Interferon-{alpha} as maintenance therapy in patients with multiple myeloma

C. G. Schaar1,*, H. C. Kluin-Nelemans2, C. te Marvelde3, S. le Cessie4, W. P. Breed5, W. E. Fibbe6, W. A. van Deijk7, M. M. Fickers8, K. J. Roozendaal9, P. W. Wijermans10 On behalf of the Dutch-Belgian Hemato-Oncology Cooperative Group HOVON

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


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: The effect of interferon-{alpha} 2b (IFN-{alpha}-2b) on progression-free and overall survival as well as quality of life (QoL) was studied in mainly elderly patients with multiple myeloma (MM), who reached a plateau phase after melphalan/prednisone induction.

Patients and methods: In an open phase III trial, 262 patients, median age 69 years (range 34–91), 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-{alpha}-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 (0–140) for those patients alive, IFN-{alpha}-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-{alpha} 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-{alpha}, maintenance therapy, multiple myeloma


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In recent years the treatment modalities available for multiple myeloma (MM) have extended enormously. High-dose melphalan supported by autologous stem-cell transplantation has become standard therapy for patients up to the age of 70 years. Allogeneic and especially non-myeloablative transplantations are being explored in the same age group. New anti-myeloma agents include immunomodulatory drugs (thalidomide, CC15013) and the proteosome inhibitor bortezomib [1Go]. All these treatment options have to be incorporated into studies to determine their value and place in the treatment of MM. Because stem-cell transplantation is often not a viable option for patients >70 years old with MM, melphalan and prednisone (MP) remains the standard therapy for this age group [1Go]. Prior to the recent development in therapies mentioned, interferon-{alpha} (IFN-{alpha}) was investigated in the treatment of MM. Two methodologically different meta-analyses on this subject, one using individual patient data [2Go] and the other using the results of published studies [3Go], reported increases in both progression-free (PFS) and overall survival (OS) when IFN-{alpha} was used either during induction or as maintenance therapy for MM [2Go, 3Go]. As IFN-{alpha} might still be of value in the treatment of MM when transplantation is not an option, we investigated the data from the HOVON-16 phase III trial, in which IFN-{alpha}-2b maintenance therapy was compared with no maintenance therapy after plateau phase was reached with MP in mainly elderly patients with MM. With a long follow-up of 8 years for those alive, mature data were obtained. The primary end points were the PFS and OS; the secondary end point was quality of life (QoL).


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Between September 1991 and September 1997, 31 HOVON centers entered patients with newly diagnosed MM (stage IB, IIA, II B, IIIA and IIIB) and a measurable M-protein in serum or urine. The diagnostic and staging criteria according to Durie and Salmon [4Go] were used. No previous treatment with either chemotherapy or IFN-{alpha} was allowed.

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-{alpha}-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-{alpha}-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 [5Go]. 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 Kaplan–Meier 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 {chi}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 {alpha}=0.05 and a power of 0.90, a sample size of 40 patients per treatment arm was considered sufficient.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients characteristics
During September 1991 to September 1997, 282 patients from 31 HOVON centers were entered in the study. Twenty patients were not eligible, mainly due to the absence of a good disease parameter: stage IA (six patients), non-secretory MM (12) and insufficient data (two). The median follow-up of all patients from start therapy was 30 months (range 0–140), and 97 months (0–140) for those alive. The median follow-up from randomization was 41 months (range 0–131) for all patients, and 78 months (range 33–131) for those alive. All data presented here are based upon the 262 evaluable patients (intention-to-treat), although eight patients actually did not receive any therapy (six died before receiving any therapy, one patient refused therapy after registration, one patient was lost to follow-up shortly after the first course of therapy) and 10 were not evaluable for response (mainly insufficient data available). Patient characteristics are given in Table 1.


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Table 1. Patients' characteristics

 
Response rate and randomization
Response to MP was achieved in 192 (73%) patients, and 16 additional patients had some regression of their M-protein (>15% but <25%). The overall response rate was 79%. No response or progression under MP was seen in, respectively, 23 (9%) and 11 (4%), whereas 56 (21%) showed a response but progressed again during the first 10 months of MP therapy. Out of the 262 patients, 128 (49%) reached a plateau phase, and of those only 90 patients could be randomized. Reasons for non-randomization of these 38 patients were: refusal (18), concomitant disease (nine), protocol violation (six), WHO performance status >2 (four) and allogeneic transplantation (one). In total, 46 patients received IFN-{alpha}-2b and 44 patients no maintenance therapy; the two groups were similar in terms of sex, age and disease stage.

