Original Article
Erythropoietin Treatment of Anemia Associated with Multiple Myeloma
N Engl J Med 1990; 322:1693-1699June 14, 1990
- Abstract
- Abstract
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. (N Engl J Med 1990; 322:1693–9.)
Media in This Article
Figure 1
Hemoglobin Levels during Six Months of Erythropoietin Therapy.Figure 2
Changes in the Concentrations of Serum Iron, Ferritin, and Transferrin during Erythropoietin Therapy.Article Activity
- Article
IN patients with multiple myeloma, anemia is a common complication that has generally been considered to indicate a poor prognosis.1 Although its frequency increases with the progression and duration of the disease,1 it may occur in the absence of overt infiltration of the bone marrow by myeloma cells and in spite of normal leukocyte and platelet counts.2 The exact pathogenic mechanisms of this anemia are unclear. According to the traditional pathophysiologic concept, bone marrow is replaced by the tumor, an effect possibly supplemented by shortened red-cell survival3 or the dilutional effects of hypervolemia.4 Because of the observations mentioned above, however, specific suppression of erythropoiesis has been suggested to have a decisive role in myeloma-associated anemia.3
The anemia of myeloma usually resolves if a remission is induced by chemotherapy but it persists in patients who do not respond and usually recurs in patients who relapse. Thus, the largest proportion of patients with multiple myeloma who have chronic anemia are those with long-standing stable or progressive disease5 and with diminished chances of becoming free of anemia by entering another remission.
The clinical consequences of myeloma-associated anemia may appreciably reduce the patient's quality of life. Depending on the degree of anemia and the general clinical condition, various symptoms such as weakness, fatigue, drowsiness, depression, impaired mental function, cardiac decompensation, and respiratory distress may occur. Many patients require blood transfusions, which are always accompanied by the risks of hepatitis, infection with cytomegalovirus, the human immunodeficiency virus, and other viruses, iron overload, and allergic reactions. Sensitization to histocompatibility antigens may reduce the efficacy of concomitant platelet transfusions.
With the introduction of genetically engineered recombinant human erythropoietin into clinical use, the treatment of chronic anemias may improve substantially. Recombinant erythropoietin, which is biologically and immunologically indistinguishable from its natural counterpart,6 7 8 has been successfully used to correct the anemia of chronic renal failure,9 , 10 and it seems to hold promise for treating certain other types of chronic anemia.11 , 12 In this trial, we tested the efficacy and safety of recombinant erythropoietin in patients with myeloma-associated anemia.
Methods
Patients
Thirteen patients with advanced multiple myeloma (nine women and four men, with a median age of 65 years; range, 52 to 79) received recombinant human erythropoietin for a median period of 30 weeks (range, 2 to 42). In most patients, the disease had been long-standing (median duration at the start of therapy, 43 months; range, 4 to 111). All patients had previously received cytostatic chemotherapy; 11 had undergone local radiotherapy (Table 1Table 1
Characteristics of Patients with Multiple Myeloma and Anemia.). All patients presented with severe anemia, as indicated by hemoglobin levels of less than 6.8 mmol per liter (11 g per deciliter); 11 patients had previously required transfusions of red cells. Renal function was normal in all but one patient (Patient 10: serum creatinine level, 248 μmol per liter; creatinine clearance, 0.47 ml per second [28 ml per minute]). The clinical symptoms of anemia ranged from slight weakness and lassitude to severe fatigue, tachycardia, palpitations, and marked impairment of physical and mental capacities. No patient had hypertension or evidence of overt hemolysis, blood loss, or iron deficiency as determined by the measurement of iron stores in bone marrow.Informed consent was obtained from all patients who participated in this trial; the study design was reviewed and approved by the ethics committee of the Medical Faculty of the University of Vienna.
Treatment Regimen
Erythropoietin (Cilag, Vienna, Austria; specific activity, 119,048 units per milligram of hormone) was administered subcutaneously every Monday, Wednesday, and Friday between 8 and 10 a.m. The initial dose was 150 units per kilogram of body weight. If no response was observed within three weeks, this dose was increased to 200 units per kilogram; if there was no substantial response within the next three weeks, the dose was increased by 50 units. If a response was noted, the dose was reduced so that the hemoglobin level was maintained at 7.4 to 8.7 mmol per liter (12 to 14 g per deciliter). In nine patients, chemotherapy or radiotherapy (or both) was continued during erythropoietin treatment. Whenever possible, erythropoietin was administered on an outpatient basis.
