High-dose therapy and immunomodulatory drugs in multiple myeloma

The principle of alkylating agent dose intensity, especially with melphalan-based tandem autotransplants, has been effective in increasing the rate of complete remission beyond 40% and effecting 10-year survivorship in about 40% of the three fourths of patients presenting without cytogenetic abnormalities (Total Therapy I). Further dose escalation and post-transplant consolidation therapy, as practiced with Total Therapy II, seems to further improve results in these patients, but not in those with chromosome 13 abnormalities or lactate dehydrogenase elevation. Phase III trials for post-transplant relapse indicate higher complete remission and near-complete remission rates among patients randomized to thalidomide added to dexamethasone versus dexamethasone alone. In a phase I/II study, thalidomide derivative CC-5013, with less sedative and neurotoxic effects, promoted responses in eight of 15 patients with post-transplant relapse, refractory to other salvage therapies, at dose levels of > or = 25 mg daily. Based on a profound graft-vs-myeloma effect with allografts, mini-allotransplants were evaluated in 31 high-risk patients with cytogenetic abnormalities and prior autotransplants; all nine with responsive disease and only one prior autotransplant remain disease-free and alive. Such mini-allotransplants are now offered as consolidation after one standard autotransplant to patients with cytogenetic abnormalities. The systematic application of gene expression profiling attempts to classify multiple myeloma (MM) patients according to molecular features and to dissect the genetic basis for drug sensitivity or resistance. Given the availability of an expanding treatment armamentarium (eg, thalidomide, CC-5013, the proteasome inhibitor PS-341, farnesyltransferase inhibitors, IL-6 receptor antibody, endothelial receptor inhibitor), gene expression profiling is anticipated to help in the selection of agents with the greatest probability of activity toward individualized treatment. Careful scrutiny of gene expression will also help in the identification of unrecognized targets for therapeutic intervention.