Melphalan-prednisone versus alternating combination VAD/MP or VND/MP as primary therapy for multiple myeloma: final analysis of a randomized clinical study

Abstract

Background and objectives: In the absence of a cure for multiple myeloma (MM) with standard-dose therapy, any strategy that can be expected to increase tumor reduction and to extend survival duration is likely to be of clinical relevance. The primary end-point of the present study was to investigate whether the alternating combination of vincristine-doxorubicin-dexamethasone (VAD) and melphalan-prednisone (MP) or vincristine-mitoxantrone-dexamethasone (VND) and MP could improve the clinical outcome of MM patients thus treated in comparison with those receiving MP alone.

Design and methods: Between November 1990 and April 1994, 527 previously untreated, stage I-III, MM patients from 29 Italian institutions were randomized to receive one of three remission induction chemotherapy regimens consisting of 8-monthly courses of either MP alone or alternating VAD/MP or VND/MP.

Results: On an intent-to-treat basis, the objective response rates were 53% with MP (objective + minor: 67%), 47% with VAD/MP (objective + minor: 61%) and 49% with VND/MP (objective + minor: 61%). Median survival duration was 36.5 months with MP, 29 months with VAD/MP and 32.5 months with VND/MP. The difference among these groups was not statistically significant, even after stratifying patients into high-risk and low-risk subgroups, as assessed by a multifactor proportional hazard analysis. In both younger and elderly patients, severe granulocytopenia and related infections were significantly more frequent with VND/MP compared to the remaining arms of treatment (p < 0.001 and p = 0.009, respectively). Similarly, the frequency of WHO grade III-IV cardiovascular events was significantly higher for patients receiving anthracycline-containing regimens (VND/MP and VAD/MP) than for those treated with MP alone (p = 0.04).

Interpretation and conclusions: Alternating VAD/MP and VND/MP failed to improve the clinical outcome for MM patients, at the cost of increased toxicity and morbidity. Resistance to standard-dose chemotherapy remains a significant obstacle to the treatment of MM.