High doses of melphalan (HDM) and dexamethasone were administered to 43 patients with advanced multiple myeloma, 36 of whom were refractory to both standard melphalan-prednisone and vincristine-adriamycin- dexamethasone (VAD). Forty-four percent responded with greater than 75% reduction in calculated tumor mass, including three patients who achieved a complete remission. The response rate to HDM was 56% in 18 relapsing patients and 50% in 12 patients with less than 12 months of primary drug resistance, but it was only 23% among the remaining 13 unresponsive patients. A high early mortality rate of 30% was confined to 26 patients with either poor performance (Zubrod greater than 1) or impaired renal function (creatinine greater than 1.4 mg%). When this toxic treatment was given to the 21 patients with good performance (Zubrod less than 2) whose disease lacked high serum lactic dehydrogenase (less than or equal to 500 U/L) as a recently recognized feature of high-grade myeloma, a superior median survival of 18 months was obtained as opposed to only 3 months for the 22 remaining patients (P less than .001). Thus, when employed in a timely fashion, HDM overcomes resistance to standard chemotherapy and VAD and benefits selected patients with advanced myeloma.