Does the addition of thalidomide to MP or low-intensity SCT improve survival in elderly multiple myeloma patients?

Paolo Corradini* and Vittorio Montefusco

This article has no abstract so we have provided the first paragraph of the full text.

After decades of slow progress, the treatment of multiple myeloma is rapidly evolving. In the 1990s the introduction of high-dose melphalan followed by hematopoietic stem-cell transplantation was shown to be beneficial in patients below 65 years of age, but older patients were excluded from such treatment because of an expected excess of morbidity and mortality. The introduction of thalidomide in 1999 further changed the therapeutic approach for patients with multiple myeloma. There are several reasons to combine thalidomide with standard chemotherapy. Firstly, the mechanism of action of thalidomide is very different from that of the standard regimen, because of its direct cytotoxic effect, inhibition of cytokine release, enhancement of T-cell-mediated cytotoxicity, and modification of cellular adhesion molecules.¹ Secondly, the clinical adverse effects of thalidomide, although potentially severe in some cases, are different from those of standard chemotherapy. To assess the clinical benefits of the MPT combination, Facon et al. compared this treatment with either MP or the intermediate-dose MEL100 followed by autologous hematopoietic stem-cell rescue, in a prospective randomized trial (IFM 99-06). The study clearly indicates that MPT is superior to MP and MEL100 both in terms of PFS (median 27 months vs 18 and 19 months, respectively), and OS (median 52 months vs 33 and 38 months, respectively). The toxicity profile of thalidomide was acceptable; however, the median duration of thalidomide treatment was 11 months despite an expected duration of 18 months. In the absence of systematic anticoagulation, the rate of thrombotic events in MPT was higher than in MP (12% vs 4%), but similar to MEL100 (8%). On an intention-to-treat basis, only 65% of MEL100 patients received the two planned transplants, explaining the worse-than-expected results in this treatment arm. Interestingly, patients relapsing after each treatment exhibited similar survival rates, suggesting that frontline thalidomide administered with MP did not affect the efficacy of subsequent salvage therapies, in contrast to the findings of the Total Therapy II trial.² The results of the IFM 99-06 trial confirm and expand upon the results of the GIMEMA trial,³ which was a prospective comparison of six courses of MPT or MP in patients aged above 65 years; the study showed a significant improvement of event-free survival with MPT at 2 years (54% vs 27%, respectively), but no difference in OS was observed, possibly because of the short follow-up (17 months vs 52 months in IFM 99-06), or effective salvage therapy, or both. The IFM 99-06 study did not include maintenance with thalidomide, unlike the GIMEMA trial. Since conflicting results have been reported regarding the usefulness of thalidomide maintenance, there is no clear consensus on this approach, which should remain limited to clinical trials. The superiority of MPT vs MP in elderly patients is also confirmed by preliminary data from the IFM 01-01 trial.⁴ The future of multiple myeloma treatment in the elderly is hard to predict, since several drugs and their combinations are under evaluation; however, the association of MP with either lenalidomide or bortezomib seems very attractive. Preliminary data from the MMY-3002 trial have shown the superiority of bortezomib–MP vs MP.⁵ Finally, trials with lenalidomide maintenance therapy are also underway. After decades of slow progress, the treatment of multiple myeloma patients has finally become rewarding for both patients and physicians.

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