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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 ≤ 0·05) improvement in more QOL measures with epoetin alfa than with placebo; multivariate analysis discerned no between-treatment differences. Significantly (P = 0·038) more epoetin alfa vs. placebo patients had improved performance scores. At the end of the open-label treatment phase, patients who had continued epoetin alfa maintained Hb status, and placebo patients who were switched to epoetin alfa had mean Hb increases of 2·4 g/dl. Adverse events were similar between treatment groups. Epoetin alfa proved effective and well tolerated for treating anaemia in patients with multiple myeloma.
Multiple myeloma is a malignant plasma cell neoplasm, the incidence of which increases with increasing age (Turesson et al, 1984; Hjorth et al, 1992). Anaemia has been reported in up to 70% of patients with multiple myeloma (Kyle, 1975; Riccardi et al, 1991; Garton et al, 1995), often caused by the inadequate production of erythropoietin (Beguin, 1995). Additional factors contributing to anaemia in multiple myeloma patients may include bone marrow infiltration by malignant cells, reduced survival of red blood cells (RBCs), chronic renal insufficiency, cytokine production and the myelosuppressive effects of chemotherapy. Anaemia can result in fatigue, exhaustion, dizziness, depressed mood, impaired cognitive function, respiratory distress, cardiac decompensation and other symptoms that impair function and diminish patient quality of life (QOL) (Winningham et al, 1994; Cella, 1998; Ludwig & Fritz, 1998; Schwartz, 1998).
In most patients with multiple myeloma, anaemia improves when the disease responds to chemotherapy (San Miguel et al, 1999). In cases where this does not occur or chemotherapy is not required, treatment options for anaemia are blood transfusions or the administration of recombinant human erythropoietin (rHuEPO, epoetin alfa). Blood transfusions are associated with several serious, albeit infrequent, risks (e.g. allergic reactions, infection, iron overload), and epoetin alfa is thus an appealing alternative (Ludwig & Fritz, 1998; Goodnough et al, 1999). A glycoprotein hormone, epoetin alfa increases the production of RBCs by stimulating the expansion of erythroid progenitor cells and decreasing apoptosis of erythroid burst-forming unit cells and granulocyte colony-forming unit cells (San Miguel et al, 1999). Clinical studies have demonstrated that epoetin alfa can prevent or ameliorate anaemia and reduce transfusion requirements in anaemic patients with a variety of cancers, including multiple myeloma (Ludwig et al, 1990, 1993; Abels, 1992; Barlogie & Beck, 1993; Leitgeb et al, 1994; Dunphy et al, 1997; Mittelman et al, 1997; Musto et al, 1997; Dammacco et al, 1998). Furthermore, several studies with a combined total of nearly 5000 evaluable patients have shown that correction of anaemia with epoetin alfa can improve the QOL in patients with cancer (Ludwig et al, 1990; Abels, 1992; Leitgeb et al, 1994; Glaspy et al, 1997; Mittelman et al, 1997; Demetri et al, 1998).
The study presented here evaluated the efficacy of epoetin alfa in correcting anaemia in patients with multiple myeloma, thereby decreasing transfusion requirements. Additionally, patients were monitored for changes in haemoglobin (Hb) levels and in performance status and improvements in QOL.
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- Patients and methods
Patients with multiple myeloma, particularly those who are chemotherapy refractory or chemotherapy resistant, often require correction of disease- or chemotherapy-related anaemia. In the double-blind, placebo-controlled study reported here, administration of epoetin alfa, compared with placebo, significantly (P = 0·017) reduced transfusion requirements and increased Hb levels by ≥ 2 g/dl in significantly more patients than did placebo (57·6% vs. 9·1%, P < 0·001). The increase in Hb levels in the placebo group presumably was due at least in part to the higher transfusion rate in this group, possibly in combination with disease response to chemotherapy.
These results further support those of other clinical studies that have documented the efficacy of epoetin alfa in increasing Hb levels and reducing transfusion requirements in anaemic patients with non-myeloid malignancies, including multiple myeloma (Abels, 1993; Ludwig et al, 1993, 1995; Dunphy et al, 1997; Glaspy et al, 1997; Demetri et al, 1998). Several studies were conducted specifically in multiple myeloma patients who had received or were receiving chemotherapy for advanced or longstanding disease and had severe anaemia. In two of these studies, response to epoetin alfa, defined in those studies as an increase of 2 g/dl or more in Hb level, was noted in 85% (11/13) (Ludwig et al, 1990) and 71% (12/17) (Mittelman et al, 1997) of patients, and transfusion requirements were completely eliminated in at least 77% (≥ 10/13) and 55% (6/11) of patients respectively.
