Single-agent HDM without autologous bone marrow transplantation is a feasible therapeutic option in myeloma, and is associated with a high objective response rate, relatively long remission durations, and good symptom control.
In this paper we will describe a series of studies carried out at the Royal Marsden Hospital and St Bartholomew's Hospital in which we have attempted to develop new approaches to the chemotherapy of myeloma. Elsewhere in this Workshop the limitations of conventional therapy have been clearly stated. Response rates to conventional therapy with alkylating agents with or without corticosteroids are only in the order of 50 per cent and the median survival of patients is 2-3 years. In 1981, studies with high dose melphalan were initiated (McElwain and Powles 1983). The encouraging results in a small number of patients led to a larger evaluation of this treatment which has been previously published (Selby et al., 1987). In that study, the use of melphalan 140 mg/m2 as a single intravenous injection was associated with a high response rate. Among patients who have not previously received any chemothcrapy, the myeloma protein became unmeasurable in one third and their bone marrows appeared normal which we defined as a complete remission. In this study complete and partial remissions lasted for a median duration of 19 months but relapse has now been seen in almost all cases. Among patients who had had previous chemotherapy, the response rate was high but their remissions were of short duration and the majority of patients had relapsed within 6 months.High dose melphalan resulted in a predictable period of myelosuppression. The median time to recover to 1 x lo9 white cells/l was 28 days in patients who had received no previous chemotherapy and 42 days in patients who had been previously treated. The myelosuppression was associated with a significant infection risk and there were eight early deaths mainly due to infection and bleeding among the first 41 patients treated in the two hospitals.Studies had shown that high doses of methylprednisolone (1 gm/m2 intravenously daily for 5 days) produced responses in myeloma patients who had received very extensive previous treatment (Selby et al., 1985). In a subsequent study, we evaluated the addition ofmethylprednisolone to high dose melphalan in 22 patients. The complete and partial remission rates in the high dose melphalan
In three studies we have attempted to increase the complete remission rate in a series of patients with multiple myeloma under the age of 69. A CR rate of 27% was seen in 63 patients treated with intravenous high-dose melphalan 140 m/m2 with or without the addition of high-dose methyl prednisolone lg/m2 for 5 days (in 22 patients). In a third study a CR rate of 50% was seen in 50 patients treated in a programme in which vincristine, adriamycin and methyl prednisolone was first given and patients then received high-dose melphalan 140-200 mg/m2 with an autologous bone marrow transplant where possible. Median remission duration in the first two studies was 19 months with a median survival of 5 years. A definition of complete remission in myeloma is proposed.This paper describes a series of studies in which we have attempted to develop new approaches to the treatment of myeloma. Response rates to conventional therapy of around 50% are clearly unsatisfactory since less than 10% of patients attain "complete" remissions, median survival is seldom more than 2-3 yr, and no patient is cured. In 1983 (1) our preliminary work indicated that high-dose intravenous melphalan 140 mg/m2 was capable of producing a state of complete remission defined as myeloma protein undetectable by immunoelectrophoresis with a morphologically normal bone marrow. This led to a series of studies in which high-dose melphalan was evaluated further.In the first study (2), high-dose melphalan (HDM) 140 mg/m2 i.v. was given to 58 patients under the age of 63 yr. Among previously untreated patients 11/41 (27%) entered a complete remission and 21 (51%) entered a partial remission (more than 50% reduction in myeloma protein and improvement in all other features). Median remission duration was 19 months. 2 patients who had responded to previous conventional treatment entered complete remission after HDM. Among 15 patients who had failed previous chemotherapy the response rate was 66% including 2 CRs, but in this group all patients had relapsed again within 1 yr. Severe myelosuppression, moderate nausea, vomiting, mucos-
Summary At a median time of 20 months following high dose melphalan for myeloma, 29 patients relapsed and were treated with induction chemotherapy to maximum response followed by a second course of high dose melphalan. The majority (90%) of patients received 200 mg m2 with an autologous bone marrow transplant. Sixteen (55%) patients achieved complete remission and 11 (38%) a partial response. The median duration of remission was 17 (4-42) months. The median survival has not been reached, with 50% of patients alive at 58 + months after presentation. The period of neutropenia was similar during both first and second high dose procedures, but the duration of thrombocytopenia was longer in patients receiving melphalan for a second time (median 22 (16-56)
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