Erythropoietin (EPO) is a growth factor normally produced by the kidney. Erythropoietin stimulates the production of red blood cells (RBCs) in the bone marrow. Most of the cells in the blood are red blood cells, whose main function is to carry oxygen throughout the body. Hemoglobin is the substance found within red blood cells that combines with oxygen in the lungs, then carries and releases it to the tissues in the body.

There are several commercially available erythropoietic agents, which are listed in the table below. Procrit, Epogen, and Eprex are the same substance (epoetin alfa) while NeoRecormon is slightly different (epoetin beta). All are man-made forms of natural erythropoietin. Aranesp® (darbepoetin alfa, Amgen, Inc.) has the same molecular make-up as natural erythropoietin and acts in the same way, but it has two additional carbohydrate chains to give it a longer half-life.

Each of these products varies in the indications in which they are marketed for usage. However, it is possible that myeloma patients who experience disease or treatment-related anemia may receive any one of these agents.

Several retrospective analyses show that both epoetin alfa and darbepoetin generally result in comparable clinical outcomes. Head-to-head comparative studies with these two agents have been completed in anemic patients with cancer who are receiving chemotherapy. These studies showed that darbepoetin dosed at 200 mcg once every 2 weeks has the same safety and efficacy as erythropoietin dosed at 40,000 units every week.

Anemia is a condition with a decrease in the number of red blood cells in the body. Anemia can be caused by a loss of red blood cells due to excessive bleeding, decreased production of red blood cells by the bone marrow, increased red blood cell destruction by the body, or due to a combination of these factors.

Anemia is typically defined as having a hemoglobin (Hb) level below a certain value. Various organizations and centers may define anemia using slightly different values. For example, the National Cancer Institute (NCI) considers normal hemoglobin levels to be 12 to 16 g/dL for women and 14 to 18 g/dL for men and defines anemia as any hemoglobin level below those values.

According to recent guidelines for cancer and treatment-related anemia developed by the National Comprehensive Cancer Network (NCCN), anemia is defined for the purpose of intervention as a hemoglobin concentration of 11 g/dL or lower. The severity of anemia can then be described as follows:

Anemia is a significant problem in myeloma. It often occurs as a result of the disease itself, but can also occur as a result of chemotherapy or radiation therapy. Almost all patients with myeloma develop disease-related anemia due to decreased production of red blood cells. Up to 60% of patients are anemic at diagnosis and most remaining patients become anemic during the course of their disease. Although patients who do not respond to therapy or who relapse often continue to experience anemia, anemia often resolves in patients who achieve complete remission.

Anemia is so prevalent in patients with myeloma for several reasons:

Symptoms of anemia in an individual patient with myeloma depend on several factors, including how severe the anemia is, how rapidly it develops, the patient's age, possible co-existing medical conditions, and whether there is organ impairment due to cancer therapy. Hence, symptoms may vary from almost none to severe and life threatening.

In moderate-to-severe anemia, cardiovascular symptoms usually predominate due to the body's effort to compensate for decreased oxygen supply by increasing the heart's pumping rate. These cardiovascular symptoms include fatigue, shortness of breath, heart palpitations, and pounding pulse, particularly during and following exercise. A further important compensatory mechanism in severe anemia that serves to increase the amount of oxygen in the blood is an increased respiratory rate (more rapid breathing). This usually contributes to breathing difficulties during exercise and even at rest. The body also compensates by directing blood flow away from the skin and abdominal organs to vital organs such as the brain and heart. This can lead to cold, pale skin, decreased blood flow to the kidneys, and fluid retention. In very severe anemia heart failure may evolve.

The end result of these impairments is decreased quality of life (QOL) with fatigue, depression, insomnia, and difficulties in concentration, memory, or language (cognitive dysfunction) as frequent symptoms. Interestingly, patients can partially adapt to these dismal circumstances and sometimes do not report diminished well-being. These patients are often surprised by the degree of improvement they experience when their hemoglobin levels are improved by therapy with erythropoietic agents.

Several organizations have published guidelines to advise physicians on the use of erythropoietic agents in patients with cancer. These organizations include:

At the time some of these guidelines were developed, Aranesp (darbepoetin) was not available for routine use in this patient population, so recommendations for its use were not made. The recently published EORTC guidelines and the recently updated NCCN guidelines, however, include recommendations for the use of darbopoetin as erythropoietic therapy.

All sets of guidelines concur that EPO is recommended as a treatment option for symptomatic patients with treatment-related anemia when anemia is moderate to severe (Hb <10 g/dL). When the anemia is mild (Hb = 10-11 g/dL), physicians should consider giving EPO on a case-by-case basis, based on symptoms of anemia. If anemia is severe and requires immediate correction, patients should receive a blood transfusion. A blood transfusion may also be warranted in cases where a patient does not respond to erythropoietin therapy. Although the ASCO/ASH guidelines make no specific recommendations for the use of EPO for cancer-related anemia in the absence of chemotherapy, the NCCN guidelines suggest that physicians use the same criteria as recommended for treatment-related anemia. The NCCN and EORTC guidelines indicate that darbepoetin can be used in the same manner as erythropoietin for treatment of cancer and treatment-related anemia.