The haematological benefits of epoetin alfa were also observed in patients with progressive multiple myeloma who were considered resistant or refractory to chemotherapy. Patients in two controlled, comparative studies were randomized to either epoetin alfa treatment or no epoetin alfa treatment (control group) (Silvestris et al, 1995; Dammacco et al, 1998). Patients were also stratified by transfusion requirements. In one of the studies, a significantly (P ≤ 0·001) greater percentage of patients who received epoetin alfa (75%), compared with control patients (21%), had increased Hb levels and/or reduced transfusion requirements, regardless of prestudy transfusion history (Dammacco et al, 1998). In the second study, 78% (21/27) of patients who received epoetin alfa had an increase in Hb of ≥ 2 g/dl; 55% (6/11) of evaluable patients transfused before study entry no longer required transfusions after 2 months of epoetin alfa treatment (Silvestris et al, 1995).
A small proportion of patients, i.e. those with smouldering multiple myeloma or non-responding, non-progressive myeloma, have asymptomatic disease and therefore should not receive chemotherapy (San Miguel et al, 1999). However, these patients often develop anaemia serious enough to require intervention, and may be treated with chemotherapy because of the anaemia. In a report of a study that included three patients with smouldering multiple myeloma, use of epoetin alfa to ameliorate anaemia in these patients, who were asymptomatic and had never received chemotherapy, allowed postponement of chemotherapy for 6 months in one patient and, as of the report date, 42 months in another patient (Garton et al, 1995). Thus, the use of epoetin alfa may obviate, at least temporarily, the need for some patients to start chemotherapy.
Changes in functional status and QOL in the study reported here were secondary efficacy assessments, and the study was not powered to measure absolute change, but rather statistical trends. Despite this limitation, analysis of within-group changes from baseline to week 12 revealed significant (P = 0·05 to P < 0·001) improvement in emotional reactions, social interaction, energy and ability to do daily activities in patients treated with epoetin alfa. Placebo-treated patients, in contrast, showed no significant improvement except in sleep. Between-group differences in effect on QOL were not detected. However, the overall change in performance scores, which was indicative of improvement, was significantly greater for patients who received epoetin alfa compared with placebo. Coupled with this finding was a two-point deterioration in performance score for more patients who received placebo compared with those who received epoetin alfa. In all, nearly 20% of epoetin alfa-treated patients experienced improved performance during the double-blind phase, compared with 6% of placebo-treated patients. These findings are consistent with those of several earlier studies that reported enhancement of functional capacity and QOL when cancer patients, including those with multiple myeloma, were treated with epoetin alfa to alleviate their anaemia (Ludwig et al, 1990; Abels, 1992; Leitgeb et al, 1994; Glaspy et al, 1997; Mittelman et al, 1997; Demetri et al, 1998). These studies generally had large patient populations (Abels, 1992; Glaspy et al, 1997; Demetri et al, 1998) or specifically evaluated QOL (Leitgeb et al, 1994) and used a variety of validated instruments to measure changes in functional capacity and QOL. In three of the studies, epoetin alfa therapy resulted in significant (P < 0·05 to P < 0·001) improvement in several measures of QOL including energy, activity, feeling of well-being and overall QOL (Leitgeb et al, 1994; Glaspy et al, 1997; Demetri et al, 1998). Another study in this series, a small (n = 13), open-label trial conducted in multiple myeloma patients only, reported QOL changes as a heightened sense of well-being and increase in exercise tolerance, which were reflected by significant (P < 0·02) changes in performance scores (Ludwig et al, 1990).
When placebo patients were given epoetin alfa in the open-label phase of the study reported here, trends towards improvement were noted in most QOL variables, although no statistically significant changes were discerned in any parameter. That no significant changes in QOL were reported in these 45 patients is not surprising, given the relatively small patient number on which this analysis was based. However, as in the double-blind phase of the study, administration of epoetin alfa during the open-label phase resulted in improvement in performance scores, with about 22% of patients experiencing increased performance – a rate comparable to that noted in patients who received epoetin alfa for the 12 weeks of double-blind treatment. Also, during the open-label phase, performance scores remained stable for more than half the patients who continued to receive epoetin alfa (59·5%), as well as for those who had previously received placebo (53·3%), while worsening in 23·8% and 20·0% of patients in the respective treatment groups. These findings suggest that epoetin alfa may be useful in both improving and maintaining QOL in multiple myeloma patients.
This study did not address the length of time epoetin alfa should be continued before a decision is made to discontinue treatment because of the improbability of the patient achieving a therapeutic response. However, the maximum times to response were 88 d for an Hb increase of ≥ 2 g/dl and 83 d for an Hb increase of ≥ 12 g/dl. These times were similar to the maximum of 84 d for an Hb level increase of ≥ 2 g/dl, haemoglobin level of ≥ 12 g/dl or both, reported in a large, community-based study that included nearly 2300 evaluable patients (Demetri et al, 1998). In the small study mentioned earlier, the maximum time to response was approximately 140 d (Ludwig et al, 1990). Based on these data, an estimated trial of epoetin alfa for 3–4 months would seem reasonable.
Epoetin alpha was well tolerated; adverse events were similar between the active drug and placebo groups during double-blind treatment and remained relatively constant and comparable during open-label treatment.
In conclusion, the results of this study provide further evidence that epoetin alfa is an effective and well-tolerated agent for the management of myeloma-associated anaemia. Benefits include prevention or amelioration of anaemia, reduction in transfusion requirements and improvement in QOL.