This study serially quantitated monoclonal plasma cells (PC) in the peripheral blood (PB) of 33 patients with multiple myeloma (MM) at diagnosis, after therapy, and at relapse using a sensitive immunofluorescence technique. The goal was to learn which disease phase is best for harvesting PB stem cells free of monoclonal PC. In 24 chemotherapy responders, 88% (21/24) had circulating PC at diagnosis; after therapy, 63% (15/24) had none, 33% (8/24) had < 3 x 10(6)/L, and only one had > or = 3 x 10(6)/L. In nine cases who failed to respond to initial chemotherapy, 89% (8/9) had high levels (> or = 3 x 10(6)/L) of circulating PC at diagnosis that remained high after therapy. In the relapse phase, 88% (21/24) had circulating PC and 63% (15/24) had high numbers. This study demonstrates that the PB is least likely to have circulating monoclonal PC during the period after successful chemotherapy. Patients who fail to respond to initial chemotherapy or are in relapse are likely to have tumor cells in the PB.