A Role for Interferon After High-Dose Chemotherapy for Myeloma
ABSTRACT & COMMENTARY
Synopsis: In this report, 84 patients with myeloma received high dose chemotherapy and most were rescued with autologous stem cells. The complete remission rate was 76%. After hematological recovery, one half the patients were randomly assigned to receive interferon-alpha while the other half were observed. Median remission was longer and survival at 52 months was greater for the interferon-treated patients. Thereafter, relapses were frequent and survival was comparable in both groups. Interferon may be a useful adjunct to high-dose therapy for selected patients with this disorder.
Source: Cunningham D, et al. A randomized trial of maintenance interferon following high-dose chemotherapy in multiple myeloma: Long-term follow-up results. Br J Haematol 1998;102:495-502.
Interferon-alpha has been studied extensively in the treatment of multiple myeloma. In general, interferon appears to add little to combination chemotherapy in either remission induction or maintenance of remission. However, the use of high-dose chemotherapy with autologous stem cell reconstitution is increasing in the disease and it is possible that interferon would be more effective in the maintenance setting following therapy that is more effective at tumor cell cytoreduction than conventional dose chemotherapy.
Eighty-four patients with multiple myeloma were treated with high-dose chemotherapy and then randomly assigned to receive maintenance interferon-alpha or no maintenance. The interferon dose was 3 ´ 106 units/m2 subcutaneously, three times weekly until relapse. The patients were those that presented over a three-year period (1988-1991). All patients (younger than 70 years) who met the established criteria for multiple myeloma and who provided informed consent were entered into study. Induction treatment consisted of vincristine, doxorubicin, and methyl prednisilone (VAMP), and VAMP plus cyclophosphamide (C-VAMP) subsequently. Cycles were repeated until a maximum response was achieved. Six weeks later, patients were evaluated for autologous marrow stem cell support. Bone marrow was harvested and patients received melphalan 200 mg/m2 (or 100 mg/m2 if there was evidence of renal insufficiency). Twelve patients had more than 20% plasma cells in the marrow at the time of harvesting and these patients received melphalan alone (140 mg/m2), without stem cell rescue. After hematological recovery, patients were randomly assigned to either receive interferon or not.
Conventional dose induction therapy produced a complete remission (CR) in 16 patients, a partial response (PR) in 38, and no response in 15. At the end of the high-dose therapy, all of the CR patients remained in CR, 38 of the 48 with PR achieved CR, and 11 of the 15 with no response at induction also attained criteria for CR. Thus, the overall CR rate was 76% (65 of 84). At the time of randomization, there were equal numbers of early, late, and non-responders in both the interferon and non-interferon groups.
At 5.8 years following the accrual of the last patient, 38 patients had died (17 in the interferon arm, 21 in the control arm). The median, progression-free survival was 46 months for the interferon-treated patients compared to 27 months in the controls. Overall survival and progression-free survival were significantly better for the interferon-treated patients at 52 months, but subsequent relapses increased in the interferon group, and progression-free survival and overall survival were no longer different between the two arms.
Despite the introduction of high-dose therapies with or without bone marrow or stem cell rescue, most currently believe that multiple myeloma is an incurable illness.1 However, these new approaches have resulted in higher remission rates, longer remission durations, and improved survival for selected patients, and the value of this approach seems to justify the toxicity and expense.2 Given the apparent improvement in tumor cytoreduction from high-dose therapy, it is possible that maintenance therapy following high-dose therapy would be more effective than maintenance delivered after conventional dose therapy. Interferon could be more effective against microscopic disease than against macroscopic disease.3
Other investigators have used interferon after high-dose therapy for myeloma,4,5 but this report is the first of a randomized study in this setting. The delay in relapse and the better median survival for those treated proves the effectiveness of interferon. Treatment, however, did not result in more long-term survivors, and it does not appear that the survival curve will reach a plateau suggesting that a subset of patients have been cured.
The study was not blinded and the controls were observed without placebo injections. Furthermore, when those patients who received no maintenance therapy relapsed, they were subsequently treated with interferon. Thus, the interpretation of survival data is not clear. Nevertheless, the time-to-relapse data are clear and the use of interferon treatment after high-dose therapy improved survival.
This was a relatively small study, but the results are intriguing. A larger, multi-institutional investigation addressing the same question might discriminate whether one or more particular myeloma prognostic subgroups would be most likely to benefit. Furthermore, other cytokines or anti-cytokines (of particular interest would be agents that interfere with IL-6) with or without interferon might also be useful under these circumstances.