become important for patients to be evaluated by a specialist in the field.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Diphosphonates; Drug Resistance; Erythropoietin; Humans; Interferon-alpha; Interleukins; Melphalan; Multiple Myeloma; Prednisolone; Prednisone

Oral mucositis (OM) as a complication of high-dose chemotherapy is frequently occurred in hematopoietic stem cell transplantation (HSCT) settings. Erythropoietin (EPO) has anti-inflammatory, antioxidant and wound-healing properties and therefore could have an important role in the prevention of OM. We conducted a double-blind, randomized, placebo-controlled trial to evaluate the EPO mouthwash effect on OM incidence and severity in 80 patients with non-Hodgkin's lymphoma, Hodgkin disease (HD) or multiple myeloma, undergoing autologous hematopoietic stem cell transplantation. Patients received either EPO mouthwash (50 IU/ml, 15 ml four times a day) (n = 40) or placebo (n = 40) from the starting day of high-dose chemotherapy until day +14 after transplantation or until the day of discharge from the hospital, whichever occurred first. OM was evaluated daily for 21 days after transplantation or until resolution of OM according to World Health Organization oral toxicity scale. The incidence of OM (grades 1-4) in the EPO mouthwash group and control group was significantly different (27.5% vs 77.5%, p < 0.001). The mean ± SD of two other parameters of OM including maximum intensity OM score (0.60 ± 1.06 vs 1.67 ± 1.27) and average intensity OM score (0.47 ± 0.80 vs 1.28 ± 0.86) was significantly lower in the intervention group (p < 0.001). Moreover, the mean ± SD duration of OM was also significantly shorter among the EPO mouthwash recipients (1.92 ± 3.42 days vs 5.42 ± 3.86 days, P < 0.001). Also, the duration of neutropenic fever was significantly shorter in the intervention group (2.12 ± 2.42 days vs 3.95 ± 4.01 days, p = 0.016). It is concluded that EPO mouthwash can reduce the incidence and duration of OM. Copyright © 2015 John Wiley & Sons, Ltd.

Topics: Adult; Double-Blind Method; Erythropoietin; Female; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Mouthwashes; Multiple Myeloma; Stomatitis; Treatment Outcome; Wound Healing

Multiple myeloma is an incurable complex disease characterized by clonal proliferation of malignant plasma cells in a hypoxic bone marrow environment. Hypoxia-dependent erythropoietin (EPO)-receptor (EPOR) signaling is central in various cancers, but the relevance of EPOR signaling in multiple myeloma cells has not yet been thoroughly investigated.. Myeloma cell lines and malignant plasma cells isolated from bone marrow of myeloma patients were used in this study. Transcript levels were analysed by quantitative PCR and cell surface levels of EPOR in primary cells by flow cytometry. Knockdown of EPOR by short interfering RNA was used to show specific EPOR signaling in the myeloma cell line INA-6. Flow cytometry was used to assess viability in primary cells treated with EPO in the presence and absence of neutralizing anti-EPOR antibodies. Gene expression data for total therapy 2 (TT2), total therapy 3A (TT3A) trials and APEX 039 and 040 were retrieved from NIH GEO omnibus and EBI ArrayExpress.. We show that the EPOR is expressed in myeloma cell lines and in primary myeloma cells both at the mRNA and protein level. Exposure to recombinant human EPO (rhEPO) reduced viability of INA-6 myeloma cell line and of primary myeloma cells. This effect could be partially reversed by neutralizing antibodies against EPOR. In INA-6 cells and primary myeloma cells, janus kinase 2 (JAK-2) and extracellular signal regulated kinase 1 and 2 (ERK-1/2) were phosphorylated by rhEPO treatment. Knockdown of EPOR expression in INA-6 cells reduced rhEPO-induced phospo-JAK-2 and phospho-ERK-1/2. Co-cultures of primary myeloma cells with bone marrow-derived stroma cells did not protect the myeloma cells from rhEPO-induced cell death. In four different clinical trials, survival data linked to gene expression analysis indicated that high levels of EPOR mRNA were associated with better survival.. Our results demonstrate for the first time active EPOR signaling in malignant plasma cells. EPO-mediated EPOR signaling reduced the viability of myeloma cell lines and of malignant primary plasma cells in vitro. Our results encourage further studies to investigate the importance of EPO/EPOR in multiple myeloma progression and treatment.. [Trial registration number for Total Therapy (TT) 2: NCT00083551 and TT3: NCT00081939 ].

Topics: Bone Marrow; Cell Death; Cell Survival; Erythropoietin; Humans; Multiple Myeloma; Phosphorylation; Protein Kinases; Receptors, Erythropoietin; RNA, Messenger; Signal Transduction; Tumor Cells, Cultured

We conducted a randomized study analyzing the impact of darbepoetin alfa (DA) administration with or without intravenous (i.v.) iron on erythroid recovery after autologous hematopoietic cell transplantation (HCT). Patients were randomized between no DA (Arm 1), DA 300 μg every 2 weeks starting on Day 28 after HCT (Arm 2), or DA plus i.v. iron 200 mg on Days 28, 42, and 56 (Arm 3). The proportion achieving complete hemoglobin (Hb) response within 18 weeks (primary end point) was 21% in Arm 1 (n = 24), 79% in Arm 2 (n = 25), and 100% in Arm 3 (n = 23; P < 0.0001). Erythropoietic response was shown to be significantly higher in Arm 3 (n = 46) than in Arm 2 (n = 50; P = 0.008), resulting in lower DA use, reduced drug costs, and improved quality of life scores, but the effect on transfusions was not significant. In multivariate analysis, DA administration (P < 0.0001), i.v. iron administration (P = 0.0010), high baseline Hb (P < 0.0001), and low baseline creatinine (P = 0.0458) were independently associated with faster achievement of complete Hb response. In conclusion, DA is highly effective to ensure full erythroid reconstitution after autologous HCT when started on Day 28 post-transplant. I.v. iron sucrose further improves erythroid recovery.

Topics: Aged; Anemia; Blood Transfusion; Combined Modality Therapy; Darbepoetin alfa; Drug Therapy, Combination; Erythropoiesis; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hematopoietic Stem Cell Transplantation; Humans; Infusions, Intravenous; Injections, Subcutaneous; Lymphoma; Male; Middle Aged; Multiple Myeloma; Postoperative Complications; Quality of Life; Transferrin; Transplantation Conditioning; Transplantation, Autologous

To compare usual care with a home-based individualized exercise program (HBIEP) in patients receiving intensive treatment for multiple myeloma (MM)and epoetin alfa therapy.. Randomized trial with repeated measures of two groups (one experimental and one control) and an approximate 15-week experimental period.. Outpatient setting of the Myeloma Institute for Research and Therapy at the Rockfellow Cancer Center at the University of Arkansas for Medical Sciences.. 187 patients with newly diagnosed MM enrolled in a separate study evaluating effectiveness of the Total Therapy regimen, with or without thalidomide.. Measurements included the Profile of Mood States fatigue scale, Functional Assessment of Cancer Therapy-Fatigue, ActiGraph® recordings, 6-Minute Walk Test, and hemoglobin levels at baseline and before and after stem cell collection. Descriptive statistics were used to compare demographics and treatment effects, and repeated measures analysis of variance was used to determine effects of HBIEP.. Fatigue, nighttime sleep, performance (aerobic capacity) as dependent or outcome measures, and HBIEP combining strength building and aerobic exercise as the independent variable.. Both groups were equivalent for age, gender, race, receipt of thalidomide, hemoglobin levels, and type of treatment regimen for MM. No statistically significant differences existed among the experimental and control groups for fatigue, sleep, or performance (aerobic capacity). Statistically significant differences (p < 0.05) were found in each of the study outcomes for all patients as treatment progressed and patients experienced more fatigue and poorer nighttime sleep and performance (aerobic capacity).. The effect of exercise seemed to be minimal on decreasing fatigue, improving sleep, and improving performance (aerobic capacity).. Exercise is safe and has physiologic benefits for patients undergoing MM treatment; exercise combined with epoetin alfa helped alleviate anemia.

Topics: Adult; Affect; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Epoetin Alfa; Erythropoietin; Exercise; Fatigue; Female; Home Care Services; Humans; Male; Middle Aged; Models, Biological; Motor Activity; Multiple Myeloma; Muscular Atrophy; Peripheral Blood Stem Cell Transplantation; Polysomnography; Recombinant Proteins; Resistance Training; Sleep Disorders, Intrinsic; Thalidomide; Walking

A successful stem cell harvest is a prerequisite for peripheral blood SCT. We investigated the number of CD34(+) cells mobilized, the number of leukaphereses needed and the expenses of treatment for 28 patients with multiple myeloma randomly assigned to receive either G-CSF alone or G-CSF+EPO for stem cell mobilization after chemotherapy with ifosfamide, epirubicin and etoposide. All patients treated with G-CSF+EPO reached the threshold of 6 x 10(6) CD34(+) cells per kg body weight (kgbw), with a mean of 1.3 leukaphereses. On average 15.4 x 10(6) CD34(+) cells/kgbw were collected. In the G-CSF-alone group, the mean number of leukaphereses was 1.8, and 12.6 x 10(6) CD34(+) cells/kgbw were collected, and two patients failed the threshold. Overall costs per patient for mobilization and leukaphereses were 8339 euro (G-CSF+EPO) and 8842 euro (G-CSF). After transplantation, fewer blood transfusions (0.6 versus 1.3, P=0.05), fewer days on antibiotics (2.3 versus 6.1, P=0.02) and a shorter hospital stay (15.2 versus 17.8, P=0.06) were noted in the G-CSF+EPO group resulting in a 19.2% reduction of costs for each transplant (P=0.018). In summary, EPO improves the mobilization efficiency of G-CSF and so reduces costs of mobilization and SCT.

Topics: Aged; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Epirubicin; Erythropoietin; Etoposide; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Leukapheresis; Leukocyte Count; Leukocytes; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Prospective Studies; Recombinant Proteins

Topics: Aged; Aged, 80 and over; Anemia; Epoetin Alfa; Erythropoietin; Female; Humans; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins; Severity of Illness Index; Treatment Outcome

The purpose of this study is to investigate the efficacy and safety of recombinant erythropoietin-beta in the treatment of anemic patients with multiple myeloma (MM), low-grade non-Hodgkin's lymphoma (NHL), and chronic lymphocytic leukemia (CLL). From December 2005 to November 2006, the patients with MM, low-grade NHL, and CLL were enrolled in this study, male or female, aged > or = 18 years, transfusion-dependant, and receiving anti-neoplasia chemotherapy. Recombinant human erythropoietin-beta was used in this study with the dose initiated at 150 IU/kg, thrice a week, subcutaneously. The total treatment duration was 12 weeks. The primary endpoint of the study is response rate (RR), which is defined as hemoglobin increasing > or = 2 g/dL comparing to baseline level, or returning to normal range, without any transfusion within 6 weeks of evaluation. Fifty out of 82 (64.6%) patients enrolled in this study responded to the treatment and 29 patients had no response. Hypertension (12.2%) is the most common adverse effect; however, all the adverse events were mild, categorized in NCI grade I or II. We conclude that recombinant erythropoietin-beta was effective in the treatment of anemia of the patients with MM, NHL, and CLL, as well as it is well-tolerated.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Asian People; Erythropoietin; Female; Ferritins; Humans; Iron; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Lymphoproliferative Disorders; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins; Treatment Outcome

Hematopoietic progenitor cells (HPC) as well as tissue committed stem cells expressing mRNA specific to various somatic tissues are thought to be part of the CD34+ bone marrow compartment. In this study, we explore and quantify their mobilization in patients with multiple myeloma undergoing chemotherapy upon administration of granulocyte colony-stimulating factor (G-CSF) plus/minus erythropoietin (EPO).. HPC were quantified by flow cytometry and functional assays within the blood of healthy donors and myeloma patients before and after chemotherapy followed by G-CSF or G-CSF + EPO given subcutaneously. The mRNA expression was studied by quantitative polymerase chain reaction (PCR). Cytokines and peripheral blood protease levels were measured by an enzyme-linked immunosorbent assay.. EPO did not significantly alter the number of HPC mobilized by G-CSF alone, and mRNA specific for liver, brain, muscle and kidney was detected in both treatment groups. Quantitative PCR analysis revealed a 2.7-fold increased expression of glial fibrillary acidic protein after G-CSF + EPO administration compared to G-CSF alone (P = 0.003). The concentration of G-CSF rose from 62 +/- 22 pg/mL and 48 +/- 10 pg/mL to 28 +/- 9 ng/mL and 85 +/- 10 ng/mL after 10 d of treatment with G-CSF and G-CSF + EPO, respectively. The concentration of neutrophil elastase (NE) rose only in the G-CSF group by a factor 1.5.. The alteration of G-CSF and NE levels as well as the expression of tissue committed RNA after the administration of EPO in addition to G-CSF indicate that different growth factors mobilize different stem cells that might potentially be used for the support of tissue repair in future treatment protocols.

Topics: Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Blood Cells; Case-Control Studies; Cell Count; Cytokines; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells; Humans; Leukocyte Elastase; Multiple Myeloma; Organ Specificity; RNA, Messenger

Topics: Adult; Aged; Erythropoietin; Female; Hematinics; Hematopoietic Stem Cell Mobilization; Hemoglobins; Humans; Male; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Recombinant Proteins; Transplantation, Autologous

To determine the effect of aerobic and strength resistance training and epoetin alfa (EPO) therapy on transfusions, stem cell collections, transplantation recovery, and multiple myeloma treatment response.. Randomized clinical trial.. A myeloma research and therapy center in the south central United States.. 135 patients with multiple myeloma, 120 evaluable.. Random assignment to exercise or usual care groups. All patients received EPO based on an algorithm. Aerobic capacity, using the six-minute walk test, was assessed prior to induction chemotherapy, prior to stem cell mobilization, and following stem cell collection for all patients and before and after transplantation for patients continuing in the study. Data analysis included analysis of variance to compare other outcome variables by groups.. Number of red blood cell and platelet transfusions during transplantation, number of attempts at and total number of days of stem cell collection, time to recovery after transplantation, and response to intensive therapy for multiple myeloma.. Recovery and treatment response were not significantly different between groups after transplantation. The exercise group had significantly fewer red blood cell transfusions and fewer attempts at stem cell collection. Serious adverse events were similar in each group.. Exercise with prophylactic EPO therapy reduces the number of RBC transfusions and attempts at stem cell collection for patients receiving intensive treatment for multiple myeloma.. Exercise is safe and has many physiologic benefits for patients receiving multiple myeloma treatment.

Topics: Adult; Aged; Analysis of Variance; Anemia; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Doxorubicin; Epoetin Alfa; Erythropoietin; Etoposide; Exercise Test; Exercise Therapy; Fatigue; Female; Hematinics; Humans; Male; Middle Aged; Multiple Myeloma; Nurse's Role; Nursing Evaluation Research; Oncology Nursing; Peripheral Blood Stem Cell Transplantation; Recombinant Proteins; Treatment Outcome; Vincristine

The aim of the study was to evaluate the role of hypochromic erythrocytes (HYPO%) compared to "traditional" and novel markers of iron status and erythropoiesis in recognizing iron-restricted erythropoiesis (IRE) and predicting response to erythropoietin (rHuEPO) in anemic patients with myeloma and lymphoma. Forty-one newly diagnosed patients who received epoetin-beta at a subcutaneous weekly dose of 30,000 IU for 6 weeks were studied. Response to rHuEPO was observed in 27 patients (65.8%). Twelve non-responders received, additionally, 200 mg of IV iron sucrose, weekly, for 4 weeks. Evaluation of markers was performed at baseline and on weeks 1, 2 and 6 for all patients and also on weeks 7-10 for non-responders to rHuEPO. Baseline HYPO%, at a cut-off value of <5%, and an increment in reticulocyte absolute number (RETICS-AB) >or= 50,000/microl and reticulocyte hematocrit (RETICS-Hct) >or= 50%, between baseline and week 2, were independent predictive factors for response to rHuEPO. We found that these markers had superior predictive value for response to rHuEPO than four widely used predictive models. Furthermore, a baseline HYPO% count of above 5% proved superior over serum ferritin < 100 ng/ml and transferrin saturation < 20% in recognizing IRE. In conclusion, baseline HYPO% either alone or in combination with RETICS-AB or RETICS-Hct after 2 weeks of rHuEPO treatment could be reliably used in predicting response to rHuEPO. Additionally, HYPO% has proved a reliable marker for recognizing IRE before rHuEPO treatment and, thus, could be used for identifying patients who will benefit from IV iron supplementation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia, Iron-Deficiency; Biomarkers; Erythrocyte Indices; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hematinics; Hematocrit; Humans; Lymphoma; Male; Middle Aged; Multiple Myeloma; Predictive Value of Tests; Recombinant Proteins

Continuous erythropoietin receptor activator (C.E.R.A.) is an innovative agent with unique erythropoietin receptor activity and a prolonged half-life, which has the potential for administration at extended dosing intervals. The objectives of this dose-finding study were to evaluate the hemoglobin (Hb) dose-response, pharmacokinetics, and safety of repeated doses of C.E.R.A. given once every 3 weeks to anemic patients with multiple myeloma (MM) receiving chemotherapy.. This was an exploratory two-stage, open-label, parallel-group, multicenter study. Patients received C.E.R.A. doses of 1.0, 2.0, 3.5, 4.2, 5.0, 6.5, or 8.0 mg/kg once every 3 weeks by subcutaneous injection initially for 6 weeks, followed by a 12-week optional extension period. The primary outcome measures were the average Hb level and its change from baseline over the initial 6-week period, based on values of the slope of the linear regression analysis and the area under the curve. Rates of Hb response (defined as an increase in Hb of > or =2 g/dL without transfusion) and blood transfusion were also evaluated.. Sixty-four patients entered the study. Dose-related increases in Hb levels were observed during the initial 6-week treatment period for C.E.R.A. doses of 1.0-4.2 mg/kg, with a similar response observed at higher doses. At least 70% of patients receiving 2.0-8.0 mg/kg of C.E.R.A. had Hb responses during the 18-week study. The elimination half-life of C.E.R.A. was found to be long (6.3-9.7 days [151.2-232.8 hours]). All doses were generally well tolerated.. Based on its unique, long elimination half-life, C.E.R.A. has been demonstrated to be an effective and well-tolerated treatment of anemia given once every 3 weeks to patients with multiple myeloma receiving chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Blood Pressure; Blood Transfusion; Dose-Response Relationship, Drug; Drug Administration Schedule; Electrocardiography; Erythropoietin; Female; Half-Life; Hematocrit; Hemoglobins; Humans; Male; Middle Aged; Multiple Myeloma; Polyethylene Glycols; Recombinant Proteins; Reticulocytes; Treatment Outcome

Epoetin beta, three-times weekly (t.i.w.), is effective in reversing anaemia in lymphoproliferative disorders. The current study investigated whether an epoetin beta dose of 30,000 IU given subcutaneously once weekly (q.w.) was at least as effective as 10,000 t.i.w. administration in anaemic patients with lymphoproliferative malignancy and defective endogenous erythropoietin (Epo) production. Overall, 241 anaemic patients with multiple myeloma, low-grade non-Hodgkin's lymphoma or chronic lymphocytic leukaemia, all with serum Epo values

Topics: Adult; Aged; Aged, 80 and over; Anemia; Area Under Curve; Blood Transfusion; Disease-Free Survival; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Lymphoproliferative Disorders; Male; Middle Aged; Multiple Myeloma; Proportional Hazards Models; Recombinant Proteins; Time

This phase 3, randomized, double-blind, placebo-controlled study was designed to evaluate the efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies. Patients (n = 344) with lymphoma or myeloma received darbepoetin alfa 2.25 microg/kg or placebo s.c., once weekly for 12 weeks. The percentage of patients achieving a haemoglobin response was significantly higher in the darbepoetin alfa group (60%) than in the placebo group (18%) (P < 0.001), regardless of baseline endogenous erythropoietin level. However, increased responsiveness was observed in patients with lower baseline erythropoietin levels. Darbepoetin alfa also resulted in higher mean changes in haemoglobin than placebo from baseline to the last value during the treatment phase (1.80 g/dl vs 0.19 g/dl) and after 12 weeks of treatment (2.66 g/dl vs 0.69 g/dl). A significantly lower percentage of patients in the darbepoetin alfa group received red blood cell transfusions than in the placebo group (P < 0.001). The efficacy of darbepoetin alfa was consistent for patients with lymphoma or myeloma. Improvements in quality of life were also observed with darbepoetin alfa. The overall safety profile of darbepoetin alfa was consistent with that expected for this patient population. Darbepoetin alfa significantly increased haemoglobin and reduced red blood cell transfusions in patients with lymphoproliferative malignancies receiving chemotherapy.