Determination of Response
A response was arbitrarily defined as an increase of at least 1.2 mmol per liter (2 g per deciliter) in the initial hemoglobin level. If red-cell transfusions became necessary at any time after the start of therapy, the attempt at treatment was considered a failure and erythropoietin therapy was terminated. A response was considered to be late if it occurred more than two months after therapy started.
Clinical and Laboratory Monitoring
A routine evaluation was performed at 8 a.m. before each injection of erythropoietin during the first 2 weeks of treatment, every week until the 12th week, every other week until the end of the first six months of treatment, and every month thereafter. Each evaluation comprised a thorough physical examination, a complete blood count including leukocyte differential, red-cell, reticulocyte, and platelet counts, measurement of hemoglobin and hematocrit, determination of serum ferritin and transferrin concentrations, coagulation tests, and an SMA-20 blood-chemistry profile including serum iron, electrolytes, and indexes of renal and liver function. Base-line studies conducted before treatment and monthly control evaluations also included an assessment of performance status according to the criteria of the World Health Organization, electrocardiography, and quantitation of immunoglobulins by serum electrophoresis to determine the serum M component, a recognized tumor marker of multiple myeloma.13
This tumor marker served as an indicator of possible changes in the tumor mass. The kinetics of the serum M component in each patient were analyzed by comparing the findings obtained during erythropoietin therapy with those obtained during the six months before the start of treatment. In this way, each patient served as his or her own control, and any change in the pattern of kinetics would be easy to detect.
Erythropoietin Measurement
Serum levels of erythropoietin were measured before the start of therapy and after six weeks of treatment. If the therapeutic attempt was considered a failure before six weeks had elapsed, the serum sample obtained on the day of the decision to terminate therapy was used instead. All serum samples were stored at −20°C until they could be processed simultaneously. Erythropoietin levels were determined with a modified specific radioimmunoassay. 14 In brief, 200 μl of the patient's serum or standard dilutions of recombinant human erythropoietin (5 to 500 units per liter) and 100 μl of diluted rabbit antiserum against erythropoietin (Boehringer–Mannheim, Federal Republic of Germany) were incubated for four days in phosphate-buffered saline—human serum albumin at 4°C; then 25 μ (10–16 mol per liter) of l25I-Radio-labeled erythropoietin (Amersham, Buckinghamshire, United Kingdom) was added, and the preparation was incubated for another four hours. To separate bound from free ligands, goat—antirabbit immunoglobulin antiserum (Oris Industrie, Gif-sur-Yvette, France) was employed. The amount of labeled erythropoietin was determined with a gamma counter (United Technologies—Packard, Downers Grove, Ill.). The reference range of this assay is 15 to 28 units per liter. To control the results obtained with this modified technique, measurement of erythropoietin levels in the first 15 samples was duplicated by a commercial testing service (Bioscientia, Ingelheim, Federal Republic of Germany). Apart from minor random variations, the results were identical.
Bone Marrow Examination
Bone marrow was aspirated from the posterior iliac crest before erythropoietin treatment and after 12 weeks of therapy. Routinely stained preparations were examined to determine iron stores.
After May—Grünwald—Giemsa staining, the levels of erythropoiesis and myelopoiesis as well as myeloma-cell infiltration were evaluated by differential counts of 500 consecutive nucleated bone marrow cells.
Fresh mononuclear bone marrow cells were cultured in vitro to determine the number of erythroid burst-forming units (BFU-E) and granulocyte colony-forming units (CFU-G). The bone marrow aspirates and part of the blood sample obtained at monitoring examinations during the first 12 weeks of erythropoietin treatment were used to establish triplicate in vitro cultures to determine the number of BFU-E and CFU-G as described by Pike and Robinson.15 The results were standardized in relation to the mononuclearcell counts in order to express the number of colonies per milliliter of whole blood or 105 mononuclear bone marrow cells.
Statistical Analysis
Since most of the variables studied did not have normal distributions, the Kruskal—Wallis test was used to determine the significance of differences. Correlations were expressed as Kendall's tau correlation coefficients. Multiple data evaluations were corrected by means of the Bonferroni method.
All reticulocyte values were corrected by standardizing them to a reference percentage of the hematocrit (45 percent). The percentage of erythropoiesis in bone marrow smears refers strictly to hematopoietic tissue — i.e., the 100 percent reference value does not include infiltrating myeloma cells.
