Phase II study of interleukin-12 for treatment of plateau phase multiple myeloma (E1A96): A trial of the Eastern Cooperative Oncology Group☆
Introduction
Multiple myeloma (MM) patients who have achieved the so-called plateau phase have stable disease with no need for chemotherapy until relapse. This population with measurable residual disease after completion of chemotherapy may be the most likely to benefit from immunologically targeted therapy. This is based on the premise that the malignant clone is responsive to host immune mediated suppression. Some studies have shown prolongation of remission with use of alpha interferon but the benefit is modest [1], [2], [3], [4], [5], [6], [7]. More recent trials have suggested a benefit using thalidomide [8], an effect that may be in part due to the immunomodulatory effects of thalidomide. New immunoregulatory agents are needed for treatment of plateau phase myeloma.
To determine the efficacy and toxicity of interleukin-12 (IL-12), the Eastern Oncology Cooperative Group (ECOG) conducted a randomized phase II trial of this agent in previously treated patients with plateau phase multiple myeloma. We hypothesized that treatment with IL-12 may help to restore a full repertoire of lymphocytes and may augment vaccine responses. In order to assess this hypothesis, we used a randomized phase II design in which half the patients received IL-12 in conjunction with vaccines against Haemophilus influenza and Streptococcus pneumoniae and half received IL-12 a month following their vaccines. Here we report the clinical results of this trial.
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Methods
To be eligible for this study, patients must have met ECOG criteria for multiple myeloma (MM). Patients must have been in stable plateau as defined by ECOG which requires objective response, no evidence of continuing improvement by any criteria, and <20% variation in M protein over at least 4 weeks prior to registration. Patients must have been off chemotherapy for at least 60 days prior to registration. Patients must have had measurable or evaluable M protein and must have been taken within 14
Results
Fifty-six patients were entered from 14 institutions. Of these 56 patients, 48 eligible patients were included in the analysis. Eight patients were ineligible, one of whom never stared the assigned therapy. Reasons for ineligibility included: not is plateau at study entry (5 patients), no evaluable M protein (3 patients). Ineligible patients were excluded from analysis regarding efficacy but included in the toxicity analysis. At study entry, patients were randomized to two arms. Since the two
Discussion
IL-12 has been used in clinical trials for B cell malignancies. Studies have shown that IL-12 given in conjunction with rituximab for low-grade non-Hodgkin lymphoma is well tolerated and may be associated with longer response duration than previous trials using rituximab alone [11], [12]. IL-12 has also been studied after autologous stem cell transplant for hematological malignancies resulting in the expansion of T, B, and NK cells in vivo[13]. Interleukin-12 alone or with GM-CSF has been used
Conflict of interest
None of the authors have any conflicts of interest.
Acknowledgements
Dr. Lacy: Grant/Research Support: Celgene Corporation, Millennium, The Takeda Oncology Company, and Genzyme.
Contributions. Dr Lacy: served as Principal Investigator; wrote the trial, analyzed data, and wrote the manuscript, Dr. Jacobus: statistician, did data analysis and edited manuscript, Emily Blood: statistician, did data analysis and edited manuscript, Dr. Kay: helped with trial design, conducted and analyzed the laboratory correlates, edited the manuscript, Dr. Rajkumar: helped with data
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This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, M.D.) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA13650 and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.