Topics: Aged; Analysis of Variance; Anemia; Blood Transfusion; Darbepoetin alfa; Diarrhea; Double-Blind Method; Erythropoietin; Fatigue; Female; Fever; Follow-Up Studies; Humans; Linear Models; Lymphoma; Lymphoproliferative Disorders; Male; Middle Aged; Multiple Myeloma; Nausea; Quality of Life

Anemia has been reported in approximately 40%-70% of patients with hematologic malignancies, with severity depending on the type and stage of disease and whether the patient has received myelosuppressive chemotherapy. Growing evidence supports the role of epoetin alfa in correcting anemia and improving quality of life (QOL) in patients with hematologic malignancies. Clinical practice guidelines recommend the use of epoetin alfa in patients with cancer-related anemia (including patients with hematologic malignancies) and hemoglobin levels < or =10 g/dL. Epoetin alfa treatment is optional for patients with cancer-related anemia and hemoglobin levels>10 g/dL and <12 g/dL, depending on clinical circumstances. A prospective, open-label, randomized trial evaluating hematologic response, transfusion use, and QOL after immediate or delayed epoetin alfa treatment in mildly anemic patients (hemoglobin< or =12 g/dL) undergoing chemotherapy for chronic lymphocytic leukemia, multiple myeloma, or lymphoma was recently completed. Study objectives included determining any correlation between changes in hemoglobin level and QOL and assessing any correlation between QOL measures and health care resource use. Interim results suggest that epoetin alfa treatment in patients with hematologic cancers and hemoglobin< or =12 g/dL who are receiving chemotherapy increases hemoglobin, functional capacity, well-being, work and productivity, and health resource use. Further evaluation of alternative epoetin alfa dosing schedules and use of epoetin alfa in treating anemia in patients with specific hematologic malignancies is ongoing.

Topics: Anemia; Clinical Trials as Topic; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Hematinics; Hematologic Neoplasms; Hemoglobins; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Linear Models; Multiple Myeloma; Myelodysplastic Syndromes; Quality of Life; Random Allocation; Recombinant Proteins

To investigate the effect of recombinant human erythropoietin (epoetin beta) on anemia, transfusion need, and quality of life (QOL) in severely anemic patients with low-grade non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), or multiple myeloma (MM).. Transfusion-dependent patients with NHL (n = 106), CLL (n = 126), or MM (n = 117) and a low serum erythropoietin concentration were randomized to receive epoetin beta 150 IU/kg or placebo subcutaneously three times a week for 16 weeks. Primary efficacy criteria were transfusion-free and transfusion- and severe anemia-free survival (hemoglobin [Hb] > 8.5 g/dL) between weeks 5 to 16. Response was defined as an increase in Hb > or = 2 g/dL with elimination of transfusion need. QOL was assessed by the Functional Assessment of Cancer Therapy scale.. Transfusion-free (P =.0012) survival and transfusion- and severe anemia-free survival (P =.0001) were significantly greater in the epoetin beta group versus placebo (Wald chi(2) test), giving a relative risk reduction of 43% and 51%, respectively. The response rate was 67% and 27% in the epoetin beta versus the placebo group, respectively (P <.0001). After 12 and 16 weeks of treatment, QOL significantly improved in the epoetin beta group compared with placebo (P <.05); this improvement correlated with an increase in Hb concentration (> or = 2 g/dL). A target Hb that could be generally recommended could not be identified.. Many severely anemic and transfusion-dependent patients with advanced MM, NHL, and CLL and a low performance status benefited from epoetin therapy, with elimination of severe anemia and transfusion need, and improvement in QOL.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Double-Blind Method; Erythropoietin; Female; Humans; Injections, Subcutaneous; Iron; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma; Quality of Life; Recombinant Proteins; Surveys and Questionnaires; Survival Rate; Treatment Outcome

Effects of epoetin alfa on transfusions, haemoglobin (Hb) and quality of life (QOL) were evaluated in a placebo-controlled study of 145 patients with multiple myeloma and anaemia (Hb < 11 g/dl). During the 12-week, double-blind phase, patients received 150 IU/kg epoetin alfa or a matching volume of placebo subcutaneously three times weekly; the dose (or volume) was doubled at week 4 if Hb response was inadequate. Patients completing this phase could enter the subsequent optional 12-week phase of open-label epoetin alfa treatment. During double-blind treatment, epoetin alfa significantly decreased the incidence of transfusion compared with placebo (28% vs. 47%, P = 0.017), regardless of patients' transfusion history, and increased mean Hb (1.8 g/dl vs. 0.0 g/dl, P < 0.001). Univariate analysis showed significant (P

Topics: Adult; Aged; Aged, 80 and over; Anemia; Blood Transfusion; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Lipoxygenase Inhibitors; Male; Middle Aged; Multiple Myeloma; Quality of Life; Recombinant Proteins

Pathogenetic mechanism of myeloma (MM) associated anaemia may involve: decreased level of erythropoietin (Epo) production, insufficient response to this hormone, bone marrow replacement by tumour cells, and cytokine mediated suppressive effect on erythropoiesis (ACD type of anaemia). We evaluated some possible causes of MM associated anaemia in a group of MM patients before treatment, using tests of in vitro culture of erythroid precursors and determination of the level of selected cytokines and evaluation of patient sera and media conditioned by patient cells for haematopoietic growth in vitro inhibitory/stimulatory activity. The study group included 15 patients with advanced MM at III clinical stage (according Durie and Salmon classification) prior treatment with a median age 61.8 women and 7 men. Diagnostic work-up included cytogenetics and serum Epo level as well as routine tests. We determined number of CFU-E, BFU-E and CFU-GM in the bone marrow of patients and healthy donors after mononuclear and T cell depletion in serum free culture under different conditions: 1) with conditioned medium (CM) by patients T cells, 2) CM by T cells of healthy donors and 3) without CM. IL-6, IL-1 alpha and TNF-alpha level in the serum and CM was determined. All patients were slightly anaemic--mean Hb 6 mmol/l (9.6 g/dl), transferrin level was increased--mean 1612 pmol/l (732 ng/ml) whereas iron level was normal. The average frequency of erythropoietic cells in myelogram was decreased (12%), however, the frequency of plasmocytes was increased (32%). Epo serum level was decreased in comparison with degree of anaemia (mean 22.2 U/ml). The average number of CFU-E/10(5) was slightly lower--212 and in the cultures containing CM by patient T cell and CM-by T cells of healthy donor decreased significantly to 138 and 183, accordingly. This phenomenon was not observed in cultures containing normal bone marrow cells. IL-6 level was increased in patients' serum and CM by patients T cells (27 ng/ml and 51 ng/ml, respectively).. The results of this study support the notion on the multifactorial origin of anaemia in myeloma patients. The factors specified in this study include 1. defective response of Epo to the degree of anaemia 2. decreased number of committed erythroid cells in the marrow 3. suppression of erythropoiesis by IL-6.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Bone Marrow; Cell Count; Cells, Cultured; Cytokines; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Humans; Interleukin-6; Male; Middle Aged; Multiple Myeloma; T-Lymphocytes; Transferrin

Anemia is a frequent complication of multiple myeloma, becoming chronic in patients who are resistant to chemotherapy. This randomized, parallel, controlled multicenter study (71 patients receiving concomitant chemotherapy) evaluated the efficacy and safety of epoetin alfa in improving anemia and eliminating the need for transfusions in multiple myeloma patients refractory to conventional first- or second-line chemotherapy. Forty patients were treated with subcutaneous epoetin alfa (150 IU/kg per dose, increasing to 300 IU/kg per dose, every 3 weeks) for 6 months, and 31 entered a control group. The epoetin alfa group had a significantly (P < or = 0.001) greater percentage of patients (75% vs. 21%) with increases in hemoglobin levels and/or reduced transfusion requirements. In 44 non pre-transfused patients (20 controls, 24 in the epoetin alfa group), the mean increase in hemoglobin was significantly (P < or = 0.0001) greater in the epoetin alfa group (+2.1 vs. -0.2 g/dl). Increases in hematocrit and red blood cells were also significantly (P < or = 0.0001) greater in epoetin alfa-treated patients, with corresponding reductions in transfusion requirement. In the 27 pre-transfused patients (11 controls, 16 in the epoetin alfa group), there was a trend towards reduced transfusional need in epoetin alfa-treated patients. Thus, in patients with multiple myeloma refractory to chemotherapy epoetin alfa is a well-tolerated treatment which improves anemia in non pre-transfused patients and appears to reduce transfusion need in those previously transfused.

Topics: Aged; Anemia; Antineoplastic Agents; Blood Transfusion; Epoetin Alfa; Erythropoietin; Female; Humans; Karnofsky Performance Status; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins

Anemia is a common symptom in multiple myeloma (MM) patients but the pathogenesis of it is still unknown. The aim of the study was to explain the causes of anemia in MM patients. Peripheral blood count, bone marrow aspirate, iron and ferritin level, serum erythropoietin (EPO) level, T cell subsets and in vitro CFU-E count were analyzed in the group od 31 MM patients. Erythropoietin and iron deficiency in the study group were not observed. EPO serum level was not significantly different in patients with multiple myeloma and in comparison to patients with sideroblastic anemia with solid tumors. Absolute CD8 T lymphocyte count was not significantly increased in the study group. CFU-E colonies count in vitro was not decreased in these patients.. In the study group of the MM patients anemia probably does not depend on EPO production. Diminished proliferative response of erythropoietic cells on normal serum level of EPO and abnormal iron utilisation probably occur in these patients. Replacement of normal erythropoiesis by tumor plasma cells is probably not decisive.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Biopsy, Needle; Blood Cell Count; Bone Marrow; CD8-Positive T-Lymphocytes; Erythropoietin; Female; Ferritins; Humans; Iron; Male; Middle Aged; Multiple Myeloma

The efficacy and safety of recombinant human erythropoietin (rhEPO) were tested when given subcutaneously (s.c.) in an escalating dose of 2000-10,000 units (U) daily in 60 patients with cancer-related anaemia (CRA). A positive response, defined as an increase in haemoglobin more than 2 g/dl and independence of blood transfusions was observed in 23 of 48 evaluable patients (48%) within a median of 8 wk. In detail, rhEPO corrected anaemia in 11 of 14 patients (79%) with malignant lymphoma, in 8 of 15 patients (53%) with multiple myeloma and in 4 of 10 patients (40%) with a solid tumour. The median dose of rhEPO in successful cases was 5000 U daily. Four patients with agnogenic myeloid metaplasia and 5 with myelodysplastic disorder failed to respond to rhEPO. No patient had any severe side effects. Pretreatment serum erythropoietin levels appeared to be a weak predictor for response to rhEPO treatment. In conclusion, rhEPO seems to be safe and effective in correcting CRA in certain groups of patients.

Topics: Adolescent; Adult; Aged; Anemia; Blood Transfusion; Erythropoietin; Female; Ferritins; Hematocrit; Hemoglobins; Humans; Injections, Subcutaneous; Iron; Lymphoma; Male; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Neoplasms; Primary Myelofibrosis; Recombinant Proteins; Reticulocyte Count; Transferrin

Recombinant erythropoietin (r-EPO) was administered to 37 patients with advanced, transfusion-dependent and chemo-resistant multiple myeloma (MM), at the fixed dose of 10,000/U s.c., 3 times a week, for 2 months. Thirteen patients (35.1%) achieved a significant response in terms of complete abolition of red cell transfusions. Factors significantly predictive of response were: a) inappropriate production of endogenous EPO, as expressed by a reduced observed/predicted ratio; b) presence of a consistent number of circulating erythroid precursors BFU-E; c) low serum levels of tumor necrosis factor (TNF) and interleukin-1 (IL-1), cytokines with inhibitory activity on erythropoiesis; d) a single line of previously received chemotherapy. Renal failure, bone marrow plasma cell infiltration, serum levels of IL-6 and other main clinical and laboratory parameters did not affect significantly the response to r-EPO. High fluorescence reticulocytes (HFR) and soluble transferrin receptor (sTfR) values were useful to detect an early stimulation of erythropoiesis in responders, while a high percentage of circulating hypochromic erythrocytes (HE), as assessed by an automated counter, identified those patients developing functional iron deficiency during r-EPO treatment. We conclude that about one-third of severely anemic patients with advanced MM, unresponsive to chemotherapy, may benefit by r-EPO therapy. The clinical management of these patients can be accomplished using non-invasive parameters, such as sTfR, HFR and HE.

Topics: Adult; Aged; Anemia; Blood Transfusion; Drug Evaluation; Erythropoiesis; Erythropoietin; Female; Humans; Interleukin-1; Interleukin-6; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins; Tumor Necrosis Factor-alpha

Multiple myeloma (MM) is commonly associated with anemia. Several causes have been implicated but inadequate erythropoietin (Epo) production appears to be important. This single-institute open-label, non-comparative clinical trial was undertaken in order to evaluate serum Epo levels in patients with MM and to study the efficacy and toxicity of recombinant human Epo (rHuEpo) in the treatment of MM-associated anemia. MM patients with a baseline hemoglobin (Hb) level of < 11 g/dl received rHuEpo 150 U/kg 3 times/week subcutaneously, with a possible dose increase to 300 U/kg if no response was observed after 4 weeks. The study was designed for 12 weeks, although some responders continued rHuEpo. The study endpoints were determined by an increase in Hb and a decrease in blood transfusion requirements (BTR). Seventeen patients were enrolled in the study. The median serum Epo level was 150 mU/ml (range 11-232). Four patients did not complete the study for reasons unrelated to rHuEpo, but to their underlying MM. Twelve patients (70.6%) responded with an increase in their Hb levels. One patient (5.9%) responded partially. The median Hb level rose from 9.4 g/dl (range 7.3-10.7) at study commencement to 12.5 g/dl (range 9.0-15.2). Six of the 11 patients who were transfusion dependent enjoyed a complete abolition of BTR. The response was also interpreted as an improved quality of life: 3 patients reported a decrease of 1 level in their WHO performance status (PS) score; in 8 patients, the PS declined by 2 grades and 1 patient enjoyed PS reduction by 4 scores. Six patients continue to receive rHuEpo up to 18 months, with a good response and a smaller maintenance dose. Four patients reported flu-like symptoms, 2 suffered from a local irritation and 1 experienced a transient controlled elevation of blood pressure.. (1) Pretreatment endogenous serum Epo levels were relatively low in all patients studied with MM-associated anemia; (2) rHuEpo was well tolerated in these patients; (3) rHuEpo was highly effective in the treatment of anemia in MM, and (4) the response to rHuEpo is characterized by an increase in Hb levels, a reduction in BTR and an improvement in the WHO PS score.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Dose-Response Relationship, Drug; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins

One hundred twenty-one anemic, transfusion-dependent patients with multiple myeloma (MM) or low-grade non-Hodgkin's lymphoma (NHL) were randomly allocated to receive (a) recombinant human erythropoietin (rhEPO) 10,000 U/d subcutaneously 7 days a week (fixed dose group) (n = 38), or (b) rhEPO 2,000 U/d subcutaneously for 8 weeks followed by step-wise escalation of the rhEPO dose (titration group) (n = 44), or (c) no rhEPO therapy (control group) (n = 39). The total treatment period was 24 weeks. There were no differences between the three groups with regard to baseline clinical, demographic, or health status measures. The cumulative response frequency, defined as elimination of the transfusion need in combination with an increase in the hemoglobin concentration by >20 g/L, was 60% in both rhEPO treatment groups and 24% in the control group (P = .01 and .02, respectively, log rank test). For patients in the titration group the response rate on the first dose level (2,000 U/d) was only 14%. Cox's univariate regression analysis revealed that an inadequately low endogenous erythropoietin concentration in relation to the degree of anemia and a baseline platelet concentration > or = 100 x 10(9)/L were significant predictors for response to rhEPO therapy (P < .01). Multivariate regression analysis showed that relative erythropoietin concentration was the most important factor and the platelet count had no additional influence on response. Treatment with rhEPO was well tolerated. We conclude that treatment with rhEPO may be indicated in anemic MM and NHL patients with a relative erythropoietin deficiency. An initial dose of 5,000 U/d subcutaneously may be recommended.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Blood Transfusion; Erythropoietin; Female; Humans; Injections, Subcutaneous; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins

To determine the efficacy of epoetin alfa for the treatment of the anemia of multiple myeloma, a prospective, randomized, placebo-controlled, double-blind clinical trial enrolled 25 patients with the anemia of multiple myeloma and a hematocrit less than 0.30.. Epoetin alfa, 150 U/kg, or a matching volume of placebo was administered subcutaneously three times per week for 6 weeks. If the criterion for a response was not met, the dose was doubled. After 12 weeks, nonresponders in the placebo arm were switched to an open-label study of epoetin alfa at a dose of 150 U/kg for 6 weeks. After 6 weeks, the dose was doubled if no response was obtained. A partial response was defined as an increase of 6 percentage points or greater in the hematocrit without transfusion. A complete response required a final hematocrit of 0.38 or greater without transfusion. Complete responders had reduction of epoetin alfa to the lowest dose capable of maintaining the complete response.. Twenty patients were evaluable for response to therapy. During the double-blind phase, six patients who were receiving epoetin alfa had a complete response, one had a partial response, and three were non-responders. No responses occurred in the placebo arm. In the open-label phase, of the 10 patients who were originally receiving placebo, three had a complete response, one had a partial response, and six were nonresponders. Chemotherapy, pretreatment serum erythropoietin levels, disease duration, and reticulocyte count did not predict the response to epoetin alfa. The median final dose for the responding group was 120 U/kg three times per week to maintain a hematocrit greater than 0.38. There was no effect on the course of the myeloma, and no hypertension was seen.. Treatment with epoetin alfa is effective and safe in patients with the anemia of multiple myeloma.

