1Department of Internal Medicine, Gelre Hospitals, Apeldoorn; 2Department of Hematology, University Medical Center, Groningen; 3Comprehensive Cancer Center West, Leiden; Departments of 4 Medical Statistics and 6 Hematology, Leiden University Medical Center, Leiden; 5 Department of Internal Medicine, Catharina Hospital, Eindhoven; 7 Department of Internal Medicine, Rode Kruis Hospital, The Hague; 8 Department of Internal Medicine, Atrium Medical Center, Heerlen; 9 Department of Internal Medicine, Onze Lieve Vrouwe Gasthuis, Amsterdam; 10 Department of Hematology, Leyenburg Hospital, The Hague, The Netherlands
* Correspondence to: Dr C. G. Schaar, Department of Internal Medicine, Gelre Hospitals, PO Box 9014, 7300 DS Apeldoorn, The Netherlands. Tel: +31-55-5818163; Fax: +31-55-5818170; Email: c.schaar{at}gelre.nl
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Abstract |
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Patients and methods: In an open phase III trial, 262 patients, median age 69 years (range 3491), received at least 10 monthly courses of melphalan/prednisone followed by response evaluation. Plateau phase was reached by 128 patients. Next, 90 patients were randomized between IFN--2b and no maintenance therapy. Reasons for non-randomization were: refusal (18), concomitant disease (nine), protocol violation (six), WHO performance status >2 (four) and allogeneic transplantation (one)
Results: At a median follow-up from diagnosis of 97 months (0140) for those patients alive, IFN--2b therapy was associated with improved progression-free survival (median 13.5 versus 8.4 months from randomization), although this did not translate in a better overall survival (41 versus 38.4 months). One-third of patients discontinued IFN-
due to toxicity. No differences were observed between patient groups in QoL.
Conclusions: IFN maintenance therapy in MM prolongs progression-free survival and, provided that the burden of toxicity is not too high, does not adversely affect QoL.
Key words:
interferon-, maintenance therapy, multiple myeloma
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Introduction |
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Patients and methods |
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Study design
All patients received induction with MP. Melphalan was given at a dose of 0.25 mg/kg for 5 days and prednisone 1 mg/kg for 5 days every 4 weeks. The minimal time of treatment with MP was 10 months, even if a plateau phase was reached earlier. If after 10 months of treatment a further response was seen, treatment with MP had to be given until a plateau phase was reached. Patients in plateau phase were candidate for randomization between IFN--2b or no further maintenance therapy. Patients who showed no response or who showed a relapse of their disease within 10 months after an initial response went off study.
IFN--2b was started at a fixed dose of 3 MU three times per week and was given till disease progression was observed. When WHO hematological grade 3 toxicity was encountered dose reduction to 50% was mandatory, and in case of grade 4 toxicity IFN had to be stopped.
Definition of disease progression and response to treatment
Response to treatment was defined as >25% regression of the M-protein. A plateau phase was reached when the mean M-protein level of the last 2 months was at least 15% lower than the mean M-protein level of the preceding 2 months. Disease progression was defined as an increase of >25% of the mean M-protein level of the last 2 months compared with the mean M-protein level of the preceding 2 months, or progression of osteolytic lesions, hypercalcemia and/or (progression of) transfusion requirement. In case of disease progression or relapse, further therapy was given according to the discretion of the responsible physician.
Quality of life
For the QoL analysis the Rotterdam Symptom Checklist (RSCL) was used [5]. The RSCL measures psychological and physical distress as experienced by cancer patients and scores for the most important three items, namely (i) physical and (ii) emotional capability, and (iii) performance of normal daily activities. This questionnaire was completed every 3 months by patients who were randomized after they reached plateau phase and enabled us to score the QoL of the three items in time. All the individual scores were calculated on a scale from 0 to 100, such that a lower score implies a better functioning or well-being.