Results
Eleven patients (85 percent) responded to treatment with recombinant human erythropoietin, according to the predetermined criterion of an increase in the hemoglobin concentration of at least 1.2 mmol per liter (2 g per deciliter). The responses occurred after a median period of 5 weeks (range, 3 to 20); a period of more than two months was required in two patients (Table 2Table 2
Response to Treatment with Recombinant Human Erythropoietin (rHuEpo). and Fig. 1Figure 1Hemoglobin Levels during Six Months of Erythropoietin Therapy.). Two patients did not respond: one had to be withdrawn from therapy after 2 weeks because she required transfusions, and the other died in the terminal stage of myeloma during the 11th week after the start of treatment, despite a promising initial increase in his hemoglobin level. One of the patients who responded (Patient 11) died after 16 weeks of treatment, without losing her status as a responding patient.Pretreatment levels of hemoglobin ranged from 5.4 mmol to 6.8 mmol per liter (median, 6.3) (8.7 to 10.9 g per deciliter; median, 10.2); the kinetics of hemoglobin during six months of erythropoietin therapy are shown in Figure 1. A sharp drop in the hemoglobin level of one patient (Patient 9) between the 16th and 20th weeks of treatment coincided with surgical treatment of a major pathologic bone fracture. The hemoglobin level rose steadily during recovery from the orthopedic procedure (Fig. 1). Red-cell counts and hematocrit values strongly correlated with the observed hemoglobin levels (r = 0.925 and r = 0.977, respectively).
The corrected reticulocyte count (median base-line level, 0.7 percent; range, 0.2 to 2.0) increased significantly during erythropoietin therapy (P<0.001). The median of the changes peaked at 370 percent of the initial level, and the maximal individual values increased by up to 10-fold. The observed changes in leukocyte and platelet counts showed random patterns and did not reach statistical significance (data not shown).
There were no obvious differences in the response patterns of the various types of M component. Changes in serum M component during erythropoietin therapy showed no statistically significant trend and were apparently random variations (data not shown). No correlation was found between the amount of serum M component and the simultaneously determined hemoglobin level (r = −0.046). The extent of myeloma-cell infiltration of the bone marrow varied over a wide range (5.0 to 93.5 percent; median, 15.5) before the start of treatment and had not changed significantly after three months of erythropoietin therapy (median, 12.0 percent; range, 3.5 to 91.0).
Pretreatment serum levels of erythropoietin did not exceed 100 units per liter in any of the patients with timely responses (median, 34 units per liter; range, 22 to 82), but were higher in the patients with late responses (156 and 165 units per liter) and those with no responses (136 and 235 units). After six weeks of therapy, serum erythropoietin concentrations had changed only marginally in all but one patient (median, 35 units per liter; range, 15 to 147 in patients with timely responses, and 128 to 208 in those with late responses and one with no response); however, the serum level in one patient with no response, in whom anemia rapidly worsened, showed a steep increase at the time erythropoietin therapy was terminated (Patient 1, 968 units per liter after two weeks of treatment).
The initial level of serum iron (median, 19.7 μmol per liter [110 μg per deciliter]; range, 10.0 to 37.6 [56 to 210]) was at the lower limit of normal in one patient, was elevated in two patients, and was within the normal range in the rest of the patients. Shortly after the start of erythropoietin therapy, serum iron concentrations dropped significantly (P<0.01) and remained below the initial values throughout the treatment period (Fig. 2Figure 2
Changes in the Concentrations of Serum Iron, Ferritin, and Transferrin during Erythropoietin Therapy.). Similar but even more pronounced changes were observed in serum ferritin concentrations (P<0.001), and serum transferrin concentrations increased significantly during the course of erythropoietin treatment (P<0.02; Fig. 2). Coagulation times and liver function were normal in all patients throughout the observation period. Renal function became stable in one patient by the fourth week of treatment (Patient 10; serum creatinine, 200 to 220 μmol per liter) and remained normal in all other patients (data not shown).Before the start of therapy, the erythropoietic-cell compartment constituted a median of 23.6 percent (range, 0.01 to 42.0) of the hematopoietic bone marrow tissue. After three months of treatment, the median had increased by exactly 50 percent, to 35.4 percent (range, 14.2 to 60.0) — a significant change (P<0.0005; Fig. 3Figure 3
Percentage of Erythropoietic Cells in Bone Marrow Smears before and after Three Months of Erythropoietin Therapy.). With the exception of Patient 4, who had not yet had a response, erythropoietic cells exceeded 20 percent of the hematopoietic-cell compartment in all patients. The relative proportion of myelopoietic cells, on the other hand, dropped significantly (P<0.0005) from an initial median of 71.3 percent (range, 50.9 to 95.8) to 60.4 percent (range, 25.9 to 82.8; data not shown).The results of in vitro cultures are shown in Figure 4Figure 4
