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Interferon-α 2b Added to Melphalan-Prednisone for Initial and Maintenance Therapy in Multiple Myeloma: A Randomized, Controlled Trial

Martin Hjorth, MD, PhD; Jan Westin, MD, PhD; Inger Marie S. Dahl, MD, PhD; Peter Gimsing, MD, PhD; Erik Hippe, MD, PhD; Erik Holmberg, MSc; Jon Lamvik, MD, PhD; Johan Lanng Nielsen, MD, PhD; Eva Lofvenberg, MD, PhD; Ilmari P. Palva, MD, PhD; Stig Rodjer, MD, PhD; Ingebrigt Talstad, MD, PhD; Ingemar Turesson, MD, PhD; Finn Wisloff, MD, PhD; and Goran Zador, MD, PhD
[+] Article and Author Information

The Nordic Myeloma Study Group* Grant Support: In part by Schering-Plough, Sweden, Norway, and Denmark. Requests for Reprints: Martin Hjorth, MD, PhD, Department of Medicine, Lidkoping Hospital, S-53185 Lidkoping, Sweden. Current Author Addresses: Dr. Hjorth: Department of Medicine, Lidkoping Hospital, S-53185 Lidkoping, Sweden.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1996;124(2):212-222. doi:10.7326/0003-4819-124-2-199601150-00004
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Objective: To evaluate the addition of low-dose interferon-α2b to standard melphalan-prednisone therapy in patients with multiple myeloma.

Design: Randomized, multicenter, phase III study.

Setting: 15 university hospitals and 92 county hospitals in Sweden, Norway, Denmark, Finland, and Iceland.

Patients: 583 patients with symptomatic multiple myeloma.

Intervention: All patients received melphalan-prednisone every 6 weeks. Melphalan-prednisone therapy was interrupted after at least 8 courses in responding patients who achieved a plateau phase, and it was reinstituted at time of relapse. Patients randomly assigned to receive melphalan-prednisone and interferon also received interferon, 5 MU three times weekly, from the start of treatment through response, plateau phase, and relapse, until definitive failure of melphalan-prednisone occurred.

Measurements: Survival was the main outcome measure. Secondary measures were response rate, response and plateau phase duration, and toxicity. All analyses were done according to the principle of intention-to-treat.

Results: 45% of patients receiving melphalan-prednisone and 44% of patients receiving melphalan-prednisone and interferon achieved at least a partial response. Response duration and plateau phase duration were longer for patients receiving melphalan-prednisone and interferon than for patients receiving melphalan-prednisone alone (P < 0.05); the difference in median duration was 5 to 6 months. Toxicity was higher with melphalan-prednisone and interferon, and this led to premature discontinuation of interferon therapy in one third of patients and to a reduced overall dose intensity for melphalan. The median survival time was 29 months for patients receiving melphalan-prednisone and 32 months for patients receiving melphalan-prednisone and interferon. The risk ratio for death for patients receiving melphalan-prednisone compared with patients receiving melphalan-prednisone and interferon was 1.02 (95% CI, 0.89 to 1.40).

Conclusions: Adding continuous low-dose interferon to standard melphalan-prednisone therapy does not improve response rate or survival. However, response duration and plateau phase duration are prolonged by maintenance therapy with interferon.

*For a listing of members of the Nordic Myeloma Study Group, see the Appendix.

Figures

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Figure 4.
Dose intensity of interferon (IFN).

The columns show, at 6-month intervals, the proportion of patients on study who were still receiving continuous interferon therapy and at what dose. tiw equals three times weekly.

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Figure 3.
Toxicity.

Toxicity grades I to IV according to World Health Organization (WHO) criteria during treatment on study with melphalan-prednisone and interferon (MP-IFN) compared with melphalan-prednisone (MP) alone. For each patient, the maximal toxicity grade during treatment on study and only one event for each class of side effects were registered. Gastrointestinal toxicity, cardiovascular events, pulmonary toxicity, and skin reactions are combined as “other adverse events.” CNS equals central nervous system.

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Figure 2.
Survival.nn

Probability of survival for patients treated with melphalan-prednisone and interferon (MP-IFN) ( = 286) and patients treated with melphalan-prednisone (MP) alone ( = 297). RR equals risk ratio.

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Figure 1.
Response and plateau phase duration.

A. Probability of maintaining response for all patients achieving at least partial response. B. Probability of maintaining response for patients achieving only minor response. C. Probability of maintaining plateau phase for patients achieving at least partial response followed by plateau phase. D. Probability of maintaining plateau phase for patients achieving minor response followed by plateau phase. IFN equals interferon; MP equals melphalan-prednisone; RR equals risk ratio for relapse in the MP group compared with the MP-IFN group.

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