Topics: Anemia; Double-Blind Method; Erythropoietin; Female; Hematocrit; Humans; Injections, Subcutaneous; Male; Multiple Myeloma; Prospective Studies; Recombinant Proteins; Treatment Outcome

Recombinant human erythropoietin (rHu-EPO) is an effective growth factor for erythroid progenitor cells in anemia provoked by several conditions, including bone marrow tumors such as multiple myeloma (MM). We studied a group of 54 patients with MM undergoing second-induction chemotherapy. Thirty of them were randomly assigned to receive rHu-EPO at an initial dosage of 150 units/kg body weight three times a week, increased to 300 units/kg from the sixth week to the end of the 24-week study. Hemoglobin (Hb) levels increased in 77.7% of these patients by the eighth week. In addition, five transfusion-dependent patients in treatment with the VMCP protocol completed the trial without requiring blood supplement after the third month, whereas seven control patients required frequent supplements. Monthly assessment of hematologic parameters demonstrated the ability of rHu-EPO to increase reticulocyte counts, whereas five patients became resistant to the second-induction chemotherapy in apparent concurrence with their rHu-EPO therapy. The response to rHu-EPO in four of the five MM patients receiving cytotoxic protocols combined with alpha-interferon (alpha-IFN) included an increase of serum IgM after the third month. This effect was not demonstrable in any other group, including three rHu-EPO-untreated patients undergoing alpha-IFN + VMCP combined therapy, as well as rHu-EPO-treated patients not receiving alpha-IFN. Our data suggest that alpha-IFN plus rHu-EPO treatment in MM patients is effective in restoring normal B cell function. These results may reflect in vivo the modulation of normal human B cells and lymphoblasts by rHu-EPO observed in vitro.

Topics: Anemia; Erythropoietin; Hemoglobins; Humans; Multiple Myeloma; Recombinant Proteins; Time

T and B lymphocyte functions were investigated in the course of a long-term trial of recombinant human erythropoietin in patients with progressing multiple myeloma. Peripheral mononuclear cell as well as T and B lymphocyte cultures were established at the 1st, 13th, and last week of the 24-week protocol from 16 treated and 15 untreated patients. Control cultures from healthy individuals were also obtained. A suppression of phytohemagglutinin-induced proliferation of T cells was noted in all 1st-week cultures, whereas a variable increase of 3H-thymidine uptake was noted at the end of the trial in the cultures from erythropoietin-treated patients. A significant increase was observed, however, in cultures from 5 erythropoietin-treated patients who also received alpha-interferon when their cells were grown in the presence of the hormone. In contrast, the pokeweed mitogen-driven in vitro synthesis of immunoglobulins was not significantly influenced by the duration of erythropoietin treatment, nor by addition of the hormone. IgG secretion by Epstein-Barr virus-transformed B cells in cultures from 9 erythropoietin-treated and 6 untreated patients was enhanced in the presence of both recombinant human erythropoietin and alpha-interferon. These data suggest that synergy between the two cytokines may variably modulate certain immune functions in vitro. This effect might account for the increase of serum IgM levels noted in some patients who received alpha-interferon.

Topics: B-Lymphocytes; Combined Modality Therapy; Drug Synergism; Erythropoietin; Humans; Immunoglobulin G; Immunoglobulin M; In Vitro Techniques; Interferon-alpha; Lymphocyte Activation; Multiple Myeloma; Phytohemagglutinins; Pokeweed Mitogens; Recombinant Proteins; T-Lymphocytes

Treatment of myeloma-associated chronic anemia with recombinant human erythropoietin (rHuEPO) has been shown to be successful in the majority of patients. We have morphometrically investigated bone marrow sections from the iliac crest of 20 anemic myeloma patients prior to rHuEPO therapy. The 15 responding patients were re-examined after three months and, if possible, after 6 and 12 months of treatment. Significant differences were found between responders and nonresponders prior to therapy. Nonresponders presented with a pronounced shift to the right in their erythroid bone marrow cell compartment and partly with higher serum levels of endogenous erythropoietin. During rHuEPO therapy, responders showed increases in all subsets of erythropoiesis and in the total amount of hemopoietic tissue. Response was accompanied by a marked drop of serum ferritin levels, a rise in serum levels of transferrin receptors and the emptying of bone marrow iron stores; the World Health Organization performance status improved. Responders tended to present with less advanced disease stages and better performance status and showed significantly longer survival times. Loss of responsiveness to rHuEPO was observed in one patient during the terminal stage of the disease. In conclusion, morphometric examination of bone marrow biopsies during the course of rHuEPO therapy showed that the response achieved in hemoglobin values was clearly mirrored in equivalent increments of the erythroid bone marrow cell compartment.

Topics: Aged; Anemia; Bone Marrow; Erythropoiesis; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Multiple Myeloma; Prognosis; Prospective Studies; Recombinant Proteins

Previous phase I-II clinical trials have shown that recombinant human erythropoietin (rHuEpo) can ameliorate anemia in a portion of patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). Therefore, we performed a randomized controlled multicenter study to define the optimal initial dosage and to identify predictors of response to rHuEpo. A total of 146 patients who had hemoglobin (Hb) levels < or = 11 g/dL and who had no need for transfusion at the time of enrollment entered this trial. Patients were randomized to receive 1,000 U (n = 31), 2,000 U (n = 29), 5,000 U (n = 31), or 10,000 U (n = 26) of rHuEpo daily subcutaneously for 8 weeks or to receive no therapy (n = 29). Of the patients, 84 suffered from MM and 62 from low- to intermediate-grade NHL, including chronic lymphocytic leukemia; 116 of 146 (79%) received chemotherapy during the study. The mean baseline Hb level was 9.4 +/- 1.0 g/dL. The median serum Epo level was 32 mU/mL, and endogenous Epo production was found to be defective in 77% of the patients, as judged by a value for the ratio of observed-to-predicted serum Epo levels (O/P ratio) of < or = 0.9. An intention-to-treat analysis was performed to evaluate treatment efficacy. The median average increase in Hb levels per week was 0.04 g/dL in the control group and -0.04 (P = .57), 0.22 (P = .05), 0.43 (P = .01), and 0.58 (P = .0001) g/dL in the 1,000 U, 2,000 U, 5,000 U, and 10,000 U groups, respectively (P values versus control). The probability of response (delta Hb > or = 2 g/dL) increased steadily and, after 8 weeks, reached 31% (2,000 U), 61% (5,000 U), and 62% (10,000 U), respectively. Regression analysis using Cox's proportional hazard model and classification and regression tree analysis showed that serum Epo levels and the O/P ratio were the most important factors predicting response in patients receiving 5,000 or 10,000 U. Approximately three quarters of patients presenting with Epo levels inappropriately low for the degree of anemia responded to rHuEpo, whereas only one quarter of those with adequate Epo levels did so. Classification and regression tree analysis also showed that doses of 2,000 U daily were effective in patients with an average platelet count greater than 150 x 10(9)/L. About 50% of these patients are expected to respond to rHuEpo. Thus, rHuEpo was safe and effective in ameliorating the anemia of MM and NHL patients who showed defective endogenous Epo production. From a practical point of view, we co

Topics: Adult; Aged; Aged, 80 and over; Anemia; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Female; Humans; Injections, Subcutaneous; Life Tables; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma; Prognosis; Proportional Hazards Models; Recombinant Proteins; Safety

Topics: Anemia; Erythropoietin; Female; Hemoglobins; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Multiple Myeloma; Prospective Studies

Safety and efficacy of recombinant human erythropoietin (epoetin alpha) were investigated in anemic patients with multiple myeloma whose hemoglobin (Hb) concentration was less than 10g/dl. Epoetin alpha (3,000IU/body) was given subcutaneously daily for two weeks and the dosage was increased to 6,000IU, 12,000IU and 24,000IU every two weeks when the increment of Hb was insufficient. Cases in which Hb concentration increased by more than 1g/dl or in which blood transfusion requirements decreased by more than 50% were judged to be effective. The overall rate of efficacy was 52.6% (10/19). Response to epoetin alpha treatment was better in patients whose blood erythropoietin level was relatively low. The majority of patients responded to the treatment with up to 6,000IU/body/day but a dosage of more than 12,000IU/body/day was required in some cases. No serious adverse effects or abnormal laboratory findings were observed. These results suggest that high-dose subcutaneous epoetin alpha treatment is effective for anemia associated with multiple myeloma in terms of increasing Hb concentration and reducing blood transfusion.

Topics: Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins

This experiment aimed to detect serum erythropoietin (EPO) levels in patients with haematological tumours and to investigate its clinical significance. For this purpose, 110 patients with haematological tumours admitted to our hospital between January 2019 and December 2020 were selected as the study population according to the inclusion and exclusion criteria, and they were included in the case group, and the clinical data of the patients were retrospectively analysed. 90 cases of people without hematological tumors who underwent physical examination during the same period were also included as a control group. The serum EPO levels of the two study groups were compared, and the clinical diagnostic value of EPO was analysed using the subject operating characteristic curve (ROC). Results indicated that of the 110 patients, 56 were leukaemia patients, 24 were multiple myeloma patients and 30 were malignant lymphoma patients. The differences in gender, age, disease history, alcohol consumption and smoking history between the two groups were not significant (P>0.05), while the EPO levels in the control group were significantly lower than those in the case group, with a statistical significant difference of P<0.05. The EPO levels in patients with leukaemia, multiple myeloma and malignant lymphoma were (165.43± 20.46) mU/mL, ( 28.14± 4.51) mU/mL and (86.25±10.33) mU/mL significantly higher than the control group, with a significant difference of P<0.05. Using the absence of haematological tumours as a control, the analysis yielded an area under the ROC curve of 0.995 for EPO diagnosis in patients with leukaemia, a 95% confidence interval of 0.987 to 1.000, a sensitivity of 97.80%, with a sensitivity of 98.2 %; the area under the ROC curve for patients with multiple myeloma was 0.910, with a 95% confidence interval of 0.818 to 1.000, with a sensitivity of 98.90% and specificity of 87.50%; the area under the ROC curve for patients with malignant lymphoma was 0.992, with a 95% confidence interval of 0.978 to 1.000, with a sensitivity of 96.70% and specificity of 96.70%. In conclusion, the serum EPO levels of patients with haematological tumours are significantly higher than those of the normal population, and the detection of serum EPO levels is valuable for the diagnosis of clinical haematological tumours.

Topics: Clinical Relevance; Erythropoietin; Hematologic Neoplasms; Humans; Leukemia; Multiple Myeloma; Retrospective Studies

Topics: Aged; Aged, 80 and over; Erythropoietin; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Male; Middle Aged; Multiple Myeloma; Prognosis; Renal Insufficiency; Retrospective Studies; Survival Rate

To clarify the role of red blood cell (RBC) lifespan in anemia of multiple myeloma (MM), RBC lifespan was detected in 40 newly diagnosed MM patients by measuring exhaled endogenous carbon monoxide concentration. Mean RBC lifespan was significantly reduced in MM patients (63 ± 23 d) than healthy controls (116 ± 17 d). RBC lifespan in MM patients without anemia (78 ± 21 d) was also significantly lower than for healthy controls. RBC lifespan in MM patients with anemia (52 ± 18 d) was significantly lower than those without. Besides, RBC lifespan in MM patients with renal insufficiency (50 ± 16 d) was lower than those without (66 ± 23 d). RBC lifespan was significantly negatively correlated with % reticulocytes, erythropoietin concentration, % clonal plasma cells, β2-microglobulin (MG) level, and creatinine level. Receiver operator characteristics curve was used to determine a cut-off point (61 d) to predict effect of RBC lifespan on chemotherapy. Overall response rates were significantly higher in MM patients with RBC lifespan ≥61 d than those <61 d. In conclusion, RBC lifespan of MM patients is reduced, and severely shortened RBC lifespan may be involved in the occurrence of anemia in MM patients. The chemotherapeutic effect of MM patients can be predicted by RBC lifespan.

Topics: Adult; Aged; Aged, 80 and over; Bortezomib; Breath Tests; Carbon Monoxide; Case-Control Studies; Dexamethasone; Erythrocytes; Erythropoietin; Exhalation; Female; Humans; Male; Middle Aged; Multiple Myeloma; ROC Curve

Topics: Abnormal Karyotype; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Erythroblasts; Erythropoietin; Female; Humans; Immunoglobulin D; Melphalan; Multiple Myeloma; Myelodysplastic Syndromes; Neutrophils; Proto-Oncogene Proteins c-myc

To explore the effect of recombinant human erythropoietin (rhEPO) on myeloma cell line MPC-11 in vitro and its anti-tumor mechamism so as to provide the theoretic evidence for treatment of multiple myeloma by using rhEPO.. The apoptosis rate in MPC-11 cells treated with 200 U/ml of rhEPO at day 21 was significantly higher than that in control group(P<0.05); the apoptosis rate in MPC-11 cells treated with 400 U/ml of rhEPO at day 10, 15, 21 was higher than that in control group at same time points, respectively (P<0.05), suggesting that the MPC-11 cell apoptosis rate was enhanced with increase of rhEPO concentration and prolonging of culture time(P<0.05), the IL-6 level in supernatant of cell treated with 400 U/ml of rhEOP for 15 days was lower than that in control group(P<0.05), while the IL-6 level in supernatant of cells treated with 100, 200, 400 U/ml of rhEPO for 21 days decreased (P<0.05); The levels of IgG and kappa light chain in supernatant of cells treated with 400 U/ml of rhEPO for 21 days all were significantly lower than those in control group(P<0.05).. The rhEPO can induce apoptosis of MPC-11 cells with concentration- and time-dependent manner, and can reduce levels of IgG, kappa light chain secreted by MPC-11 cells with time-dependent manner.

Topics: Apoptosis; Cells, Cultured; Erythropoietin; Humans; Multiple Myeloma; Recombinant Proteins

Increasing evidences suggest several biological roles for erythropoietin and its receptor (Epo and EpoR), unrelated to erythropoiesis, including angiogenesis. Here, we detected the expression of EpoR in bone marrow-derived endothelial cells from monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) patients (MGECs and MMECs, respectively) and assessed whether Epo plays a role in MGECs- and MMECs-mediated angiogenesis. We show that EpoR is expressed by both MGECs and MMECs even though at a higher level in the first ones. Both EC types respond to rHuEpo in terms of cell proliferation, whereas other responses, including activation of JAK2/STAT5 and PI3K/Akt pathways, cell migration and capillarogenesis are enhanced by Epo in MGECs, but not in MMECs. In addition, the conditioned media of both Epo-treated cells induce a strong angiogenic response in vivo in the chorioallantoic membrane assay, comparable to that of vascular endothelial growth factor (VEGF). Overall, these data highlight the effect of Epo on MGECs- and MMECs-mediated angiogenesis: MGECs are more responsive to Epo treatment than MMECs, probably because over-angiogenic phenotype of MMECs is already activated by their autocrine/paracrine loops occurring in the "angiogenic switch" from MGUS.

Topics: Animals; Apoptosis; Biomarkers, Tumor; Bone Marrow; Cell Movement; Cell Proliferation; Chickens; Culture Media, Conditioned; Endothelial Cells; Erythropoietin; Humans; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Neovascularization, Pathologic; Receptors, Erythropoietin; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

Multiple myeloma (MM) is a plasma cell malignancy, characterized by osteolytic lesions and monoclonal immunoglobulins. The anemia, accompanying the disease is often treated with recombinant human EPO. Diverse non-erythropoietic effects of EPO have led us to question its combined action on the immune system and bone in the 5T33MM mouse model. EPO administration to MM mice attenuated disease progression as demonstrated by a decrease in serum MM IgG2b, splenic CD138 expressing cells, IL-6 and RORγτ transcripts in bone marrow (BM). IFN-γ transcript levels and macrophages (F4/80(+)CD11b(+)) in the BM both increased ~1.5 fold in the EPO-treated MM mice. In-vitro, EPO stimulated phagocytosis of 5T33MM cells (+30%) by BM-derived macrophages. In contrast, high-resolution microCT analysis of distal femurs revealed EPO-associated bone loss in both healthy and 5T33MM mice. EPO significantly increased expression of the osteoclastogenic nuclear factor-kappa B ligand (RANKL) in healthy mice, but not in MM mice, likely due to antagonizing effects on MM progression. Thus, in MM, EPO may act as a double-edged-sword stimulating immune response, while accelerating bone resorption, possibly via direct action on BM macrophages. This study supports a prudent approach of treating anemia in MM patients, aiming to maintain EPO-associated anti-MM effects, while considering bone damage.

