In a retrospective and prospective follow-up study from 1968 to 1989, bone marrow biopsy specimens, serum beta-2-microglobulin (SB2M) levels, and the clinical features of 251 patients with multiple myeloma (MM) and 28 patients with monoclonal gammopathy of undetermined significance (MGUS) were investigated. The main histologic variables (tumor cell type, tumor growth, tumor load, and fibrosis), SB2M level, serum thymidine kinase (STK) level, and various clinical parameters were analyzed to determine factors of value in monitoring the clinical phases of activity in MM. Our recently proposed prognostic strategy combining bone marrow histologic type, SB2M level, and signs of organ failure was tested for its ability to (1) diagnose the early and smoldering variants; (2) facilitate decisions on the time of initiation, the type and duration of initial induction therapy in the pretreatment phases (active and rapidly progressive phases); and (3) characterize variations in tumor regression and tumor-host interactions during chemotherapy (early treatment, plateau, relapse, transition, and refractory phases). The results indicate that this clinicopathologic monitoring combines information both on stage and aggressivity of MM and thus facilitates therapeutic decisions in the various clinical phases of MM.