Response duration
The median PFS from randomization for patients randomized to IFN-{alpha}-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-{alpha}-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-{alpha}-2b group versus 21% in the control group.



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Figure 1. Progression-free survival since randomization. The solid curve represents the patients receiving interferon (IFN) maintenance, the broken curve those patients not receiving maintenance therapy.

 
Survival
At the time of evaluation (August 2004), 21 patients were still alive, of whom one was still in the study. In total, 241 patients died, of whom 169 of MM, 70 due to other causes, one patient due to MP-related toxicity and in one patient the cause of death was unknown. The median OS of the whole patient group (n=262) was 35.1 months (95% CI 28.9–41.4) from the date of diagnosis (Figure 2), and 29.9 months (95% CI 23.4–36.4) from start of MP therapy. For patients with IgG, IgA and Bence–Jones M-protein, the median survival from start of therapy was 33.4, 22.9 and 20.2 months, respectively. Survival from randomization showed an advantage for patients treated with IFN-{alpha} during the first years, but later survival seemed to be similar to those patients who did not receive IFN-{alpha} (Figure 2). Median survival from randomization was equal, being 41 and 38.4 months, respectively, which demonstrates that the better PFS did not translate in a better OS. The median OS from diagnosis of those patients who reached plateau phase but could not be randomized was 42.8 months (95% CI 34.5–51.1), versus 53.5 months (95% CI 43.1–64) for patients treated with IFN-{alpha} and 50.2 months (95% CI 30.9–69.5) for the control group.



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Figure 2. Survival since randomization. The solid curve represents the patients receiving interferon (IFN) maintenance, the broken curve those patients without maintenance therapy.

 
Toxicity
Toxicity was evaluated in the 254 patients who actually started induction therapy, of whom 17 (7%) had to end MP therapy because of toxicity. Myelotoxicity leading to dose modification and/or treatment delay in the first five MP cycles was observed in 155 patients (61%). One patient died (0.3%) due to neutropenic sepsis. Treatment with IFN-{alpha} was experienced as toxic, because 17 (37%) patients had to stop because of adverse events. The reasons why patients went off study are shown in Table 2.


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Table 2. Reasons for going off study

 
Quality of life
The QoL score could be calculated up to 3 years after randomization. Data are visualized in Figure 3. The score for physical well being started at 20 points (out of a range of 0 to 100, a score of 0 meaning no complaints at all), and although there was a slight increase in time there was no difference between the two groups (P=0.32). The score for psychological/emotional well-being started also at a score of 20 (out of a range of 0 to 100, a score of 0 meaning no complaints at all) and showed some fluctuations in time, but there was no difference between the two groups (P=0.71). There was hardly any fluctuation in the score for daily activity. Both groups started at a score of 20 (out of a range of 0 to 100, a score of 0 reflecting complete normal functioning) and ended after 3 years at almost the same score without any significant difference (P=0.77).



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Figure 3. Estimated mean quality of life scores with 95% confidence interval. The solid curve represents the patients receiving interferon (IFN) maintenance, the broken curve those patients not receiving maintenance therapy. All scales are transformed into 0–100, such that a lower score implies better functioning or well-being.

 

    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In this study we demonstrated that only one-third of typical elderly MM patients were candidates for IFN-{alpha} as maintenance therapy. Of these patients, more than one-third had to stop therapy due to its toxicity. This means that only a minority could receive this kind of maintenance treatment for a longer period. It is thus remarkable that in the small groups studied, a significant PFS was seen in favor of those patients who received IFN-{alpha}. This did not translate in a better OS, most likely because the groups were too small to detect minor differences.

IFN-{alpha} maintenance therapy in MM has yielded conflicting results, as was recently addressed in a review on therapy in MM [6Go]. Two methodologically different meta-analyses on the subject of IFN-{alpha} treatment in MM have been performed investigating nearly the same data of all randomized trials on this subject [2Go, 3Go]. 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-{alpha} maintenance therapy (7 months) [2Go]. However, the survival from progression was worse in the IFN-{alpha}-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-{alpha} treatment arms [3Go]. Both meta-analyses demonstrated a benefit of IFN-{alpha}, whether it was used during induction or maintenance therapy. The greatest benefit was seen in IFN-{alpha} maintenance therapy with an OS of 7 months [2Go] and 3.1 months [3Go], compared with a prolongation of the OS of 2.4 months [3Go] and 2 months [2Go] 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 [2Go], and OS by 4 [2Go] and 3.7 months [3Go].