Topics: Anemia; Animals; Bone Marrow; Bone Resorption; Cells, Cultured; Erythropoietin; Female; Macrophages; Mice; Mice, Inbred C57BL; Multiple Myeloma; Phagocytosis; Signal Transduction

Autologous stem-cell transplantation (ASCT) has shown to provide curative benefit in patients with relapsed lymphoma and multiple myeloma (MM), often requiring hematopoietic support until marrow engraftment. Because of Jehovah's Witnesses' (JW) refusal of blood products, treatment challenges arise. This study represents 125 JWs with lymphoma (n = 55), MM (n = 68), or amyloidosis (n = 2), treated with high-dose chemotherapy (HDC) and ASCT without transfusions.. Priming with intravenous iron and erythropoietin occurred to increase hemoglobin (Hb) pretransplantation. Cytokine mobilization of stem-cells was used. Delay to HDC was done to allow Hb and platelets to approach 11 g/dL and 100 × 10(3)/μL, respectively. Patients with MM received a standard dose of melphalan 200 mg/m(2), with dose reduction for severe kidney dysfunction. Patients with lymphoma received carmustine 300 mg/m(2), cyclophosphamide 1,500 mg/m(2) on days 2 through 5 (total 6 g/m(2)), and etoposide 700 mg/m(2) per day on days 2 through 4 (total 2,100 mg/m(2)). Post-transplantation, a combination of granulocyte colony-stimulating factor, erythropoietin, aminocaproic acid, and phytonadione was administered.. There were two major and 15 minor bleeding complications, none occurring at platelets less than 5.0 × 10(3)/μL, with six (4.8%) treatment-related mortalities. The median decrease in Hb was 5.0 g/dL, with median Hb nadir of 7.0 g/dL. The median number of days with platelet count less than 10 × 10(3)/μL was 3, with median platelet nadir of 5.0 × 10(3)/μL. Cardiac complications occurred in 40 patients (32%).. ASCT can safely be performed without transfusion support. A platelet transfusion trigger of ≤ 5 × 10(3)/μL may be appropriate in select patients. Pharmacotherapy and cardiac monitoring are effective in the management of cardiac complications.

Topics: Adult; Aged; Aminocaproic Acid; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Carmustine; Combined Modality Therapy; Cyclophosphamide; Erythropoietin; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Hemoglobins; Humans; Iron; Jehovah's Witnesses; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Recurrence; Stem Cell Transplantation; Transplantation, Autologous; Vitamin K 1; Young Adult

Erythropoietin (Epo) is the crucial cytokine regulator of red blood cell production, and recombinant human erythropoietin (rHuEpo) is widely used in clinical practice for the treatment of anemia, primarily in kidney disease and in cancer. Increasing evidence suggests several biological roles for Epo and its receptor, Epo-R, unrelated to erythropoiesis, including angiogenesis. Epo-R has been found expressed in various non-haematopoietic cells and tissues, and in cancer cells. Here, we detected the expression of Epo-R in bone marrow-derived macrophages (BMMAs) from multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) patients and assessed whether Epo/Epo-R axis plays a role in MM macrophage-mediated angiogenesis. We found that Epo-R is over-expressed in BMMAs from MM patients with active disease compared to MGUS patients. The treatment of BMMAs with rHuEpo significantly increased the expression and secretion of key pro-angiogenic mediators, such as vascular endothelial growth factor, hepatocyte growth factor and monocyte chemotactic protein (MCP-1/CCL-2), through activation of JAK2/STAT5 and PI3 K/Akt pathways. In addition, the conditioned media harvested from rHuEpo-treated BMMAs enhanced bone marrow-derived endothelial cell migration and capillary morphogenesis in vitro, and induced angiogenesis in the chorioallantoic membrane of chick embryos in vivo. Furthermore, we found an increase in the circulating levels of several pro-angiogenic cytokines in serum of MM patients with anemia under treatment with Epo. Our findings highlight the direct effect of rHuEpo on macrophage-mediated production of pro-angiogenic factors, suggesting that Epo/Epo-R pathway may be involved in the regulation of angiogenic response occurring in MM.

Topics: Aged; Androstadienes; Angiogenic Proteins; Animals; Bone Marrow; Bone Marrow Cells; Capillaries; Cell Movement; Cells, Cultured; Chick Embryo; Chorioallantoic Membrane; Chromones; Culture Media, Conditioned; Cytokines; Epoetin Alfa; Erythropoietin; Humans; Macrophages; Middle Aged; Monoclonal Gammopathy of Undetermined Significance; Morpholines; Multiple Myeloma; Neoplasm Proteins; Neovascularization, Pathologic; Receptors, Erythropoietin; Recombinant Proteins; RNA Interference; RNA, Small Interfering; Signal Transduction; Up-Regulation; Vascular Endothelial Growth Factor A; Wortmannin

Venous thromboembolism (VTE) is a significant but poorly understood complication in patients with newly diagnosed multiple myeloma (NDMM). As a result, most patients receive thromboprophylaxis with low molecular weight heparin (LMWH). The purpose of this retrospective study was to identify risk factors for VTE in NDMM and evaluate the effectiveness of LMWH.. A total of 604 patients with newly diagnosed myeloma completed 3 induction cycles with multiagent chemotherapy with up-front randomization to thalidomide between 1998 and 2004. Prophylactic enoxaparin was given to thalidomide recipients beginning in June 2001, and 122 subjects received prophylactic epoetin alfa (EPO) as part of an exercise trial. The primary study endpoint was grades 3-4 VTE.. A total of 72 patients (11.9%) developed VTE (mostly deep venous thrombosis), with a higher incidence among EPO recipients (P = .001), although only significant for upper extremity DVT (P = .0002). The EPO-treated patients had higher hemoglobin (Hb) levels throughout the study (P < .0005), although no relationship between higher Hb levels and increasing incidence of VTE could be shown. A history of VTE was a strong predictor of VTE on univariate analysis (P < .000005). Enoxaparin did not reduce the rate of VTE (P = .158). Logistic regression analysis identified thalidomide therapy (P = .001; odds ratio [OR], 2.428; 95% confidence interval [CI], 1.418-4.159) and prophylactic EPO (P = .002; OR, 2.488; 95% CI, 1.432-4.324) as risk factors for VTE. Myeloma response and survival were not negatively affected by prophylactic EPO or VTE.. Prophylactic EPO, thalidomide therapy, and VTE history, but not higher Hb levels, were found to increase the risk of VTE among NDMM patients receiving multiagent chemotherapy. This risk was not found to be reduced in this population by LMWH thromboprophylaxis.

Topics: Adult; Aged; Anticoagulants; Enoxaparin; Epoetin Alfa; Erythropoietin; Female; Humans; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins; Risk Factors; Thalidomide; Venous Thromboembolism

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Erythropoietin; Female; Genotype; Humans; Male; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Polymorphism, Single Nucleotide; Promoter Regions, Genetic

Autoimmune hyperlipidemia (AIH) is a rare cause of secondary hyperlipidemia. A few cases of AIH have been reported in multiple myeloma.. A female in her fifties was referred to the outpatient clinic presenting with headache, blurred vision and skin rash. Physical examination with subsequent laboratory and histological examinations revealed severe hyperlipidemia secondary to secretory multiple myeloma with monoclonal IgG kappa protein and erythrocytosis secondary to a erythropoietin secreting adenoma in the liver.. Treatment for multiple myeloma (induction treatment and autologous hematological stem cell transplantation) gained partial remission and was associated with normalization of serum lipids. There was no need for further medical treatment of the hyperlipidemia. Three years after the initial treatment, serum concentrations of triglycerides and total cholesterol increased in parallel with monoclonal IgG kappa protein. Total cholesterol and triglycerides decreased and remained within the reference ranges after retreatment with a second autologous stem cell transplantation. Surgical removal of the hepatic adenoma caused normalisation of the erythropoietin concentration and resolution of the erythrocytosis. The present case reports two rare complications (AIH and erythrocytosis) to multiple myeloma and hepatic adenoma, with regression of complaints and normalisation of laboratory tests after adequate treatment of underlying diseases.

Topics: Adenoma, Liver Cell; Antibodies, Monoclonal; Anticholesteremic Agents; Antineoplastic Agents; Autoimmune Diseases; Erythropoietin; Fatty Acids, Omega-3; Female; Humans; Hyperlipidemias; Immunoglobulin A; Immunosuppressive Agents; Liver Neoplasms; Middle Aged; Multiple Myeloma; Polycythemia

This study was purposed to investigate the effect of multiple myeloma patients' sera on hepcidin mRNA expression of Hep-3b hepatoma cell line and effect of human interleukin-6 (IL-6) antibody or recombinant human erythropoietin (rhEPO) on hepcidin mRNA expression. The clinical information and serum of multiple myeloma patients were collected. Their sera of a final concentration of 10% were added into Hep-3b cell medium. The mRNA from Hep-3b cells was extracted, and hepcidin mRNA expression was detected by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). A final concentration of 10 ng/ml human IL-6 antibody and 2 U/ml rhEPO were added into the medium respectively. The results showed that the sera of untreated multiple myeloma patients elevated hepcidin mRNA expression of Hep-3b cells, compared with healthy controls and iron deficiency anemia patients. This effect was fully neutralized by human IL-6 antibody or rhEPO. The hemoglobin (Hb) level was stable during the follow up of regularly treated multiple myeloma patients and the effect of MM patient serum on Hep-3b cell hepcidin mRNA expression was reduced. It is concluded that the hepcidin mRNA expression of Hep-3b cell can be increased by untreated multiple myeloma patient serum. This promotive effect can be antagonised by IL-6, which suggests that IL-6 may be possible to elevate expression level of hepcidin in Hep-3b cells and results in anemia of chronic disease (ACD). The above mentioned promotive effects also can be suppressed by rhEPO, which indicates that the rhEPO may possess curative effect for ACD disease. During short-term follow-up of treated patients with multiple myeloma the Hb level is stable, the influence of patients serum on hepcidin mRNA of Hep-3b cells decreases, which shows the stabilization of disease and amelioration of ACD patient status.

Topics: Adult; Aged; Antibodies, Monoclonal; Antimicrobial Cationic Peptides; Cell Line, Tumor; Erythropoietin; Female; Hepcidins; Humans; Interleukin-6; Male; Middle Aged; Multiple Myeloma; RNA, Messenger

To test the effects and to identify appropriate dosage and possible mechanisms of recombinant human erythropoietin (rHuEPO) in treating MPC-11 myeloma in the BALB/c murine models.. A total of 420 BALB/c mice were divided into five groups. 410 of which were injected with 10(4) MPC-11 cells. The 10 mice without myeloma cell inoculation served as normal controls. On the fifth day after inoculation, 50 tumor-bearing mice were arbitrarily assigned into the placebo group, while the other 360 mice were randomly allocated into three experimental groups. Each experimental group had 120 mice and received 10, 20 and 30 units subcutaneous injection of rHuEPO, respectively. A daily injection was administered for 14 days, followed by three injections per week. The mice in the placebo group were administered with saline following the same scheme. Dynamic monitoring of serum M-protein and hemoglobin levels of the mice were performed after myeloma cell inoculation. The subcutaneous nodules were sent for pathological biopsy to ascertain the successful establishment of the murine models. The mice were randomly chosen from each group to be tested for the levels of monoclonal IgG and kappa light chain in their sera (immunofixation electrophoresis and ELISA), counts of CD4 and CD8 positive cells in whole blood (flow cytometry), microvessel density (by marking CD31) and cell apoptosis (TdT-mediated dUTP-biotin nick end labeling, TUNEL) of tumor tissues, as well as the levels of cytokines such as IL-6 and TNF-alpha in sera (ELISA) at each month after the injection of rHuEPO.. The serum monoclonal immunoglobulin appeared on the 22nd day after inoculation of MPC-11 cells. rHuEPO increased Hb level and survival time of the mice with multiple myeloma. The serum levels of IL-6, IgG and kappa light chain decreased significantly in the mice in the treatment groups compared with those in the placebo group. The overall survival time showed a positive correlation with the Hb level (P = 0.000), and a negative correlation with the serum levels of IL-6 (P = 0.009).. rHuEPO increases Hb levels and survival time and reduces serum IL-6 and M-protein of the mice with multiple myeloma.

Topics: Animals; Erythropoietin; Female; Hemoglobins; Immunoglobulins; Interleukin-6; Mice; Mice, Inbred BALB C; Multiple Myeloma; Random Allocation; Recombinant Proteins

Topics: Aged; Combined Modality Therapy; Disease Progression; Epoetin Alfa; Erythropoietin; Female; Ferric Compounds; Hematinics; Hemostatic Techniques; Humans; Jehovah's Witnesses; Male; Middle Aged; Multiple Myeloma; Patient Acceptance of Health Care; Peripheral Blood Stem Cell Transplantation; Recombinant Proteins; Serum Albumin; Sodium Chloride; Thrombocytopenia; Transplantation, Autologous

Elevated haemoglobin and erythrocytosis are frequent causes for investigation.. A 50-year-old woman with elevated haemoglobin and erythrocytosis was referred to our hospital for investigation.. She had elevated serum erythropoietin and iron deficiency. Mutational status of the JAK2 gene was negative with respect to polycythemia vera, and no secondary reasons for polycythemia - including tumours - were revealed. A bone marrow biopsy and bone marrow smear showed a moderately increased number of lambda- positive monoclonal plasma cells, and small amounts of lambda light chains were detected in the urine. Serum electrophoreses showed no gammopathy. The reason for her elevated haemoglobin could be an erythropoietin-producing tumour or an idiopathic erythrocytosis based on a mutation in exon 12 of the JAK2 gene. Investigation of her plasma cells revealed a 10-fold increase in erythropoietin mRNA expression, indicating the reason for her elevated serum erythropoietin and haemoglobin values.

Topics: Bone Marrow Examination; Diagnosis, Differential; Erythropoietin; Female; Gene Expression; Hemoglobins; Humans; Iron Deficiencies; Middle Aged; Multiple Myeloma; Myeloproliferative Disorders; Polycythemia; Polycythemia Vera; RNA, Messenger

Haematological toxicities and thromboembolic (TE) events are common complications of myeloma therapy. TE risk may be elevated with combination regimens, notably thalidomide/lenalidomide plus high-dose dexamethasone; concomitant erythropoietin appears to further increase the risk with lenalidomide-dexamethasone. We characterised thrombocytopenia and neutropenia in the phase 3 APEX (Assessment of Proteasome Inhibition for Extending Remissions) study of bortezomib versus high-dose dexamethasone in relapsed myeloma, and calculated the incidences of deep-vein thrombosis (DVT)/pulmonary embolism (PE) with: bortezomib or dexamethasone +/- erythropoietin in APEX; bortezomib +/- dexamethasone +/- erythropoietin in two phase 2 studies of relapsed/refractory myeloma. Bortezomib-associated thrombocytopenia and neutropenia were transient, predictable and manageable; mean platelet and neutrophil counts followed a cyclical pattern, and improved over the treatment course. Grade 3/4 thrombocytopenia incidence was higher with bortezomib versus dexamethasone (26%/4% vs. 5%/1%), but significant bleeding events were comparable (4% vs. 5%). DVT/PE incidence was low (< or =3.1%) in all analyses; addition of dexamethasone/erythropoietin did not affect TE risk. In APEX, TE risk appeared lower with bortezomib versus dexamethasone. Bortezomib caused transient and cyclical thrombocytopenia and was not associated with elevated TE risk, alone or with dexamethasone +/- erythropoietin. Preliminary data suggest bortezomib may reduce the thrombogenic potential of combination regimens via inhibition of platelet function or other mechanism-specific effects on coagulation.

Topics: Boronic Acids; Bortezomib; Clinical Trials as Topic; Dexamethasone; Drug Therapy, Combination; Erythropoietin; Female; Humans; Immunosuppressive Agents; Logistic Models; Male; Middle Aged; Multiple Myeloma; Protease Inhibitors; Pulmonary Embolism; Pyrazines; Recombinant Proteins; Recurrence; Risk; Treatment Outcome; Venous Thrombosis

Neutrophilic disease is characterized by aseptic visceral infiltration by normal polymorphonuclear leukocytes that can occur in any organ. Association with an underlying systemic disease, particularly haematological malignancy or inflammatory bowel disease, is frequent. This may produce a multisystem disorder, but diagnosis is usually based on skin lesions because of their clinical and histological accessibility. Pulmonary manifestations are the most common extracutaneous symptoms but may be misdiagnosed, as in our case report.. A 77-year-old woman with IgA myeloma presented with an inflammatory bullous plaque of the leg coupled with fever lasting one week. The clinical and histological examinations were evocative of a neutrophilic dermatosis such as Sweet's syndrome. Significant improvement was initially obtained with systemic corticosteroids and colchicine. The course became complicated by necrotic neutrophilic papulopustular lesions of the upper limbs and pulmonary manifestations, with fever and decline in overall condition occurring the day after administration of erythropoietin. A hypothesis of septic aetiology prompted antibiotic and antifungal therapy, which remained ineffective. The patient died the day after the second erythropoietin injection.. This case involved late identification of the aseptic neutrophilic aetiology of pulmonary manifestations. Several factors favouring their appearance and the fatal outcome may be suggested: the existence of a myeloma, association with myelodysplastic syndrome and the possible iatrogenic action of erythropoietin. To the best of our knowledge, this is the first reported case of extracutaneous neutrophilic infiltrate occurring in a patient treated with this haematopoietic hormone.

Topics: Aged; Erythropoietin; Fatal Outcome; Female; Humans; Inflammation; Lung Diseases; Multiple Myeloma; Sweet Syndrome

Recombinant human erythropoietin (rhEPO) is effective for the treatment of anemia associated with multiple myeloma. Data from animal studies and case reports suggest that rhEPO has antineoplastic properties.. Two hundred and ninety-two patients enrolled on different chemotherapy clinical trials at the Cleveland Clinic Myeloma Program between 1997 and 2003 were the subjects of this study. Information on erythropoietin use as well as baseline prognostic variables were collected retrospectively.. The population consisted of 257 patients with multiple myeloma treated at the Cleveland Clinic Foundation from 1997 to 2003 and followed for at least 1 month. Thirty-five patients were excluded from this analysis because information on erythropoietin use was not available. One hundred and twenty-seven patients received rhEPO for at least 1 month and the rest did not received rhEPO. On average, patients who received rhEPO were older, had a higher Southwest Oncology Group (SWOG) stage, higher serum creatinine, lower serum hemoglobin, higher beta2-microglobulin, lower platelet counts, and a longer time from diagnosis to enrollment at the myeloma program (p < 0.001 for all). After adjusting for age, months from diagnosis to enrollment, serum creatinine, hemoglobin, platelet count, and beta2-microglobulin, the use of rhEPO was associated with improved overall survival (hazard ratio = 0.6; 95% CI = 0.38-0.94) in patients with SWOG stages II, III and IV but not in patients with SWOG stage I.. rhEPO was associated with improved overall survival in this population of anemic multiple myeloma patients with SWOG stages of II, III and IV. A prospective randomized trial is warranted to corroborate this finding.