In clinical practice, physicians should consider erythropoietic therapy for their patients with myeloma if they have symptomatic anemia. Therapy should also be considered for patients with asymptomatic anemia who are at risk of developing symptomatic anemia (ie, they have had a transfusion within the last 6 months, prior or current myelosuppressive therapy, or prior radiotherapy, or are of advanced age, or low baseline hemoglobin). NCCN guidelines suggest that, if an improvement in patient function is a goal, treatment should be considered if hemoglobin drops to 11 g/dL.

Data support early intervention with erythropoietic agents in chemotherapy-induced anemia (ie, when anemia is mild, Hb = 10-11 g/dL). A recent systematic review of the literature showed that early intervention with erythropoietic agents reduced blood transfusions by approximately 50% in patients with chemotherapy-induced anemia and allowed more patients to achieve a target Hb >11g/dL. (Lyman GH, Glaspy J. Cancer. 2006; 106(1):223-33.)

Erythropoietic agents are typically administered as injections under the skin as needed to maintain hemoglobin levels at the desired level, typically 12 g/dL. Erythropoietic agents may sometimes be given intravenously. The dose and frequency of administration is dependent on the specific agent used and is adjusted according to the individual patient. Supplemental iron is given as needed.

General recommendations for initial dosage and administration of erythropoietic therapy in patients with chemotherapy-related anemia, as well as recommendations when patients do not respond to the initial dose, are found in the table below. While these dosing schedules have been evaluated in cancer patients receiving chemotherapy, they are also appropriate for use in patients with cancer-related anemia.

In March 2007, the FDA approved every 3-week dosing of darbepoetin for the treatment of chemotherapy-induced anemia in patients with non-myeloid cancers. Although longer dosing intervals of various erythropoiesis-stimulating agents continue to be investigated, darbepoetin is currently the only agent approved by the FDA for this administration schedule, which allows anemia treatment to be synchronized with every-3-week chemotherapy regimens.

Guidelines for dose reductions of these agents are as follows:

• For epoetin alfa, the dose should be reduced by 25% if there is more than a 1-g/dL rise in hemoglobin in any 2-week period. If the concentration rises above 12 g/dL, therapy is held. Therapy is reinitiated at a 25% dose reduction of the prior dose if the hemoglobin concentration falls below 12 g/dL.


• For darbepoetin, the dose should be reduced by 40% if there is more than a 1-g/dL rise in hemoglobin in any 2-week period or the hemoglobin exceeds 11 g/dL. The dose should be adjusted for each patient to maintain a target hemoglobin not to exceed 12 g/dL. If the concentration rises above 13 g/dL, therapy is held. Therapy is reinitiated at a 40% dose reduction of the prior dose once the hemoglobin concentration falls below 12 g/dL.


• For epoetin beta, the dose should be reduced by 50% if there is more than a 2-g/dL rise in hemoglobin within 4 weeks. If the concentration rises above 14 g/dL, therapy is held. Therapy is reinitiated at a 50% dose reduction of the prior dose if the hemoglobin concentration falls below 13 g/dL.

Other dosing regimens are being evaluated in clinical trials. Examples include:

• Epoetin alfa: 40,000 U weekly to achieve target hemoglobin followed by maintenance therapy with 80,000 U every 3 weeks; Results of an open-label study evaluating this regimen reported at ASH in December 2005 suggest that such maintenance therapy is effective. (Montoya et al. Blood. 2005;106(11). Abstract 3555.)


• Epoetin alfa: 40,000 U weekly for 8 weeks followed by maintenance therapy with 120,000 U every 3 weeks


• Darbepoetin: 300 mcg administered every 3 weeks as maintenance therapy

The effectiveness of erythropoietic agents is measured by the increase in hemoglobin and a related measure called hematocrit following therapy. It takes some time for the bone marrow to produce new blood cells, so the effect of erythropoietic agents may not be seen for 2 to 6 weeks. The amount of time it takes, and the dose needed varies from patient to patient. Overall, about 60% to 70% of cancer patients receiving chemotherapy respond to erythropoietic agents. An early hemoglobin response to therapy (≥1 g/dL rise after 4 weeks of therapy) in patients with chemotherapy-related anemia is often associated with reduced transfusion requirements, higher hemoglobin response rates, and improved quality of life scores.

Because patient response to erythropoietic therapy is somewhat variable, researchers are looking for ways to identify patients most likely to respond to therapy. The most important predictive factor for response is a low baseline level of erythropoietin in the blood (<100 mU/ml). Further, response is likely if patients display early evidence of a response following administration of an erythropoietic agent (an increase in hemoglobin level by 0.5 g/dL or erythropoietic activity within 2 weeks). Having adequate iron may also contribute to improved response.

Patients less likely to respond to erythropoietic therapy include those with compromised bone marrow function, indicated by low platelet counts (<100,000/µl) at the start of erythropoietic treatment, and/or those with heavy transfusion needs (≥2 units of red cells per month), as well as patients with persistent infections.

