Thalidomide, age, and future use in multiple myeloma

The introduction of thalidomide into the management of relapsed refractory multiple myeloma has been the most significant advancement in the treatment of the disease since the introduction of melphalan and prednisone in the 1960s. Not only did the drug impact the disease therapeutically, but scientists intrigued by its mode of action have added to the knowledge of the patho-physiology of the malignant plasma cell.

The study by Mileshkin and colleagues in this issue (page 69) attempts to combine this immunomodulator with interferon, another biologically active molecule known to have some activity in myeloma. Unfortunately, because of direct or indirect side effects of the combination, no conclusions could be made as to the impact of combining both drugs. Of interest, however, is the finding that patient age was a prognosticator that influenced not only response and progression-free survival but also overall survival. The authors have offered several hypotheses as to why this finding was not observed in previous studies. This observation prompts this question: should thalidomide be used early in the course of the disease (ie, at the time of diagnosis) to benefit more patients before the described cutoff age of 65 years?

There are several questions that must be answered before we can proceed with this concept. (1) Will the age cutoff be validated by other investigators, and if so, would it apply to the newly diagnosed patients? (2) The use of thalidomide as a single agent or in combination with steroids in smoldering and active newly diagnosed myeloma patients has not shown an improved result when compared with results for the drug in relapsed refractory patients (Weber et al, J Clin Oncol. 2003;21:16-19; Rajkumar et al, J Clin Oncol. 2002;20:4319-4323), and long-term effects are yet to be determined; is it worth foregoing an active agent early in the course of the disease and continuing to use standard chemotherapy that has not shown a significant impact on the overall survival since the introduction of melphalan and prednisone (Attal et al, N Engl J Med. 1996;335:91)? (3) Considering its immunomodulatory effects that involve integrin modulation and the resultant unfastening of the myeloma cell from the stroma, could this increase the incidence of extramedullary relapses, especially when used in the absence of an active chemotherapeutic agent? These issues will be addressed with further study and longer follow-up of the current trials. The introduction of new, less toxic interferons may allow us to revisit the question of synergism of thalidomide and other immunomodulatory agents (Borden et al, Semin Cancer Biol. 2000;10:125-144).