Statistical methods
This report contains all the data as they were available on May 2004. Response data are presented an intention-to-treat basis (n=262) or on the basis of those patients who actually received any therapy (n=254). All the survival analyses were performed using KaplanMeier plots and log-rank tests. Median survival estimates were calculated with 95% confidence intervals (95% CIs). In the calculation of PFS, patients who died without progression were censored. Response rates were compared using 2-tests. The mean QoL values at different time-points were estimated using a linear mixed model and the QoL scores were compared by testing the significance of the interaction between treatment arm and time. In this way account was taken of missing measurements due to the drop out of patients. The sample size was calculated as follows: a mean ± SD PFS from randomization of 9 ± 3 months was expected. An increase of 50% of this PFS was considered as clinical useful. To show such a difference with
=0.05 and a power of 0.90, a sample size of 40 patients per treatment arm was considered sufficient.
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Results |
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Response duration
The median PFS from randomization for patients randomized to IFN--2b was 13.5 months, whereas those patients who did not receive any maintenance therapy showed a median PFS of 8.4 months (P=0.04) (Figure 1). The PFS at 3 years was 25% in the IFN-
-2b group and only 4% in the control group. The median PFS from diagnosis for patients randomized was 27.3 and 20 months, respectively (P=0.01). At 3 years after diagnosis, the PFS was 36% in the IFN-
-2b group versus 21% in the control group.
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Discussion |
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IFN- maintenance therapy in MM has yielded conflicting results, as was recently addressed in a review on therapy in MM [6
]. Two methodologically different meta-analyses on the subject of IFN-
treatment in MM have been performed investigating nearly the same data of all randomized trials on this subject [2
, 3
]. The meta-analysis of the Myeloma Trialists' Collaborative Group used individual patient data and observed a similar PFS to this study. In this meta-analysis, the OS was better in patients treated with IFN-
maintenance therapy (7 months) [2
]. However, the survival from progression was worse in the IFN-
-treated patients, which may also explain why the better PFS of our patients did not lead to a better OS. The meta-analysis by Fritz and Ludwig used published data instead of individual patient data and also reported a benefit for the IFN-
treatment arms [3
]. Both meta-analyses demonstrated a benefit of IFN-
, whether it was used during induction or maintenance therapy. The greatest benefit was seen in IFN-
maintenance therapy with an OS of 7 months [2
] and 3.1 months [3
], compared with a prolongation of the OS of 2.4 months [3
] and 2 months [2
] when IFN was used during induction therapy. For all patients (IFN-induction and IFN maintenance therapy combined) the PFS was prolonged by, respectively, 6 and 4.6 months [2
], and OS by 4 [2
] and 3.7 months [3
].
IFN as maintenance therapy is associated with a wide range of possible serious side-effects, especially in elderly patients. In the Nordic Myeloma Study with patients between 55 and 81 years, >50% had to reduce the dose of IFN or had to stop treatment completely [7]. Also in our study, a substantial number of patients discontinued IFN-
therapy. Ludwig et al. [8
] have shown, in a cohort of 355 US myeloma patients, that 58% of them were willing to undergo this kind of potential toxic therapy if a 6 months gain of PFS or OS could be expected. In the Canadian study on the role of IFN maintenance therapy, patients treated with IFN experienced substantial toxicity, but also in this study patients indicated that the clinical benefits of IFN outweighed these negative effects [9
]. On the other hand, in the Nordic QoL study in patients who received chemotherapy in combination with IFN-
, the reduction of the QoL was not considered by patients to justify the positive effect of IFN-
[10
].
We conclude therefore that although improvement of the PFS and sometimes also OS can be observed when patients with MM receive IFN- as maintenance therapy after standard MP treatment, many will never be eligible for this kind of immunotherapy. However, those patients that tolerate IFN-
maintenance therapy can derive benefit in terms of substantial prolongation of both PFS and OS. Evidently, one must conclude that IFN-
does play a role in the treatment of these patients, and should be investigated further alongside with the most recent therapeutic advances in the treatment for MM.
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Acknowledgements |
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Received for publication September 14, 2004. Revision received November 22, 2004. Accepted for publication December 1, 2004.
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References |
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