Topics: Aged; Anemia; Erythropoietin; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins; Retrospective Studies; Survival Analysis; Treatment Outcome

Erythropoietin (Epo) is the main erythropoietic hormone. Recombinant human Epo (rHuEpo) is thus used in clinical practice for the treatment of anemia. Accumulating data reveals that Epo exerts pleiotropic activities. We have previously shown an anti-neoplastic activity of Epo in murine multiple myeloma (MM) models, and in MM patients. Our findings that this anti-neoplastic effect operates via CD8+ T lymphocytes led us to hypothesize that Epo possesses a wider range of immunomodulatory functions. Here we demonstrate the effect of Epo on B lymphocyte responses, focusing on three experimental models: (i) tumor-bearing mice, (5T2 MM mouse); (ii) antigen-injected healthy mice; and (iii) antigen-injected transgenic mice (tg6), overexpressing human Epo. In the MM model, despite bone marrow dysfunction, Epo-treated mice retained higher levels of endogenous polyclonal immunoglobulins, compared to their untreated controls. In both Epo-treated wild type and tg6 mice, Epo effect was manifested in the higher levels of splenocyte proliferative response induced in vitro by lipopolysaccharide. Furthermore, these mice had increased in vivo production of anti-dinitrophenyl (DNP) antibodies following immunization with DNP-keyhole limpet hemocyanin. Epo-treated mice showed an enhanced immune response also to the clinically relevant hepatitis B surface antigen. These findings suggest a potential novel use of rHuEpo as an immunomodulator.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Monoclonal; Antibody Formation; B-Lymphocytes; CD3 Complex; Cell Proliferation; Erythropoietin; Female; Hemocyanins; Hepatitis B Surface Antigens; Humans; Immunoglobulin G; Immunoglobulin gamma-Chains; Immunoglobulin kappa-Chains; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Multiple Myeloma; Recombinant Proteins; Survival Analysis; T-Lymphocytes; Vaccination

There is a growing interest in the non-erythropoietic, tissue-protective and restorative actions of erythropoietin (EPO). While studies in this field have indicated that EPO can ameliorate chemotherapy-induced peripheral neuropathy and cardiotoxicity, the issue whether EPO can positively or negatively affect cancer patients is a hot one. In this debate, many activities of EPO are being considered, including tissue/neuroprotection, angiogenesis, anti-inflammatory activity, growth promotion, and inhibition of apoptosis. However, few studies have explored the interactions of EPO with the immune system. A study in this issue of the European Journal of Immunology by Katz et al. adds one new piece to the puzzle by showing that EPO can stimulate B cell-mediated immunity.

Topics: Animals; Antibody Formation; Erythropoietin; Humans; Lymphocytes; Mice; Multiple Myeloma; Neoplasms

Topics: Aged; Erythropoietin; Hematinics; Humans; Immunosuppressive Agents; Male; Middle Aged; Multiple Myeloma; Risk Factors; Thalidomide; Treatment Outcome; Venous Thrombosis

Erythropoietin (EPO) and EPO receptor (EPO-R) expression have been reported in solid tumors and are claimed to regulate tumor growth; however, no data have been published on this issue in B-cell malignancies or normal lymphoid cells. This report describes genomic/protein EPO-R expression and in vitro effects of recombinant human EPO (epoetin) in B-cell chronic lymphocytic leukemia (B-CLL), mantle-cell lymphoma (MCL), and multiple myeloma (MM).. Blood samples were obtained from patients with B-CLL, MCL, and healthy volunteers, and bone marrow was obtained from MM patients. EPO-R mRNA was detected by reverse transcription-PCR. EPO-R surface expression was investigated by flow cytometry using digoxigenin-labeled epoetin and polyclonal rabbit anti-EPO-R antibody for intracellular receptor. Tumor cell stimulation was determined in vitro using [(3)H]thymidine incorporation and CD69 expression after exposure to epoetin alpha or beta or darbepoetin alpha.. EPO-R mRNA was detected in mononuclear cells from 32 of 41 (78%) B-CLL and 5 of 7 (71%) MCL patients, and 21 of 21 (100%) MM samples. Expression was also detected in highly purified T cells from six of eight B-CLL patients, four of four MM patients, and normal donor B and T cells. Surface EPO-R protein was not detected. Intracellular EPO-R staining with anti-EPO-R antibodies was unspecific. No tumor-stimulatory effect was observed with high epoetin concentrations.. EPO-R gene is frequently expressed in lymphoid malignancies and normal B and T cells. However, there was no surface protein expression and no epoetin-induced in vitro stimulation of tumor B cells, indicating that epoetin therapy in vivo is likely to be safe in patients with lymphoid malignancies.

Topics: Aged; Aged, 80 and over; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Erythropoietin; Female; Flow Cytometry; Gene Expression; Humans; In Vitro Techniques; Lectins, C-Type; Leukemia, B-Cell; Lymphoma, Mantle-Cell; Male; Middle Aged; Multiple Myeloma; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Topics: Adolescent; Adult; Aged; Anemia; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma

The purpose of this study was to evaluate the sTfR-F index and hypochromic erythrocytes (HYPO%) as potential predictors of response to recombinant human erythropoietin (r-HuEPO) of anemic patients with multiple myeloma (MM) before treatment, as well as early in the course of treatment. Twenty-six newly diagnosed anemic MM patients received r-HuEPO 30,000 IU/wk sc, for six weeks. The sTfR-F index and HYPO% were determined at baseline and at weeks 2 and 6. Patients were classified in 1 of 4 categories of a diagnostic plot, according to erythropoietic state (ES I-IV), defined by the combination of sTfR-F index and HYPO%. Sixteen of 20 patients in ES I and II before treatment responded to r-HuEPO, whereas none of the 6 patients in ES III and IV responded (P < .001). At week 2, 44% of patients who responded and 60% of the nonresponders were in functional iron deficiency (FID) and the proportion increased to 69% and 80%, respectively, by week 6. Seven of the patients who did not respond received in addition 200 mg iron sucrose IV weekly, for the next 4 weeks, and 6 of them responded. These results suggest that combination of sTfR-F index and HYPO% in a diagnostic plot can be used as a predictive model to recognize patients who will benefit from r-HuEPO and identify FID requiring iron supplementation, before treatment and early in the course of treatment, contributing thus to optimization of r-HuEPO therapy.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Hypochromic; Erythrocyte Count; Erythropoietin; Female; Humans; Male; Middle Aged; Monitoring, Physiologic; Multiple Myeloma; Recombinant Proteins

Topics: Anti-Inflammatory Agents; Dexamethasone; Drug Therapy, Combination; Erythropoietin; Humans; Lenalidomide; Multiple Myeloma; Multivariate Analysis; Thalidomide; Venous Thrombosis

Erythropoietin (Epo) is the main growth regulator of red blood cells, and recombinant human erythropoietin (rHuEpo) is thus used in clinical practice for the treatment of anaemia, primarily in kidney disease and cancer. rHuEpo treatment was found to be associated with prolonged survival of multiple myeloma (MM) patients. This clinical observation was then supported by studies on murine myeloma models. It thus appeared that rHuEpo had an anti-myeloma effect, causally related to an immunomodulatory function of rHuEpo. The present study investigated whether rHuEpo-treated MM patients acquire improved immunological functions. Treatment with rHuEpo, prescribed for anaemia that occurs in advanced disease, was associated with effects on a variety of immunological parameters and functions. This was expressed in an actual normalisation of the CD4:CD8 cell ratio, enhanced T cell phytohaemagglutinin-mediated activation and proliferation potential, T cell expression of the costimulatory CD28 and inhibitory CTLA-4 molecules, as well as reduced interleukin-6 serum values to normal levels. Furthermore, it was demonstrated that immunological abnormalities manifest in patients even in the early stages of MM. Our findings thus suggest that rHuEpo treatment might be effective in the early stages of MM, before anaemia develops. It is expected that this would boost the immune system, consequently achieving an anti-myeloma function; affecting disease progression and improving the prognosis.

Topics: Aged; Antigens, CD; Antigens, Differentiation; Antigens, Differentiation, T-Lymphocyte; Biomarkers; Case-Control Studies; CD28 Antigens; CD4-CD8 Ratio; CTLA-4 Antigen; Disease Progression; Erythropoietin; Female; Hemoglobins; Humans; Immunophenotyping; Interleukin-6; Lectins, C-Type; Leukocyte Count; Lymphocyte Activation; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins; T-Lymphocytes

Recombinant human erythropoietin administered after peripheral blood stem cell transplantation (PBSCT) has been ineffective for the treatment of anemia. We administered recombinant human erythropoietin alpha (rHuEPO) prior to high-dose therapy after peripheral blood stem cell (PBSC) collection to evaluate its efficacy on transfusion requirements and hematological parameters during the post-transplant aplastic phase. Twenty-two multiple myeloma patients (EPO-MM) were included in the trial to receive rHuEPO 10,000 IU subcutaneous daily starting 30 days before PBSCT. Forty hemoglobin (Hb)-matched patients who had not received rHuEPO before transplant were retrospectively selected (Ctr-MM) for comparative data. None of the patients received transfusions at study entry. All but one patient responded to rHuEPO. However, no significant differences in Hb levels were obtained between the two groups at the time of transplantation. At nadir, the EPO-MM cases had a significantly higher Hb level (median 10 g/dl versus 7.6 g/d; p=0.001). Consequently, less than 20% of EPO-MM patients required packed red blood cell (PRBC) transfusions compared to more than half the Ctr-MM patients (p=0.007). Furthermore, the number of PRBC transfusions performed in the EPO-MM group was significantly lower (median 0 versus 1; p=0.008). Independently of Hb levels at PBSCT, rHuEPO therapy was significantly associated with a lower risk of transfusion requirement. In conclusion, rHuEPO is shown to be effective when administered prior to high-dose therapy in MM.

Topics: Adult; Aged; Blood Transfusion; Case-Control Studies; Combined Modality Therapy; Erythropoietin; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Probability; Recombinant Proteins; Risk Assessment; Severity of Illness Index; Statistics, Nonparametric; Survival Rate; Transplantation, Autologous; Treatment Outcome

To decrease red blood cell (RBC) transfusion requirements during high-dose therapy (HDT) for hematological malignancies, we conducted a pilot study to assess the effect of recombinant human erythropoietin (rHuEpo) given during chemotherapy before HDT and autologous peripheral stem-cell transplantation (APSCT). The transfusion histories of 15 HDT and APSCT for hematological disease performed in 11 consecutive patients who received rHuEpo (10 000 U subcutaneously three times/week) were compared to those of 22 HDT and ASCT performed in 17 consecutive historical controls matched for hematological parameters. rHuEpo increased the hemoglobin (Hb) level from 10.3+/-2.3 g/dl at diagnosis to 12.9+/-2.2 g/dl at the time of HDT in 11 patients; no major adverse effects occurred. Compared to historical controls (95%, 21/22), RBC transfusion requirements were significantly lower for rHuEpo recipients (26%, 4/15) (P=0.00001) and rHuEpo responders (15%, 2/13) (P=0.000002). After HDT and APSCT, fewer RBC transfusions were needed: 3.3, 1.2 and 0.3 RBC units for controls, rHuEpo recipients and rHuEpo responders, respectively (P=0.006 and 0.00002). Therefore, rHuEpo should be administered before, and not after HDT and APSCT, to lower RBC transfusion requirements after HDT and APSCT.

Topics: Adult; Aged; Erythrocyte Transfusion; Erythropoietin; Humans; Lymphoma, Mantle-Cell; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Pilot Projects; Recombinant Proteins; Transplantation, Autologous

The increasing use of new drugs in cancer therapy, especially growth factors, hormones, and chemotherapies resulted in several reports of unusual skin eruptions. We studied a patient with erythroderma who had received erythropoietin because of myeloma with tumor anemia. The histological features were characterized by a lichenoid, focally granulomatous infiltrate with predominance of histiocytes. It is important for dermatopathologists to recognize this interesting pattern induced by erythropoietin.

Topics: Anemia; Antigens, CD; Dermatitis, Exfoliative; Erythropoietin; Granuloma; Histiocytes; Humans; Lichenoid Eruptions; Male; Middle Aged; Multiple Myeloma; T-Lymphocytes

Earlier studies showing a negative impact of anaemia on quality of life (QOL) lack adequate adjustment for confounding factors such as disease stage and tumour response. We examined the impact of haemoglobin concentration on QOL scores of 745 multiple myeloma patients followed from diagnosis, adjusting for objective disease parameters. Data from two Nordic studies with the EORTC QLQ-C30 questionnaire were analysed using linear regression analysis. Haemoglobin was independently related only to fatigue at baseline (P = 0.001) and at 12 months (P = 0.010). In multivariate analysis, extent of skeletal disease was at least as strong a predictor for fatigue at diagnosis as haemoglobin and was also related to other important QOL scores such as physical functioning, role functioning, global QOL and pain (P < 0.001). At 12 months' follow-up, response to therapy was related to physical functioning (P < 0.001) and pain (P = 0.001). In conclusion, haemoglobin and extent of skeletal disease were both predictors for fatigue in patients with newly diagnosed multiple myeloma, but extent of skeletal disease was also associated with other important QOL scores. During follow-up, response to therapy emerged as an important predictor variable. When examining the effect of haemoglobin on QOL, it is essential to adjust for disease parameters and response to therapy in order not to overestimate the impact of haemoglobin on QOL. Our findings imply that uncontrolled studies on the effect of erythropoietin (EPO) in cancer patients may be making exaggerated claims for the effect of EPO on QOL.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Bone Diseases; Erythropoietin; Fatigue; Female; Hemoglobins; Humans; Male; Middle Aged; Multiple Myeloma; Neoplasms; Norway; Physical Endurance; Quality of Life; Regression Analysis; Surveys and Questionnaires; Treatment Outcome

Topics: Aged; Aged, 80 and over; Erythropoietin; Humans; Immunoglobulin A; Male; Multiple Myeloma; Treatment Outcome

Recombinant human erythropoietin (rHuEpo) was introduced into clinical practice more than a decade ago, and has been found to be effective in the treatment of several types of anemia, including anemia of end-stage renal failure and cancer-related anemia. No study has suggested that Epo might have an effect on the biology of the disease, nor any survival advantage to cancer patients treated with Epo for anemia has been reported. Here we report six patients with advanced multiple myeloma (MM) with very poor prognostic features, whose expected survival was <6 months. All six patients were treated with rHuEpo for their anemia, either without any chemotherapy or very mild chemotherapy for a short time. Yet, surprisingly they lived for 45-133 months totally from MM diagnosis and 38-94 months with rHuEpo (with a good quality of life). In fact, one patient, is still alive and well, more than 8 yr after chemotherapy was discontinued because of a resistant aggressive disease. The course in these six MM patients led us to hypothesize that Epo might have an antineoplastic or antimyeloma effect. We proceeded and tested that hypothesis in mouse models of myeloma (Mittelman M et al., Proc Natl Acad Sci USA 98:5181,2001). In these models we confirmed that rHuEpo induced tumor regression in about 50% of the BALB/c mice inoculated with MOPC-315 myeloma cells. We then presented evidence that the mechanism is a new immune-mediated phenomenon, via activation of CD8+ T cells. Furthermore, evidence from the literature supports the antineoplastic effect of Epo. Epo might be used as an adjunct immune treatment in various malignant diseases, in addition to the current regimens and chemotherapeutic protocols. Future trials should determine the role of Epo in myeloma and cancer treatment, besides clarifying concerns about the presence of Epo receptors on some tumor cells.

Topics: Adult; Aged; Anemia; Animals; Antineoplastic Agents; CD8-Positive T-Lymphocytes; Disease Models, Animal; Disease Progression; Erythropoietin; Female; Humans; Male; Mice; Mice, Inbred BALB C; Middle Aged; Multiple Myeloma; Prognosis; Recombinant Proteins; Remission Induction; Survival Rate; Treatment Outcome

Anti-rhEPO McAb is valuable for the determination of recombinant human erythropoietin (rhEPO) levels for diagnosis of renal anemia and for doping control analysis. In this paper, anti-rhEPO hybridoma was prepared by fusion of SP2/0 murine myeloma cells with spleen cells isolated from immunized BALB/c mouse, using an enzyme-linked immunosorbent assay (ELISA) method to screen the positive hybridoma. The purified McAb was characterized by ELISA, SDS-PAGE, and Western-blotting. Experimental results showed that the subclass and the light chain of anti-rhEPO McAb was IgG1 and kappa light chain. The molecular weight of anti-rhEPO McAb was 166,000 Daltons. The affinity constant (K(aff)) of anti-rhEPO McAb with coated antigen was 5.0 x 10(5)L/mol.

Topics: Animals; Antibodies, Monoclonal; Antibody Affinity; Blotting, Western; Cell Fusion; Cell Line, Tumor; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Hybridomas; Immunization; Mice; Mice, Inbred BALB C; Multiple Myeloma; Recombinant Proteins

We compared the use of G-CSF plus EPO in a group of 32 multiple myeloma and lymphoma patients with historical controls receiving G-CSF alone. Haemopoietic reconstitution was significantly faster in patients receiving G-CSF+EPO (group B), with a median time of 10 days to achieve an ANC count >0.5 x 10(9)/l, compared to 11 days in the historical group (A). The median duration of severe neutropenia (ANC count <100/ml) was significantly shorter in group B compared to group A; platelet counts >20 x 10(9) and >50 x 10(9)/l were achieved at days + 13 and + 17, respectively in group B, compared to days + 14 and + 24, respectively, in group A (P = 0.015, 0.002) patients. The transfusion requirement was reduced in group B, with 0 (0-6) RBC units and 1 (0-5) platelet unit transfused in group B vs 2 RBC (0-9) and 2 platelet units (0-8) in group A. Median days of fever, antibiotic therapy and hospital stay were reduced in group B (9.5 days vs 22). The mean cost of autotransplantation per group A patient was 23,988 Euro, compared with 18,394 Euro for a group B patient. Our study suggests that the EPO + G-CSF combination not only accelerates engraftment kinetics, but can also improve the clinical course of ASCT.