Several study groups have sought to develop algorithms for better prediction of response in an individual patient but none of them has yet been accepted for use in clinical practice. Recently, Agrawal et al. (Blood. 2005;106(11), Abstract 588l.) reported a predictive model based on the patient’s erythropoietic status and his/her need for iron supplementation to support erythropoiesis. Using this model, which is built on readily available laboratory tests, they were able to achieve a response rate of 92% by carefully selecting patients with chronic lymphocytic leukemia, lymphoma or myeloma for erythropoietin therapy and, if indicated by their model, for additional use of intravenous iron supplementation. Although highly interesting, this approach warrants further investigation and validation.

Erythropoietic agents are generally well tolerated. A recent study showed no significant difference in the frequency and type of side effects between patients with multiple myeloma or lymphoma treated with erythropoietic agents or placebo (Hedenus, et al. Br J Haematol. 2003;122(3):394-403). However, pain at the injection site, skeletal pain, and low white blood cell counts were found more frequently in patients receiving erythropoietic agents in a recent study (Dammacco et al, British Journal of Haematology. 2001;113:172-179).

In studies of patients with solid tumors or other hematologic disorders treated with erythropoietic agents, an increased risk for complications related to blood clots (thromboembolic events) has been observed. This has not been reported in patients with myeloma, but prophylactic treatment with an anticoagulant such as low-dose molecular weight heparin may be considered in patients with myeloma and a history of thromboembolic events.

Treating anemia allows more oxygen to circulate throughout the body, which can result in more energy, reduced fatigue, and the restored ability to be active. Several clinical trials have shown that treating anemia associated with cancer or chemotherapy with erythropoietin:

Numerous studies support the above cited recommendations that erythropoietic agents should be offered to every patient with myeloma with hemoglobin levels <10 g/dL and without contraindications for erythropoietic therapy. Treatment should also be considered in patients with higher hemoglobin levels (10-12 g/dL or higher) and severe symptoms due to anemia.

Anemia is a common side effect of high-dose chemotherapy and autologous stem cell transplant due to the chemotherapy’s effect on the blood-producing cells in the bone marrow. Administration of erythropoietin following transplant has been less effective in treating this type of anemia. However, administration of erythropoietin prior to high-dose therapy in patients with myeloma has been shown to reduce the need for transfusions. In a small study involving 22 myeloma patients, administration of erythropoietin (10,000 IU daily) starting 30 days prior to transplant was significantly associated with a lower risk of transfusion requirement than that seen with 40 retrospectively selected control myeloma patients. (Martino et al. Support Care Cancer. 2005;13(3):182-187.)

Numerous studies demonstrate that anemia has a negative impact on quality of life in patients with cancer. However, studies often lack an adequate adjustment for confounding factors such as stage of disease and tumor response to therapy, which can also affect quality of life. A review of data from two Nordic studies examined the impact of hemoglobin concentration on quality of life scores of 745 myeloma patients, adjusting for objective disease parameters. The authors state that it is essential to adjust for disease parameters and response to therapy in order not to overestimate the impact of hemoglobin values on quality of life. (Wisloff et al. Eur J Haematol. 2005;75(4):293-298. For example, in addition to hemoglobin concentration, extent of skeletal disease and response to therapy were important predictors of fatigue and impacted quality of life scores.

Cognitive dysfunction (difficulties in concentration, memory, or language) can occur in patients receiving chemotherapy, as well as patients who are anemic. Interim results of an open-label Phase III trial (EPOLYM) evaluating the cognitive effects of epoetin alfa in anemic patients with hematologic malignancies receiving chemotherapy suggest that increased hemoglobin levels are associated with improvement in several aspects of cognitive function. (Gisselbrecht et al. Blood. 2004;104(11). Abstract 2217.) These preliminary results will need to be confirmed.

CERA (Continuous Erythropoiesis Receptor Activator, Roche) is a novel agent under investigation in clinical trials for the treatment of anemia associated with cancer or chronic renal disease. It acts by stimulating red blood cell formation. Phase III studies of CERA are nearing completion for the treatment of anemia in renal disease and Phase II studies in cancer patients are ongoing.

Results of a Phase I/II study in patients with myeloma-related anemia who were receiving chemotherapy indicate that CERA delivered rapid, sustained, dose-related increases in hemoglobin levels when given once every 3 weeks as an injection under the skin. (Dmoszynska et al. ASCO 2004. Abstract 6552.) The 3-week dosing interval coincides with many chemotherapy dosing regimens, which can be convenient for patients.

In this study, there was a dose-dependent increase in hemoglobin levels with CERA administered at 1.0 to 4.2 µg/kg. After 6 weeks, CERA (3.5-8.0 µg/kg) produced a mean increase in hemoglobin of approximately 1.8 g/dL and approximately 60% of patients had an increase of ≥2 g/dL. These elevated hemoglobin levels were maintained or improved further during a 12-week extension period. Adverse events included high blood pressure (4 instances) and fever (1 instance).

Reviewed by:

Heinz Ludwig, MD
Director, Center for Medical Oncology
Wilhelminen Hospital
Vienna, Austria
4/10/06