Long-term follow-up on Total Therapy I revealed, with a median follow-up of about 10 years, median durations of event-free survival (EFS) and overall survival (OS) of 37 and 80 mos in the 88% of patients lacking cytogenetic abnormalities (CA) of chromosome 13 compared to only 28 and 34 mos in those with CA 13. Total Therapy II (TT II) was developed to test whether more intensive remission induction and post-tandem transplant consolidation chemotherapy prior to interferon maintenance could further improve clinical outcome. All patients were also randomized to +/- thalidomide at a starting dose of 400 mg. Results obtained in the first 231 patients enrolled in TT II are presented for the two study arms combined (data for effect of thalidomide still blinded). Three-year projection of EFS and OS are 71% and 77%. On an intent-to-treat basis, 66% achieved complete remission (CR) or near-CR. Major independent adverse features associated with shortened survival included CA and chromosome 13 deletion using interphase FISH. CA identified 29 among 102 patients with FISH 13 deletion who had a very grave prognosis (3 yr EFS, 32%; OS 49%) compared to all remaining patients who enjoyed 3 yr EFS of 79% and OS of 83%. Thus, both cytogenetics and FISH are recommended in the initial evaluation of patients with MM.