A phase I-II study of high-dose (HD) alkylating agents in newly diagnosed patients with multiple myeloma after maximum response to Z-Dex (idarubicin, dexamethasone) therapy and DHAP (cisplatin, HD cytosine arabinoside, dexamethasone), stem cell mobilization is reported. Twenty-six patients, median age 56 years (range 42-66), completed Z-Dex chemotherapy and peripheral blood stem cells (PBSC) were mobilized with DHAP. Patients then preceded to cyclophosphamide (HD Cy: 6 g/m(2)) with granulocyte colony-stimulating factor followed by busulphan-melphalan-conditioned PBSC autograft. Interferon alpha was introduced at 3 months post transplant as maintenance therapy. Six patients failed to complete the full protocol. Median time from diagnosis to transplantation was 8 months (range 6-12). Mean CD34+ cell dose collected was 15.8 x 10(6)/kg (CI 11.8, 19.8). Median time from DHAP to HD-Cy was 6 weeks (range 4-12) and from HD-Cy to transplant was 8 weeks (range 6-12). The median follow-up was 36 months (range 6-63). On an intent-to-treat basis, the response rates were three complete response (CR, 12%), 21 partial response (PR, 80%) and two stable disease (SD, 8%) post Z-Dex, five CR (19%) and 21 PR (81%) post HD-Cy, and 14 CR (54%) and 12 PR (46%) post transplant. The treatment-related mortality (TRM) was 4% (1 patient). Median overall survival (OS) and progression-free survival (PFS) have not been reached; estimated values were 60 and 48 months respectively. The 3-year OS and PFS were 72% and 62%. Actuarial 5-year OS and event-free survival were 49% and 32%. DHAP produces effective PBSC mobilization and sequential HD therapy, including autologous PBSCT, in patients who received Z-Dex; this offers significant durable disease response rates with acceptable TRM.