Median Changes in the Number of BFU-E and CFU-G during Therapy.. The number of BFU-E in the bone marrow was very low before erythropoietin treatment (median, 0; range, 0 to 7). After three months of therapy, the median had increased significantly (P<0.05) to 4.5 colonies per 105 mononuclear bone marrow cells (range, 0 to 17). Similarly, the median number of BFU-E in the peripheral blood was 0 (range, 0 to 70) before the start of erythropoietin therapy and increased significantly (P<0.001) during treatment, reaching maximal values of more than 1000 per milliliter of whole blood. No significant changes were observed in the number of CFU-G. Even though the slight increase in the median number of bone marrow CFU-G (Fig. 4) seemed to correspond to the increase in bone marrow BFU-E, the initial range of values (0 to 88) precluded any significant change.The clinical symptoms of anemia either resolved completely or at least improved considerably in all patients with responses. Most of these patients also reported a heightened sense of well-being and a noticeably increased tolerance of physical exertion. These subjective improvements in the quality of life were reflected by significant changes in performance status (mean change, —0.62; P<0.02). Figure 5Figure 5
Performance Status before Therapy and after Two Months of Treatment, According to the Criteria of the World Health Organization (WHO). shows the changes in performance status after two months of erythropoietin therapy, when 12 patients were available for evaluation.Clinical examinations and thorough questioning of the patients detected no undesirable side effects of recombinant human erythropoietin, particularly episodes of hypertension.
Discussion
The results of this pilot study show that in the majority of patients with myeloma, anemia can be corrected by subcutaneous injections of recombinant human erythropoietin given three times a week. Patients responding to this treatment no longer need blood transfusions and — without the often incapacitating symptoms of anemia — enjoy an improved quality of life. The simultaneous administration of chemotherapy or local irradiation does not diminish the benefits of erythropoietin treatment.
Since myeloma-associated anemia represents a specific form of chronic anemia of cancer, the excellent response rate observed in our patients with multiple myeloma must not be indiscriminately generalized to results in all patients with cancer. However, multiple myeloma seems to be well suited as a study model, because it contains a continuously available, easily measurable tumor marker with which to examine possible interactions between the basic disease and its associated anemia. Observation of kinetics of the serum M component during erythropoietin treatment has helped to clarify two important issues. The first issue is whether — especially in patients receiving chemotherapy — improvement in anemia could have been caused solely by a reduction of the tumor mass. In such a case, the rise in the hemoglobin level would have coincided with a drop in the serum M component. Careful analysis showed that no such decrease had occurred. The second issue is of major importance to the use of recombinant erythropoietin to treat any hematologic neoplastic disease. Since stimulation of the processes of bone marrow cell compartments other than erythropoiesis has been reported,16 , 17 any proliferative effect of recombinant erythropoietin on the malignant plasma-cell clone must be ruled out before this symptomatic treatment can be recommended. For this reason, we included the results of serum M component measurements during the six months preceding erythropoietin treatment in our analysis. A possible stimulation of the myeloma-cell clone by recombinant erythropoietin would have been detectable as a distinct change in pattern after the beginning of erythropoietin therapy. However, the pattern changed only gradually and remained well within the range of random variations. Furthermore, the number of myeloma cells in the bone marrow remained nearly constant after three months of erythropoietin therapy.
The hemoglobin levels conform to the general pattern of response and also show wide fluctuations in individual patients in response to adjustment of the dose of erythropoietin. Some patients require relatively long periods and higher doses before their anemia is relieved. Most of our patients, however, had steep increases in their hemoglobin levels within four weeks of the start of treatment. Once a response occurred, maintenance therapy was intended to keep the red-cell count within the normal range or slightly below it. However, even after several months of close monitoring, the individual curves for hemoglobin levels did not level off to a constant concentration. Therapeutic administration of erythropoietin seems to affect a complex, dynamic system that apparently is highly susceptible to disturbances in its balance. Even though no correlation was found between the degree of anemia and the concentration of the tumor marker, our clinical impression was that complications of myeloma, especially infections, may greatly reduce the benefits of erythropoietin treatment. Until we possess a better understanding of the mechanisms involved in the therapeutic effects of recombinant human erythropoietin, continuous monitoring of each patient remains absolutely necessary.
