Two patients with progressive myeloma were treated with pamidronate disodium every 2-4 weeks. Pamidronate therapy resulted in a significant reduction of marrow plasmacytosis and plasma cell labelling index (PCLI), together with durable (> or = 20 months) stabilization of immunoglobulin (Ig) levels and an increase in bone mineral density in the first patient and > 50%, reduction in Ig levels and bone marrow plasmacytosis in the second. This, to our knowledge, is the first report of an anti-myeloma effect of bisphosphonates in humans and provides evidence that a therapeutic intervention largely directed at the myeloma microenvironment may alter the natural history of the disease.