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 [7Go]. Also in our study, a substantial number of patients discontinued IFN-{alpha} therapy. Ludwig et al. [8Go] 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 [9Go]. On the other hand, in the Nordic QoL study in patients who received chemotherapy in combination with IFN-{alpha}, the reduction of the QoL was not considered by patients to justify the positive effect of IFN-{alpha} [10Go].

We conclude therefore that although improvement of the PFS and sometimes also OS can be observed when patients with MM receive IFN-{alpha} as maintenance therapy after standard MP treatment, many will never be eligible for this kind of immunotherapy. However, those patients that tolerate IFN-{alpha} maintenance therapy can derive benefit in terms of substantial prolongation of both PFS and OS. Evidently, one must conclude that IFN-{alpha} 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.


    Acknowledgements
 
List of participating centers: Onze Lieve Vrouwe Gasthuis, Amsterdam, Dr K. J. Roozendaal; Slotervaart Hospital, Amsterdam, Dr M. Soesan; Free University Hospital, Amsterdam, Professor Dr P. C. Huijgens; University Medical Center Amsterdam, Amsterdam, Professor Dr R. van Oers; Jeroen Bosch Hospital, ‘s-Hertogenbosch, Dr H. A. M. Sinnige, Dr P. A. van Liessum; Hospital Gooi Noord, Blaricum, Dr H. P. Mulder; Amfia Hospital, Breda, Dr A. Holdrinet Brunssum; Atrium Medical Center, Breda, Dr J. Wals, Dr M. M. F. Fickers; Leyenburg Hospital, The Hague, Dr P. W. Wijermans; Red Cross Hospital, The Hague, Dr W. A. van Deyk; Haaglanden Medical Center, The Hague, Dr E. J. Buurke, Dr M. G. Herben; Reinier de Graaf Hospital, Delft, Dr E. Maartense; Deventer Hospital, Deventer, Dr Th. M. Brouwer; Catharina Hospital, Eindhoven, Dr W. Breed; Diaconessen Hospital, Eindhoven, Dr J. A. van Marion-Kievit; Groene Hart Hospital, Gouda, Dr K. J. Heering; St Jansdal Hospital, Harderwijk, Dr P. J. C. Zoon; Elkerliek Hospital, Helmond, Dr P. H. Th Koch; Regional Hospital Midden Twente, Hengelo, Dr H. Dankbaar; Leiden University Medical Center, Leiden, Dr W. Fibbe; Rijnland Hospital, Leiderdorp, Dr F. H. M. Cluitmans; Academic Hospital Maastricht, Maastricht, Dr E van Pampus; St Radboud Hospital, Nijmegen, Dr A. J. Croockewit; Medical Spectrum Twente, Oldenzaal, Dr A. H. O. D. Hovink; St Franciscus Hospital, Rotterdam, Dr J. G. Pegels; Maasland Hospital, Sittard, Dr F. L. G. Erdkamp; Bernhoven Hospital, Veghel, Dr L. H. van Hulsteyn; Maxima Medical Center, Veldhoven, Dr G. Vreugdenhil; St Jans Hospital, Weert, Dr J. G. S. Breed; Hospital De Heel, Zaandam, Dr van Bochove; Lange Land Hospital, Zoetermeer, Dr A. Folmer.

Received for publication September 14, 2004. Revision received November 22, 2004. Accepted for publication December 1, 2004.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Barlogie B, Shaughnessy J, Tricot G et al. Treatment of multiple myeloma. Blood 2004; 103: 20–32.[Abstract/Free Full Text]

2. The Myeloma Trialists' Collaborative Group. Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients. Br J Haematol 2001; 113: 1020–1034.[CrossRef][ISI][Medline]

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7. The Nordic Myeloma Study Group. Interferon-alpha 2b added to melphalan-prednisone for initial and maintenance therapy in multiple myeloma. A randomized, controlled trial. Ann Intern Med 1996; 124: 212–222.[Abstract/Free Full Text]

8. Ludwig H, Cohen AM, Polliack A et al. Interferon-alpha for induction and maintenance in multiple myeloma: results of two multicenter randomized trials and summary of other studies. Ann Oncol 1995; 6: 467–476.[Abstract]

9. Zee B, Cole B, Li T et al. Quality-adjusted time without symptoms or toxicity analysis of interferon maintenance in multiple myeloma. J Clin Oncol 1998; 16: 2834–2839.[Abstract]

10. Wisloff F, Eika S, Hippe E et al. Measurement of health-related quality of life in multiple myeloma. Nordic Myeloma Study Group. Br J Haematol 1996; 92: 604–613.[CrossRef][ISI][Medline]