Guidelines on the Diagnosis and Management of Multiple Myeloma
6. Interferon
The interferons are a family of compounds produced by leucocytes, fibroblasts and T lymphocytes which have anti-proliferative activity against viruses and human tumour cells. The therapeutic effects of α-interferon (IFNα) have been assessed in myeloma patients at induction, plateau phase, following HDT and in patients with relapse/refractory disease, both as monotherapy and combined with chemotherapy. Most studies have been with recombinant IFNα; the two main types (α2a and α2b) appear clinically indistinguishable.
Induction
IFNα cannot be recommended as monotherapy. Response rates are lower than with alternative therapy (Peest et al, 1996). IFNα has been combined with standard induction chemotherapy in a number of studies and results show no benefit (Cooper et al, 1993) or are conflicting (Avvisati et al, 1995).
A meta-analysis (Myeloma Trialists' Collaborative Group, 2001) has evaluated individual patient data from 2469 patients: in 12 induction trials, complete (17% vs 14%, p = 0.08) and complete plus partial (58% vs 53%, p = 0.01) response rates were slightly better with IFNα. Median progression-free survival was increased by about 6 months with IFNα (p=0.0003), but overall survival was prolonged by only 2 months, and this difference was not statistically significant. A meta-analysis using published data rather than individual patient data yielded similar results, with prolongation of median PFS by about 5 months and OS by 3 months (Fritz and Ludwig, 2000). In a large randomised study, the Nordic myeloma group showed no gain in survival for IFNα in induction and maintenance (Wisloff et al, 1996), and this study also showed a significant reduction in quality of life during the first year of therapy for patients receiving IFNα.
Maintenance
A number of studies have examined the therapeutic role of IFNα maintenance therapy following induction chemotherapy (Mandelli et al, 1990; Westin et al, 1995; Browman et al, 1995; Joshua et al, 1997; Drayson et al, 1998) and autologous transplantation (Cunningham et al, 1998; Bjorkstrand et al, 2001).
A meta-analysis has evaluated individual patient data on 1543 patients in 12 trials (Myeloma Trialists' Collaborative Group, 2001). Progression-free survival (PFS) was again significantly improved in IFNα-treated patients (p = 0.00001), with a prolongation of about 6 months in median PFS, and median OS was also prolonged by about 7 months. Similar results were obtained in the meta-analysis of published data on IFN trials (Fritz and Ludwig, 2000). Median PFS was prolonged by 4 months and OS by 7 months. Retrospective case controlled data from the EBMT registry have suggested significant gains in PFS and OS for interferon treated patients; however such data are non-randomised and subject to selection bias (Bjorkstrand et al, 2001).
Overall, the data do not show significantly better response or survival in any particular patient groups. Trials generally show a greater gain in PFS than in overall survival, suggesting that survival following relapse/progression is shorter among interferon treated patients.
Dosages of IFNα have varied, but no benefit for doses greater than 3MU/m2, 3 x week, sc., has been shown. There are no data on duration of therapy.
Relapsed and refractory disease
IFNα does have activity in primary refractory disease and in relapsed patients. However, response rates are low, and there are no good clinical trial data to guide therapy.Side effects
Most patients experience some side effects, which are significant in up to one third. Flu-like symptoms are common a few hours after each of the initial injections and generally resolve after the first 2-3 weeks of therapy. The symptoms will respond to paracetamol; which should be taken at the time of each initial injection.
Fatigue and depression are recognised side effects of longer term interferon therapy and will resolve on cessation of interferon. Some 20-25% of patients may prove intolerant to interferon therapy.
Conclusion
IFNα has a role in multiple myeloma. Small, statistically significant increases in PFS and OS of up to 6 months are identified in meta-analysis, most clearly observed for patients receiving maintenance therapy following chemotherapy or autologous transplant. However, published data suggest that only 5-10% of myeloma patients achieve a significant gain in survival from IFNα (Blade and Esteve, 2000). Potential benefits must be balanced against possible toxicity and the financial costs of interferon. Cost-utility analysis of IFNα therapy suggests a cost of $50,000-100,000 per quality-adjusted life year gained (Wisloff et al, 1999). There are no clear data on which patients are most likely to benefit, on optimum dose, or duration of therapy.
Recommendations:
- Interferon therapy is not indicated during induction therapy (Grade A recommendation; level 1a evidence)
- Interferon therapy has activity as maintenance therapy during plateau phase following conventional chemotherapy or following HDT (Level 1a evidence) but an unfavourable cost per QALY
- No recommendation can be made regarding duration of treatment
- Careful consideration should be given as to whether interferon should be continued in the face of side effects which impair quality of life (Grade C recommendation; level IV evidence)