Topics: Adult; Aged; Blood Transfusion; Cost-Benefit Analysis; Erythropoietin; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Kinetics; Lymphoproliferative Disorders; Male; Middle Aged; Multiple Myeloma; Multivariate Analysis; Platelet Count; Recombinant Proteins; Stem Cell Transplantation; Time Factors; Treatment Outcome

Among 199 patients treated with thalidomide for multiple myeloma, four thromboses occurred in 49 cases during erythropoietin therapy (prevalence 8.1%; annual rate 7.25%), and another 14 events occurred in patients not on erythropoietin (9.3%; 7.56%). Thus, erythropoietin would seem not to increase the risk of thrombosis of myeloma patients receiving thalidomide.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Antineoplastic Agents; Drug Synergism; Erythropoietin; Female; Humans; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins; Risk; Thalidomide; Thrombosis; Venous Thrombosis; Warfarin

The presence of hypoxic areas is a common feature of solid tumors and has been associated with decreased sensitivity of the tumors to radiation therapy and oxygen-dependent chemotherapeutic agents, as well as worsened outcomes, including survival. Anemia is also common in cancer patients and is believed to contribute to tumor hypoxia. Thus, the rationale exists for administering recombinant human erythropoietin (rHuEPO, epoetin alfa) in an effort to increase hemoglobin levels, correct anemia, and thereby possibly increase the sensitivity of tumors to standard cancer treatment and improve patient outcomes. The results of several preclinical studies that examined the impact of anemia prevention by rHuEPO on tumor sensitivity to radiation therapy in rodent models of cancer showed that induction of anemia increased hypoxia in tumor cells and that correction of anemia with rHuEPO could improve tumor oxygenation. Further studies in rodent models showed significantly delayed tumor growth in both irradiated mice and irradiated rats treated with rHuEPO. In those studies, the increased radiosensitivity observed was believed to be due to improved tumor oxygenation following the correction of anemia. Similarly, enhancements in chemosensitivity were found in rHuEPO-treated rodent models. In the chemosensitivity studies, as in the radiosensitivity studies, the therapeutic benefit obtained was believed to reflect improved tumor oxygenation subsequent to an rHuEPO-related increase in oxygen availability. One study evaluated the potential biologic effects of epoetin alfa on tumor progression using murine myeloma models (MOPC-315 and 5T33 MM). Treatment of MOPC-315 tumor-bearing mice with epoetin alfa induced complete tumor regression in 30%-60% of mice. Regression was found to be tumor specific, and the effect of epoetin alfa was shown to be T-cell mediated. Additionally, epoetin alfa administration prolonged survival and reduced morbidity and mortality in the 5T33 MM tumor model. Those investigators suggested that epoetin alfa may have antitumor activity in addition to its hematopoietic effects. Overall, these preclinical findings suggest that correction of anemia by rHuEPO can increase tumor sensitivity to both radiation therapy and chemotherapy and that epoetin alfa may exert an immunomodulatory effect in multiple myeloma.

Topics: Anemia; Animals; Antineoplastic Combined Chemotherapy Protocols; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Hypoxia; Disease Models, Animal; Drug Interactions; Erythropoietin; Female; Mice; Mice, Inbred BALB C; Multiple Myeloma; Radiation Tolerance; Recombinant Proteins; Survival Analysis; Treatment Outcome

Anaemia is the most common haematological complication in patients with malignant diseases. It is found in 60%-90% of cases with multiple myeloma. The pathogenesis of this hypoproliferative, normochromic, normocytic anaemia is complex. Results from clinical studies which evaluate the efficacy of recombinant human erythropoietin (rHuEpo) refer to the possibility that patients with multiple myeloma independently of renal function could have Epo deficiency. Based on this finding, the aim of the study was to evaluate the erythropoietin production in patients with multiple myeloma in order to define clinical conditions of Epo deficiency and thereby enable rational use of this expensive drug. 42 patients with multiple myeloma were examined. The control group consisted of 25 patients with iron deficiency anaemia. 14 healthy volunteers represented the so-called "normal" control. The adequacy of Epo production was estimated from the graphic representation of the linear regression between Epo and haemoglobin (Hb) in the control group, as well as from O/PEpo ratio as a measure of the degree of adequacy of Epo production (O -- observed Epo value, P -- predicted Epo value from the regression equation of the control group). The erythropoietic activity was estimated from the graphic representation of the linear regression between soluble transferin receptors (sTfR) and Hb in the control group, as well as from O/PsTfR ratio, as a measure of the degree of adequacy of erythropoietic activity (O -- observed sTfR value, P -- predicted sTfR value from the regression equation of the control group). Significant inverse correlation between Epo and Hb was found in patients with multiple myeloma but preserved renal function, which was not the case in patients with renal insufficiency. 43% of patients without renal insufficiency and 85% of patients with renal insufficiency had inadequate Epo response to anaemia. In both patient groups (with and without renal insufficiency) instead of the expected inverse relationship between Hb and sTfR as in the control group, a positive correlation was found. 76% of patients had inadequate sTfR response to anaemia. There is a positive correlation between O/PEpo and O/PsTfR which is in favour of Epo driven erythropoiesis. O/PEpo and O/PsTfR in patients with multiple myeloma are significantly lower in comparison to the control group, which also points to the inadequacy of erythropoietin production, respectively erythropoietic activity. In conclusio

Topics: Adult; Aged; Anemia; Anemia, Iron-Deficiency; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Multiple Myeloma; Receptors, Transferrin

Topics: Anemia; Diphosphonates; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Multiple Myeloma; Osteolysis; Pain; Paraneoplastic Syndromes; Recombinant Proteins

Topics: Anemia; Bone Marrow; Epoetin Alfa; Erythropoietin; Humans; Injections, Intravenous; Injections, Subcutaneous; Iron; Iron Deficiencies; Leukemia, Lymphocytic, Chronic, B-Cell; Multiple Myeloma; Recombinant Proteins

We evaluated the ability of recombinant human erythropoietin (rHuEpo) therapy, given before high-dose therapy (HDT), to allow autologous peripheral blood stem cell transplantation (PBSCT) without red blood cell (RBC) transfusions. Eleven multiple myeloma patients underwent tandem HDT and autologous PBSC, receiving 500 U/kg/week rHuEpo from d 30 after initial transplant. Haemoglobin levels were 9.5 +/- 1.1 g/dl and 12.5 +/- 0.9 g/dl at the first and second transplant respectively (P < 0.001). RBC transfusions were required for 10/11 patients for the first transplant versus 1/11 for the second (P < 0.001). To conclude, a short course of rHuEpo therapy before HDT facilitates the performance of an autologous transplant without RBC transfusions.

Topics: Adult; Blood Transfusion; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Recombinant Proteins; Reoperation; Transplantation, Autologous

THE DEBATE: Although some believe that rHu-EPO should not be widely used in malignant affections, others think that because of the varied impact of these anaemia, its wider use should be recommended. FOR A TARGET USE: Various observations (influence of the degree of extension of the myelomas to the skeleton and response to specific treatment in the case of myeloma, whatever the haemoglobin concentration, degree of prevention of rHu-EPO chemo-induced anaemia) are in favour of its use in selected patients. FOR A WIDER USE: The benefits of treatment with rHu-EPO are not limited to the symptomatology of anaemia but extend to its potential complications in the most fragile patients. Other than the risks of infection, the heavy costs of transfusions must also be taken into account.

Topics: Anemia, Aplastic; Blood Transfusion; Cost-Benefit Analysis; Erythropoietin; Hemoglobinometry; Humans; Multiple Myeloma; Neoplasms; Prognosis; Recombinant Proteins; Red-Cell Aplasia, Pure

The authors review an elderly woman suffering from leg ulcer with bad curability which was a consequence of a malignant haematologic disease. Multiple relapse of this ulcer was observed and did not react to usual conservative therapy. The only sign of multiple myeloma was the extremely high level of iron measured in the blood serum bound to a monoclonal paraprotein. Sternum aspiration was made and the sample showed presence of plasmoblasts supporting diagnosis of multiple myeloma. The poor therapeutical results were caused by hyperviscosity syndrome in consequence of the high level of the monoclonal component in the blood serum. The ulcer was cured within eight weeks by suppression of the monocloclonal component and thus, elimination of hyperviscosity. This case is a special one from several points of view. Leg ulcers not reacting to usual therapy may be caused by haematologic disease thus the physician should consider this and extend examinations as well and necessarily hospitalize patient. Appearance of multiple myeloma is unusual in this case. Hystology made from the skin excised from the periphery of the wound has not showed signs of pyoderma gangrenosum, which is known mostly being associated with multiple myeloma.

Topics: Aged; Biopsy, Needle; Bone Marrow; Diagnosis, Differential; Erythropoietin; Female; Humans; Leg Ulcer; Multiple Myeloma; Plasmapheresis; Sternum

We investigated the role of stem cell purification and G-CSF (early vs. delayed vs. no G-CSF) administration on hemopoietic recovery and supportive care requirements after stem cell transplantation. Thirty-two patients submitted to autologous CD34(+) peripheral blood stem cell transplantation (PBSCT) were studied, and data were compared to patients undergoing unfractionated peripheral blood stem cell transplantation (uPBSCT) matched for age, disease, and conditioning regimen. Except for PMN, hemopoietic recovery was significantly slower and supportive care requirements were significantly higher after CD34(+) PBSCT. Median time to PMN >0.5 x 10(9)/l was 13 days (range 9-27) and 13 d (range 9-23); reticulocytes (Ret) >1% was 14.5 d (range 12-34) and 12 d (range 10-27); high-fluorescence reticulocytes (HFR) >5% was 12 d (range 9-26) and 9 d (range 7-11); platelets >50 x 10(9)/l and >100 x 10(9)/l was 20 d (range 10-240), 12 d (range 9-60) and 33 d (range 15-720), 15 d (range 11-210). When the analysis was performed on subgroups of patients (early/delayed/no G-CSF), early G-CSF significantly promoted PMN recovery (>0.5 x 10(9)/l and >1.0 x 10(9)/l) compared to no G-CSF, without affecting RBCs or platelet recovery. Delayed G-CSF did not improve PMN recovery compared to patients not receiving G-CSF, did not result in a significant reduction of drug requirements, and had a negative impact on erythroid and platelet recovery. In conclusion, these preliminary data suggest that G-CSF is useful if given early after CD34(+) PBSCT. CD34(+) PBSCT may overall require a significant increase of resource utilization that should be outweighed by proven clinical benefit.

Topics: Adolescent; Adult; Antigens, CD34; Cell Separation; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Hodgkin Disease; Humans; Kinetics; Leukocyte Count; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma; Neutrophils; Platelet Count; Reticulocyte Count; Transplantation Conditioning; Treatment Outcome

Recombinant human erythropoietin (rHuEpo) has been used successfully in the treatment of cancer-related anemia. Clinical observations with several patients with multiple-myeloma treated with rHuEpo has shown, in addition to the improved quality of life, a longer survival than expected, considering the poor prognostic features of these patients. Based on these observations, we evaluated the potential biological effects of rHuEpo on the course of tumor progression by using murine myeloma models (MOPC-315-IgAlambda(2) and 5T33 MM-IgG(2b)). Here we report that daily treatment of MOPC-315 tumor-bearing mice with rHuEpo for several weeks induced complete tumor regression in 30-60% of mice. All regressors that were rechallenged with tumor cells rejected tumor growth, and this resistance was tumor specific. The Epo-triggered therapeutic effect was shown to be attributed to a T cell-mediated mechanism. Serum Ig analysis indicated a reduction in MOPC-315 lambda light chain in regressor mice. Intradermal inoculation of 5T33 MM tumor cells followed by Epo treatment induced tumor regression in 60% of mice. The common clinical manifestation of myeloma bone disease in patients with multiple-myeloma was established in these myeloma models. Epo administration to these tumor-bearing mice markedly prolonged their survival and reduced mortality. Therefore, erythropoietin seems to act as an antitumor therapeutic agent in addition to its red blood cell-stimulating activity.

Topics: Animals; Blotting, Western; Disease Models, Animal; Disease Progression; Erythropoietin; Female; Hemoglobins; Humans; Immunoglobulin lambda-Chains; Immunophenotyping; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred Strains; Multiple Myeloma; Remission Induction; Survival Rate; T-Lymphocytes

Topics: Aged; Aged, 80 and over; Anemia; Biopsy; Bone Marrow; Cell Nucleus; Diagnosis, Differential; Epoetin Alfa; Erythropoietin; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Leukopenia; Multiple Myeloma; Recombinant Proteins

To study the role of some soluble factors in the process of angiogenesis that accompanies multiple myeloma (MM).. The concentrations of three well-known angiogenic peptides, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF) were evaluated by an ELISA method. All of these factors were measured in the plasma obtained from peripheral blood (PB) and bone marrow (BM) aspirates of 34 patients affected by plasma cell disorders. This series included one patient with a solitary extramedullary plasmacytoma, 17 patients with MM at diagnosis, and 16 with previously treated MM.. In all the patients, the concentration of each angiogenic factor was higher in bone marrow than in peripheral blood. Mean values of the three angiogenic factors in BM or in PB were lower in stage I than stage II-III. One patient with extramedullary solitary myeloma had high levels of VEGF and bFGF but this increase was not found in the other 6 patients with extramedullary disease when compared with patients without extramedullary disease. VEGF and bFGF did not correlate with each other while HGF showed a weak correlation with VEGF and a stronger one with bFGF. Moreover, VEGF correlated with features of disease activity, such as C-reactive protein, and 2-microglobulin, while both bFGF and HGF showed an inverse correlation with albumin level. No correlation was found between VEGF, bFGF and HGF levels and age, M protein level, osteolytic lesions, or percentage of BM plasma cells. Since angiogenic factors may be released by normal cells in response to hypoxia, we also evaluated erythropoietin (EPO) levels (which correlate with the hypoxic stimulus) both in PB and BM plasma of these patients but none of the measured angiogenic factors correlated with EPO levels. Interpretation and Conclusions. Several soluble factors may play a role in the angiogenic activity described in MM but their contribution to the progression of disease may be different. The finding of higher levels of these factors in BM than in PB might indicate that the bone marrow environment is their major source. Concentrations of angiogenic factors parallel the activity of disease and are independent of the hypoxic stimulus.

Topics: Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Bone Marrow; Cell Count; Endothelial Growth Factors; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Fibroblast Growth Factor 2; Hepatocyte Growth Factor; Humans; Interferon-alpha; Lymphokines; Male; Middle Aged; Multiple Myeloma; Neoplasm Proteins; Neoplasm Staging; Neoplastic Stem Cells; Neovascularization, Pathologic; Plasma Cells; Plasmacytoma; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

In the literature various regimes are described for successful collection of haematopoietic stem cells in patients with multiple myeloma. Most frequently cyclophosphamide is used, 5 g/m2 combined with different doses of haematopoietic growth factors. In our group the yields and tolerance of three stimulating regimes are compared: 1. cyclophosphamide 5 g/m2 and filgrastim (G-CSF) 5 micrograms/kg 2. cyclophosphamide 5 mg/m2 and filgrastim 10 micrograms/kg 3. cyclophosphamide 5 g/m2 and figrastim 5 micrograms/kg along with erythropoitin 50 IU/kg. Cyclophsphamide is administered always on the first day and the haematopoietic growth factors then from the third day till the end of collection of haematopoitic cells. In patients with multiple myeloma where only four cycles of VAD chemotherapy preceded and where radiotherapy of the axial skeleton was not used, optimal collection of haematopoietic stem cells was achieved after administration of cyclohosphamide 5 g/m2 with subsequent administration of 5 micrograms/kg G-CSF. By increasing the dose of G-CSF to 10 micrograms/kg or adding 50 IU/kg erthropoietin did not lead to a significant improvement of the tolerance and yield of this procedure.

Topics: Cyclophosphamide; Drug Administration Schedule; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Multiple Myeloma; Recombinant Proteins

We describe two patients admitted to our hospital because of renal failure. We diagnosed multiple myeloma in both. One patient had high peripheral blood eosinophilia, that normalized during therapy. The patients were treated with melphalan and prednisone, hemodialysis and one patient with recombinant human erythropoietin. Both patients responded to that treatment: after 7 months the number of plasma cell in bone marrow decreased from 65 to 10% in the first patient, and from 38 to 4% in the second patient. They returned to work and were on maintenance hemodialysis 2 times weekly. The patients have been observed for 21 months.

Topics: Aged; Erythropoietin; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Treatment Outcome

Growth factors or humoral agents can support haemopoiesis in various bone marrow disorders. They have the ability to act on multiple cell lineages and in myeloid cells, and the potential to act on the neoplastic equivalent of normal cells. Anaemia is a common feature of multiple myeloma seen in at least two-thirds of patients at presentation. Erythropoietin is increasingly being used with variable effect for the treatment of this anaemia, especially in cases associated with renal failure and in patients in whom blood transfusion may be undesirable or contraindicated. We describe a patient treated with recombinant erythropoietin who developed fulminating malignant transformation. The demonstration of erythropoietin receptors on a human myeloma cell line and the occurrence of the rare complication of plasma cell leukaemia in our patient stresses the need for caution and invites detailed clinical and laboratory studies before its general use.

Topics: Anemia; Cell Transformation, Neoplastic; Disease Progression; Erythropoietin; Fatal Outcome; Humans; Leukemia, Plasma Cell; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins

The prognosis of patients with IgD myeloma is poorest among all types of multiple myeloma. We report a case of a patient with IgD myeloma who survived for an extraordinarily long period post-diagnosis (65 months). According to the new risk grouping of IgD myeloma (Shimamoto Y. et al., Eur. J. Haematol. 47, 262 (1991), he was classified as being in the high-risk group, with a zero percent expected 5-yr survival. Nevertheless, he survived for 65 months. We discuss the usefulness of interferon-alpha and erythropoietin for the treatment of IgD myeloma.

Topics: Antineoplastic Agents; Erythropoietin; Humans; Immunoglobulin D; Interferon-alpha; Male; Middle Aged; Multiple Myeloma; Prognosis; Time Factors

The efficacy of recombinant human erythropoietin (r-HuEPO) in patients with multiple myeloma (MM) has been confirmed in several clinical trials. We report our experience of r-HuEPO treatment in 5 myeloma patients with renal failure. The therapy with r-HuEPO (Eprex, Janssen-Cilag or Recormon, Boehringer, Mannheim) was started after 4-8 months from diagnosis, the drug was administered intravenously (in one patient subcutaneously after cessation of hemodialysis treatment), two or three times weekly. The initial doses were 4-12,000 units/week (mean 8,400). In all patients good response during the first month of therapy was observed. Median Hb and hematocrit increased from 70 g/l and 20.8% to 87 g/l and 26% after 1 month and to 105 g/l and 30.3% after 4-6 months, respectively. The need for blood transfusion decreased significantly--from 2.72 TU/month to 0.13 TU/month. WHO performance status and patients self-assessment of quality of live improved substantially after r-HuEPO. No serious adverse events, including hypertension and/or thromboembolic events were observed. In accordance with some previous reports we conclude r-HuEPO is effective and safe treatment in patients with MM and renal failure. Moreover, lower doses of growth factor could be effective in this particular group of patients.