To date, no information has been available on levels of endogenous erythropoietin in patients with multiple myeloma. In view of the degree of their anemia, most of our patients presented with relatively low serum erythropoietin concentrations.18 , 19 The finding that the levels were highest in our patients with late responses or none could merely be a phenomenon of chance, but preliminary data on patients with other chronic diseases seem to corroborate our findings. Among patients with the chronic anemia of the acquired immunodeficiency syndrome, those with comparatively high levels of endogenous erythropoietin did not respond to erythropoietin therapy.12 If our findings are confirmed in a larger series of patients with myeloma, at least two types of myeloma-associated anemia would have to be distinguished, as proposed for the anemia of cancer.20 One type, similar to the anemia of chronic infection and inflammation,18 would involve a relative deficiency of erythropoietin and should respond to substitution therapy. Another type could prove to be the result of suppression or impairment of the bone marrow response to stimulation by erythropoietin; substitution treatment could not be expected to benefit patients with this type of anemia.
In our patients, serum iron levels at the start of therapy were not typically decreased18 , 21 but were mostly within the normal range or sometimes elevated. The reason for this discrepancy seems to be that since the primary disease was long-standing in these patients, serum iron levels had been monitored regularly and corrected if necessary. Most of our patients had received blood transfusions and had thus received considerable amounts of iron.
The number of erythroid precursor BFU-E in bone marrow and peripheral blood increased significantly during the course of therapy, confirming the stimulatory effect of recombinant erythropoietin on the earliest stages of erythropoiesis.22 , 23 The induced proliferation and differentiation of early erythroid-progenitor cells was manifested in an increased proportion of erythropoiesis in bone marrow smears after three months of erythropoietin therapy. Our plan of investigation did not include quantitation of the hematopoietic bone marrow tissue, but tentative conclusions may be drawn from the combined findings of changes: absolute increases in red-cell counts and relative increases in erythropoietic-cell counts coincided with relative decreases in myelopoietic-cell counts and fairly stable leukocyte counts. Thus, it seems unlikely that erythropoiesis had increased at the expense of other activities of hematopoietic-cell compartments. Myeloma-cell infiltration may have undergone a slight diminution, but this change did not reach statistical significance. The observed therapeutic benefits at the level of erythroid-precursor cells were possibly augmented by other effects of erythropoietin such as its stabilizing influence on mild subclinical hemolysis24 — a characteristic feature of anemia of cancer25 — or its enhancement of the release mechanisms that shift cellular bone marrow elements into the circulation.26 , 27
No side effects occurred during our clinical trial. In particular, none of our patients had hypertension, seizures, or thrombohemorrhagic complications —symptoms that have occurred during erythropoietin treatment in patients with anemia of chronic renal disorders.24 One must remember, however, that patients with renal dysfunction are intrinsically susceptible to hypertension and other severe complications.28 Performance status, an objective measure, improved in some of our patients, and all patients with responses experienced subjective improvement in their quality of life. It was partly because of this subjective sense of well-being that most of our patients were highly motivated to adhere to the treatment schedule.
This study of therapy with recombinant human erythropoietin in patients with myeloma-associated anemia showed excellent tolerance of the treatment regimen and a surprisingly high response rate that approached the almost universal response of patients with anemia of chronic renal disease.9 , 10 , 29 Future trials should determine whether the response persists throughout the course of progressive myeloma and how to adjust individual doses in relation to various complications of advanced disease. It also seems important to find out whether the successful results of treatment can be extended to patients with other neoplasms, such as lymphomas, solid tumors, and nonlymphomatoid hematologic cancers.
Supported by an Austrian Research Grant (4999) and the Ludwig Boltzmann Institute for Gerontology, Vienna, Austria.
Source Information
From the Department of Medicine II (H.L., E.F., H.K., H.G., U.B.), University of Vienna, and the Blood Bank of the General Hospital (P.H.), Vienna, Austria. Address reprint requests to Dr. Ludwig at Department of Medicine II, University of Vienna, Garnisongasse 13, A-1090, Vienna, Austria.
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- Citing Articles (141)
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