Thalidomide Should Be Added To The Standard Regimen For Patients With Multiple Myeloma Who Are Unable To Undergo High-Dose Therapy

Main Category: Lymphoma / Leukemia / Myeloma
Article Date: 22 Oct 2007 - 1:00 PDT

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Adding newer agents to a widely used treatment regimen for patients with multiple myeloma who cannot withstand the toxic effects of high-dose therapy is a promising approach for extending survival in this disease, according to a study published in The Lancet, which reports positive results for the inclusion of thalidomide with melphalan and prednisone in elderly patients.

The most successful treatment for multiple myeloma, a cancer of the plasma cells of the bone marrow, involves high doses of chemotherapeutic drugs followed by stem-cell transplantation. However, for many patients diagnosed with this type of cancer, high-dose therapy is not an option because they are either considered too old to withstand the toxic effects of such a treatment or are not eligible for the therapy for other reasons. For these patients, a combination of melphalan and prednisone has been the most widely used treatment for over 40 years. But this intervention results in median survival of just 3 years, so new treatments are desperately needed.

Several research groups have tested alternative drug combinations, involving complex regimens of alkalating agents or other types of drugs, in an effort to improve the survival of non-high-dose-eligible patients. Unfortunately, however, most approaches have proved more toxic than melphalan and prednisone without showing any overall survival benefit. By contrast, thalidomide, which has shown substantial anti-tumour activity in relapsed or refractory myeloma, has also shown some benefit when added to other treatments. But there is little evidence supporting its use in newly diagnosed patients. Another strategy that has been tested for patients unable to undergo high-dose therapy is an intermediate dose of melphalan, rather than the full high dose. Trial results indicate this approach seems to be safe! in patients up to 75 years of age and may be better than melphalan plus prednisone.

To identify which of these possible new treatment options might provide the best alternative to melphalan and prednisone for patients who are unable to undergo high-dose therapy, the Intergroupe Francophone du Myélome initiated a randomised clinical trial comparing three treatment options: the standard treatment of melphalan and prednisone; melphalan and prednisone with thalidomide added; and intermediate-dose melphalan therapy, as a potentially less toxic alternative to high-dose treatment. The researchers' aim was to monitor the effects on overall survival.

A total of 447 patients aged between 65 and 75 years were recruited to the study. All had stage II and III multiple myeloma and had been deemed ineligible for high-dose therapy. 196 were assigned to the first group receiving melphalan and prednisone alone; 125 were also given thalidomide; and 126 were assigned to intermediate-dose melphalan. Those in the first group were given twelve 6-week cycles of drugs, administered orally on 4 days of 7. For the thalidomide arm, the patients were given a daily dose, administered orally and taken every day until completion of the chemotherapy cycles. For the intermediate-dose therapy, patients were first prepared for their melphalan infusion with two lots of chemotherapy to reduce the numbers of myeloma cells in the body and an extra round of treatment to aid h! arvesting of stem cells. The melphalan was given after this process and the harvested stem cells were reinfused 3 days later. Two months later, the treatment was repeated. All patients in all groups received sodium chrondronate to treat their bone lesions throughout their treatment course.

Two preplanned analyses were done: one at 37 months and one at 51.5 months. With a median survival of 51•6 months, the thalidomide-containing regimen was significantly better than both melphalan and prednisone alone (33•2 months) and the intermediate-dose melphalan plus stem-cell support (38•3 months) in terms of overall survival. There was no statistically significant difference between the latter two treatments with respect to survival. Toxic effects showed a different picture, however. In the group receiving thalidomide there was an unexpectedly higher incidence of neutropenia, which exceeded that observed with the melphalan and prednisone, although the incidences of grade 3/4 anaemia or thrombocytopaenia were much the same between the two arms. What is more, the incidence of thromboembolism was! significantly higher for patients assigned to thalidomide than for those assigned to just melphalan and prednisone. Overall, the incidence all non-haematological toxic effects of grade 3 or more was lower with melphalan and prednisone than with either thalidomide or the intermediate dose arm. However, the toxic effects of the thalidomide regimen were counterbalanced by a low incidence of toxic and early deaths.

The researchers concluded that their study "has shown that the addition of thalidomide to standard melphalan and prednisone significantly extended survival for elderly patients with previously untreated multiple myeloma." They suggest that although the toxic effects observed with melphalan and prednisone plus thalidomide were acceptable, efforts should be made to reduce the impact of these symptoms on patients' quality of life through use of a lower dose of drug and shorter treatment durations.

"After 40 years of unsuccessful attempts to find a more effective treatment than the standard melphalan and prednisone, the thalidomide, melphalan, and prednisone combination opens an era of progress for elderly patients with this disease," the authors conclude.

Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial.
Facon T, Mary J-Y, Hulin C, Benboubker L, Attal M, Pegourie B, Renaud M, Harousseau JL, Guillerm G, Chaleteix C, Dib M, Voillat L, Maisonneuve H, Troncy J, Dorvaux V, Monconduit M, Martin C, Casassus P, Jaubert J, Jardel H, Doyen C, Kolb B, Anglaret B, Grosbois B, Yakoub-Agha I, Mathiot C, Avet-Loiseau H, on behalf of the Intergroupe Francophone du Myélome. Lancet 2007; 370: 1209-18

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