Topics: Adult; Aged; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins

The etiology of anaemia associated with tumours is multifactorial. One of the mechanisms of development of anaemia in tumours are so-called chronic diseases anaemias, the main feature of which is inadequate production of endogenous erythropoietin (EPO). The objective of the investigation was to test the effect of recombinant human erythropoietin (rHuEPO) in the treatment of anaemia (rise of haematocrit, Hb) in patients with chronic lymphatic leukaemia (CLL) and multiple myeloma (MM) and the effect of this treatment on the quality of life. The authors evaluated at the same time the impact of the endogenous EPO level before treatment and its predictive value as regards the therapeutic response.. The investigation comprised a total of 14 patients (6 CLL, 8 MM). The basic criterion for inclusion in the group was a Ht value lower than 0.32 and Hb less than 105 g/l. The examination protocol was focused on elimination of other causes of anaemia. During the 12-week investigation the patients completed a questionnaire "Quality of life" which reflected their subjective evaluation of the effect of treatment. The patients themselves administered r-HuEPO three times a week by the s.c. route--an initial dose of 150 U/kg with the possibility to increase the dose to 300 U/kg.. A therapeutic response was obtained in four patients with CLL and eight patients with MM. Respondents with CLL had endogenous EPO values lower than 300 U/l, seven MM respondents lower than 200 U/l, one 400 U/l. The Hb level of the patients rose and the quality of life improved. All patients tolerated treatment very well and the authors did not observe any serious undesirable effects.. The investigation confirmed the therapeutic effect of r-HuEPO in patients with a lower baseline value of EPO. Subjective evaluation (questionnaire) correlated with objective evaluation (Ht, Hb). Assessment of the endogenous EPO level before treatment is according to the authors one of the important primary predictive parameters and EPO values between 200 and 300 U/l are the upper range where a therapeutic effect can be expected with the highest probability. The authors conclude also that a secondary predictive criterion of the response is evaluation of the therapeutic effect after 4-5 weeks treatment when a rise of Hb by at least 20 g/l is an argument for further treatment.

Topics: Aged; Anemia; Erythropoietin; Female; Hematocrit; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Multiple Myeloma; Quality of Life; Recombinant Proteins

The diurnal rhythm in the circulating serum levels of erythropoietin (EPO) were determined in a group of 20 adult clinically-healthy subjects, in a group of 10 patients with myeloma without renal impairment and 10 patients with myeloma and renal failure. Venous blood samples were drawn during the span of a whole day and every 4 hr, starting from midnight, for the measurement of serum EPO levels by radioimmunoassay (RIA). Statistical analysis was carried out by means of the "cosinor" method. Results show that the controls and the myeloma patients without renal insufficiency present significant (P < 0.05) circadian rhythms in serum EPO levels; no rhythm (P < 0.05) was detected in patients with myeloma and renal failure. Patients with myeloma and renal failure have significant (P < 0.05) lower mean daily levels and diurnal fluctuations of EPO than the other groups, whereas the patients with myeloma without renal involvement present higher (P < 0.05) mean daily levels and lower (P < 0.05) diurnal variations of EPO than controls; no differences (P > 0.05) exist between the groups regarding peaks of rhythms. These data confirm the existence of a physiological circadian rhythm in serum EPO concentrations, with maximum in the afternoon, and they suggest that renal failure is an important cause of anemia and loss of EPO circadian rhythm in patients with myeloma.

Topics: Aged; Circadian Rhythm; Erythropoietin; Female; Humans; Male; Middle Aged; Multiple Myeloma; Radioimmunoassay; Renal Insufficiency

Anemia is common complication in multiple myeloma (MM). Its etiology is multifactorial-bone marrow infiltration, cytokines production, renal failure and effect of chemotherapy are main contributing factors. The red cell substitution therapy, which is administrated in 34 - 53% of patients, is frequently associated with the risk of well-known side effects. The use of recombinant erythropoietin (r-HuEPO) is a novel therapy in patients with MM.. We have investigated the effect of r-HuEPO (Eprex. Cilag) in the group of 8 patients with MM. The growth factor was administrated in the dose of 150 U/kg. 3 times/ week s.c. The criterium of response was the increase of Hb levels of 20 g/L. All patients responded to r-HuEPO treatment. The medium period of response was 6,5 weeks. In two patients the doses of r-HuEPO could be reduced due to excellent effect of therapy. The energy level, ability to daily activities and overall quality of life significantly improved during the course of therapy. Neither effect of growth factor on thrombopoiesis and/or leukopoiesis nor serious adverse events due to r-HuEPO therapy were observed. The activity of underlying disease did not seem to be affected by r-HuEPO. In one patient the disease rapidly progressed after the end of study. The progression had some features of plasmablastic leukemia and leads to the death of patient.. According to our experience, r-HuEPO is highly effective in the treatment of anemia in MM. The stimulation of erythropoiesis was associated with significant improvement of quality of life of patients. The effect of r-HuEPO treatment on activity of MM was not found, however, in one patient rapid progression of disease was observed after the end of study.

Topics: Aged; Anemia; Erythropoietin; Female; Humans; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins

Recombinant human erythropoietin (rHuEPO) was used to treat the anaemia in a hemodialyzed 60 year old man with multiple myeloma requiring chemotherapy; the type of serum M component was IgA kappa. During the 5 months before rHuEPO treatment the patient was given multiple blood transfusions. rHuEPO was started 125 U/kg/week subcutaneously in divided doses after dialysis. After introduction of rHuEPO, blood transfusions were no longer required and haemoglobin concentration increased from 5.2 mmol/l to 6.9 mmol/l after 8 weeks of treatment. We conclude that rHuEPO treatment in haemodialysed patients with multiple myeloma may be safe, well tolerated and clinically effective.

Topics: Anemia; Blood Transfusion; Erythropoietin; Hemoglobins; Humans; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins; Renal Dialysis

Multiple myeloma is very frequently associated with anaemia which has the character of hypo-proliferative anaemia of chronic diseases. In this type of anaemia the erythropoietin formation is frequently inadequate. According to data in the literature pharmacological doses of erythropoietin lead to an increase of the haemoglobin concentration in blood. Erythropoietin (Eprex Cilag) was administered to 11 patients whose haemoglobin concentration was lower than 100 g/l. The results from 10 patients were finally evaluated. During the first month all patients were given erythropoietin - 150 U/kg three times per week. Unless during the first month of treatment the haemoglobin concentration increased by 10 g/l, the dose was doubled to 300 U/kg. In patients where the haemoglobin value had risen above 120 g/l, the authors assessed an individual maintenance dose. In case three-month erythropoietin treatment did not lead to an increase of haemoglobin by 20 g/l as compared with the baseline value, erythropoietin administration was discontinued. The haemoglobin concentration increased by 20 g/l in a total of 8 (80%) of 10 evaluated patients. In all five patients where the haemoglobin concentration increased by 20 g/l during the first month, the endogenous erythropoietin concentration was less than 60 U/l. In another three patients the mentioned therapeutic response was recorded only during the 2nd or 3rd month of treatment after the erythropoietin dose had been increased. These three patients had higher baseline concentrations of endogenous erythropoietin, 100 to 350 U/l. During treatment no undesirable effects of erythropoietin were observed. Erythropoietin is a useful drug for anaemic patients with the diagnosis of multiple myeloma. According to the results of the authors work and data in the literature it is obvious that in patients with endogenous serum erythropoietin below 100 U/l a rapid riae of haemoglobin can be observed already during the first month. Patients with a higher baseline concentration of endogenous erythropoietin (100 to 500 U/l) respond less frequently to treatment and larger doses of erythropoietin must be administered. In patients with an erythropoietin value above 500 U/l there is a minimal probability that a response will be produced.

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Humans; Male; Middle Aged; Multiple Myeloma

6 patients with anaemia associated with myeloma multiplex were treated with human recombinant erythropoietin (rHuEPO, Exprex*) at a dose of 150 units/kg s.c. three times a week for 12 weeks. A good response, defined as an increase of hemoglobin > 20 milligrams above the pretreatment level, was achieved in 4 patients. The erythropoietin serum concentration was measured four times in each patient: twice before commencing and twice after completing the treatment. In patients who responded to rHuEPO therapy the Epo serum concentration decreased whereas in non-responders increased.

Topics: Aged; Anemia; Erythropoietin; Female; Humans; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Multiple Myeloma

Multiple myeloma is very frequently associated with anemia which has the character of hypoproliferative anemia of chronic diseases. In this type of anemia there is often insufficient production of endogenous erythropoietin. According to literature pharmacological doses of erythropoietin result in the increase of blood hemoglobin concentration. Erythropoietin (Eprex Cilag) was given to 11 patients whose hemoglobin concentration in blood was lower than 100 g/l. 10 patients could be evaluated at the end of the study. Within the first month all patients were given erythropoietin in the dose of 150 U/kg 3 times a week. The dose was doubled, when the blood hemoglobin concentration did not increase by more than 10 g/l within the first month. In patients with hemoglobin level above 120 g/l we were trying to find the individual maintenance dose. In patients who had not reached a blood hemoglobin concentration increase of at least 20 g/l, as compared with the initial level, further erythropoietin administration was stopped. The concentration of hemoglobin increased of 20 g/l in 8 (80%) out of 10 patients evaluated. All 5 patients who responded within the first month, had had pretreatment concentration of endogenous erythropoietin below 60 U/l. Three other patients had not been responding before their dose of erythropoietin was increased in the 2nd and 3rd months of therapy. The therapy response appeared only in the 2nd and the 3rd months of treatment. These 3 patients had higher pretreatment concentrations of endogenous erythropoietin, from 100 to 350 U/l. During the treatment no adverse effects of erythropoietin were observed. Erythropoietin is a useful drug for anemic patients with the diagnosis of multiple myeloma. According to the results mentioned above and also according to the data from literature it is evident that in patients with the endogenous blood erythropoietin value below 100 U/l it is possible to expect a sudden rise in hemoglobin concentration already within the first month. Patients with a higher concentration of endogenous erythropoietin (100 to 500 U/l) respond to the therapy less frequently and for the increase in hemoglobin it is necessary to give higher doses of erythropoietin. Patients with the initial value of erythropoietin above 500 U/l are not likely to respond.

Topics: Adult; Aged; Anemia, Hypochromic; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Hemoglobinometry; Humans; Injections, Subcutaneous; Male; Middle Aged; Multiple Myeloma

Topics: Anemia; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Middle Aged; Multiple Myeloma; Recombinant Proteins; Renal Dialysis

Patients with relatively higher endogenous EPO levels (> 100 U/L) in the Arkansas study showed late responses or failed to respond, analogous to earlier observations by Ludwig et al, as well as by Fischl et al, and colleagues, who studied r-HuEPO administration in acquired immunodeficiency syndrome patients receiving r-HuEPO for anemia associated with zidovudine therapy. Thus, r-HuEPO substitution therapy is more likely to benefit patients whose anemia is associated with inappropriately low EPO serum levels. Granulopoiesis and thrombopoiesis were unaffected, and multiple myeloma cell stimulation has not been observed. The relative lack of toxicity from subcutaneously administered r-HuEPO at a dose of 150 U/kg three times weekly makes this approach an effective adjunct in the management of patients with multiple myeloma, especially those unresponsive to chemotherapy and remaining symptomatic from their anemia.

Topics: Anemia; Blood Transfusion; Erythropoietin; Humans; Multiple Myeloma; Recombinant Proteins

Nowadays, maintenance dialysis can be proposed to patients suffering from myeloma with end-stage chronic renal failure. We report here data from eight patients dialysed either by hemo- (6) or peritoneal dialysis (2), together with chemotherapy in half of them. Six patients died; the longest survival has been about 6 years. The main cause of morbidity was sepsis, especially in peritoneal dialysis patients; therefore we now favour hemodialysis in patients exposed to aggressive chemotherapy. We think dialysis justified in all cases, including those with high tumor mass, in order to expect the effect of chemotherapy; then, provided good response to drugs, further survival can be consistently improved. Once on maintenance dialysis, main drawbacks for these patients are cardiovascular complications (AL amyloidosis) and above all anemia; the latter however can be markedly improved, thanks to erythropoietin therapy which provides these patients with much better quality of life.

Topics: Aged; Aged, 80 and over; Erythropoietin; Female; Humans; Infections; Kidney Failure, Chronic; Male; Middle Aged; Multiple Myeloma; Peritoneal Dialysis; Prognosis; Renal Dialysis; Retrospective Studies

Anemia is a common complication of patients with multiple myeloma (MM) and myelodysplastic syndrome (MDS). Most of these patients often require blood transfusion. 12 patients, including 7 cases of MM and 5 cases of MDS, were treated with rhEPO 10,000 micrograms three times a week for 15 weeks. The hemoglobin in 6 of 7 cases of MM steadily increased and eventually reached normal level without blood transfusion. The number of erythroid precursors in bone marrow was increased significantly and serum ferritin concentration was decreased gradually during EPO administration. However 5 patients with MDS did not show any response to EPO. The adverse side effects were hardly observed in any patients received EPO treatment. It is suggested that rhEPO is a promising preparation for treating MM-associated anemia rather than MDS-associated anemia.

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Male; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes

Recombinant human erythropoietin (rHuEpo) was used to treat the anaemia of four haemodialysed patients (3 males, 1 female) with advanced multiple myeloma; the type of serum M component was IgG kappa in all cases. During the 6-month period preceding rHuEpo therapy the patients received multiple blood transfusions (range 4-22 units of packed red cells per patient). After the first month of treatment haematocrit increased from 23 +/- 3 (SD) to 32 +/- 4% and during the last 3 months the maintenance dose of rHuEpo was 143 +/- 37 U/kg per week to achieve a mean haematocrit of 35 +/- 1%. After introduction of rHuEpo, blood transfusions were no longer required and the patients reported an improvement in wellbeing. No apparent worsening of multiple myeloma has been observed over the treatment period ranging from 5 to 34 months (cumulative duration of treatment 55 months). Anti-hypertensive therapy was started in one case and increased in two patients. We conclude that rHuEpo appears to be effective and safe in treating anaemia associated with multiple myeloma in patients requiring haemodialysis.

Topics: Aged; Anemia; Erythropoietin; Female; Humans; Immunoglobulin G; Immunoglobulin kappa-Chains; Male; Middle Aged; Multiple Myeloma; Neoplasm Staging; Recombinant Proteins; Renal Dialysis; Time Factors

Still few data are available on efficacy and safety of recombinant erythropoietin (rEPO) in patients with myeloma and end-stage renal failure (ESRF); two such hemodialysed patients are reported in whom only partial response was observed, despite iron, folic acid supplementation and, in one case, high doses of rEPO (320 IU/kg/week). Despite improvement in well being and no need of further transfusion, hemoglobin did not reach 80 g/l. One patient developed recurrence 4 weeks after starting rEPO. Patients with ESRF and myeloma should benefit from rEPO but particular attention should be paid to marrow proliferation.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Erythropoietin; Humans; Kidney Failure, Chronic; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins; Renal Dialysis

The aim of this study was to examine whether altered plasma viscosity could contribute to the inappropriately low production rate of erythropoietin (EPO) observed in patients suffering from hypergammaglobulinemias associated with multiple myeloma or Waldenström's disease. We found that the EPO formation in response to anemia in these patients was inversely related to plasma viscosity. A similar inverse relationship between plasma viscosity and EPO production was seen in rats in which EPO formation had been stimulated by exchange transfusion and the plasma viscosity of which was thereby altered by using exchange solutions of different composition to alter plasma viscosity and thus whole blood viscosity independently from hematocrit. Raising the gammaglobulin concentration to approximately 40 mg/ml plasma in the rats almost totally blunted the rise in serum EPO levels despite a fall of the hematocrit to 20%. Determination of renal EPO mRNA levels by RNase protection revealed that the reductions in serum EPO levels at higher plasma viscosities were paralleled by reductions in renal EPO mRNA levels. Taken together, our findings suggest that plasma viscosity may be a significant inhibitory modulator of anemia-induced EPO formation. The increased plasma viscosity in patients with hypergammaglobulinemias may therefore contribute to the inappropriate EPO production, which is a major reason for the anemia developing in these patients.

Topics: Adult; Aged; Animals; Blood Pressure; Blood Viscosity; Erythropoietin; Exchange Transfusion, Whole Blood; Female; Hematocrit; Humans; Kidney; Male; Middle Aged; Multiple Myeloma; Oxygen; Rats; Rats, Sprague-Dawley; Rats, Wistar; RNA, Messenger; Waldenstrom Macroglobulinemia

Neoplasias, especially in their more advanced stages, are often associated with chronic anemia of malignancy which impairs the patient's physical ability and quality of life.. Forty-two patients with chronic anemia associated with hematological malignancies (18 multiple myelomas, 10 myelodysplastic syndromes) or solid tumors (9 breast cancers, 5 colon cancers) were treated with 150-300 units/kg rHuEPO for a median time period of 16 weeks. Response was defined as an increase of the initial hemoglobin level by at least 2 g/dl.. The response rates for solid tumors were comparable (44.4% and 40% for breast cancer and colon cancer, respectively), whilst the response in patients with hematological malignancies depended strongly on the disease entity (77.8% for multiple myeloma, 10% for myelodysplastic syndrome). Pretreatment serum levels of endogenous erythropoietin (EPO) were significantly higher in non-responding patients than in responders. During rHuEPO therapy, EPO levels in non-responders increased even further, while they remained basically unchanged in responding patients. In responders, the WHO performance status before the start of rHuEPO therapy was more favorable and showed impressive improvement during the course of treatment. The median survival time of responders was 28.0 months as compared to only 9.2 months for non-responders. Clinical symptoms of anemia subsided or at least considerably improved under successful rHuEPO therapy. With the exception of occasional flu-like symptoms, no undesirable effects of rHuEPO treatment were observed.. In conclusion, rHuEPO treatment corrected anemia of malignancy both in patients with hematologic disease and in those with solid tumors, but responsiveness varied considerably amongst the different disease entities.

Topics: Aged; Aged, 80 and over; Anemia; Breast Neoplasms; Chronic Disease; Colonic Neoplasms; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Survival Rate; Treatment Outcome

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Multiple Myeloma; Recombinant Proteins

In 30 patients with multiple myeloma (MM) and mild to moderate anaemia (mean Hb 107 g/l, 95% confidence limit (CL) 102-113) but no evidence of renal failure (serum creatinine < 110 mumol/l), serum erythropoietin (EPO) showed significant inverse logarithmic correlation with the haemoglobin level (r = -0.57, p = 0.001). The observed/expected ratio of log-EPO in patients with MM (mean 0.96, CL 0.89-1.04) was similar to that of 119 subjects (mean 1.01, CL 0.96-1.05) with or without anaemia (mean Hb 116 g/L, CL 110-121) but without renal failure. The concentration of circulating erythroid progenitors (BFU-E) in 10 MM patients in plateau phase was significantly reduced (mean 0.70 x 10(5)/l of blood, CL 0.34-1.06) compared to that of 8 normal controls (mean 3.57, CL 1.60-5.55, p = 0.011) In vitro sensitivity of the BFU-E to EPO in the patients with MM was comparable to that of the normal controls. It appears that in MM there is an appropriate EPO response to anaemia but even in the plateau phase the number of circulating BFU-E is reduced, reflecting a degree of marrow failure. However, the progenitors are normally sensitive to EPO in such patients, and therapeutic doses of EPO may correct the anaemia by a pharmacological rather than a physiological effect.

Topics: Anemia; Blood Cell Count; Erythroid Precursor Cells; Erythropoietin; Hemoglobins; Humans; Immunologic Factors; Multiple Myeloma; Recombinant Proteins; Renal Insufficiency

The responsiveness of bone marrow erythroid progenitors (CFU-E and BFU-E) to recombinant human erythropoietin (rh-Ep) was investigated in vitro in 21 patients with multiple myeloma to assess the clinical usefulness of rh-Ep in this disease. CFU-E and BFU-E assays were performed by methylcellulose culture methods. The myeloma patients were divided into two groups according to the percentage of plasma cells in the bone marrow (over 50% and under 50%). Among the patients with few plasma cells, some revealed normal CFU-E and BFU-E growth at 2 units of rh-Ep, and no further increase was observed even with an increasing dose of rh-Ep. Among the other patients, more than half demonstrated a good response to rh-Ep. Among the patients with a high percentage of plasma cells, some revealed no response to rh-Ep, but there were patients with a high percentage of plasma cells in the bone marrow who had a good response to rh-Ep. High doses of rh-Ep may be clinically effective in some patients with multiple myeloma independently of the level of plasma cells in the bone marrow.

Topics: Aged; Aged, 80 and over; Bone Marrow; Cell Count; Erythroid Precursor Cells; Erythropoietin; Female; Humans; In Vitro Techniques; Male; Middle Aged; Multiple Myeloma; Plasma Cells; Recombinant Proteins; Tumor Cells, Cultured

Immunoreactive erythropoietin levels were measured in 42 patients with lymphoid malignancies with anaemia and bone marrow involvement. Results were compared to a control group of 16 patients suffering from anaemia due to other causes. Significant inverse correlations between serum erythropoietin level and haemoglobin concentration were shown for the patients with lymphoid malignancies and also for the control subjects. Overall, the erythropoietin levels of patients with lymphoid malignancies with bone marrow infiltration and with normal renal function did not differ significantly from erythropoietin levels of the anaemic controls. We conclude that anaemia in patients with lymphoproliferative disorders with bone marrow infiltration and normal renal function is caused primarily by a diminished/inadequate response to erythropoietin at the level of the target cell.

Topics: Anemia; Bone Marrow Diseases; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Lymphoma; Lymphoproliferative Disorders; Male; Multiple Myeloma; Neoplasm Metastasis

Serum erythropoietin (Epo) levels were measured in 53 patients with multiple myeloma (MM), 49 normal subjects and 53 patients with some hematological diseases including aplastic anemia (AA), iron deficiency anemia, etc. to study the significance of erythropoietin in anemia of MM. The serum Epo level was 72.0 +/- 94.4 mIU/ml (mean +/- SD) in MM patients, which was significantly higher than in normal subjects (24.1 +/- 6.1 mIU/ml), but lower than in AA patients (7069.9 +/- 9406 mIU/ml). A significant inverse correlation was found between the hemoglobin (Hb) levels and the logarithmic values of serum Epo levels (r = -0.543, p < 0.05) in MM patients. This inverse correlation was stronger (r = -0.636, p < 0.05) in MM patients without renal dysfunction than in whole MM patients, while no correlation was observed in MM patients with renal dysfunction. These results indicate that MM patients with renal dysfunction have a low ability to synthesize Epo and that the supplemental therapy of recombinant Epo is effective to improve their anemia. In addition, the circadian rhythm of serum Epo level was lower in the morning than in the afternoon in both MM patients and normal controls. Serum Epo levels after chemotherapy in MM patients were elevated temporarily and then decreased in spite of no change of blood Hb level.

Topics: Adult; Aged; Circadian Rhythm; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Multiple Myeloma; Radioimmunoassay

We investigated the pathophysiology of erythropoiesis in 62 patients with multiple myeloma and examined whether it would establish a rational basis for the treatment of their anaemia with recombinant human erythropoietin. Erythropoietin (Epo) production was evaluated by serum levels and erythropoiesis was quantitated by serum transferrin receptor (TfR) levels, both assessed relative to the degree of anaemia. Instead of the expected stimulation of erythropoiesis in response to anaemia, haematocrit correlated positively with marrow erythropoietic activity, indicating that the mechanism of anaemia was primarily defective red cell production. Erythropoiesis decreased and anaemia worsened significantly with advancing clinical stage. 25% of the patients had inadequate Epo production and this proportion increased to 50% in stage 3. Inappropriate Epo production was seen in 60% of patients with renal impairment but was also observed in a number of patients with normal renal function. Erythropoiesis correlated strongly with the adequacy of Epo production, particularly in advanced disease. We conclude that most myeloma patients have defective red cell production even in the absence of massive marrow infiltration and that inappropriate Epo production contributes to their anaemia.

Topics: Adult; Aged; Aged, 80 and over; Erythropoiesis; Erythropoietin; Female; Hematocrit; Humans; Male; Middle Aged; Multiple Myeloma; Receptors, Transferrin; Reference Values

Recombinant human erythropoietin (rHuEpo) is an established, effective treatment for the anemia of chronic renal failure. Recent reports also suggest it may be efficacious in the anemias of drug toxicity, rheumatoid arthritis, and multiple myeloma without renal failure. We describe the positive response to rHuEpo in an end-stage renal disease patient with active multiple myeloma and ongoing chemotherapy. Before rHuEpo therapy, the patient was transfusion dependent, but after rHuEpo was initiated, transfusions were not required. Multiple myeloma with renal failure does not preclude a response to rHuEpo. Further trials of rHuEpo in the treatment of multiple myeloma with and without renal failure are warranted.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Middle Aged; Multiple Myeloma; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins

Topics: Anemia; Erythropoietin; Female; Humans; Middle Aged; Multiple Myeloma; Recombinant Proteins

Topics: Anemia; Erythropoietin; Humans; Multiple Myeloma; Recombinant Proteins; Testosterone

Topics: Anemia; Blood Transfusion; Erythropoietin; Female; Hodgkin Disease; Humans; Middle Aged; Multiple Myeloma; Patient Compliance

Immunoreactive levels of serum erythropoietin (EPO) have been measured in 95 patients with multiple myeloma (MM) and 12 patients with Waldenström's macroglobulinaemia (MW). Of the MM patients 23% were uraemic (mostly light and moderate renal failure) and 61.7% were anaemic. In the anaemic nonuraemic MM patients the mean serum EPO titre was 106.8 +/- 30.4 mU/ml which, when related to the extent of anaemia, was found to be appropriately elevated for the degree of anaemia (the mean haemoglobin (B-HGB) concentration was 6.66 +/- 1.31 mmol/l). The mean serum EPO concentration in uraemic and anaemic MM patients was 39.2 +/- 9.2 mU/ml, which was markedly lower than serum EPO levels in the non-uraemic MM patients, but still higher than in nonanaemic control subjects (22.5 +/- 8.5 mU/ml). The mean B-HGB concentration in uraemic MM patients was 6.04 mmol/l. In the anaemic MM patients with severe renal failure (S-creatinine levels greater than 400 mumol/l) the compensatory secretion of EPO was inadequate in relation to the degree of anaemia. The data indicate that unless the hypoproliferative anaemia of MM is accompanied by considerable renal failure the anaemia does not appear to be associated with a deficient biogenesis of EPO. Likewise the anaemia found in patients with MW also seems, generally, to elicit an appropriate increase in EPO secretion. Reasonably clinically stable MM patients with anaemia and uraemia may be candidates for replacement therapy with recombinant human erythropoietin (rhEPO).

Topics: Anemia; Erythropoietin; Female; Hemoglobins; Humans; Male; Multiple Myeloma; Uremia; Waldenstrom Macroglobulinemia

We demonstrated the expression of the erythropoietin (EPO) receptor by a human myeloma cell line (MM-S1) which was established in our laboratory. EPO dose-dependently stimulated the proliferation of MM-S1 cells. Binding of radioiodinated EPO (125I-Epo) to MM-S1 cells was competitively inhibited by unlabeled EPO, but not by other recombinant cytokines. Specific binding of 125I-Epo to MM-S1 cells was saturable, and the Scatchard analysis revealed 330 EPO binding sites per cell with a Kd of 0.56 nmol/L. Bound EPO was internalized by MM-S1 cells during incubation at 37 degrees C. This is the first report describing the expression of the EPO receptor by human cells other than those of the erythroid lineage.

Topics: Cell Division; Erythropoietin; Humans; Multiple Myeloma; Receptors, Cell Surface; Receptors, Erythropoietin; Tumor Cells, Cultured

Anemia of malignancy is a complication of neoplastic disease which causes impairing symptoms and often requires blood transfusions. In this clinical trial, we have treated 13 patients suffering from chronic anemia of malignancy and multiple myeloma with recombinant human erythropoietin (rHuEPO) three times a week. Eleven patients responded to the treatment by appropriate increases of their hemoglobin levels and the eventual correction of the anemic state, one non-responding patient had to terminate the treatment early because of transfusion requirements. Under rHuEPO therapy, the evaluated parameters of iron metabolism indicated the enhanced synthesis of hemoglobin. The symptoms of anemia subsided in the responding patients and most of them reported a hightened subjective sense of well-being. No adverse side effects, particularly no episodes of hypertension, were observed in any patient.

Topics: Aged; Anemia; Erythropoietin; Female; Ferritins; Hemoglobinometry; Humans; Iron; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins; Transferrin

Topics: Anemia; Erythropoietin; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Multiple Myeloma; Renal Dialysis

Topics: Anemia; Erythropoietin; Humans; Male; Middle Aged; Multiple Myeloma; Stimulation, Chemical

Recombinant human erythropoietin was administered to an anemic patient with multiple myeloma (IgD, lambda type) and renal dysfunction who had been dependent on blood transfusions. Three thousand units of the recombinant human erythropoietin was given intravenously three times a week. Thereafter transfusion requirements, hemoglobin level, and reticulocyte responses have been monitored. An increase in hemoglobin level and reticulocyte counts was observed within 10 days and then further blood transfusion was not necessary. Neither organ dysfunction nor toxic effects were observed. The administration of recombinant human erythropoietin can be a new method to treat anemia associated with multiple myeloma and renal dysfunction.

Topics: Anemia, Refractory; Erythropoietin; Female; Humans; Kidney Diseases; Middle Aged; Multiple Myeloma; Recombinant Proteins

Anemia is a common complication of multiple myeloma. It resolves early in the disease if chemotherapy induces a complete remission, but persists if the disease progresses, causing disabling symptoms and often requiring blood transfusions. We treated 13 patients with myeloma-associated anemia by administering recombinant human erythropoietin three times a week for six months. Eleven patients (85 percent) had steady increases in hemoglobin levels and eventual correction of the anemia. Their symptoms of anemia subsided, and they reported a heightened sense of well-being. No patient had any adverse side effects, particularly episodes of hypertension. Monitoring of the serum M component showed a predominantly stable tumor load without apparent interaction between the underlying disease and the response to erythropoietin therapy. The number of erythroid burst-forming units in the bone marrow and peripheral blood and the level of erythropoiesis in bone marrow smears increased significantly during therapy. Pretreatment serum levels of erythropoietin were higher in the patients who did not respond and in those who required more than two months of treatment before they responded. Serum iron, ferritin, and transferrin concentrations reflected responses to treatment. We conclude that recombinant human erythropoietin is a promising therapeutic tool for treating myeloma-associated anemia.

Topics: Aged; Anemia; Blood Proteins; Bone Marrow; Erythropoiesis; Erythropoietin; Female; Ferritins; Hematopoietic Stem Cells; Hemoglobins; Humans; Immunoglobulins; Iron; Male; Middle Aged; Multiple Myeloma; Myeloma Proteins; Recombinant Proteins; Transferrin

In a 59-year-old man with multiple myeloma (kappa-light chain paraproteinaemia) in stage IIIB, bone marrow infiltration with atypical plasma cells was reduced by five cytostatic treatment courses with vincristine, melphalan, cyclophosphamide and prednisone (VMCP protocol), but anaemia requiring blood transfusion persisted (haemoglobin concentration 5.3 g/dl). Even administration of interferon alpha-2b (5 million units s.c. every other day) failed to alter this. Only a combination of interferon and erythropoietin (150 U/kg i.v. every other day) achieved lasting regression of the anaemia (haemoglobin concentration up to 14 g/dl). In four other anaemic patients with multiple myeloma, stage III, treated according to the VMCP protocol but without additional interferon, erythropoietin did not improve erythropoiesis.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cyclophosphamide; Erythropoiesis; Erythropoietin; Female; Humans; Interferon alpha-2; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Recombinant Proteins; Vincristine

Twenty-four untreated patients with myelomatosis were studied in order to characterize their anaemia, using standard haematological and ferrokinetic techniques, together with measurements of circulating erythropoietin, erythropoietin sensitivity of marrow cultures and in vitro measurements of haem synthesis. There is a reduction in total erythroid output by the marrow, together with a minor degree of plasma expansion. In patients with normal renal function there is an appropriate increase in erythropoietin in response to anaemia, but in a few cases there may be reduced response of CFU-E to the hormone in vitro. No abnormality of iron status or haem synthesis was found. One case of folate deficiency was discovered.

Topics: Adult; Aged; Anemia; Blood Volume; Bone Marrow; Creatinine; Erythrocytes; Erythropoietin; Female; Heme; Hemoglobinometry; Humans; Immunoglobulins; Iron; Male; Middle Aged; Multiple Myeloma; Paraproteins; Urea

Topics: Dithiothreitol; Erythropoietin; Ethylmaleimide; Female; Hemoglobinuria, Paroxysmal; Humans; Male; Molecular Weight; Multiple Myeloma

Erythropoietin activity in serum was measured using 59Fe incorporation into erythrocytes in protein-starved, hypoxic mice. The activity in serum from 20 patients with untreated myelomatosis was not significantly different from that in 31 saline controls. Only three patients had detectable erythropoietin levels in serum: 0.24 IU/ml, 0.27 IU/ml and 0.50 IU/ml (standard B), respectively. The venous haematocrit was correlated positively with the glomerular filtration rate as measured by 51Cr EDTA-clearance. No correlation could be established between venous haematocrit and serum albumin or serum transferrin. The results are in agreement with the assumption of a defective erythropoietin activity due to renal failure in myelomatosis.

Topics: Erythropoietin; Female; Glomerular Filtration Rate; Humans; Male; Multiple Myeloma

Topics: Anemia; Animals; Biological Assay; Erythropoiesis; Erythropoietin; Evaluation Studies as Topic; Female; Humans; Iron; Male; Methods; Mice; Mice, Inbred AKR; Multiple Myeloma; Rabbits

Topics: Agammaglobulinemia; Antibiotics, Antineoplastic; Antibodies, Heterophile; Blood Protein Disorders; Cell Differentiation; Cell Transformation, Neoplastic; Clone Cells; Erythropoietin; Fluorescent Antibody Technique; Humans; Immunoglobulin kappa-Chains; Immunoglobulin lambda-Chains; Multiple Myeloma; Myeloma Proteins; Plasma Cells; Waldenstrom Macroglobulinemia

Topics: Acetone; Adrenal Cortex Hormones; Anemia; Animals; Chemical Precipitation; Chromatography, DEAE-Cellulose; Chromatography, Thin Layer; Dialysis; Erythropoiesis; Erythropoietin; Ethanol; Female; Hemoglobinuria, Paroxysmal; Humans; Hydrogen-Ion Concentration; Iron Radioisotopes; Male; Membranes, Artificial; Mice; Molecular Weight; Multiple Myeloma; Solubility; Solvents

Topics: Binding Sites, Antibody; Bone Marrow; Bone Marrow Cells; Cells, Cultured; Culture Techniques; Erythropoietin; Hematopoiesis; Hematopoietic Stem Cells; Humans; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukocytes; Macrophages; Methods; Microscopy, Electron; Mitosis; Multiple Myeloma; Neoplasms; Phagocytosis; Thymidine; Tritium; Waldenstrom Macroglobulinemia

Topics: Adolescent; Adult; Aged; Anemia, Aplastic; Anemia, Hemolytic; Anemia, Sickle Cell; Bone Marrow Diseases; Creatinine; Erythropoietin; Female; Hematocrit; Hemolysis; Humans; Iron; Leukemia; Lymphoma; Male; Middle Aged; Multiple Myeloma; Sex Factors

Topics: Adult; Aged; Alkaline Phosphatase; Anemia, Aplastic; Aspartate Aminotransferases; Bilirubin; Blood Transfusion; Bone Marrow Diseases; Chromium Isotopes; Erythropoiesis; Erythropoietin; Female; Hematocrit; Humans; Iron; Iron Isotopes; Lymphoma; Male; Middle Aged; Multiple Myeloma; Oxymetholone; Primary Myelofibrosis

Topics: Body Weight; Chromatography, DEAE-Cellulose; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Filtration; Hemoglobinuria, Paroxysmal; Humans; Hydrogen-Ion Concentration; Iron Isotopes; Male; Membranes, Artificial; Methods; Multiple Myeloma; Urine

Topics: Chemistry Techniques, Analytical; Erythropoiesis; Erythropoietin; Filtration; Hemoglobinuria, Paroxysmal; Humans; Hydrogen-Ion Concentration; Male; Molecular Weight; Multiple Myeloma; Protein Binding; Proteins

Topics: Albumins; Anemia; Animals; Binding Sites; Cellulose; Chromatography; Dialysis; Erythropoietin; gamma-Globulins; Hemoglobinuria, Paroxysmal; Humans; Immunoelectrophoresis; Methods; Mice; Multiple Myeloma; Phenols; Rabbits

Topics: Adult; Aged; Anemia; Blood Cell Count; Child; Child, Preschool; Erythropoiesis; Erythropoietin; Female; Hematocrit; Humans; Iron Isotopes; Male; Multiple Myeloma; Reticulocytes; Testosterone

Topics: Adult; Anemia, Aplastic; Erythropoietin; Female; Fluoxymesterone; Hemoglobinuria, Paroxysmal; Humans; Male; Methods; Middle Aged; Multiple Myeloma; Primary Myelofibrosis; Sex Factors; Time Factors